Ketamine is FDA Approved for use as an anesthetic in surgical settings.

Ketamine is not (yet) FDA Approved for the following conditions, however increasing scientific evidence is accumulating that it may be safe and effective. At this time, the use of ketamine for these disorders is 'off label'

Off label drug use (OLDU) is both legal and common. In fact some medications, are used more for off label than approved conditions (eg gabapentin & amitriptyline both >80%)

On the one hand, in the ideal world, every use of medication would be supported by high quality scientific evidence. On the other hand, in the real world, each patient is unique and waiting for adequate scientific evidence or FDA approval would deprive physicians and patients the use of helpful treatments.

We believe that use of ketamine for psychiatric conditions is reasonable under some circumstances because 1) the safety is excellent 2) the effectiveness, although not durable or dependable, can help some people.

Ketamine is an exciting new tool to rapidly reduce symptoms of depression.

It is an anesthetic used in surgery and long known as a safe medication with few if any side effects on breathing or heart function.

More than 1000 patients have been given ketamine in published studies, and about 10,000 more in clinical settings as an "off label" treatment for depression.

Depending on the way it is given (route of administration) it has different side effects

Intravenous (IV) directly into the vein (possible bleeding and infection)

Intramuscular (IM) into the muscle (possible bruising)

Intranasal (IN) into the nose (nasal irritation)

Sublingual and Oral (SL & PO) into the mouth under the tongue or swallowed

Cost is about $1,000 (IV), $750 (IM) and $500 (Oral and Sublingual) ....insurance does not cover

In the psychiatric setting, relaxing medication is given before the ketamine to prevent any anxiety reaction. Patients arrive about an hour before the treatment to get comfortable and take the sedative, allowing time for it to begin working before the test dose of ketamine is given.

After the medication is given, after a few minutes, there is a brief period of dizziness, followed by 20-30 minutes of a strange feeling of disconnection, possible euphoria and a sensation of release as if weighty issues have gently floated away like a helium ballon let go on a calm day, drifting up and away. Some people simply feel dizzy for a while.

Then, as the experience concludes there is a relaxed feeling of contentment and calm, but some people just feel a bit tired.

Within 2-3 hours the patient has returned to baseline but usually feeling a sense of lightness and reduction of sadness and return of the ability to be interested in things and experience pleasure. Most patients are able to walk normally and even drive, but having a friend or family member present and ready to drive home is recommended.

How long the positive effects lasts varies - some people a few days, others for months.

Ketamine for Depression is not an FDA approved treatment

it is too soon to know if this treatment will prove useful

Here are some relevant publications about ketamine for Depression since 2006:

1. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jan 4;64:218-24. doi:
10.1016/j.pnpbp.2015.01.002. Epub 2015 Jan 10.

Has psychiatry tamed the "ketamine tiger?" Considerations on its use for
depression and anxiety.

Rasmussen KG(1).

Author information:
(1)Mayo Clinic, Department of Psychiatry, Rochester, MN, United States.
Electronic address: rasmussen.keith@mayo.edu.

Ketamine has been available for approximately 50years as an anesthetic agent. It
is known to have potent effects on the central nervous system glutamatergic
system, in particular blockade of N-methyl-d-aspartate (NMDA) receptors. Based
upon pre-clinical evidence of involvement of the glutamatergic system in mood
disorders, studies have been undertaken to test the antidepressant properties of
ketamine. Several well-controlled studies, along with open-label case series,
have established that ketamine can have rapid antidepressant effects.
Additionally, data exist showing benefits of ketamine in post-traumatic stress
disorder as well as obsessive compulsive disorder. However, improvements in these
conditions tend to be short-lived with single infusions of ketamine. Of concern,
ketamine has been associated with neurotoxicity in pre-clinical rodent models and
is well-known to cause psychotomimetic effects and addiction in humans. While
ketamine has been proven safe for use in sub-anesthetic doses administered once
or a few times, the safety profile of prolonged use has not been established.
Aspects of safety, possible mechanisms of action, and future directions of
ketamine research are discussed in addition to the clinical literature on its use
in psychiatric conditions.

PMID: 25582770 [PubMed - in process]

3. J Affect Disord. 2015 Nov 1;186:306-11. doi: 10.1016/j.jad.2015.06.033. Epub 2015
Jul 29.

Serum BDNF as a peripheral biomarker of treatment-resistant depression and the
rapid antidepressant response: A comparison of ketamine and ECT.

Allen AP(1), Naughton M(2), Dowling J(3), Walsh A(3), Ismail F(2), Shorten G(3),
Scott L(2), McLoughlin DM(4), Cryan JF(5), Dinan TG(6), Clarke G(1).

Author information:
(1)Department of Psychiatry, University College Cork, Cork, Ireland; Alimentary
Pharmabiotic Centre, University College Cork, Cork, Ireland. (2)Department of
Psychiatry, University College Cork, Cork, Ireland. (3)Department of Anaesthesia
and Intensive Care Medicine, University College Cork, Cork, Ireland. (4)St.
Patrick's University Hospital, Dublin 8, Ireland; Trinity College Institute of
Neuroscience, Trinity College Dublin, Dublin 2, Ireland. (5)Alimentary
Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of
Anatomy & Neuroscience, University College Cork, Cork, Ireland. (6)Department of
Psychiatry, University College Cork, Cork, Ireland; Alimentary Pharmabiotic
Centre, University College Cork, Cork, Ireland. Electronic address:
t.dinan@ucc.ie.

BACKGROUND: Ketamine is associated with rapid antidepressant efficacy but the
biological mechanisms underpinning this effect are unclear. Serum brain-derived
neurotrophic factor (sBDNF) is a potential circulating biomarker of
treatment-resistant depression (TRD) and ketamine response but it is unclear if
this is a common target of both ketamine and electroconvulsive therapy (ECT), the
current gold standard for TRD. Moreover, the impact of multiple ketamine
infusions on sBDNF has not yet been established.
METHODS: Thirty five TRD patients with a current DSM-IV diagnosis of recurrent
depressive disorder received up to 12 ECT sessions (N=17) or up to three
intravenous infusions of low-dose (0.5mg/kg) ketamine (N=18). Blood samples were
taken over the course of the study for assessment of sBDNF. Symptom severity and
response were monitored using the 17-item Hamilton Depression Rating Scale
(HDRS). sBDNF was assessed in 20 healthy controls to allow comparison with TRD
patients.
RESULTS: As expected, sBDNF was lower in TRD patients at baseline compared to
healthy controls. Ketamine and ECT treatment were both associated with
significant reductions in depressive symptoms. However, sBDNF was significantly
elevated only at one week following the first ketamine infusion in those
classified as responders one week later. sBDNF was not elevated following
subsequent infusions. ECT reduced depressive symptoms, as expected, but was not
associated with an enhancement in BDNF.
LIMITATIONS: Patients continued with their psychotropic medications throughout
this trial.
CONCLUSIONS: SBDNF normalisation does not appear to be a prerequisite for
symptomatic improvement in TRD following ketamine or ECT treatment.

PMID: 26275358 [PubMed - in process]

5. Am J Psychiatry. 2015 Oct 1;172(10):950-66. doi: 10.1176/appi.ajp.2015.15040465.

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible
Mechanisms in Depression.

Newport DJ(1), Carpenter LL(1), McDonald WM(1), Potash JB(1), Tohen M(1),
Nemeroff CB(1); APA Council of Research Task Force on Novel Biomarkers and
Treatments.

Author information:
(1)From the University of Miami Miller School of Medicine, Department of
Psychiatry and Behavioral Sciences, Miami; the University of Miami Miller School
of Medicine, Department of Obstetrics and Gynecology, Miami; the University of
Miami Miller School of Medicine, Center on Aging, Miami; the Alpert Medical
School of Brown University, Department of Psychiatry and Human Behavior,
Providence, R.I.; Emory University School of Medicine, Department of Psychiatry
and Behavioral Sciences, Atlanta; the University of Iowa Carver College of
Medicine, Department of Psychiatry, Iowa City, Iowa; and the University of New
Mexico Health Science Center, Department of Psychiatry and Behavioral Sciences,
Albuquerque, N.M.

OBJECTIVE: The authors conducted a systematic review and meta-analysis of
ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists in the
treatment of major depression.
METHOD: Searches of MEDLINE, PsycINFO, and other databases were conducted for
placebo-controlled, double-blind, randomized clinical trials of NMDA antagonists
in the treatment of depression. Primary outcomes were rates of treatment response
and transient remission of symptoms. Secondary outcomes included change in
depression symptom severity and the frequency and severity of dissociative and
psychotomimetic effects. Results for each NMDA antagonist were combined in
meta-analyses, reporting odds ratios for dichotomous outcomes and standardized
mean differences for continuous outcomes.
RESULTS: Ketamine (seven trials encompassing 147 ketamine-treated participants)
produced a rapid, yet transient, antidepressant effect, with odds ratios for
response and transient remission of symptoms at 24 hours equaling 9.87
(4.37-22.29) and 14.47 (2.67-78.49), respectively, accompanied by brief
psychotomimetic and dissociative effects. Ketamine augmentation of ECT (five
trials encompassing 89 ketamine-treated participants) significantly reduced
depressive symptoms following an initial treatment (Hedges' g=0.933) but not at
the conclusion of the ECT course. Other NMDA antagonists failed to consistently
demonstrate efficacy; however, two partial agonists at the NMDA coagonist site,
d-cycloserine and rapastinel, significantly reduced depressive symptoms without
psychotomimetic or dissociative effects.
CONCLUSIONS: The antidepressant efficacy of ketamine, and perhaps D-cycloserine
and rapastinel, holds promise for future glutamate-modulating strategies;
however, the ineffectiveness of other NMDA antagonists suggests that any
forthcoming advances will depend on improving our understanding of ketamine's
mechanism of action. The fleeting nature of ketamine's therapeutic benefit,
coupled with its potential for abuse and neurotoxicity, suggest that its use in
the clinical setting warrants caution.

PMID: 26423481 [PubMed - in process]

12. World Psychiatry. 2015 Oct;14(3):348-50. doi: 10.1002/wps.20269.

Ketamine for depression: evidence, challenges and promise.

Zarate CA Jr(1), Niciu MJ(1).

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, National Institute of
Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA.

PMCID: PMC4592658
PMID: 26407791 [PubMed]

14. Cochrane Database Syst Rev. 2015 Sep 23;9:CD011612. doi:
10.1002/14651858.CD011612.pub2.

Ketamine and other glutamate receptor modulators for depression in adults.

Caddy C(1), Amit BH, McCloud TL, Rendell JM, Furukawa TA, McShane R, Hawton K,
Cipriani A.

Author information:
(1)Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford,
UK, OX3 7JX.

BACKGROUND: Considering the ample evidence of involvement of the glutamate system
in the pathophysiology of depression, pre-clinical and clinical studies have been
conducted to assess the antidepressant efficacy of glutamate inhibition, and
glutamate receptor modulators in particular. This review focuses on the use of
glutamate receptor modulators in unipolar depression.
OBJECTIVES: To assess the effects - and review the acceptability - of ketamine
and other glutamate receptor modulators in comparison to placebo (or saline
placebo), other pharmacologically active agents, or electroconvulsive therapy
(ECT) in alleviating the acute symptoms of depression in people with unipolar
major depressive disorder.
SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review
Group's Specialised Register (CCDANCTR, to 9 January 2015). This register
includes relevant randomised controlled trials (RCTs) from: the Cochrane Library
(all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to
date). We did not apply any restrictions to date, language or publication status.
SELECTION CRITERIA: Double- or single-blind RCTs comparing ketamine, memantine,
or other glutamate receptor modulators with placebo (or saline placebo), other
active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with
unipolar major depression.
DATA COLLECTION AND ANALYSIS: Three review authors independently identified
studies, assessed trial quality and extracted data. The primary outcomes for this
review were response rate and adverse events.
MAIN RESULTS: We included 25 studies (1242 participants) on ketamine (9 trials),
memantine (3), AZD6765 (3), D-cycloserine (2), Org26576 (2), atomoxetine (1),
CP-101,606 (1), MK-0657 (1), N-acetylcysteine (1), riluzole (1) and sarcosine
(1). Twenty-one studies were placebo-controlled and the majority were two-arm
studies (23 out of 25). Twenty-two studies defined an inclusion criteria
specifying the severity of depression; 11 specified at least moderate depression;
eight, severe depression; and the remaining three, mild-moderate depression. Nine
studies recruited only treatment-resistant patients.We rated the risk of bias as
low or unclear for most domains, though lack of detail regarding masking of
treatment in the studies reduced our certainty in the effect for all outcomes. We
rated three studies as having high risk for selective outcome reporting. Many
trials did not provide information on all the prespecified outcomes and we found
no data, or very limited data, on very important issues like suicidality,
cognition, quality of life, costs to healthcare services and dropouts due to lack
of efficacy.Among all glutamate receptor modulators, only ketamine (administered
intravenously) proved to be more efficacious than placebo, though the quality of
evidence was limited by risk of bias and small sample sizes. There was low
quality evidence that treatment with ketamine increased the likelihood of
response after 24 hours (odds ratio (OR) 10.77, 95% confidence interval (CI) 2.00
to 58.00; 3 RCTs, 56 participants), 72 hours (OR 12.59, 95% CI 2.38 to 66.73; 3
RCTs, 56 participants), and one week (OR 2.58, 95% CI 1.08 to 6.16; 4 RCTs, 131
participants). The effect of ketamine was even less certain at two weeks, as data
were available from only one trial (OR 0.93, 95% CI 0.31 to 2.83; 51
participants, low quality evidence). This was consistent across all efficacy
outcomes. Ketamine caused more confusion and emotional blunting compared to
placebo. There was insufficient evidence to determine if this increased the
likelihood of leaving the study early (OR 1.90, 95% CI 0.43 to 8.47; 5 RCTs, 139
participants, low quality evidence).One RCT with 72 participants reported higher
numbers of responders on ketamine than midazolam at 24 hours (OR 0.36, 95% CI
0.14 to 0.58), 72 hours (OR 0.37, 95% CI 0.16 to 0.59), and one week (OR 0.29,
95% CI 0.08 to 0.49). However, midazolam was better tolerated than ketamine in
terms of blurred vision, dizziness, general malaise and nausea/vomiting at 24
hours post-infusion. The evidence contributing to these outcomes was of low
quality.We found better efficacy of sarcosine over citalopram at four weeks (OR
6.93, 95% CI 1.53 to 31.38; 1 study, 40 participants), but not at two weeks (OR:
8.14, 95% CI 0.88 to 75.48); fewer participants in the sarcosine group
experienced adverse events (OR 0.04, 95% CI 0.00 to 0.68; P = 0.03, 1 study, 40
participants). This was based on low quality evidence. No significant results
were found for the remaining glutamate receptor modulators.In one study with 18
participants, ketamine was more effective than ECT at 24 hours (OR 28.00, 95% CI
2.07 to 379.25) and 72 hours (OR 12.25, 95% CI 1.33 to 113.06), but not at one
week (OR 3.35, 95% CI 0.12 to 93.83), or two weeks (OR 3.35, 95% CI 0.12 to
93.83). No differences in terms of adverse events were found between ketamine and
ECT, however the only adverse events reported were blood pressure and heart rate.
This study was rated as very low quality.
AUTHORS' CONCLUSIONS: We found limited evidence for ketamine's efficacy over
placebo at time points up to one week in terms of the primary outcome, response
rate. The effects were less certain at two weeks post-treatment. No significant
results were found for the remaining ten glutamate receptor modulators, except
for sarcosine being more effective than citalopram at four weeks. In terms of
adverse events, the only significant differences in favour of placebo over
ketamine were in regards to confusion and emotional blunting. Despite the
promising nature of these preliminary results, our confidence in the evidence was
limited by risk of bias and the small number of participants. Many trials did not
provide information on all the prespecified outcomes and we found no data, or
very limited data, on very important issues like suicidality, cognition, quality
of life, costs to healthcare services and dropouts due to lack of efficacy.All
included studies administered ketamine intravenously, which can pose practical
problems in clinical practice. Very few trials were included in the meta-analyses
for each comparison; the majority of comparisons contained only one study.
Further RCTs (with adequate blinding) are needed to explore different modes of
administration of ketamine with longer follow-up, which test the comparative
efficacy of ketamine and the efficacy of repeated administrations.

PMID: 26395901 [PubMed - in process]

18. Clin Neuropharmacol. 2015 Sep-Oct;38(5):212-6. doi: 10.1097/WNF.0000000000000104.

Augmentation Therapy With Serial Intravenous Ketamine Over 18 Months in a Patient
With Treatment Resistant Depression.

Hassamal S(1), Spivey M, Pandurangi AK.

Author information:
(1)*Department of Psychiatry, Virginia Commonwealth University, Richmond, VA; and
†Department of Addiction Psychiatry, UCLA Kern, Bakersfield, CA.

Major depressive disorder is a severe illness that affects 3% to 7% of adults
annually in the United States. About 30% of these individuals are refractory to
multiple treatment trials. Recent reports have found a significant and almost
immediate improvement in depressive symptoms after single or multiple ketamine
intravenous infusions (IVIs) in such patients. We present the case of A.B., a
patient with treatment-resistant depression (TRD) including to subgenual deep
brain stimulation, who went into remission after augmentation with 6 ketamine
IVIs (0.5 mg/kg) over a 3-week period. However, she had a reemergence of
depressive symptoms 4 months later and received a second series of 3 ketamine
IVIs over the course of a week. A.B. again went into remission and maintained
this for the next 8 months. At this time, she experienced a reemergence of
depressive symptoms and was treated with the third series of ketamine IVIs (3
infusions over the course of a week). Because A.B. has now been in remission for
6 months. A.B. has received a total of 12 ketamine IVIs over the course of 18
months. No significant adverse events have occurred. To our knowledge, this is
the first case of long-term ketamine efficacy as augmentation therapy in TRD over
the course of 18 months. There is a need for studies examining the long-term
management of TRD with IV ketamine. Guidelines for maintenance ketamine IVIs in
TRD also need to be developed.

PMID: 26366968 [PubMed - in process]

22. J Psychoactive Drugs. 2015 Sep-Oct;47(4):276-85. doi:
10.1080/02791072.2015.1072653. Epub 2015 Aug 28.

Long-Term Ketamine Self-Injections in Major Depressive Disorder: Focus on
Tolerance in Ketamine's Antidepressant Response and the Development of Ketamine
Addiction.

Bonnet U(1,)(2).

Author information:
(1)a Head of the Department of Psychiatry, Psychotherapy and Psychosomatic
Medicine , Evangelisches Krankenhaus Castrop-Rauxel, Academic Teaching Hospital
of the University of Duisburg-Essen , Castrop-Rauxel , Germany. (2)b Professor,
University of Duisburg-Essen , Essen , Germany.

Sub-anaesthetic ketamine is of special interest for depression research due to
its rapid and potent but short-lived antidepressant response (after-effect). The
presented case is the first one in the literature which deals in detail with the
transfer from ketamine's antidepressant action to ketamine addiction. A
50-year-old anaesthetic nurse, who had never been treated with antidepressants
before, started with self-injecting ketamine racemate 50 mg IM once a week to
cope with her major depression. She continuously stole ketamine from hospital
stocks. Due to a gradually developing tolerance to ketamine's antidepressant
action, she stepwise increased dose and frequency of ketamine self-injections up
to daily 2 g IM (three-fold her anaesthetic dose) over six months. This was
accompanied by the development of ketamine addiction, loss of consciousness,
dissociative immobility, and amnesia. Inpatient detoxification treatment was
characterized by a strong craving for ketamine and, later on, by the occurrence
of a severe depressive episode remitting on venlafaxine. A 14-week follow-up
documented a normal condition without any ketamine sequelae, such as craving,
psychosis, depression, or cognitive abnormalities. Thus, awareness of ketamine
addiction potential, even in patients who received ketamine for antidepressant
purposes, is important.

PMID: 26317449 [PubMed - in process]

23. Lancet Psychiatry. 2015 Sep;2(9):783-4. doi: 10.1016/S2215-0366(15)00392-2.

Ketamine for depression: the highs and lows.

Kirby T.

PMID: 26360893 [PubMed - in process]

25. Pharmacol Res. 2015 Sep;99:23-35. doi: 10.1016/j.phrs.2015.05.003. Epub 2015 May
15.

Ketamine and suicidal ideation in depression: Jumping the gun?

Rajkumar R(1), Fam J(2), Yeo EY(1), Dawe GS(3).

Author information:
(1)Department of Pharmacology, Yong Loo Lin School of Medicine, National
University Health System, National University of Singapore, Singapore;
Neurobiology and Ageing Programme, Life Sciences Institute, National University
of Singapore, Singapore; Singapore Institute for Neurotechnology (SINAPSE),
Singapore. (2)Department of Psychological Medicine, National University Health
System, National University of Singapore, Singapore. (3)Department of
Pharmacology, Yong Loo Lin School of Medicine, National University Health System,
National University of Singapore, Singapore; Neurobiology and Ageing Programme,
Life Sciences Institute, National University of Singapore, Singapore; Singapore
Institute for Neurotechnology (SINAPSE), Singapore. Electronic address:
gavin_dawe@nuhs.edu.sg.

Depression and suicide are known to be intricately entwined but the
neurobiological basis underlying this association is yet to be understood.
Ketamine is an N-methyl d-aspartate (NMDA) receptor antagonist used for induction
and maintenance of general anaesthesia but paradoxically its euphoric effects
lead to its classification under drugs of abuse. The serendipitous finding of
rapid-onset antidepressant action of subanaesthetic dosing with ketamine by
intravenous infusion has sparked many preclinical and clinical investigations. A
remarkable suppression of suicidal ideation was also reported in depressed
patients. This review focuses on the clinical trials on ketamine that reported
remedial effects in suicidal ideation in depression and addresses also the
molecular mechanisms underlying the antidepressant and psychotomimetic actions of
ketamine. The neuropsychiatric profile of subanaesthetic doses of ketamine
encourages its use in the management of suicidal ideation that could avert
emergent self-harm or suicide. Finally, the need for neuroimaging studies in
suicidal patients to identify the brain region specific and temporal effects of
ketamine, and the possibility of employing ketamine as an experimental tool in
rodent-based studies to study the mechanisms underlying suicidal behaviour are
highlighted.

PMID: 25982932 [PubMed - in process]

26. Psychopharmacology (Berl). 2015 Sep;232(17):3123-33. doi:
10.1007/s00213-015-3957-3. Epub 2015 May 20.

Antidepressant-like cognitive and behavioral effects of acute ketamine
administration associated with plasticity in the ventral hippocampus to medial
prefrontal cortex pathway.

Jett JD(1), Boley AM, Girotti M, Shah A, Lodge DJ, Morilak DA.

Author information:
(1)Department of Pharmacology and Center for Biomedical Neuroscience, University
of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7764,
San Antonio, TX, 78229-3900, USA.

RATIONALE: Acute low-dose administration of the N-methyl-D-aspartate (NMDA)
receptor antagonist, ketamine, produces rapid and sustained antidepressant-like
effects in humans and rodents. Recently, we found that the long-lasting effect of
ketamine on the forced swim test requires ventral hippocampal (vHipp) activity at
the time of drug administration. The medial prefrontal cortex (mPFC), a target of
the vHipp dysregulated in depression, is important for cognitive flexibility and
response strategy selection. Deficits in cognitive flexibility, the ability to
modify thoughts and behaviors in response to changes in the environment, are
associated with depression. We have shown that chronic stress impairs cognitive
flexibility on the attentional set-shifting test (AST) and induces a shift from
active to passive response strategies on the shock-probe defensive burying test
(SPDB).
OBJECTIVE: In this study, we tested the effects of ketamine on chronic
stress-induced changes in cognitive flexibility and coping behavior on the AST
and SPDB, respectively. Subsequently, we investigated vHipp-mPFC plasticity as a
potential mechanism of ketamine's therapeutic action.
RESULTS: Ketamine reversed deficits in cognitive flexibility and restored active
coping behavior in chronically stressed rats. Further, high frequency stimulation
in the vHipp replicated ketamine's antidepressant-like effects on the forced swim
test and AST, but not on the SPDB.
CONCLUSION: These results show that ketamine restores cognitive flexibility and
coping response strategy compromised by stress. Activity in the vHipp-mPFC
pathway may represent a neural substrate for some of the antidepressant-like
behavioral effects of ketamine, including cognitive flexibility, but other
circuits may mediate the effects of ketamine on coping response strategy.

PMCID: PMC4536154 [Available on 2016-09-01]
PMID: 25986748 [PubMed - in process]

30. J Neurosci. 2015 Aug 19;35(33):11694-706. doi: 10.1523/JNEUROSCI.0903-15.2015.

Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA
and AMPA-Mediated Frontoparietal Connectivity in Humans.

Muthukumaraswamy SD(1), Shaw AD(2), Jackson LE(3), Hall J(3), Moran R(4), Saxena
N(5).

Author information:
(1)Schools of Pharmacy and Psychology, The University of Auckland, Auckland 1142,
New Zealand, sd.muthu@auckland.ac.nz. (2)Cardiff University Brain Research
Imaging Centre, Cardiff University, Cardiff CF103AT, United Kingdom.
(3)Department of Anaesthetics, Intensive Care and Pain Medicine, Cwm Taf
University Health Board, Llantrisant CF72 8XR, United Kingdom. (4)Virginia Tech
Carilion Research Institute, Bradley Department of Electrical and Computer
Engineering, Roanoke, Virginia 24016, and. (5)Department of Anaesthetics,
Intensive Care and Pain Medicine, Cwm Taf University Health Board, Llantrisant
CF72 8XR, United Kingdom, Department of Anaesthetics, Intensive Care and Pain
Medicine, School of Medicine, Cardiff University, Cardiff CF144XW, United
Kingdom.

Following the discovery of the antidepressant properties of ketamine, there has
been a recent resurgence in the interest in this NMDA receptor antagonist.
Although detailed animal models of the molecular mechanisms underlying ketamine's
effects have emerged, there are few MEG/EEG studies examining the acute
subanesthetic effects of ketamine infusion in man. We recorded 275 channel MEG in
two experiments (n = 25 human males) examining the effects of subanesthetic
ketamine infusion. MEG power spectra revealed a rich set of significant
oscillatory changes compared with placebo sessions, including decreases in
occipital, parietal, and anterior cingulate alpha power, increases in medial
frontal theta power, and increases in parietal and cingulate cortex high gamma
power. Each of these spectral effects demonstrated their own set of temporal
dynamics. Dynamic causal modeling of frontoparietal connectivity changes with
ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal
connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min
after ketamine infusion had ceased, by which time perceptual distortions were
absent. The results also indicated a decrease in gain of parietal pyramidal
cells, which was correlated with participants' self-reports of blissful state.
Based on these results, we suggest that the antidepressant effects of ketamine
may depend on its ability to change the balance of frontoparietal connectivity
patterns.SIGNIFICANCE STATEMENT: In this paper, we found that subanesthetic doses
of ketamine, similar to those used in antidepressant studies, increase anterior
theta and gamma power but decrease posterior theta, delta, and alpha power, as
revealed by magnetoencephalographic recordings. Dynamic causal modeling of
frontoparietal connectivity changes with ketamine indicated a decrease in NMDA
and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity
changes were sustained for up to 50 min after ketamine infusion had ceased, by
which time perceptual distortions were absent. The results also indicated a
decrease in gain of parietal pyramidal cells, which was correlated with
participants' self-reports of blissful state. The alterations in frontoparietal
connectivity patterns we observe here may be important in generating the
antidepressant response to ketamine.

PMCID: PMC4540803 [Available on 2016-02-19]
PMID: 26290246 [PubMed - in process]

31. Mol Psychiatry. 2015 Aug 18. doi: 10.1038/mp.2015.83. [Epub ahead of print]

A pilot in vivo proton magnetic resonance spectroscopy study of amino acid
neurotransmitter response to ketamine treatment of major depressive disorder.

Milak MS(1), Proper CJ(2), Mulhern ST(2), Parter AL(2), Kegeles LS(1), Ogden
RT(3), Mao X(4), Rodriguez CI(1), Oquendo MA(1), Suckow RF(5), Cooper TB(5),
Keilp JG(1), Shungu DC(6), Mann JJ(7).

Author information:
(1)1] Department of Psychiatry, Columbia University, College of Physicians and
Surgeons, New York, NY, USA [2] Molecular Imaging and Neuropathology Division,
New York State Psychiatric Institute, New York, NY, USA. (2)Department of
Psychiatry, Columbia University, College of Physicians and Surgeons, New York,
NY, USA. (3)1] Department of Psychiatry, Columbia University, College of
Physicians and Surgeons, New York, NY, USA [2] Molecular Imaging and
Neuropathology Division, New York State Psychiatric Institute, New York, NY, USA
[3] Department of Biostatistics, Columbia University, Mailman School of Public
Health, New York, NY, USA. (4)Department of Radiology, Weill Medical College of
Cornell University, New York, NY, USA. (5)1] Molecular Imaging and Neuropathology
Division, New York State Psychiatric Institute, New York, NY, USA [2] Analytical
Psychopharmacology Laboratory, the Nathan S. Kline Institute for Psychiatric
Research, Orangeburg, NY, USA. (6)1] Molecular Imaging and Neuropathology
Division, New York State Psychiatric Institute, New York, NY, USA [2] Department
of Radiology, Weill Medical College of Cornell University, New York, NY, USA.
(7)1] Department of Psychiatry, Columbia University, College of Physicians and
Surgeons, New York, NY, USA [2] Molecular Imaging and Neuropathology Division,
New York State Psychiatric Institute, New York, NY, USA [3] Department of
Radiology, Columbia University, College of Physicians and Surgeons, New York, NY,
USA.

The N-methyl-D-aspartate receptor antagonist ketamine can improve major
depressive disorder (MDD) within hours. To evaluate the putative role of
glutamatergic and GABAergic systems in ketamine's antidepressant action, medial
prefrontal cortical (mPFC) levels of glutamate+glutamine (Glx) and γ-aminobutyric
acid (GABA) were measured before, during, and after ketamine administration using
proton magnetic resonance spectroscopy. Ketamine (0.5 mg kg(-1) intravenously)
was administered to 11 depressed patients with MDD. Glx and GABA mPFC responses
were measured as ratios relative to unsuppressed voxel tissue water (W)
successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in
24-item Hamilton Depression Rating Scale and total score ⩽10) within 230 min of
commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1%
above baseline in ~26 min. Mean areas under the curve for Glx/W (P=0.025) and
GABA/W (P=0.005) increased and correlated (r=0.796; P=0.018). Clinical
improvement correlated with 90-min norketamine concentration (df=6, r=-0.78,
P=0.023), but no other measures.Molecular Psychiatry advance online publication,
18 August 2015; doi:10.1038/mp.2015.83.

PMID: 26283639 [PubMed - as supplied by publisher]

32. Psychol Med. 2015 Aug 12:1-10. [Epub ahead of print]

Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial.

Murrough JW(1), Soleimani L(1), DeWilde KE(1), Collins KA(1), Lapidus KA(2),
Iacoviello BM(1), Lener M(1), Kautz M(1), Kim J(3), Stern JB(4), Price RB(5),
Perez AM(6), Brallier JW(6), Rodriguez GJ(7), Goodman WK(7), Iosifescu DV(1),
Charney DS(1).

Author information:
(1)Mood and Anxiety Disorders Program,Department of Psychiatry,Icahn School of
Medicine at Mount Sinai,New York,NY,USA. (2)Departments of Psychiatry and
Neurobiology,Stony Brook University,Stony Brook,NY,USA. (3)Deparment of
Psychology,UCLA,Los Angeles,CA,USA. (4)Department of Psychology,Drexel
University,Philadelphia,PA,USA. (5)Department of Psychiatry,University of
Pittsburgh School of Medicine,Pittsburgh,PA,USA. (6)Department of
Anesthesiology,Icahn School of Medicine at Mount Sinai,New York,NY,USA.
(7)Department of Psychiatry,Icahn School of Medicine at Mount Sinai,New
York,NY,USA.

BACKGROUND: Suicide is a devastating public health problem and very few
biological treatments have been found to be effective for quickly reducing the
intensity of suicidal ideation (SI). We have previously shown that a single dose
of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is
associated with a rapid reduction in depressive symptom severity and SI in
patients with treatment-resistant depression.
METHOD: We conducted a randomized, controlled trial of ketamine in patients with
mood and anxiety spectrum disorders who presented with clinically significant SI
(n = 24). Patients received a single infusion of ketamine or midazolam (as an
active placebo) in addition to standard of care. SI measured using the Beck Scale
for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome.
Secondary outcomes included the Montgomery-Asberg Depression Rating Scale -
Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the
24-h time-point.
RESULTS: The intervention was well tolerated and no dropouts occurred during the
primary 7-day assessment period. BSI score was not different between the
treatment groups at 24 h (p = 0.32); however, a significant difference emerged at
48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to
midazolam group at 24 h (p = 0.05). The treatment effect was no longer
significant at the end of the 7-day assessment period.
CONCLUSIONS: The current findings provide initial support for the safety and
tolerability of ketamine as an intervention for SI in patients who are at
elevated risk for suicidal behavior. Larger, well-powered studies are warranted.

PMID: 26266877 [PubMed - as supplied by publisher]

33. Eur Neuropsychopharmacol. 2015 Aug 6. pii: S0924-977X(15)00239-4. doi:
10.1016/j.euroneuro.2015.07.021. [Epub ahead of print]

Combination of intravenous S-ketamine and oral tranylcypromine in
treatment-resistant depression: A report of two cases.

Bartova L(1), Vogl SE(2), Stamenkovic M(1), Praschak-Rieder N(1), Naderi-Heiden
A(1), Kasper S(1), Willeit M(3).

Author information:
(1)Division of Biological Psychiatry, Department of Psychiatry and Psychotherapy,
Medical University of Vienna, Austria. (2)Division of Gynecological Oncology,
Department of Gynecology and Obstetrics, Medical University of Vienna, Austria.
(3)Division of Biological Psychiatry, Department of Psychiatry and Psychotherapy,
Medical University of Vienna, Austria. Electronic address:
matthaeus.willeit@meduniwien.ac.at.

Ketamine, a rapid-acting antidepressant and anti-suicidal agent, is thought to
increase brain monoamine levels by enhancing monoamine release or inhibiting
presynaptic monoamine-reuptake. Here we present two female inpatients suffering
from treatment-resistant depression with recurrent severe suicidal crises
receiving a combination of intravenous S-ketamine and oral tranylcypromine, which
is a well-known irreversible monoamine oxidase(MAO) inhibitor. Since inhibition
of monoamine-reuptake with concurrent blockade of MAO might trigger
sympathomimetic crisis, this combination is considered hazardous. Nonetheless,
cardiovascular parameters remained stable in both patients, while good
anti-suicidal effects were observed. Hence, we put serious doubt on whether
monoamine-reuptake inhibition is a relevant pharmacological effect of ketamine in
humans.

PMID: 26302763 [PubMed - as supplied by publisher]

36. Eur Neuropsychopharmacol. 2015 Aug;25(8):1136-46. doi:
10.1016/j.euroneuro.2015.04.012. Epub 2015 May 27.

Ketamine amplifies induced gamma frequency oscillations in the human cerebral
cortex.

Shaw AD(1), Saxena N(2), E Jackson L(3), Hall JE(3), Singh KD(4),
Muthukumaraswamy SD(5).

Author information:
(1)Cardiff University Brain Research Imaging Centre, School of Psychology,
Cardiff CF103AT, UK; Institute of Psychological Medicine and Clinical
Neurosciences, School of Medicine, Cardiff University, Cardiff CF103AT, UK.
(2)Department of Anaesthetics, Intensive Care and Pain Medicine, School of
Medicine, Cardiff University, Cardiff CF144XW, UK; Department of Anaesthetics,
Intensive Care and Pain Medicine, Cwm Taf University Health Board, Llantrisant
CF72 8XR, UK. (3)Department of Anaesthetics, Intensive Care and Pain Medicine,
School of Medicine, Cardiff University, Cardiff CF144XW, UK. (4)Cardiff
University Brain Research Imaging Centre, School of Psychology, Cardiff CF103AT,
UK. (5)School of Pharmacy, Faculty of Medical and Health Sciences, Auckland
University, Auckland 1123, New Zealand; School of Psychology, Faculty of Medical
and Health Sciences, Auckland University, Auckland 1123 New Zealand. Electronic
address: sd.muthu@auckland.ac.nz.

At subanaesthetic doses, ketamine, an N-methyl-d-aspartate (NMDA) receptor
antagonist, has demonstrated remarkable and rapid antidepressant efficacy in
patients with treatment-resistant depression. The mechanism of action of ketamine
is complex and not fully understood, with altered glutamatergic function and
alterations of high-frequency oscillatory power (Wood et al., 2012) noted in
animal studies. Here we used magnetoencephalography (MEG) in a single blind,
crossover study to assess the neuronal effects of 0.5mg/kg intravenous ketamine
on task-related high-frequency oscillatory activity in visual and motor cortices.
Consistent with animal findings, ketamine increased beta amplitudes, decreased
peak gamma frequency in visual cortex and significantly amplified gamma-band
amplitudes in motor and visual cortices. The amplification of gamma-band activity
has previously been linked in animal studies to cortical pyramidal cell
disinhibition. This study provides direct translatable evidence of this
hypothesis in humans, which may underlie the anti-depressant actions of ketamine.

PMID: 26123243 [PubMed - in process]

44. Indian J Pharmacol. 2015 Jul-Aug;47(4):454-5. doi: 10.4103/0253-7613.161277.

Ketamine-induced affective switch in a patient with treatment-resistant
depression.

Banwari G(1), Desai P(1), Patidar P(1).

Author information:
(1)Department of Psychiatry, Smt. N. H. L. Municipal Medical College and Sheth V.
S. General Hospital, Ahmedabad, Gujarat, India.

There is growing evidence to support the rapid, albeit short-lived antidepressant
effect of subanesthetic dose of ketamine, a noncompetitive glutamate
N-methyl-D-aspartate receptor antagonist in treatment-resistant unipolar and
bipolar depression. Ketamine is known to cause transient mood elevation or
euphoria, psychotomimetic effects, and dissociative symptoms, but its use in
unipolar or bipolar depression has not been reported to induce an affective
switch amounting to persistent or prolonged hypomania/mania or manic-like
syndrome. We report the case of a 52-year-old male with first episode,
continuous, nonpsychotic, treatment-resistant, unipolar major depression of 10
years duration, who manifested a switch from depression to mania while being
treated with subanesthetic dose of ketamine, given intramuscularly. This case
suggests that polarity switch should be considered as a potential side effect
while using ketamine for treatment-resistant depression.

PMCID: PMC4527073
PMID: 26288483 [PubMed - in process]

51. Aust N Z J Psychiatry. 2015 Jun 9. pii: 0004867415590631. [Epub ahead of print]

Benzodiazepines may reduce the effectiveness of ketamine in the treatment of
depression.

Ford N(1), Ludbrook G(2), Galletly C(3).

Author information:
(1)Discipline of Psychiatry, The University of Adelaide, Adelaide, SA, Australia.
(2)Discipline of Acute Care Medicine, The University of Adelaide, Adelaide, SA,
Australia. (3)Discipline of Psychiatry, The University of Adelaide, Adelaide, SA,
Australia cherrie.galletly@adelaide.edu.au.

PMID: 26058787 [PubMed - as supplied by publisher]

52. Biol Psychiatry. 2015 Jun 4. pii: S0006-3223(15)00465-5. doi:
10.1016/j.biopsych.2015.05.016. [Epub ahead of print]

The Use of Ketamine for the Treatment of Depression in the Context of Psychotic
Symptoms: To the Editor.

da Frota Ribeiro CM(1), Sanacora G(2), Hoffman R(2), Ostroff R(3).

Author information:
(1)Federal University of Ceará, Fortaleza, Ceará, Brazil. Electronic address:
carolinamfr@gmail.com. (2)Departments of Psychiatry and Nursing; Yale Depression
Research Program; and Intensive Outpatient Program, Adult Inpatient Service, and
Electroconvulsive Therapy Service, Yale-New Haven Psychiatric Hospital, Yale
School of Medicine, New Haven, Connecticut. (3)Federal University of Ceará,
Fortaleza, Ceará, Brazil.

PMID: 26212896 [PubMed - as supplied by publisher]

55. Eur Psychiatry. 2015 Jun;30(4):504-10. doi: 10.1016/j.eurpsy.2014.11.007. Epub
2015 Mar 18.

Repeated ketamine administration redeems the time lag for citalopram's
antidepressant-like effects.

Zhang GF(1), Liu WX(1), Qiu LL(1), Guo J(2), Wang XM(1), Sun HL(1), Yang JJ(3),
Zhou ZQ(4).

Author information:
(1)Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing
University, Nanjing 210002, China. (2)Department of Anesthesiology, Affiliated
Hospital of Nanjing, University of Traditional Chinese Medicine, Nanjing, China.
(3)Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing
University, Nanjing 210002, China; Jiangsu Province Key Laboratory of
Anesthesiology, Xuzhou Medical College, Xuzhou, China; Jiangsu Province Key
Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, China.
Electronic address: yjyangjj@126.com. (4)Department of Anesthesiology, Jinling
Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.
Electronic address: zq-zhou@163.com.

Current available antidepressants exhibit low remission rate with a long response
lag time. Growing evidence has demonstrated acute sub-anesthetic dose of ketamine
exerts rapid, robust, and lasting antidepressant effects. However, a long term
use of ketamine tends to elicit its adverse reactions. The present study aimed to
investigate the antidepressant-like effects of intermittent and consecutive
administrations of ketamine on chronic unpredictable mild stress (CUMS) rats, and
to determine whether ketamine can redeem the time lag for treatment response of
classic antidepressants. The behavioral responses were assessed by the sucrose
preference test, forced swimming test, and open field test. In the first stage of
experiments, all the four treatment regimens of ketamine (10mg/kg ip, once daily
for 3 or 7 consecutive days, or once every 7 or 3 days, in a total 21 days)
showed robust antidepressant-like effects, with no significant influence on
locomotor activity and stereotype behavior in the CUMS rats. The intermittent
administration regimens produced longer antidepressant-like effects than the
consecutive administration regimens and the administration every 7 days presented
similar antidepressant-like effects with less administration times compared with
the administration every 3 days. In the second stage of experiments, the
combination of ketamine (10 mg/kg ip, once every 7 days) and citalopram (20 mg/kg
po, once daily) for 21 days caused more rapid and sustained antidepressant-like
effects than citalopram administered alone. In summary, repeated sub-anesthestic
doses of ketamine can redeem the time lag for the antidepressant-like effects of
citalopram, suggesting the combination of ketamine and classic antidepressants is
a promising regimen for depression with quick onset time and stable and lasting
effects.

PMID: 25795441 [PubMed - in process]

56. J Clin Psychiatry. 2015 Jun;76(6):738-40. doi: 10.4088/JCP.15com09904.

Maintaining the initial clinical response after ketamine in bipolar and unipolar
depression: an important next-step challenge.

Iosifescu DV(1).

Author information:
(1)One Gustave L. Levy Pl, Box 1230, New York, NY 10029 dan.iosifescu@mssm.edu.

Comment on
J Clin Psychiatry. 2015 Jun;76(6):737-8.

PMID: 26132676 [PubMed - indexed for MEDLINE]

58. J Clin Psychopharmacol. 2015 Jun;35(3):334-6. doi: 10.1097/JCP.0000000000000316.

Concomitant benzodiazepine use attenuates ketamine response: implications for
large scale study design and clinical development.

Frye MA(1), Blier P, Tye SJ.

Author information:
(1)Department of Psychiatry and Psychology Mayo Clinic Depression Center Mayo
Clinic Rochester, MN mfrye@mayo.edu University of Ottawa Institute of Mental
Health Research Mood Disorders Research Ottawa, Ontario, Canada Department of
Psychiatry and Psychology Mayo Clinic Depression Center Mayo Clinic Rochester,
MN.

PMID: 25928701 [PubMed - in process]

62. J Intensive Care Med. 2015 May 28. pii: 0885066615587868. [Epub ahead of print]

Low-Dose Ketamine in Chronic Critical Illness.

Moitra VK(1), Patel MK(2), Darrah D(3), Moitra A(4), Wunsch H(5).

Author information:
(1)Department of Anesthesiology, College of Physicians & Surgeons, Columbia
University, New York, NY, USA Vm2161@cumc.columbia.edu. (2)Department of
Pharmacy, New York Presbyterian Hospital, Columbia University, New York, NY, USA.
(3)Department of Anesthesiology, College of Physicians & Surgeons, Columbia
University, New York, NY, USA. (4)Department of Pharmacy, College of Pharmacy,
University of Illinois at Chicago, Chicago, IL, USA. (5)Department of Anesthesia,
University of Toronto, Toronto, Ontario, Canada.

We report a case series on the observed effects of low-dose ketamine infusions in
4 critically ill patients with varying complications related to prolonged
critical illness. Doses of ketamine infusion ranged from 0.5 to 4 μg/kg/min. A
low-dose ketamine infusion was used to reduce agitation in a patient requiring
high doses of sedatives and analgesics. In a second patient, ketamine improved
depression and anxiety symptoms. In a third patient, ketamine may have
facilitated liberation from mechanical ventilation. In a fourth patient, ketamine
was used for palliation to avoid lethargy. Ketamine may be considered to help
decrease agitation, manage pain, facilitate opioid and benzodiazepine withdrawal,
prevent respiratory depression, and potentially manage depression and anxiety in
chronically critically ill patients.

PMID: 26025196 [PubMed - as supplied by publisher]

63. Transl Psychiatry. 2015 May 26;5:e573. doi: 10.1038/tp.2015.66.

The positive effect on ketamine as a priming adjuvant in antidepressant
treatment.

Melo A(1), Kokras N(2), Dalla C(2), Ferreira C(1), Ventura-Silva AP(1), Sousa
N(1), Pêgo JM(1).

Author information:
(1)1] Life and Health Sciences Research Institute (ICVS), School of Health
Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's - PT Government
Associate Laboratory, Braga/Guimarães, Portugal. (2)Department of Pharmacology,
Medical School, University of Athens, Athens, Greece.

Ketamine is an anesthetic with antidepressant properties. The rapid and lasting
effect of ketamine observed in preclinical and clinical research makes it a
promising therapeutic to improve current major depression (MD) treatment. Our
work intended to evaluate whether the combined use of classic antidepressants
(imipramine or fluoxetine) and ketamine would improve the antidepressant
response. Using an animal model of depressive-like behavior, we show that the
addition of ketamine to antidepressants anticipates the behavioral response and
accelerates the neuroplastic events when compared with the use of antidepressants
alone. In conclusion, our results suggest the need for a reappraisal of the
current pharmacological treatment of MD.

PMCID: PMC4471295
PMID: 26080090 [PubMed - in process]

64. J Neuroimmunol. 2015 May 15;282:33-8. doi: 10.1016/j.jneuroim.2015.03.012. Epub
2015 Mar 13.

Immunomodulatory activity of ketamine in human astroglial A172 cells: Possible
relevance to its rapid antidepressant activity.

Yuhas Y(1), Ashkenazi S(2), Berent E(3), Weizman A(4).

Author information:
(1)Laboratory of Pediatric Infectious Diseases, Felsenstein Medical Research
Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University,
Tel Aviv, Israel. Electronic address: Yuhas@post.tau.ac.il. (2)Laboratory of
Pediatric Infectious Diseases, Felsenstein Medical Research Center, Petach Tikva,
Israel; Department of Pediatrics A, Schneider Children's Medical Center of
Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University,
Tel Aviv, Israel. (3)Laboratory of Pediatric Infectious Diseases, Felsenstein
Medical Research Center, Petach Tikva, Israel. (4)Laboratory of Biological
Psychiatry, Felsenstein Medical Research Center, Petach Tikva, Israel; Sackler
Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Research Unit, Geha
Mental Health Center, Petach Tikva, Israel.

To determine if the immunomodulatory effect of ketamine is relevant to its rapid
antidepressant activity, cultured human astroglial cells were incubated with
ketamine, cytokine mix, or both. At 24h, ketamine dose-dependently (100-500 μM)
decreased IL-6 and TNFα production and gene expression and, at clinically
relevant concentration (100 μM), augmented IL-β release and gene expression in
both unstimulated and cytokine-stimulated cells. In unstimulated cells, ketamine
also increased IL-8 production and mRNA expression. The reduction in IL-6 mRNA
was significant within 1h in unstimulated cells and at 4h after stimulation.
Ketamine suppressed the production of the only established depression-relevant
proinflammatory cytokines, IL-6 and TNFα.

PMID: 25903726 [PubMed - indexed for MEDLINE]

67. Ann N Y Acad Sci. 2015 May;1344:66-77. doi: 10.1111/nyas.12718. Epub 2015 Feb 27.

Ketamine as a promising prototype for a new generation of rapid-acting
antidepressants.

Abdallah CG(1), Averill LA, Krystal JH.

Author information:
(1)Clinical Neurosciences Division, United States Department of Veterans Affairs,
National Center for Posttraumatic Stress Disorder, VA Connecticut Healthcare
System, West Haven, Connecticut; Department of Psychiatry, Yale University School
of Medicine, New Haven, Connecticut.

The discovery of ketamine's rapid and robust antidepressant effects opened a
window into a new generation of antidepressants. Multiple controlled trials and
open-label studies have demonstrated these effects across a variety of patient
populations known to often achieve little to no response from traditional
antidepressants. Ketamine has been generally well tolerated across patient
groups, with transient mild-to-moderate adverse effects during infusion. However,
the optimal dosing and route of administration and the safety of chronic
treatment are not fully known. This review summarizes the clinical effects of
ketamine and its neurobiological underpinnings and mechanisms of action, which
may provide insight into the neurobiology of depression, relevant biomarkers, and
treatment targets. Moreover, we offer suggestions for future research that may
continue to advance the field forward and ultimately improve the
psychopharmacologic interventions available for those individuals struggling with
depressive and trauma-related disorders.

Published 2015. This article is U.S. Government work and is in the public domain
in the USA.

PMCID: PMC4412785 [Available on 2016-05-01]
PMID: 25727103 [PubMed - indexed for MEDLINE]

68. Ann N Y Acad Sci. 2015 May;1345:47-58. doi: 10.1111/nyas.12646. Epub 2015 Feb 3.

The promise of ketamine for treatment-resistant depression: current evidence and
future directions.

DeWilde KE(1), Levitch CF(1), Murrough JW(1), Mathew SJ(2), Iosifescu DV(1).

Author information:
(1)Mood and Anxiety Disorders Program, Icahn School of Medicine at Mount Sinai,
New York, New York. (2)Menninger Department of Psychiatry and Behavioral
Sciences, Baylor College of Medicine, Houston, Texas.

Major depressive disorder (MDD) is one of the most disabling diseases worldwide
and is becoming a significant public health threat. Current treatments for MDD
primarily consist of monoamine-targeting agents and have limited efficacy.
However, the glutamate neurotransmitter system has recently come into focus as a
promising alternative for novel antidepressant treatments. We review the current
data on the glutamate NMDA receptor antagonist ketamine, which has been shown in
clinical trials to act as a rapid antidepressant in MDD. We also examine ketamine
efficacy on dimensions of psychopathology, including anhedonia, cognition, and
suicidality, consistent with the NIMH Research Domain Criteria initiative. Other
aspects of ketamine reviewed in this paper include safety and efficacy, different
administration methods, and the risks of misuse of ketamine outside of medical
settings. Finally, we conclude with a discussion of glutamatergic agents other
than ketamine currently being tested as novel antidepressants.

PMCID: PMC4447578 [Available on 2016-05-01]
PMID: 25649308 [PubMed - indexed for MEDLINE]

69. Hum Psychopharmacol. 2015 May;30(3):152-63. doi: 10.1002/hup.2475. Epub 2015 Apr
7.

The use of ketamine as an antidepressant: a systematic review and meta-analysis.

Coyle CM(1), Laws KR.

Author information:
(1)School of Life and Medical Sciences, University of Hertfordshire, Hatfield,
UK.

OBJECTIVE: The current meta-analysis examines the effects of ketamine infusion on
depressive symptoms over time in major depressive disorder (MDD) and bipolar
disorder (BD).
METHODS: Following a systematic review of the literature, data were extracted
from 21 studies (n = 437 receiving ketamine) and analysed at four post-infusion
time points (4 h, 24 h, 7 days and 12-14 days). The moderating effects of several
factors were assessed including: repeat/single infusion, diagnosis,
open-label/participant-blind infusion, pre-post/placebo-controlled design and the
sex of patients.
RESULTS: Effect sizes were significantly larger for repeat than single infusion
at 4 h, 24 h and 7 days. For single infusion studies, effect sizes were large and
significant at 4 h, 24 h and 7 days. The percentage of males was a predictor of
antidepressant response at 7 days. Effect sizes for open-label and
participant-blind infusions were not significantly different at any time point.
CONCLUSIONS: Single ketamine infusions elicit a significant antidepressant effect
from 4 h to 7 days; the small number of studies at 12-14 days post infusion
failed to reach significance. Results suggest a discrepancy in peak response time
depending upon primary diagnosis - 24 h for MDD and 7 days for BD. The majority
of published studies have used pre-post comparison; further placebo-controlled
studies would help to clarify the effect of ketamine over time.

PMID: 25847818 [PubMed - in process]

70. J Clin Psychiatry. 2015 May;76(5):628-31. doi: 10.4088/JCP.15f10026.

Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for
refractory depression.

Andrade C(1).

Author information:
(1)Department of Psychopharmacology, National Institute of Mental Health and
Neurosciences, Bangalore, India candrade@psychiatrist.com.

Intranasal drug delivery (INDD) systems offer a route to the brain that bypasses
problems related to gastrointestinal absorption, first-pass metabolism, and the
blood-brain barrier; onset of therapeutic action is rapid, and the inconvenience
and discomfort of parenteral administration are avoided. INDD has found several
applications in neuropsychiatry, such as to treat migraine, acute and chronic
pain, Parkinson disease, disorders of cognition, autism, schizophrenia, social
phobia, and depression. INDD has also been used to test experimental drugs, such
as peptides, for neuropsychiatric indications; these drugs cannot easily be
administered by other routes. This article examines the advantages and
applications of INDD in neuropsychiatry; provides examples of test, experimental,
and approved INDD treatments; and focuses especially on the potential of
intranasal ketamine for the acute and maintenance therapy of refractory
depression.

PMID: 26035196 [PubMed - indexed for MEDLINE]

71. J Psychopharmacol. 2015 May;29(5):596-607. doi: 10.1177/0269881114568041. Epub
2015 Feb 17.

Neural correlates of change in major depressive disorder anhedonia following
open-label ketamine.

Lally N(1), Nugent AC(2), Luckenbaugh DA(2), Niciu MJ(2), Roiser JP(3), Zarate CA
Jr(2).

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, National Institutes of
Health/National Institute of Mental Health, Bethesda, MD, USA Institute of
Cognitive Neuroscience, University College London, London, UK
lallynm@mail.nih.gov. (2)Experimental Therapeutics and Pathophysiology Branch,
National Institutes of Health/National Institute of Mental Health, Bethesda, MD,
USA. (3)Institute of Cognitive Neuroscience, University College London, London,
UK.

Anhedonia is a cardinal symptom of major depression and is often refractory to
standard treatment, yet no approved medication for this specific symptom exists.
In this exploratory re-analysis, we assessed whether administration of
rapid-acting antidepressant ketamine was associated specifically with reduced
anhedonia in medication-free treatment-refractory patients with major depressive
disorder in an open-label investigation. Additionally, participants received
either oral riluzole or placebo daily beginning 4 hours post-infusion. A subgroup
of patients underwent fluorodeoxyglucose positron emission tomography scans at
baseline (1-3 days pre-infusion) and 2 hours post-ketamine infusion. Anhedonia
rapidly decreased following a single ketamine infusion; this was sustained for up
to three days, but was not altered by riluzole. Reduced anhedonia correlated with
increased glucose metabolism in the hippocampus and dorsal anterior cingulate
cortex (dACC) and decreased metabolism in the inferior frontal gyrus and
orbitofrontal cortex (OFC). The tentative relationship between change in
anhedonia and glucose metabolism remained significant in dACC and OFC, and at
trend level in the hippocampus, a result not anticipated, when controlling for
change in total depression score. Results, however, remain tenuous due to the
lack of a placebo control for ketamine. In addition to alleviating overall
depressive symptoms, ketamine could possess anti-anhedonic potential in major
depressive disorder, which speculatively, may be mediated by alterations in
metabolic activity in the hippocampus, dACC and OFC.

PMID: 25691504 [PubMed - in process]

72. J Psychopharmacol. 2015 May;29(5):591-5. doi: 10.1177/0269881114544776. Epub 2014
Aug 13.

Hippocampal volume and the rapid antidepressant effect of ketamine.

Abdallah CG(1), Salas R(2), Jackowski A(3), Baldwin P(2), Sato JR(4), Mathew
SJ(5).

Author information:
(1)Clinical Neuroscience Division, National Center for Post-traumatic Stress
Disorder (PTSD), West Haven, CT, USA Department of Psychiatry, Yale University
School of Medicine, New Haven, CT, USA chadi.abdallah@yale.edu. (2)Menninger
Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine,
Houston, TX, USA. (3)Department of Psychiatry, Universidade Federal de São Paulo,
São Paulo, Brazil. (4)Department of Psychiatry, Universidade Federal de São
Paulo, São Paulo, Brazil Center of Mathematics, Computation and Cognition;
Universidade Federal do ABC, Santo Andre, Brazil. (5)Menninger Department of
Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA
Mental Health Care Line, Michael E Debakey Veterans' Administration (VA) Medical
Center, Houston, TX, USA.

Accumulating evidence underscores the utility of ketamine in treating severely
treatment-resistant depressed patients. We investigated the relationship between
the rapid antidepressant effects of ketamine and hippocampal volume, a biomarker
of antidepressant treatment outcome. We gave 16 medication-free, major depressive
disorder (MDD) patients a single, sub-anesthetic dose infusion of ketamine (0.5
mg/kg, over 40 min). We assessed depression severity pre-treatment, and at 24 h
post-treatment, with the Montgomery-Åsberg Depression Rating Scale (MADRS). Prior
to treatment, patients underwent magnetic resonance imaging (MRI) to estimate
their hippocampal volume: We obtained viable MRI data in 13 patients. Delta MADRS
(post- minus pre-treatment) was significantly correlated with the pre-treatment
volumes of the left hippocampus (r = 0.66; p = 0.01), but not the right
hippocampus (r = 0.49; p = 0.09). The correlation between delta MADRS and the
left hippocampus remained high (r > 0.6; p = 0.13), after controlling for several
demographic and clinical variables, although the p value increased due to the
reduced degree of freedom (df = 5). Ketamine exerts enhanced antidepressant
effects in patients with a relatively smaller hippocampus, a patient population
that has been repeatedly shown to be refractory to traditional antidepressants.

PMID: 25122038 [PubMed - in process]

73. Ther Adv Chronic Dis. 2015 May;6(3):97-114. doi: 10.1177/2040622315579059.

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of
depression: a perspective review.

Iadarola ND(1), Niciu MJ(1), Richards EM(1), Vande Voort JL(1), Ballard ED(1),
Lundin NB(1), Nugent AC(1), Machado-Vieira R(1), Zarate CA Jr(2).

Author information:
(1)National Institutes of Health/National Institute of Mental Health,
Experimental Therapeutics and Pathophysiology Branch, Bethesda, MD, USA.
(2)National Institutes of Health/National Institute of Mental Health,
Experimental Therapeutics and Pathophysiology Branch, 10 Center Dr., Building
10/CRC, Room 7-5545, Bethesda, MD 20892, USA.

Current pharmacotherapies for major depressive disorder (MDD) and bipolar
depression (BDep) have a distinct lag of onset that can generate great distress
and impairment in patients. Furthermore, as demonstrated by several real-world
effectiveness trials, their efficacy is limited. All approved antidepressant
medications for MDD primarily act through monoaminergic mechanisms, agonists or
antagonists with varying affinities for serotonin, norepinephrine and dopamine.
The glutamate system has received much attention in recent years as an avenue for
developing novel therapeutics. A single subanesthetic dose infusion of the
noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been
shown to have rapid and potent antidepressant effects in treatment-resistant MDD
and BDep. In a reverse translational framework, ketamine's clinical efficacy has
inspired many preclinical studies to explore glutamatergic mechanisms of
antidepressant action. These studies have revealed enhanced synaptic
plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release
of local translational inhibition of brain-derived neurotrophic factor and
secretion from dendritic spines, mammalian target of rapamycin activation and
glycogen synthase kinase-3 inhibition. Current efforts are focused on extending
ketamine's antidepressant efficacy, uncovering the neurobiological mechanisms
responsible for ketamine's antidepressant activity in biologically enriched
subgroups, and identifying treatment response biomarkers to personalize
antidepressant selection. Other NMDA receptor antagonists have been studied both
preclinically and clinically, which have revealed relatively modest
antidepressant effects compared with ketamine but potentially other favorable
characteristics, for example, decreased dissociative or psychotomimetic effects;
therefore, there is great interest in developing novel glutamatergic
antidepressants with greater target specificity and/or decreased adverse effects.

PMCID: PMC4416968
PMID: 25954495 [PubMed]

74. Am J Ther. 2015 Apr 24. [Epub ahead of print]

Ketamine-A Narrative Review of Its Uses in Medicine.

Radvansky BM(1), Puri S, Sifonios AN, Eloy JD, Le V.

Author information:
(1)Department of Anesthesiology and Perioperative Medicine, Rutgers University
New Jersey Medical School, Newark, NJ.

One of the most fascinating drugs in the anesthesiologist's armament is ketamine,
an N-methyl-D-aspartate receptor antagonist with a myriad of uses. The drug is a
dissociative anesthetic and has been used more often as an analgesic in numerous
hospital units, outpatient pain clinics, and in the prehospital realm. It has
been used to treat postoperative pain, chronic pain, complex regional pain
syndrome, phantom limb pain, and other neuropathic conditions requiring
analgesia. Research has also demonstrated its efficacy as an adjunct in
psychotherapy, as a treatment for both depression and posttraumatic stress
disorder, as a procedural sedative, and as a treatment for respiratory and
neurologic conditions. Ketamine is not without its adverse effects, some of which
can be mitigated with certain efforts. Such effects make it necessary for the
clinician to use the drug only in situations where it will provide the greatest
benefit with the fewest adverse effects. To the best of our knowledge, none of
the reviews regarding ketamine have taken a comprehensive look at the drug's uses
in all territories of medicine. This review will serve to touch on its chemical
data, pharmacokinetics and pharmacodynamics, medical uses, and adverse effects
while focusing specifically on the drugs usage in anesthesia and analgesia.

PMID: 25923225 [PubMed - as supplied by publisher]

81. J Clin Pharm Ther. 2015 Apr;40(2):125-30. doi: 10.1111/jcpt.12238. Epub 2014 Dec
26.

Rapid-onset antidepressant action of ketamine: potential revolution in
understanding and future pharmacologic treatment of depression.

Drewniany E(1), Han J, Hancock C, Jones RL, Lim J, Nemat Gorgani N, Sperry JK
3rd, Yu HJ, Raffa RB.

Author information:
(1)Department of Pharmaceutical Sciences, Temple University School of Pharmacy,
Philadelphia, PA, USA.

WHAT IS KNOWN AND OBJECTIVE: The current pharmacotherapeutic treatment of major
depressive disorder (MDD) generally takes weeks to be effective. As the molecular
action of these drugs is immediate, the mechanistic basis for this lag is
unclear. A drug that has a more rapid onset of action would be a major
therapeutic advance and also be a useful comparator to provide valuable
mechanistic insight into the disorder and its treatment.
COMMENT: Recent evidence suggests that ketamine produces rapid-onset
antidepressant action. Important questions are as follows: is it specific or
coincidental to other effects; is there a dose-response relationship; and is the
mechanism related to that of current antidepressants. NMDA receptor antagonism is
unlikely the explanation for ketamine's antidepressant action.
WHAT IS NEW AND CONCLUSION: It is not an exaggeration to state that the new
findings, if validated, might produce a revolution in understanding and treating
depressive disorders.

PMID: 25545040 [PubMed - in process]

84. Neuropsychopharmacology. 2015 Mar 13;40(5):1084-90. doi: 10.1038/npp.2014.298.

Neurocognitive effects of ketamine and association with antidepressant response
in individuals with treatment-resistant depression: a randomized controlled
trial.

Murrough JW(1), Burdick KE(2), Levitch CF(3), Perez AM(4), Brallier JW(4), Chang
LC(5), Foulkes A(6), Charney DS(7), Mathew SJ(8), Iosifescu DV(1).

Author information:
(1)1] Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School
of Medicine at Mount Sinai, New York, NY, USA [2] Fishberg Department of
Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA [3]
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY,
USA. (2)1] Fishberg Department of Neuroscience, Icahn School of Medicine at Mount
Sinai, New York, NY, USA [2] Friedman Brain Institute, Icahn School of Medicine
at Mount Sinai, New York, NY, USA [3] Department of Psychiatry, Icahn School of
Medicine at Mount Sinai, New York, NY, USA. (3)Mood and Anxiety Disorders
Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New
York, NY, USA. (4)Department of Anesthesiology, Icahn School of Medicine at Mount
Sinai, New York, NY, USA. (5)Department of Anesthesiology, Baylor College of
Medicine, Houston, TX, USA. (6)Menninger Department of Psychiatry and Behavioral
Sciences, Baylor College of Medicine, Houston, TX, USA. (7)1] Mood and Anxiety
Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount
Sinai, New York, NY, USA [2] Fishberg Department of Neuroscience, Icahn School of
Medicine at Mount Sinai, New York, NY, USA [3] Department of Pharmacology and
Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
(8)1] Michael E. Debakey VA Medical Center, Houston, TX, USA [2] Menninger
Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine,
Houston, TX, USA.

The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine displays
rapid antidepressant effects in patients with treatment-resistant depression
(TRD); however, the potential for adverse neurocognitive effects in this
population has not received adequate study. The current study was designed to
investigate the delayed neurocognitive impact of ketamine in TRD and examine
baseline antidepressant response predictors in the context of a randomized
controlled trial. In the current study, 62 patients (mean age = 46.2 ± 12.2) with
TRD free of concomitant antidepressant medication underwent neurocognitive
assessments using components of the MATRICS Consensus Cognitive Battery (MCCB)
before and after a single intravenous infusion of ketamine (0.5 mg/kg) or
midazolam (0.045 mg/kg). Participants were randomized to ketamine or midazolam in
a 2:1 fashion under double-blind conditions and underwent depression symptom
assessments at 24, 48, 72 h, and 7 days post treatment using the
Montgomery-Asberg Depression Rating Scale (MADRS). Post-treatment neurocognitive
assessment was conducted once at 7 days. Neurocognitive performance improved
following the treatment regardless of treatment condition. There was no
differential effect of treatment on neurocognitive performance and no association
with antidepressant response. Slower processing speed at baseline uniquely
predicted greater improvement in depression at 24 h following ketamine (t = 2.3,
p = 0.027), while controlling for age, depression severity, and performance on
other neurocognitive domains. In the current study, we found that ketamine was
devoid of adverse neurocognitive effects at 7 days post treatment and that slower
baseline processing speed was associated with greater antidepressant response.
Future studies are required to further define the neurocognitive profile of
ketamine in clinical samples and to identify clinically useful response
moderators.

PMCID: PMC4367458 [Available on 2016-04-01]
PMID: 25374095 [PubMed - in process]

85. CNS Drugs. 2015 Mar;29(3):181-8. doi: 10.1007/s40263-015-0232-4.

Does ketamine have anti-suicidal properties? Current status and future
directions.

Price RB(1), Mathew SJ.

Author information:
(1)Department of Psychiatry, University of Pittsburgh School of Medicine, 3811
O'Hara St., Pittsburgh, PA, 15213, USA, rebecca.price@stanfordalumni.org.

Ketamine, a widely used anesthetic agent, is currently being investigated as a
novel therapeutic for depression and suicidality. Ketamine has garnered
substantial attention from researchers, clinicians, media outlets, and patients
alike, but numerous questions remain. One of the compelling features of ketamine
is the rapidity of its antidepressant effects, which peak just 24 h after
infusion, setting it apart from other existing treatments. Ketamine's rapid time
course has inspired research efforts to explore its potential as a life-saving
therapy for patients at imminent risk of suicide. In this article, we review
current evidence supporting the rapid effects of ketamine on suicidal ideation in
the context of unipolar and bipolar depression. We then discuss several future
directions that are necessary before ketamine can be considered a viable
treatment option for suicidality in clinical settings. These include: testing for
a specific anti-suicidal effect-separate from overall antidepressant effects-to
ascertain whether ketamine might hold promise for a broader class of suicidal
patients; ensuring that acute benefits of ketamine can be prolonged over a
clinically meaningful timeframe; and developing a better understanding of the
mechanisms by which ketamine might reduce suicide risk. Such efforts will enable
the field to more accurately assess the potential of ketamine, as well as its
limitations, allowing for appropriate placement within the context of
comprehensive clinical care for suicide prevention.

PMCID: PMC4380583 [Available on 2016-03-01]
PMID: 25715884 [PubMed - in process]

86. Drugs R D. 2015 Mar;15(1):37-43. doi: 10.1007/s40268-015-0081-0.

Ketamine as a potential treatment for suicidal ideation: a systematic review of
the literature.

Reinstatler L(1), Youssef NA.

Author information:
(1)Department of Psychiatry, Medical College of Georgia at Georgia Regents
University, Augusta, GA, USA.

OBJECTIVE: To review the published literature on the efficacy of ketamine for the
treatment of suicidal ideation (SI).
METHODS: The PubMed and Cochrane databases were searched up to January 2015 for
clinical trials and case reports describing therapeutic ketamine administration
to patients presenting with SI/suicidality. Searches were also conducted for
relevant background material regarding the pharmacological function of ketamine.
RESULTS: Nine publications (six studies and three case reports) met the search
criteria for assessing SI after administration of subanesthetic ketamine. There
were no studies examining the effect on suicide attempts or death by suicide.
Each study demonstrated a rapid and clinically significant reduction in SI, with
results similar to previously described data on ketamine and treatment-resistant
depression. A total of 137 patients with SI have been reported in the literature
as receiving therapeutic ketamine. Seven studies delivered a dose of 0.5 mg/kg
intravenously over 40 min, while one study administered a 0.2 mg/kg intravenous
bolus and another study administered a liquid suspension. The earliest
significant results were seen after 40 min, and the longest results were observed
up to 10 days postinfusion.
CONCLUSION: Consistent with clinical research on ketamine as a rapid and
effective treatment for depression, ketamine has shown early preliminary evidence
of a reduction in depressive symptoms, as well as reducing SI, with minimal
short-term side effects. Additional studies are needed to further investigate its
mechanism of action, long-term outcomes, and long-term adverse effects (including
abuse) and benefits. In addition, ketamine could potentially be used as a
prototype for further development of rapid-acting antisuicidal medication with a
practical route of administration and the most favorable risk/benefit ratio.

PMCID: PMC4359177
PMID: 25773961 [PubMed - in process]

87. Gen Hosp Psychiatry. 2015 Mar-Apr;37(2):178-84. doi:
10.1016/j.genhosppsych.2015.01.003. Epub 2015 Jan 15.

Ketamine as a novel treatment for major depressive disorder and bipolar
depression: a systematic review and quantitative meta-analysis.

Lee EE(1), Della Selva MP(1), Liu A(1), Himelhoch S(1).

Author information:
(1)Department of Psychiatry, University of Maryland School of Medicine,
Baltimore, MD.

OBJECTIVE: Given the significant disability, morbidity and mortality associated
with depression, the promising recent trials of ketamine highlight a novel
intervention. A meta-analysis was conducted to assess the efficacy of ketamine in
comparison with placebo for the reduction of depressive symptoms in patients who
meet criteria for a major depressive episode.
METHOD: Two electronic databases were searched in September 2013 for
English-language studies that were randomized placebo-controlled trials of
ketamine treatment for patients with major depressive disorder or bipolar
depression and utilized a standardized rating scale. Studies including
participants receiving electroconvulsive therapy and adolescent/child
participants were excluded. Five studies were included in the quantitative
meta-analysis.
RESULTS: The quantitative meta-analysis showed that ketamine significantly
reduced depressive symptoms. The overall effect size at day 1 was large and
statistically significant with an overall standardized mean difference of 1.01
(95% confidence interval 0.69-1.34) (P<.001), with the effects sustained at 7
days postinfusion. The heterogeneity of the studies was low and not statistically
significant, and the funnel plot showed no publication bias.
CONCLUSIONS: The large and statistically significant effect of ketamine on
depressive symptoms supports a promising, new and effective pharmacotherapy with
rapid onset, high efficacy and good tolerability.

PMID: 25698228 [PubMed - in process]

88. Int J Neurosci. 2015 Mar;125(3):232-4. doi: 10.3109/00207454.2014.933834. Epub
2014 Jul 23.

Combination therapy utilizing ketamine and transcranial magnetic stimulation for
treatment-resistant depression: a case report.

Best SR(1), Griffin B.

Author information:
(1)1The Neuroscience Center, Deerfield, IL, USA.

In the present article, we report on the case of a 23-year-old woman with a
history of treatment-resistant depression who achieved significant symptom
improvement with a novel treatment consisting of ketamine, a dissociative
anesthetic, and external neuromodulation with transcranial magnetic stimulation
(TMS). This case highlights the need for further investigation of treatments
pairing external neuromodulation with dissociative anesthetics.

PMID: 24927244 [PubMed - in process]

89. J Clin Psychiatry. 2015 Mar;76(3):247-52. doi: 10.4088/JCP.13m08852.

Ketamine safety and tolerability in clinical trials for treatment-resistant
depression.

Wan LB(1), Levitch CF, Perez AM, Brallier JW, Iosifescu DV, Chang LC, Foulkes A,
Mathew SJ, Charney DS, Murrough JW.

Author information:
(1)Department of Psychiatry, Mood and Anxiety Disorders Program.

OBJECTIVE: Ketamine has demonstrated rapid antidepressant effects in patients
with treatment-resistant depression (TRD); however, the safety and tolerability
of ketamine in this population have not been fully described. Herein we report
the largest study to date of the safety, tolerability, and acceptability of
ketamine in TRD.
METHOD: Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40
minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD)
were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic
medical centers. Safety and tolerability measures included attrition, adverse
events (AEs), hemodynamic changes, and assessments of psychosis and dissociation.
RESULTS: The overall antidepressant response rate, defined as a ≥ 50% improvement
in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97
participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The
overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the
infusion, the most common general AEs were drowsiness, dizziness, poor
coordination, blurred vision, and feeling strange or unreal. Approximately one
third of individuals experienced protocol-defined hemodynamic changes. Ketamine
resulted in small but significant increases in psychotomimetic and dissociative
symptoms (all P < .05). There were no cases of persistent psychotomimetic
effects, adverse medical effects, or increased substance use in a subgroup of
patients with available long-term follow-up information.
CONCLUSIONS: In this relatively large group of patients with TRD, ketamine was
safe and well tolerated. Further research investigating the safety of ketamine in
severe and refractory depression is warranted.
TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and
NCT00768430.

PMID: 25271445 [PubMed - indexed for MEDLINE]

91. J Okla State Med Assoc. 2015 Mar;108(3):88-9.

Frontiers in Therapy of Treatment-Resistant-Depression: A Future Role of
Ketamine?

Kwak S, Tiller D, Tucker P.

Many patients treated for major depression in mental health and primary care
settings fail to respond to adequate trials of available evidence-based
treatments. Antidepressants, psychotherapy, and brain stimulation therapies have
had some success, but many individuals do not respond to these treatments.
Ketamine, a dissociative general anesthetic agent, is emerging as an unexpected
possible future treatment to help individuals who suffer from refractory major
depression.

PMID: 26242015 [PubMed - indexed for MEDLINE]

95. Psychol Med. 2015 Mar;45(4):693-704. doi: 10.1017/S0033291714001603. Epub 2014
Jul 10.

A systematic review and meta-analysis of randomized, double-blind,
placebo-controlled trials of ketamine in the rapid treatment of major depressive
episodes.

McGirr A(1), Berlim MT(2), Bond DJ(3), Fleck MP(4), Yatham LN(1), Lam RW(1).

Author information:
(1)Department of Psychiatry,University of British Columbia,Vancouver, BC,Canada.
(2)Neuromodulation Research Clinic,Douglas Mental Health University Institute and
McGill University,Montréal, Québec,Canada. (3)Department of Psychiatry,University
of Minnesota,Minneapolis, MN,USA. (4)Depressive Disorders Program, Douglas Mental
Health University Institute and McGill University,Montréal, Québec,Canada.

BACKGROUND: There is growing interest in glutamatergic agents in depression,
particularly ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor
antagonist. We aimed to assess the efficacy of ketamine in major depressive
episodes.
METHOD: We searched EMBASE, PsycINFO, CENTRAL, and Medline from 1962 to January
2014 to identify double-blind, randomized controlled trials with allocation
concealment evaluating ketamine in major depressive episodes. Clinical remission,
response and depressive symptoms were extracted by two independent raters. The
primary outcome measure was clinical remission at 24 h, 3 days and 7 days
post-treatment. Analyses employed a random-effects model.
RESULTS: Data were synthesized from seven RCTs employing an intravenous infusion
and one RCT employing intranasal ketamine, representing 73 subjects in parallel
arms and 110 subjects in cross-over designs [n = 34 with bipolar disorder (BD), n
= 149 with major depressive disorder (MDD)]. Ketamine was associated with higher
rates of clinical remission relative to comparator (saline or midazolam) at 24 h
[OR 7.06, number needed to treat (NNT) = 5], 3 days (OR 3.86, NNT = 6), and 7
days (OR 4.00, NNT = 6), as well as higher rates of clinical response at 24 h (OR
9.10, NNT = 3), 3 days (OR 6.77, NNT = 3), and 7 days (OR 4.87, NNT = 4). A
standardized mean difference of 0.90 in favor of ketamine was observed at 24 h
based on depression rating scale scores, with group comparisons revealing greater
efficacy in unipolar depression compared to bipolar depression (1.07 v. 0.68).
Ketamine was associated with transient psychotomimetic effects, but no persistent
psychosis or affective switches.
CONCLUSION: Our meta-analysis suggests that single administrations ketamine are
efficacious in the rapid treatment of unipolar and bipolar depression. Additional
research is required to determine optimal dosing schedules, route, treatment
schedules, and the potential efficacy of other glutamatergic agents.

PMID: 25010396 [PubMed - in process]

96. Transl Psychiatry. 2015 Feb 17;5:e509. doi: 10.1038/tp.2015.10.

Regulation of neural responses to emotion perception by ketamine in individuals
with treatment-resistant major depressive disorder.

Murrough JW(1), Collins KA(2), Fields J(2), DeWilde KE(2), Phillips ML(3), Mathew
SJ(4), Wong E(5), Tang CY(5), Charney DS(6), Iosifescu DV(1).

Author information:
(1)1] Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School
of Medicine at Mount Sinai, New York, NY, USA [2] Fishberg Department of
Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA [3]
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY,
USA. (2)Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn
School of Medicine at Mount Sinai, New York, NY, USA. (3)Department of
Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
(4)1] Michael E. DeBakey VA Medical Center, Houston, TX, USA [2] Menninger
Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine,
Houston, TX, USA. (5)1] Department of Radiology, Icahn School of Medicine at
Mount Sinai, New York, NY, USA [2] Translational and Molecular Imaging Institute,
Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6)1] Mood and
Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at
Mount Sinai, New York, NY, USA [2] Fishberg Department of Neuroscience, Icahn
School of Medicine at Mount Sinai, New York, NY, USA [3] Department of
Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai,
New York, NY, USA.

The glutamate N-methyl-D-aspartate receptor antagonist ketamine has demonstrated
antidepressant effects in individuals with treatment-resistant major depressive
disorder (TRD) within 24 h of a single dose. The current study utilized
functional magnetic resonance imaging (fMRI) and two separate emotion perception
tasks to examine the neural effects of ketamine in patients with TRD. One task
used happy and neutral facial expressions; the other used sad and neutral facial
expressions. Twenty patients with TRD free of concomitant antidepressant
medication underwent fMRI at baseline and 24 h following administration of a
single intravenous dose of ketamine (0.5 mg kg(-1)). Adequate data were available
for 18 patients for each task. Twenty age- and sex-matched healthy volunteers
were scanned at one time point for baseline comparison. Whole-brain, voxel-wise
analyses were conducted controlling for a family-wise error rate (FWE) of P<0.05.
Compared with healthy volunteers, TRD patients showed reduced neural responses to
positive faces within the right caudate. Following ketamine, neural responses to
positive faces were selectively increased within a similar region of right
caudate. Connectivity analyses showed that greater connectivity of the right
caudate during positive emotion perception was associated with improvement in
depression severity following ketamine. No main effect of group was observed for
the sad faces task. Our results indicate that ketamine specifically enhances
neural responses to positive emotion within the right caudate in depressed
individuals in a pattern that appears to reverse baseline deficits and that
connectivity of this region may be important for the antidepressant effects of
ketamine.

PMCID: PMC4445748
PMID: 25689570 [PubMed - indexed for MEDLINE]

97. Behav Brain Res. 2015 Feb 15;279:100-5. doi: 10.1016/j.bbr.2014.11.016. Epub 2014
Nov 15.

Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid
antidepressant-like effects of ketamine in the forced swim test.

Li Y(1), Zhu ZR(1), Ou BC(2), Wang YQ(2), Tan ZB(2), Deng CM(2), Gao YY(2), Tang
M(1), So JH(1), Mu YL(1), Zhang LQ(3).

Author information:
(1)Department of Physiology, School of Basic Medicine, Huazhong University of
Science and Technology, Wuhan, China; The Institute of Brain Research, Huazhong
University of Science and Technology, Wuhan, China. (2)Department of Physiology,
School of Basic Medicine, Huazhong University of Science and Technology, Wuhan,
China. (3)Department of Physiology, School of Basic Medicine, Huazhong University
of Science and Technology, Wuhan, China; The Institute of Brain Research,
Huazhong University of Science and Technology, Wuhan, China; Tianjin Nankai
Hospital, Tianjin, China. Electronic address: Lanqiuzhang@126.com.

Major depressive disorder is one of the most prevalent and life-threatening forms
of mental illnesses. The traditional antidepressants often take several weeks,
even months, to obtain clinical effects. However, recent clinical studies have
shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts
rapid antidepressant effects within 2h and are long-lasting. The aim of the
present study was to investigate whether dopaminergic system was involved in the
rapid antidepressant effects of ketamine. The acute administration of ketamine
(20 mg/kg) significantly reduced the immobility time in the forced swim test.
MK-801 (0.1 mg/kg), the more selective NMDA antagonist, also exerted rapid
antidepressant-like effects. In contrast, fluoxetine (10 mg/kg) did not
significantly reduced the immobility time in the forced swim test after 30 min
administration. Notably, pretreatment with haloperidol (0.15 mg/kg, a
nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1 mg/kg, a
selective dopamine D1 receptor antagonist), significantly prevented the effects
of ketamine or MK-801. Moreover, the administration of sub-effective dose of
ketamine (10 mg/kg) in combination with pramipexole (0.3 mg/kg, a dopamine D2/D3
receptor agonist) exerted antidepressant-like effects compared with each drug
alone. In conclusion, our results indicated that the dopamine D2/D3 receptors,
but not D1 receptors, are involved in the rapid antidepressant-like effects of
ketamine.

PMID: 25449845 [PubMed - indexed for MEDLINE]

98. J Neuropsychiatry Clin Neurosci. 2015 Feb 6:appineuropsych14100243. [Epub ahead
of print]

The Effect of Repeated Ketamine Infusion Over Facial Emotion Recognition in
Treatment-Resistant Depression: A Preliminary Report.

Shiroma PR(1), Albott CS, Johns B, Thuras P, Wels J, Lim KO.

Author information:
(1)From the Minneapolis VA Medical Center, Mental Health Service Line,
Minneapolis MN.

In contrast to improvement in emotion recognition bias by traditional
antidepressants, the authors report preliminary findings that changes in facial
emotion recognition are not associated with response of depressive symptoms after
repeated ketamine infusions or relapse during follow-up in treatment-resistant
depression.

PMID: 25658683 [PubMed - as supplied by publisher]

100. Curr Opin Neurobiol. 2015 Feb;30:139-43. doi: 10.1016/j.conb.2014.12.004. Epub
2015 Jan 3.

Antidepressant actions of ketamine: from molecular mechanisms to clinical
practice.

Monteggia LM(1), Zarate C Jr(2).

Author information:
(1)Department of Neuroscience, University of Texas Southwestern Medical Center,
5323 Harry Hines Boulevard, Dallas, TX 75390-9111, USA. Electronic address:
lisa.monteggia@utsouthwestern.edu. (2)Experimental Therapeutics and
Pathophysiology Branch, National Institute of Mental Health, National Institutes
of Health, and Department of Health and Human Services, Bethesda, MD, USA.

In the past decade the emergence of glutamate N-methyl-d-aspartate (NMDA)
receptor blockers such as ketamine as fast-acting antidepressants fostered a
major conceptual advance by demonstrating the possibility of a rapid
antidepressant response. This discovery brings unique mechanistic insight into
antidepressant action, as there is a substantial amount of basic knowledge on
glutamatergic neurotransmission and how blockade of NMDA receptors may elicit
plasticity. The combination of this basic knowledge base and the growing clinical
findings will facilitate the development of novel fast acting antidepressants.

PMCID: PMC4343533 [Available on 2016-02-01]
PMID: 25562451 [PubMed - indexed for MEDLINE]

101. Curr Opin Pharmacol. 2015 Feb;20:35-9. doi: 10.1016/j.coph.2014.11.005. Epub 2014
Nov 25.

How does ketamine elicit a rapid antidepressant response?

Kavalali ET(1), Monteggia LM(2).

Author information:
(1)Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX
75390-9111, USA; Department of Physiology, UT Southwestern Medical Center,
Dallas, TX 75390-9111, USA. Electronic address: ege.kavalali@utsouthwestern.edu.
(2)Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX
75390-9111, USA. Electronic address: lisa.monteggia@utsouthwestern.edu.

A single sub-psychotomimetic dose of ketamine, an ionotropic glutamatergic
n-methyl-D-aspartate (NMDA) receptor antagonist, produces a fast-acting
antidepressant response in patients suffering from major depressive disorder.
Depressed patients report alleviation of core symptoms within 2 h of a single
low-dose intravenous infusion of ketamine with effects lasting up to 2 weeks. The
rapidity of ketamine action implies that major symptoms of depression can be
alleviated without substantial structural plasticity or circuit rewiring.
Therefore, the ability of ketamine to exert a rapid effect provides a unique
opportunity to elucidate the types of acute synaptic plasticity changes that can
be recruited to counter depression symptoms.

PMCID: PMC4318725 [Available on 2016-02-01]
PMID: 25462290 [PubMed - indexed for MEDLINE]

102. Fortschr Neurol Psychiatr. 2015 Feb;83(2):91-7. doi: 10.1055/s-0034-1398967. Epub
2015 Feb 27.

[Ketamine--a new treatment option for therapy-resistant depression].

[Article in German]

Köhler S, Betzler F.

The anaesthetic ketamine has been demonstrated to have an antidepressive effect
in several randomised controlled studies. Patients with a severe
therapy-resistant depression showed response rates of up to 70 % after one single
ketamine infusion. In contrast to all other antidepressant treatment options,
this effect was already apparent at 24 hours post infusion. However, the
antidepressant effect is limited and after two weeks the relapse rate is around
70 %. This review gives a summary of the clinical value of ketamine in the
treatment of depression focussing on clinical trials and the therapeutic
mechanism of action.

PMID: 25723773 [PubMed - in process]

103. J Mol Neurosci. 2015 Feb;55(2):372-3. doi: 10.1007/s12031-014-0340-5. Epub 2014
May 30.

Downregulation of neuregulin 1-ErbB4 signaling and antidepressant properties of
ketamine: ErbB4 expressing pyramidal neurons may play a role.

Bernstein HG(1), Keilhoff G, Steiner J, Laube G, Bogerts B.

Author information:
(1)Department of Psychiatry, Faculty of Medicine, Otto-von-Guericke University,
Leipziger Str. 44, 39120, Magdeburg, Germany, Hans-Gert.Bernstein@med.ovgu.de.

Comment on
J Mol Neurosci. 2014;54(2):211-8.

We comment on a recent paper of Wang et al. (J Mol Neurosci, 2014), who have
shown that ketamine reduces neuregulin1-ErbB4 signaling in interneurons.

PMID: 24874581 [PubMed - indexed for MEDLINE]

104. Psychiatry Res. 2015 Jan 30;225(1-2):216. doi: 10.1016/j.psychres.2014.08.023.

Comparison of ketamine vs. ECT in major depressive disorder: need for ECT
standard dosing and duration parameters.

Campion P(1).

Author information:
(1)Fellow, Geriatric Psychiatry, Mount Sinai School of Medicine, New York, NY
10032, USA. Electronic address: pic203@med.nyu.edu.

Comment on
Psychiatry Res. 2014 Feb 28;215(2):355-61.

PMID: 25511507 [PubMed - indexed for MEDLINE]

105. Psychiatry Res. 2015 Jan 30;225(1-2):215. doi: 10.1016/j.psychres.2014.08.021.

Speed of response to electroconvulsive therapy compared with ketamine.

Kellner CH(1); PRIDE Investigators Group, Lisanby SH(2), Weiner R(2), Prudic
J(2), Rudorfer MV(2), Young RC(2), Petrides G(2), Vaughn McCall W(2), Husain
M(2), Greenberg RM(2), Knapp RG(2).

Author information:
(1)Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York,
NY 10029, USA. Electronic address: charles.kellner@mssm.edu. (2)Department of
Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Comment on
Psychiatry Res. 2014 Feb 28;215(2):355-61.

PMID: 25511506 [PubMed - indexed for MEDLINE]

106. Psychiatry Res. 2015 Jan 30;225(1-2):1-13. doi: 10.1016/j.psychres.2014.10.028.
Epub 2014 Nov 13.

Ketamine and other potential glutamate antidepressants.

Dutta A(1), McKie S(2), Deakin JF(2).

Author information:
(1)Neuroscience & Psychiatry Unit, Institute of Brain, Behaviour and Mental
Health, Stopford Building, University of Manchester, Manchester M13 9PT, UK.
Electronic address: arpan.dutta@postgrad.manchester.ac.uk. (2)Neuroscience &
Psychiatry Unit, Institute of Brain, Behaviour and Mental Health, Stopford
Building, University of Manchester, Manchester M13 9PT, UK.

The need for rapid acting antidepressants is widely recognised. There has been
much interest in glutamate mechanisms in major depressive disorder (MDD) as a
promising target for the development of new antidepressants. A single intravenous
infusion of ketamine, a N-methyl-d-aspartate (NMDA) receptor antagonist
anaesthetic agent, can alleviate depressive symptoms in patients within hours of
administration. The mechanism of action appears to be in part through glutamate
release onto non-NMDA receptors including
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and metabotropic
receptors. However these are also reported effects on 5-HT, dopamine and
intracellular effects on the mammalian target of rapamycin (mTOR) pathway. The
effects of SSRI (Selective Serotonin Reuptake Inhibitor) antidepressants may also
involve alterations in NMDA function. The article reviews the effect of current
antidepressants on NMDA and examines the efficacy and mechanism of ketamine.
Response to ketamine is also discussed and comparison with other glutamate drugs
including lamotrigine, amantadine, riluzole, memantine, traxoprodil, GLYX-13,
MK-0657, RO4917523, AZD2066 and Coluracetam. Future studies need to link the
rapid antidepressant effects seen with ketamine to inflammatory theories in MDD.

PMID: 25467702 [PubMed - indexed for MEDLINE]

107. CNS Spectr. 2015 Jan 26:1-11. [Epub ahead of print]

Ameliorating treatment-refractory depression with intranasal ketamine: potential
NMDA receptor actions in the pain circuitry representing mental anguish.

Opler LA(1), Opler MG(1), Arnsten AF(2).

Author information:
(1)1Department of Psychiatry,Columbia University Medical Center,New York,New
York,USA. (2)4Department of Neurobiology,Yale University School of Medicine,New
Haven,Connecticut,USA.

This article reviews the antidepressant actions of ketamine, an
N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a
potential neural mechanism for intranasal ketamine's ultra-rapid actions based on
the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although
intravenous ketamine infusions can lift mood within hours, the current review
describes how intranasal ketamine administration can have ultra-rapid
antidepressant effects, beginning within minutes (5-40 minutes) and lasting
hours, but with repeated treatments needed for sustained antidepressant actions.
Research in rodents suggests that increased synaptogenesis in PFC may contribute
to the prolonged benefit of ketamine administration, beginning hours after
administration. However, these data cannot explain the relief that occurs within
minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid
effects of intranasal administration in humans may be due to ketamine blocking
the NMDAR circuits that generate the emotional representations of pain (eg,
Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive
in depression and which sit above the nasal epithelium. In contrast, NMDAR
blockade in the dorsolateral PFC following systemic administration of ketamine
may contribute to cognitive deficits. This novel view may help to explain how
intravenous ketamine can treat the symptoms of depression yet worsen the symptoms
of schizophrenia.

PMCID: PMC4515405 [Available on 2016-07-26]
PMID: 25619798 [PubMed - as supplied by publisher]

110. Annu Rev Med. 2015;66:509-23. doi: 10.1146/annurev-med-053013-062946. Epub 2014
Oct 17.

Ketamine and rapid-acting antidepressants: a window into a new neurobiology for
mood disorder therapeutics.

Abdallah CG(1), Sanacora G, Duman RS, Krystal JH.

Author information:
(1)Department of Psychiatry, Yale University School of Medicine, New Haven,
Connecticut 06511; email: chadi.abdallah@yale.edu , gerard.sanacora@yale.edu ,
ronald.duman@yale.edu , john.krystal@yale.edu.

Ketamine is the prototype for a new generation of glutamate-based antidepressants
that rapidly alleviate depression within hours of treatment. Over the past
decade, there has been replicated evidence demonstrating the rapid and potent
antidepressant effects of ketamine in treatment-resistant depression. Moreover,
preclinical and biomarker studies have begun to elucidate the mechanism
underlying the rapid antidepressant effects of ketamine, offering a new window
into the biology of depression and identifying a plethora of potential treatment
targets. This article discusses the efficacy, safety, and tolerability of
ketamine, summarizes the neurobiology of depression, reviews the mechanisms
underlying the rapid antidepressant effects of ketamine, and discusses the
prospects for next-generation rapid-acting antidepressants.

PMCID: PMC4428310
PMID: 25341010 [PubMed - indexed for MEDLINE]

112. Case Rep Psychiatry. 2015;2015:815673. doi: 10.1155/2015/815673. Epub 2015 Mar 4.

Robust and sustained effect of ketamine infusions coadministered with
conventional antidepressants in a patient with refractory major depression.

Montes JM(1), Luján E(2), Pascual F(2), Beleña JM(3), Perez-Santar JL(3),
Irastorza LJ(2), Saiz-Ruiz J(1).

Author information:
(1)Psychiatry Service, Hospital Universitario Ramón y Cajal, Universidad de
Alcalá, CIBERSAM, IRYCIS, Carretera Colmenar km. 9.1, 28034 Madrid, Spain.
(2)Psychiatry Service, Hospital Universitario del Sureste, Universidad Rey Juan
Carlos, Ronda del Sur 10, 28500 Madrid, Spain. (3)Anaesthesiology Service,
Hospital Universitario del Sureste, Universidad Rey Juan Carlos, Ronda del Sur
10, 28500 Madrid, Spain.

Antidepressant treatments show low capacity to achieve full clinical remissions.
Electroconvulsive therapy is an alternative treatment which has been shown to be
more effective but it is not well tolerated and there are concerns regarding its
safety. We present the case of a patient with resistant depression and modest and
transient response to ECT and who showed a robust and maintained response after
six i.v. ketamine (0.5 mg/kg) infusions without withdrawing her antidepressant
regimen. Ketamine was very well tolerated. This case illustrates the potential
role of ketamine as a booster to standard antidepressants.

PMCID: PMC4364451
PMID: 25821622 [PubMed]

114. Front Neurosci. 2015 Jul 21;9:249. doi: 10.3389/fnins.2015.00249. eCollection
2015.

Antidepressant mechanism of ketamine: perspective from preclinical studies.

Scheuing L(1), Chiu CT(1), Liao HM(1), Chuang DM(1).

Author information:
(1)Molecular Neurobiology Section, National Institute of Mental Health, National
Institutes of Health Bethesda, MD, USA.

A debilitating mental disorder, major depressive disorder is a leading cause of
global disease burden. Existing antidepressant drugs are not adequate for the
majority of depressed patients, and large clinical studies have demonstrated
their limited efficacy and slow response onset. Growing evidence of low-dose
ketamine's rapid and potent antidepressant effects offers strong potential for
future antidepressant agents. However, ketamine has considerable drawbacks such
as its abuse potential, psychomimetic effects, and increased oxidative stress in
the brain, thus limiting its widespread clinical use. To develop superior
antidepressant drugs, it is crucial to better understand ketamine's
antidepressant mechanism of action. Recent preclinical studies indicate that
ketamine's antidepressant mechanism involves mammalian target of rapamycin
pathway activation and subsequent synaptogenesis in the prefrontal cortex, as
well as glycogen synthase kinase-3 beta (GSK-3β) inactivation. Adjunct GSK-3β
inhibitors, such as lithium, can enhance ketamine's efficacy by augmenting and
prolonging its antidepressant effects. Given the potential for depressive
relapses, lithium in addition to ketamine is a promising solution for this
clinical issue.

PMCID: PMC4508505
PMID: 26257598 [PubMed]

115. Innov Clin Neurosci. 2015 Jan-Feb;12(1-2):29-31.

Use of ketamine in acute cases of suicidality.

Lee J(1), Narang P(1), Enja M(1), Lippmann S(1).

Author information:
(1)Dr. Lee is resident physician at Hennepin-Regions Psychiatry Program,
Minneapolis-St. Paul, Minnesota; Dr. Narang is staff physician and ECT
psychiatrist, Regions Hospital, Minneapolis- St. Paul, Minnesota; Dr. Enja is
observer physician, University of Louisville School of Medicine, Louisville,
Kentucky; and Dr. Lippmann is Professor of Psychiatry, University of Louisville
School of Medicine, Louisville, Kentucky.

Ketamine is an N-methyl-D- aspartate antagonist with rapid antidepressant
effects. Research shows that ketamine has a fast onset of reduction in depressive
symptoms and shows sustained remission of suicidal ideation in some patients.
This article provides a brief review of the literature on the use of ketamine for
depression and in acute cases of suicidality. The authors conclude that, while
further investigation is needed, ketamine may be a useful treatment option for
acute suicidality in emergency room settings.

PMCID: PMC4382138
PMID: 25852977 [PubMed]

117. Neuropsychopharmacology. 2015 Jan;40(2):259-67. doi: 10.1038/npp.2014.261. Epub
2014 Sep 26.

Ketamine: promising path or false prophecy in the development of novel
therapeutics for mood disorders?

Sanacora G(1), Schatzberg AF(2).

Author information:
(1)Yale University School of Medicine, New Haven, CT, USA. (2)Stanford University
School of Medicine, Stanford, CA, USA.

Erratum in
Neuropsychopharmacology. 2015 Apr;40(5):1307.

Comment in
Neuropsychopharmacology. 2015 Jan;40(2):257-8.

Large 'real world' studies demonstrating the limited effectiveness and slow onset
of clinical response associated with our existing antidepressant medications has
highlighted the need for the development of new therapeutic strategies for major
depression and other mood disorders. Yet, despite intense research efforts, the
field has had little success in developing antidepressant treatments with
fundamentally novel mechanisms of action over the past six decades, leaving the
field wary and skeptical about any new developments. However, a series of
relatively small proof-of-concept studies conducted over the last 15 years has
gradually gained great interest by providing strong evidence that a unique, rapid
onset of sustained, but still temporally limited, antidepressant effects can be
achieved with a single administration of ketamine. We are now left with several
questions regarding the true clinical meaningfulness of the findings and the
mechanisms underlying the antidepressant action. In this Circumspectives piece,
Dr Sanacora and Dr Schatzberg share their opinions on these issues and discuss
paths to move the field forward.

PMCID: PMC4443967 [Available on 2016-01-01]
PMID: 25257213 [PubMed - in process]

119. Psychopharmacology (Berl). 2015 Jan;232(2):399-409. doi:
10.1007/s00213-014-3669-0. Epub 2014 Jul 24.

D-serine plasma concentration is a potential biomarker of (R,S)-ketamine
antidepressant response in subjects with treatment-resistant depression.

Moaddel R(1), Luckenbaugh DA, Xie Y, Villaseñor A, Brutsche NE, Machado-Vieira R,
Ramamoorthy A, Lorenzo MP, Garcia A, Bernier M, Torjman MC, Barbas C, Zarate CA
Jr, Wainer IW.

Author information:
(1)Intramural Research Program, National Institute on Aging, National Institutes
of Health (NIH), Baltimore, MD, USA.

RATIONALE: (R,S)-ketamine is a rapid and effective antidepressant drug that
produces a response in two thirds of patients with treatment-resistant depression
(TRD). The underlying biochemical differences between a (R,S)-ketamine responder
(KET-R) and non-responder (KET-NR) have not been definitively identified but may
involve serine metabolism.
OBJECTIVES: The aim of the study was to examine the relationship between baseline
plasma concentrations of D-serine and its precursor L-serine and antidepressant
response to (R,S)-ketamine in TRD patients.
METHODS: Plasma samples were obtained from 21 TRD patients at baseline, 60 min
before initiation of the (R,S)-ketamine infusion. Patients were classified as
KET-Rs (n = 8) or KET-NRs (n = 13) based upon the difference in Montgomery-Åsberg
Depression Rating Scale (MADRS) scores at baseline and 230 min after infusion,
with response defined as a ≥50 % decrease in MADRS score. The plasma
concentrations of D-serine and L-serine were determined using liquid
chromatography-mass spectrometry.
RESULTS: Baseline D-serine plasma concentrations were significantly lower in
KET-Rs (3.02 ± 0.21 μM) than in KET-NRs (4.68 ± 0.81 μM), p < 0.001. A
significant relationship between baseline D-serine plasma concentrations and
percent change in MADRS at 230 min was determined using a Pearson correlation,
r = 0.77, p < 0.001, with baseline D-serine explaining 60 % of the variance in
(R,S)-ketamine response. The baseline concentrations of L-serine (L-Ser) in
KET-Rs were also significantly lower than those measured in KET-NRs (66.2 ± 9.6
μM vs 242.9 ± 5.6 μM, respectively; p < 0.0001).
CONCLUSIONS: The results demonstrate that the baseline D-serine plasma
concentrations were significantly lower in KET-Rs than in KET-NRs and suggest
that this variable can be used to predict an antidepressant response following
(R,S)-ketamine administration.

PMID: 25056852 [PubMed - indexed for MEDLINE]

122. Biol Psychiatry. 2014 Dec 15;76(12):970-6. doi: 10.1016/j.biopsych.2014.03.026.
Epub 2014 Apr 3.

A randomized controlled trial of intranasal ketamine in major depressive
disorder.

Lapidus KA(1), Levitch CF(2), Perez AM(3), Brallier JW(3), Parides MK(4),
Soleimani L(5), Feder A(2), Iosifescu DV(6), Charney DS(7), Murrough JW(8).

Author information:
(1)Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of
Medicine at Mount Sinai, New York; Fishberg Department of Neuroscience, Icahn
School of Medicine at Mount Sinai, New York. (2)Mood and Anxiety Disorders
Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New
York. (3)Department of Anesthesiology, Icahn School of Medicine at Mount Sinai,
New York. (4)Department of Health Evidence and Policy, Icahn School of Medicine
at Mount Sinai, New York. (5)Mood and Anxiety Disorders Program, Department of
Psychiatry, Icahn School of Medicine at Mount Sinai, New York; James J. Peters
Veterans Affairs Medical Center, Bronx, New York. (6)Mood and Anxiety Disorders
Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New
York; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount
Sinai, New York; Friedman Brain Institute, Icahn School of Medicine at Mount
Sinai, New York. (7)Mood and Anxiety Disorders Program, Department of Psychiatry,
Icahn School of Medicine at Mount Sinai, New York; Fishberg Department of
Neuroscience, Icahn School of Medicine at Mount Sinai, New York; Department of
Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai,
New York. (8)Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn
School of Medicine at Mount Sinai, New York; Fishberg Department of Neuroscience,
Icahn School of Medicine at Mount Sinai, New York; Friedman Brain Institute,
Icahn School of Medicine at Mount Sinai, New York. Electronic address:
james.murrough@mssm.edu.

BACKGROUND: The N-methyl-D-aspartate glutamate receptor antagonist ketamine,
delivered via an intravenous route, has shown rapid antidepressant effects in
patients with treatment-resistant depression. The current study was designed to
test the safety, tolerability, and efficacy of intranasal ketamine in patients
with depression who had failed at least one prior antidepressant trial.
METHODS: In a randomized, double-blind, crossover study, 20 patients with major
depression were randomly assigned, and 18 completed 2 treatment days with
intranasal ketamine hydrochloride (50 mg) or saline solution. The primary
efficacy outcome measure was change in depression severity 24 hours after
ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating
Scale. Secondary outcomes included persistence of benefit, changes in
self-reports of depression, changes in anxiety, and proportion of responders.
Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects
associated with ketamine were also measured.
RESULTS: Patients showed significant improvement in depressive symptoms at 24
hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean
Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95%
confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients
(44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after
placebo (p = .033). Intranasal ketamine was well tolerated with minimal
psychotomimetic or dissociative effects and was not associated with clinically
significant changes in hemodynamic parameters.
CONCLUSIONS: This study provides the first controlled evidence for the rapid
antidepressant effects of intranasal ketamine. Treatment was associated with
minimal adverse effects. If replicated, these findings may lead to novel
approaches to the pharmacologic treatment of patients with major depression.

Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All
rights reserved.

PMCID: PMC4185009 [Available on 2015-12-15]
PMID: 24821196 [PubMed - indexed for MEDLINE]

124. CNS Neurosci Ther. 2014 Dec;20(12):1015-20. doi: 10.1111/cns.12363.

Ketamine-an update on its clinical uses and abuses.

Xu J(1), Lei H.

Author information:
(1)Department of Laboratory Medicine, Chang Hai Hospital, Second Military Medical
University, Shanghai, China.

This review highlights the recent clinical research that supports the therapeutic
utility of ketamine as a multifaceted drug. After long-term use as a dissociative
anesthetic, it has re-emerged as a useful agent for ameliorating pain,
asthmaticus, and depression. In addition, it is also a substance of abuse.
Chronic ketamine abuse over prolonged periods (weeks, months, and years) can
produce toxicity to the gastrointestinal and urinary tract. In this review, we
described the recent progress on its clinical uses and abuses.

PMID: 25417928 [PubMed - indexed for MEDLINE]

125. Curr Psychiatry Rep. 2014 Dec;16(12):527. doi: 10.1007/s11920-014-0527-z.

Proceed with caution: off-label ketamine treatment for major depressive disorder.

Sisti D(1), Segal AG, Thase ME.

Author information:
(1)Department of Medical Ethics & Health Policy, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, USA, sistid@mail.med.upenn.edu.

Ketamine offers a promising new option for the treatment of depression, but its
increasing off-label use is ethically and clinically inappropriate at the moment.

PMID: 25308395 [PubMed - indexed for MEDLINE]

126. Drug Discov Today. 2014 Dec;19(12):1848-54. doi: 10.1016/j.drudis.2014.08.017.
Epub 2014 Sep 16.

Ketamine: repurposing and redefining a multifaceted drug.

Potter DE, Choudhury M.

This short review will highlight recent clinical and basic research that supports
the therapeutic utility of ketamine as a rapid-acting, life-saving antidepressant
and a versatile analgesic. After 50 years of use as a dissociative anesthetic and
misuse as a street drug, ketamine has re-emerged as a useful off-label agent for
ameliorating various types of pain and resistant depression. In addition to its
ability to inhibit N-methyl-D-aspartate (NMDA) receptors, the diverse actions of
ketamine might involve epigenetic mechanisms such as microRNA regulation. Thus,
ketamine is transitioning from being the pharmacologist's nightmare to one of the
most interesting developments in the pharmacology of depression and pain.

Published by Elsevier Ltd.

PMID: 25224017 [PubMed - indexed for MEDLINE]

129. Eur Arch Psychiatry Clin Neurosci. 2014 Nov;264 Suppl 1:S55-65. doi:
10.1007/s00406-014-0535-3. Epub 2014 Sep 13.

Multistage drug effects of ketamine in the treatment of major depression.

Walter M(1), Li S, Demenescu LR.

Author information:
(1)Clinical Affective Neuroimaging Laboratory (CANLAB),
Otto-von-Guericke-University, ZENIT, Leipziger Str. 44, 39120, Magdeburg,
Germany, martin.walter@med.ovgu.de.

A substantial number of patients diagnosed with major depression disorder show
poor or no response to standard antidepressive drugs. Recent studies showed that
ketamine promotes a rapid and sustained antidepressive effect in
treatment-resistant depression. Importantly, after a single dose, such
antidepressant action appears very fast, reaching maximum efficacy after 1-2 days
before it slowly decays after 3-7 days. This temporal pattern is especially
interesting since most effects are investigated following single, subanesthetic
doses. This means that effects are observed at time points when the blood levels
have long fallen below any active threshold. Mechanisms of action thus may be
sought either in secondary or compensatory processes, which develop after acute
systemic derangement or in molecular downstream mechanisms of action, which after
initiation do not require the presence of active drug levels. We here review
acute and delayed effects of subanesthetic ketamine infusion and discuss
potential origins of antidepressant drug action. We will provide evidences that
both acute effects on abnormal network configuration and delayed effects at the
level of homeostatic synaptic plasticity may be necessary for antidepressant
action. We further argue that such effects should be followed by a temporally
well-defined exploitation of these transient changes by therapeutic processes,
aiming at sustained changes of network configuration via psychotherapeutic or
other methods.

PMID: 25217177 [PubMed - indexed for MEDLINE]

130. Int J Neuropsychopharmacol. 2014 Nov;17(11):1805-13. doi:
10.1017/S1461145714001011. Epub 2014 Jun 25.

Neurocognitive performance and serial intravenous subanesthetic ketamine in
treatment-resistant depression.

Shiroma PR(1), Albott CS(1), Johns B(2), Thuras P(1), Wels J(3), Lim KO(1).

Author information:
(1)Mental Health Service Line,Minneapolis VA Medical Center,Minneapolis, MN,USA.
(2)Department of Psychiatry,University of Minnesota Medical School,Minneapolis,
MN,USA. (3)Department of Anesthesiology,Minneapolis VA Medical
Center,Minneapolis, MN,USA.

The N-methyl-D-aspartate glutamate receptor antagonist ketamine has demonstrated
rapid antidepressant effects in treatment-resistant depression (TRD). However,
evaluation of ketamine's neurocognitive aspects in TRD has started to be
explored. This study aims to (1) examine baseline neurocognitive performance and
change in severity of depressive symptoms through six ketamine infusions, (2)
examine the neurocognitive effects after completion of serial infusions and
whether changes were associated to relapse to depression. Six IV infusions of 0.5
mg/Kg ketamine over 40 min were conducted on a Monday-Wednesday-Friday schedule
during a 12-d period on 15 patients with TRD followed by a 4-wk observational
period. Neurocognitive functioning was assessed using the CogState battery at
baseline and at each follow-up visit. Tasks were designed to test attention,
memory (working, visual, and verbal), speed of processing, and set shifting. The
likelihood of response through six infusions was greater among depressed subjects
with lower attention at baseline (F(1,13)=5.59, p=0.034). Significant improvement
was found in scores of visual memory (F(4,33.82)=5.12, p=0.002), simple working
memory (F(4, 24.85)=3.29, p=0.027) and complex working memory (F(4, 32.76)=4.18,
p=0.008) after the last ketamine infusion. However, neurocognitive changes were
accounted for by improvement in the severity of depressive symptom. The acute
neurocognitive effect after completion of repeated infusions was not associated
with the likelihood of subsequent relapse during follow-up. Our findings suggest
a potential baseline neurocognitive predictor of ketamine response and the
apparently lack of short-term neurocognitive impairment after completion of six
ketamine infusions in TRD.

PMID: 24963561 [PubMed - indexed for MEDLINE]

131. J Psychiatr Res. 2014 Nov;58:161-6. doi: 10.1016/j.jpsychires.2014.07.027. Epub
2014 Aug 12.

Improvement in suicidal ideation after ketamine infusion: relationship to
reductions in depression and anxiety.

Ballard ED(1), Ionescu DF(2), Vande Voort JL(2), Niciu MJ(2), Richards EM(2),
Luckenbaugh DA(2), Brutsché NE(2), Ameli R(2), Furey ML(2), Zarate CA Jr(2).

Author information:
(1)Experimental Therapeutics & Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health,
Bethesda, MD 20892, USA. Electronic address: Elizabeth.Ballard@nih.gov.
(2)Experimental Therapeutics & Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health,
Bethesda, MD 20892, USA.

OBJECTIVE: Suicide is a psychiatric emergency. Currently, there are no approved
pharmacologic treatments for suicidal ideation. Ketamine is an
N-methyl-D-aspartate (NMDA) receptor antagonist that rapidly reduces suicidal
ideation as well as depression and anxiety, but the dynamic between these
symptoms is not known. The aim of this analysis was to evaluate whether ketamine
has an impact on suicidal thoughts, independent of depressive and anxiety
symptoms.
METHODS: 133 patients with treatment-resistant depression (major depressive
disorder or bipolar I/II disorder) received a single subanesthetic infusion of
ketamine (0.5 mg/kg over 40 min). Post-hoc correlations and linear mixed models
evaluated the relationship between suicidal ideation and depression and anxiety
symptoms using the Hamilton Depression Rating Scale (HAMD), Scale for Suicidal
Ideation (SSI), Beck Depression Inventory (BDI), and Hamilton Anxiety Rating
Scale (HAMA) focusing on 230 min post-infusion.
RESULTS: At 230 min post-infusion, correlations between changes in suicidal
ideation and depression ranged from 0.23 to 0.44 (p < .05), accounting for up to
19% in the variance of ideation change. Correlations with anxiety ranged from
0.23 to 0.40 (p < .05), accounting for similar levels of variance. Ketamine
infusion was associated with significant reductions in suicidal ideation compared
to placebo, when controlling for the effects of ketamine on depression (F1,587 =
10.31, p = .001) and anxiety (F1,567 = 8.54, p = .004).
CONCLUSIONS: Improvements in suicidal ideation after ketamine infusion are
related to, but not completely driven by, improvements in depression and anxiety.
Investigation of the specific effects of ketamine on suicidal thoughts is
warranted.

Published by Elsevier Ltd.

PMCID: PMC4163501 [Available on 2015-11-01]
PMID: 25169854 [PubMed - in process]

133. Nervenarzt. 2014 Nov;85(11):1432-5. doi: 10.1007/s00115-014-4132-5.

[Ketamine as antidepressant: the current study situation].

[Article in German]

Ritter PS(1), Bauer M, Pilhatsch M.

Author information:
(1)Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum
Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307,
Dresden, Deutschland, philipp.ritter@uniklinikum-dresden.de.

The treatment of depressive episodes is characterized by a delay in response of
antidepressant medications and high rates of therapeutic failure. In recent years
several open and five controlled trials have demonstrated the antidepressant
efficacy of ketamine for major depression. In addition a recent study established
the utility of nasal ketamine which may render the necessity of intravenous
administration obsolete. The current state of evidence is reviewed and discussed.

PMID: 25324145 [PubMed - in process]

137. Int J Neuropsychopharmacol. 2014 Oct 31;18(1). pii: pyu033. doi:
10.1093/ijnp/pyu033.

BDNF release is required for the behavioral actions of ketamine.

Lepack AE(1), Fuchikami M(1), Dwyer JM(1), Banasr M(1), Duman RS(2).

Author information:
(1)Departments of Psychiatry and Neurobiology, Yale University School of
Medicine, New Haven, CT (Drs Lepack, Fuchikami, Dwyer, Banasr, and Duman).
(2)Departments of Psychiatry and Neurobiology, Yale University School of
Medicine, New Haven, CT (Drs Lepack, Fuchikami, Dwyer, Banasr, and Duman).
ronald.duman@yale.edu.

BACKGROUND: Recent studies demonstrate that the rapid antidepressant ketamine
increases spine number and function in the medial prefrontal cortex (mPFC), and
that these effects are dependent on activation of glutamate
α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and
brain-derived neurotrophic factor (BDNF). In vitro studies also show that
activation of AMPA receptors stimulates BNDF release via activation of L-type
voltage-dependent calcium channels (VDCC).
METHODS: Based on this evidence, we examined the role of BDNF release and the
impact of L-type VDCCs on the behavioral actions of ketamine.
RESULTS: The results demonstrate that infusion of a neutralizing BDNF antibody
into the mPFC blocks the behavioral effects of ketamine in the forced swim test
(FST). In addition, we show that pretreatment with nifedipine or verapamil, two
structurally-different L-type calcium channel antagonists, blocks the behavioral
effects of ketamine in the FST. Finally, we show that ketamine treatment
stimulates BDNF release in primary cortical neurons and that this effect is
blocked by inhibition of AMPA receptors or L-type VDCCs.
CONCLUSIONS: Taken together, these results indicate that the antidepressant
effects of ketamine are mediated by activation of L-type VDCCs and the release of
BDNF. They further elucidate the cellular mechanisms underlying this novel
rapid-acting antidepressant.

PMCID: PMC4368871
PMID: 25539510 [PubMed - indexed for MEDLINE]

142. Psychopharmacology (Berl). 2014 Oct;231(20):4081-2. doi:
10.1007/s00213-014-3735-7. Epub 2014 Sep 5.

Blood D-serine levels as a predictive biomarker for the rapid antidepressant
effects of the NMDA receptor antagonist ketamine.

Hashimoto K(1).

Author information:
(1)Division of Clinical Neuroscience, Chiba University Center for Forensic Mental
Health, 1-8-1 Inohana, Chiba, 260-8670, Japan, hashimoto@faculty.chiba-u.jp.

PMID: 25189793 [PubMed - indexed for MEDLINE]

143. Psychopharmacology (Berl). 2014 Oct;231(19):3907-8. doi:
10.1007/s00213-014-3731-y. Epub 2014 Sep 2.

A comment on Fond and colleagues' systematic review and meta-analysis of ketamine
in the treatment of depressive disorders (Psychopharmacology 2014; Jul 20 [Epub
ahead of print]).

McGirr A(1), Berlim MT.

Author information:
(1)Department of Psychiatry, University of British Columbia, 11th Floor, 2775
Laurel Street, Vancouver, BC, V5Z 1M9, Canada, alexander.mcgirr@alumni.ubc.ca.

Comment in
Psychopharmacology (Berl). 2014 Nov;231(22):4417-8.

Comment on
Psychopharmacology (Berl). 2014 Sep;231(18):3663-76.

PMID: 25176174 [PubMed - indexed for MEDLINE]

145. Behav Brain Res. 2014 Sep 1;271:111-5. doi: 10.1016/j.bbr.2014.05.065. Epub 2014
Jun 5.

Requirement of AMPA receptor stimulation for the sustained antidepressant
activity of ketamine and LY341495 during the forced swim test in rats.

Koike H(1), Chaki S(2).

Author information:
(1)Pharmacology I, Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd.,
1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan. (2)Pharmacology I,
Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho,
Kita-ku, Saitama, Saitama 331-9530, Japan. Electronic address:
s-chaki@so.taisho.co.jp.

Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, and group
II metabotropic glutamate (mGlu2/3) receptor antagonists produce antidepressant
effects in animal models of depression, which last for at least 24h, through the
transient increase in glutamate release, leading to activation of the
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor. Both ketamine
and an mGlu2/3 receptor antagonist reportedly increase the expression of GluR1,
an AMPA receptor subunit, within 24h, which may account for the sustained
enhancement of excitatory synaptic transmission following ketamine
administration. However, whether the sustained increase in AMPA receptor-mediated
synaptic transmission is associated with the antidepressant effects of ketamine
and mGlu2/3 receptor antagonists has not yet been investigated. In the present
study, to address this question, we tested whether AMPA receptor stimulation at
24h after a single injection of ketamine or an mGlu2/3 receptor antagonist,
(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid
(LY341495) was necessary for the antidepressant effect of these compounds using a
forced swim test in rats. A single injection of ketamine or LY341495 at 24h
before the test significantly decreased the immobility time. An AMPA receptor
antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide
(NBQX), administered 30min prior to the test significantly and dose-dependently
reversed the antidepressant effects of ketamine and LY341495, while NBQX itself
had no effect on the immobility time. Our findings suggest that AMPA receptor
stimulation at 24h after a single injection of ketamine or LY341495 is required
to produce the anti-immobility effects of these compounds. Moreover, the present
results provide additional evidence that an mGlu2/3 receptor antagonist may share
some of neural mechanisms with ketamine to exert antidepressant effects.

PMID: 24909673 [PubMed - indexed for MEDLINE]

146. Curr Neuropharmacol. 2014 Sep;12(5):444-61. doi:
10.2174/1570159X12666140619204251.

The role of ketamine in treatment-resistant depression: a systematic review.

Serafini G(1), Howland RH(2), Rovedi F(1), Girardi P(1), Amore M(3).

Author information:
(1)Department of Neurosciences, Mental Health and Sensory Organs - Sant'Andrea
Hospital, Sapienza University of Rome, Italy. (2)University of Pittsburgh School
of Medicine, Pittsburgh, PA, USA. (3)Department of Neuroscience, Rehabilitation,
Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry,
University of Genova, Genova, Italy.

BACKGROUND: At least 10-20% of the patients suffering from depression meet
criteria for treatment-resistant depression (TRD). In the last decades, an
important role of glutamate in mood modulation has been hypothesized and
ketamine, a non noncompetitive antagonist of the N-methyl-D-aspartate (NMDA)
receptors, has been demonstrated to be effective in both MDD and TRD. However,
concerns emerged about the optimal dosage, and frequency of administration of
this treatment.
METHODS: aiming to systematically review the current literature focusing on the
main pharmacological properties and impact of ketamine in TRD, a detailed
literature search in PubMed/Medline and ScienceDirect databases was conducted.
Twenty-four manuscripts including a total of 416 patients fulfilled inclusion
criteria.
RESULTS: Most studies demonstrated that the NMDA antagonist ketamine has rapid
antidepressant effects in TRD patients, confirming the active role of glutamate
in the pathophysiology of this complex condition. Ketamine has been demonstrated
to be rapidly effective and was associated with a significant clinical
improvement in depressive symptoms within hours after administration. Also,
ketamine was also found to be effective in reducing suicidality in TRD samples.
LIMITATIONS: The long-term efficacy of ketamine has not been investigated by most
studies. The psychotomimetic properties may complicate the application of this
pharmacological agent.
CONCLUSIONS: Ketamine may be considered a valid and intriguing antidepressant
option for the treatment of TRD. Further studies are needed to evaluate its
long-term antidepressant efficacy in patients with TRD.

PMCID: PMC4243034
PMID: 25426012 [PubMed]

149. J Clin Psychiatry. 2014 Sep;75(9):e932-8. doi: 10.4088/JCP.14m09049.

Effect of baseline anxious depression on initial and sustained antidepressant
response to ketamine.

Ionescu DF(1), Luckenbaugh DA, Niciu MJ, Richards EM, Slonena EE, Vande Voort JL,
Brutsche NE, Zarate CA Jr.

Author information:
(1)Bldg 10, CRC Room 7-5545, 10 Center Drive, MSC 1282, Bethesda, MD 20892
dionescu@partners.org.

OBJECTIVE: Patients with anxious depression are typically more difficult to treat
with monoaminergic antidepressants compared to those with nonanxious depression.
Although novel research has shown that the N-methyl-D-aspartate (NMDA) receptor
antagonist ketamine has rapidly acting, relatively sustained effects in treating
depression, we predicted that, consistent with the existent literature on
traditional antidepressants, patients with anxious depression would have a poorer
antidepressant response.
METHOD: Twenty-six inpatients with treatment-resistant major depressive disorder
(MDD) (DSM-IV criteria) received a single infusion of ketamine (0.5 mg/kg over 40
minutes) from January 2006-March 2013 and were followed for 28 days. A post hoc
analysis compared treatment response and relapse using the Montgomery-Asberg
Depression Rating Scale (MADRS) in patients with anxious versus nonanxious
depression. Anxious depression was defined as MDD plus a Hamilton Depression
Rating Scale anxiety/somatization factor score ≥ 7.
RESULTS: Both anxious and nonanxious depressed patients responded positively to
ketamine. A linear mixed model controlling for baseline with the MADRS revealed a
significant group main effect (P = .03) and group-by-time interaction (P = .01).
Post hoc tests indicated that patients with anxious depression had significantly
fewer depression symptoms compared to those with nonanxious depression at days 1
through 5, 9 through 12, 15 through 17, and 25, with no significant group
differences in dissociative (P = .62) or psychotic (P = .41) side effects.
Regarding responders, patients with anxious depression relapsed significantly
later than those with nonanxious depression (median ± SE = 19.0 ± 17.9 vs 1.0 ±
0.0 days to relapse, respectively; χ² = 9.30; P = .002).
CONCLUSIONS: Unexpectedly, patients with anxious depression responded better to
ketamine than those with nonanxious depression, with longer time to relapse and
no side effect differences. This finding gives promise for the role of novel
glutamatergic medications for the treatment of those with anxious depression, a
traditionally difficult-to-treat subgroup of depressed patients.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00088699.

PMID: 25295436 [PubMed - indexed for MEDLINE]

151. J ECT. 2014 Sep;30(3):e31-2. doi: 10.1097/YCT.0000000000000104.

Remission of treatment-resistant depression with electroconvulsive therapy and
ketamine.

Niemegeers P(1), Schrijvers D, Madani Y, Sabbe BG.

Author information:
(1)Collaborative Antwerp Psychiatric Research Institute (CAPRI) Faculty of
Medicine and Health Sciences University of Antwerp Antwerp, Belgium
peter.niemegeers@uantwerpen.be Collaborative Antwerp Psychiatric Research
Institute (CAPRI) Faculty of Medicine and Health Sciences University of Antwerp
Antwerp, Belgium Psychiatric Hospital Duffel Duffel, Belgium Psychiatric Hospital
Duffel Duffel, Belgium Collaborative Antwerp Psychiatric Research Institute
(CAPRI) Faculty of Medicine and Health Sciences University of Antwerp Antwerp,
Belgium Psychiatric Hospital Duffel Duffel, Belgium.

PMID: 24625710 [PubMed - indexed for MEDLINE]

154. Psychopharmacology (Berl). 2014 Sep;231(18):3663-76. doi:
10.1007/s00213-014-3664-5. Epub 2014 Jul 20.

Ketamine administration in depressive disorders: a systematic review and
meta-analysis.

Fond G(1), Loundou A, Rabu C, Macgregor A, Lançon C, Brittner M,
Micoulaud-Franchi JA, Richieri R, Courtet P, Abbar M, Roger M, Leboyer M, Boyer
L.

Author information:
(1)Pôle de psychiatrie des hôpitaux universitaires H Mondor, Université Paris
Est-Créteil, INSERM U955, Eq Psychiatrie Génétique, Fondation FondaMental
Fondation de coopération scientifique en santé mentale, 40, rue de Mesly, 94010,
Créteil, France, guillaume.fond@gmail.com.

Comment in
Psychopharmacology (Berl). 2014 Oct;231(19):3907-8.

INTRODUCTION: Ketamine's efficacy in depressive disorders has been established in
several controlled trials. The aim of the present study was to determine whether
or not ketamine administration significantly improves depressive symptomatology
in depression and more specifically in major depressive disorder (MDD), bipolar
depression, resistant depression (non-ECT studies), and as an anesthetic agent in
electroconvulsive therapy (ECT) for resistant depression (ECT studies). Secondary
outcomes were the duration of ketamine's effect, the efficacy on suicidal
ideations, the existence of a dose effect, and the safety/tolerance of the
treatment.
METHODS: Studies were included if they met the following criteria (without any
language or date restriction): design: randomized controlled trials,
intervention: ketamine administration, participants: diagnosis of depression, and
evaluation of severity based on a validated scale. We calculated standardized
mean differences (SMDs) with 95 % confidence intervals (CIs) for each study. We
used fixed and random effects models. Heterogeneity was assessed using the I2
statistic.
RESULTS: We included nine non-ECT studies in our quantitative analysis (192
patients with major depressive disorder and 34 patients with bipolar depression).
Overall, depression scores were significantly decreased in the ketamine groups
compared to those in the control groups (SMD = -0.99; 95 % CI -1.23, -0.75;
p < 0.01). Ketamine's efficacy was confirmed in MDD (resistant to previous
pharmacological treatments or not) (SMD = -0.91; 95 % CI -1.19,-0.64; p < 0.01),
in bipolar depression (SMD = -1.34; 95 % CI -1.94, -0.75), and in drug-free
patients as well as patients under medication. Four ECT trials (118 patients)
were included in our quantitative analysis. One hundred and three patients were
diagnosed with major depressive disorder and 15 with bipolar depression. Overall,
depression scores were significantly improved in the 58 patients receiving
ketamine in ECT anesthesia induction compared to the 60 patients (SMD = -0.56; 95
% CI -1.10, -0.02; p = 0.04; I2 = 52.4 %). The duration of ketamine's effects was
assessed in only two non-ECT studies and seemed to persist for 2-3 days; this
result needs to be confirmed. Three of four studies found significant decrease of
suicidal thoughts and one found no difference between groups, but suicidal
ideations were only studied by the suicide item of the depressive scales. It was
not possible to determine a dose effect; 0.5 mg/kg was used in the majority of
the studies. Some cardiovascular events were described (mostly transient blood
pressure elevation that may require treatment), and ketamine's use should remain
cautious in patients with a cardiovascular history.
CONCLUSION: The present meta-analysis confirms ketamine's efficacy in depressive
disorders in non-ECT studies, as well as in ECT studies. The results of this
first meta-analysis are encouraging, and further studies are warranted to detail
efficacy in bipolar disorders and other specific depressed populations. Middle-
and long-term efficacy and safety have yet to be explored. Extrapolation should
be cautious: Patients included had no history of psychotic episodes and no
history of alcohol or substance use disorders, which is not representative of all
the depressed patients that may benefit from this therapy.

PMID: 25038867 [PubMed - indexed for MEDLINE]

155. World J Biol Psychiatry. 2014 Sep;15(7):579-84. doi:
10.3109/15622975.2014.922697. Epub 2014 Jun 9.

Pilot dose-response trial of i.v. ketamine in treatment-resistant depression.

Lai R(1), Katalinic N, Glue P, Somogyi AA, Mitchell PB, Leyden J, Harper S, Loo
CK.

Author information:
(1)South Eastern Sydney Local Health District and University of New South Wales ,
Sydney.

OBJECTIVES: Research studies have reported impressive antidepressant effects with
ketamine but significant knowledge gaps remain over the best method of
administering ketamine, and the relationships between dose, antidepressant
response and adverse effects.
METHODS: In this pilot dose-finding study, the efficacy and tolerability of
ketamine given by rapid intravenous (i.v.) infusion were assessed in a
double-blind, placebo-controlled, crossover design, in four subjects with
treatment- resistant depression. Each subject received up to four i.v. doses of
ketamine (0.1, 0.2, 0.3, 0.4 mg/kg), given over 2-5 min, 1 week apart, and one
randomly inserted placebo treatment.
RESULTS: Three of four subjects achieved antidepressant response (≥ 50% decrease
in Montgomery-Asberg Depression Rating Scale scores), two at the minimum 0.1
mg/kg dose, though all relapsed within a week. For two subjects, the greatest
improvement occurred at the highest dose received. Rapid infusion over 2 min led
to significant adverse psychotomimetic effects which also increased
proportionately with ketamine dosage.
CONCLUSIONS: This is the first trial to present dose-response data of ketamine
efficacy and psychomimetic effects in depressed subjects. Antidepressant efficacy
may be dose-related. Psychotomimetic effects were dose-related. Rapid infusion
over 2 min may not be a feasible clinical approach to treatment, given poor
tolerability.

PMID: 24910102 [PubMed - indexed for MEDLINE]

156. Intravenous Ketamine for the Treatment of Mental Health Disorders: A Review of
Clinical Effectiveness and Guidelines [Internet].

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2014 Aug.
CADTH Rapid Response Reports.

Ketamine emerged as a novel treatment for certain mental health disorders in 2000
when Berman et al. published a seven patient RCT of intravenous (IV) ketamine
compared to a saline placebo showing a reduction in the Hamilton Depression
Rating Scale (Ham-D). This was the first suggestion that ketamine could be a
benefit for treating mental health disorder and since previous investigations on
treatment of mental health disorders have focused on the monoamines (dopamine,
norepinephrine and serotonin) this approach may have great potential. Current
psychiatric guidelines for treatment of major depressive disorder (MDD),
post-traumatic stress disorder (PTSD), and suicidal ideation do not include
statements regarding the use of ketamine however research continues to be
published. Ketamine is a rapid acting, non-competitive N-methyl-D-aspartate
(NMDA) receptor antagonist that is used as a general anesthetic with analgesic
properties used in human and veterinary medicine. The NMDA receptor mediates
glutamate excitatory neurotransmission in the brain, and it is hypothesized that
a dysfunction in this regulation may play a role in the etiology of depressive
symptoms. Ketamine is proposed to help balance the dysfunction, however, by
blocking the NMDA receptor; side effects such as vivid dreams and a dissociative
effect (where the patient experiences a separation of body and mind) occur
frequently. While these side effects are undesirable for the therapeutics, it has
created an illicit market for ketamine in certain populations where it is better
known as “Special K”. Ketamine can be given through several routes including
intravenous push or infusions, intramuscular, intranasal, and orally.
Investigations have mainly utilized IV infusions due to the precise dosing and
ability to adjust if known side effects occur. Patients who receive ketamine
require close monitoring of blood pressure, heart rate, respiratory rate,
transcutaneous O2 saturation as well as for emergence reactions (recovery
reaction including agitation, hallucinations, dreams and depersonalization) when
ketamine wears off. For this reason, current practice is for patients to receive
the infusions in clinics with monitoring capabilities, which may be a significant
shift in practice from current oral pharmacotherapy where patients can be
monitored as outpatients. Given the lack of direction from major psychiatric
associations, the utility of ketamine for certain mental health disorders is
uncertain. The purpose of this report is to review the clinical effectiveness of
intravenous ketamine for the treatment of depression, PTSD, and suicidal
ideation, as well as the evidence-based guidelines for its use in these
conditions.

PMID: 25411673 [PubMed]

157. Biol Psychiatry. 2014 Aug 1;76(3):e1-2. doi: 10.1016/j.biopsych.2013.12.010. Epub
2014 Jan 3.

Long-lasting effects of a single subcutaneous dose of ketamine for treating
melancholic depression: a case report.

Gálvez V(1), O'Keefe E(1), Cotiga L(1), Leyden J(2), Harper S(3), Glue P(4),
Mitchell PB(1), Somogyi AA(5), DeLory A(6), Loo CK(7).

Author information:
(1)School of Psychiatry, University of New South Wales, Black Dog Institute.
(2)Department of Anaesthesia and Pain Management, Royal North Shore Hospital, St.
Leonards. (3)School of Medicine, University of New South Wales. (4)Psychological
Medicine, University of Otago, Dunedin, New Zealand. (5)Discipline of
Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide,
Australia. (6)Wesley Hospital, Kogarah, Sydney. (7)School of Psychiatry,
University of New South Wales, Black Dog Institute. Electronic address:
colleen.loo@unsw.edu.au.

Comment on
Biol Psychiatry. 2000 Feb 15;47(4):351-4.

PMID: 24507509 [PubMed - indexed for MEDLINE]

159. Clin Psychopharmacol Neurosci. 2014 Aug;12(2):83-93. doi:
10.9758/cpn.2014.12.2.83. Epub 2014 Aug 12.

Therapeutic modalities for treatment resistant depression: focus on vagal nerve
stimulation and ketamine.

Shah A(1), Carreno FR(1), Frazer A(2).

Author information:
(1)Department of Pharmacology and Center for Biomedical Neuroscience, University
of Texas Health Science Center, San Antonio, TX, USA. (2)Department of
Pharmacology and Center for Biomedical Neuroscience, University of Texas Health
Science Center, San Antonio, TX, USA. ; South Texas Veterans Health Care System
(STVHCS), Audie L. Murphy Division, San Antonio, TX, USA.

Treatment resistant depression (TRD) is a global health concern affecting a large
proportion of depressed patients who then require novel therapeutic options. One
such treatment option that has received some attention in the past several years
is vagal nerve stimulation (VNS). The present review briefly describes the
relevance of this treatment in the light of other existing pharmacological and
non-pharmacological options. It then summarizes clinical findings with respect to
the efficacy of VNS. The anatomical rationale for its efficacy and other
potential mechanisms of its antidepressant effects as compared to those employed
by classical antidepressant drugs are discussed. VNS has been approved in some
countries and has been used for patients with TRD for quite some time. A newer,
fast-acting, non-invasive pharmacological option called ketamine is currently in
the limelight with reference to TRD. This drug is currently in the
investigational phase but shows promise. The clinical and preclinical findings
related to ketamine have also been summarized and compared with those for VNS.
The role of neurotrophin factors, specifically brain derived neurotrophic factor
and its receptor, in the beneficial effects of both VNS and ketamine have been
highlighted. It can be concluded that both these therapeutic modalities, while
effective, need further research that can reveal specific targets for
intervention by novel drugs and address concerns related to side-effects,
especially those seen with ketamine.

PMCID: PMC4153868
PMID: 25191499 [PubMed]

162. J Clin Psychopharmacol. 2014 Aug;34(4):533-5. doi: 10.1097/JCP.0000000000000146.

Rapid resolution of suicidal behavior and depression with single low-dose
ketamine intravenous push even after 6 months of follow-up.

Aligeti S(1), Quinones M, Salazar R.

Author information:
(1)Adult Psychiatry Program Department of Psychiatry School of Medicine The
University of Texas Health Science Center at San Antonio San Antonio, TX
Department of Psychiatry and Behavioral Medicine The University of Texas Health
Science Center at San Antonio San Antonio, TX Department of Psychiatry and
Behavioral Medicine The University of Texas Health Science Center at San Antonio
San Antonio, TX salazarr1@uthscsa.edu.

PMID: 24875072 [PubMed - indexed for MEDLINE]

163. J Psychiatr Res. 2014 Aug;55:15-21. doi: 10.1016/j.jpsychires.2014.04.010. Epub
2014 Apr 18.

MAPK signaling correlates with the antidepressant effects of ketamine.

Réus GZ(1), Vieira FG(2), Abelaira HM(2), Michels M(3), Tomaz DB(2), dos Santos
MA(2), Carlessi AS(2), Neotti MV(2), Matias BI(2), Luz JR(2), Dal-Pizzol F(4),
Quevedo J(5).

Author information:
(1)Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde,
Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense,
88806-000 Criciúma, SC, Brazil; Center for Experimental Models in Psychiatry,
Department of Psychiatry and Behavioral Sciences, The University of Texas Medical
School at Houston, Houston, TX, USA. Electronic address:
gislainezilli@hotmail.com. (2)Laboratório de Neurociências, Programa de
Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde,
Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil.
(3)Programa de Pós-Graduação em Ciências da Saúde, Universidade do Sul de Santa
Catarina, Tubarão, SC, Brazil. (4)Laboratório de Fisiopatologia Experimental,
Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da
Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil.
(5)Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde,
Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense,
88806-000 Criciúma, SC, Brazil; Center for Experimental Models in Psychiatry,
Department of Psychiatry and Behavioral Sciences, The University of Texas Medical
School at Houston, Houston, TX, USA.

Studies have pointed to a relationship between MAPK kinase (MEK) signaling and
the behavioral effects of antidepressant drugs. So, in the present study we
examined the behavioral and molecular effects of ketamine, an antagonist of the
N-methyl-d-aspartate receptor (NMDA), which has been shown to have an
antidepressant effect after the inhibition of MEK signaling in Wistar rats. Our
results showed that acute administration of the MEK inhibitor PD184161, produced
depressive-like behavior and stopped antidepressant-like effects of ketamine in
the forced swimming test. The phosphorylation of extracellular signal-regulated
kinase 1/2 (pERK 1/2) was decreased by PD184161 in the amygdala and nucleus
accumbens, and the effects of ketamine on pERK 1/2 in the prefrontal cortex and
hippocampus were inhibited by PD184161. The ERK 2 levels were decreased by
PD184161 in the nucleus accumbens; and the effects of ketamine were blocked in
this brain area. The p38 protein kinase (p38MAPK) and proBDNF were inhibited by
PD184161, and the MEK inhibitor prevented the effects of ketamine in the nucleus
accumbens. In addition, ketamine increased pro-BDNF levels in the hippocampus. In
conclusion, our findings demonstrated that an acute blockade of MAPK signaling
lead to depressive-like behavior and stopped the antidepressant response of
ketamine, suggesting that the effects of ketamine could be mediated, at least in
part, by the regulation of MAPK signaling in these specific brain areas.

PMID: 24819632 [PubMed - indexed for MEDLINE]

166. Anesthesiology. 2014 Jul;121(1):A29. doi: 10.1097/01.anes.0000450454.48366.e7.

Ketamine as an antidepresessant: a brief research history.

Wanderer JP(1), Rathmell JP.

Author information:
(1)Vanderbilt University School of Medicine Massachusetts General
Hospital/Harvard Medical School.

PMID: 24936933 [PubMed - indexed for MEDLINE]

168. Anesthesiology. 2014 Jul;121(1):4-5. doi: 10.1097/ALN.0000000000000286.

Ketamine metabolomics in the treatment of major depression.

van Velzen M(1), Dahan A.

Author information:
(1)From the Department of Anesthesiology, Leiden University Medical Center,
Leiden, The Netherlands.

Comment on
Anesthesiology. 2014 Jul;121(1):149-59.

PMID: 24936919 [PubMed - indexed for MEDLINE]

169. Aust N Z J Psychiatry. 2014 Jul;48(7):686. doi: 10.1177/0004867414520754. Epub
2014 Jan 22.

Oral ketamine augmentation for chronic suicidality in treatment-resistant
depression.

De Gioannis A(1), De Leo D(2).

Author information:
(1)Australian Institute for Suicide Research and Prevention, National Centre of
Excellence in Suicide Prevention, WHO Collaborating Centre for Research and
Training in Suicide Prevention, Mt Gravatt Campus, Griffith University,
Queensland, Australia a.degioannis@griffith.edu.au. (2)Australian Institute for
Suicide Research and Prevention, National Centre of Excellence in Suicide
Prevention, WHO Collaborating Centre for Research and Training in Suicide
Prevention, Mt Gravatt Campus, Griffith University, Queensland, Australia.

PMID: 24452289 [PubMed - in process]

170. Contemp Clin Trials. 2014 Jul;38(2):314-20. doi: 10.1016/j.cct.2014.06.004. Epub
2014 Jun 16.

Rationale and design of a multicenter randomized clinical trial with memantine
and dextromethorphan in ketamine-responder patients.

Pickering G(1), Pereira B(2), Morel V(3), Tiberghien F(4), Martin E(5),
Marcaillou F(6), Picard P(6), Delage N(6), de Montgazon G(7), Sorel M(8), Roux
D(3), Dubray C(9).

Author information:
(1)Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et
Clinique de la Douleur, Laboratoire de Pharmacologie, Facultés de
Médecine/Pharmacie, F-63000 Clermont-Ferrand, France; Inserm, U1107 Neuro-Dol,
F-63001 Clermont-Ferrand, France.; CHU Clermont-Ferrand, Inserm CIC 1405, Centre
de Pharmacologie Clinique, F-63003 Clermont-Ferrand, France.. Electronic address:
gisele.pickering@udamail.fr. (2)CHU de Clermont-Ferrand, Délégation Recherche
Clinique & Innovation - Villa annexe IFSI, 58 Rue Montalembert, F-63003
Clermont-Ferrand Cedex, France. (3)CHU Clermont-Ferrand, Inserm CIC 1405, Centre
de Pharmacologie Clinique, F-63003 Clermont-Ferrand, France. (4)Centre
d'Evaluation et de Traitement de la Douleur/Soins palliatifs, CHU Jean Minjoz,
Besançon, France. (5)Clermont Université, Université d'Auvergne, Pharmacologie
Fondamentale et Clinique de la Douleur, Laboratoire de Pharmacologie, Facultés de
Médecine/Pharmacie, F-63000 Clermont-Ferrand, France. (6)Centre d'Evaluation et
de Traitement de la Douleur, CHU de Clermont-Ferrand, France. (7)Centre
d'Evaluation et de Traitement de la Douleur/Soins palliatifs, CH de La Rochelle,
France. (8)Centre d'Evaluation et de Traitement de la Douleur/Soins palliatifs,
Nemours, France. (9)Clermont Université, Université d'Auvergne, Pharmacologie
Fondamentale et Clinique de la Douleur, Laboratoire de Pharmacologie, Facultés de
Médecine/Pharmacie, F-63000 Clermont-Ferrand, France; Inserm, U1107 Neuro-Dol,
F-63001 Clermont-Ferrand, France.; CHU Clermont-Ferrand, Inserm CIC 1405, Centre
de Pharmacologie Clinique, F-63003 Clermont-Ferrand, France.

The N-methyl-D-aspartate receptor plays an important role in central
sensitization of neuropathic pain and N-methyl-D-aspartate receptor antagonists,
such as ketamine, memantine and dextromethorphan may be used for persistent pain.
However, ketamine cannot be repeated too often because of its adverse events. A
drug relay would be helpful in the outpatient to postpone or even cancel the next
ketamine infusion. This clinical trial evaluates if memantine and/or
dextromethorphan given as a relay to ketamine responders may maintain or induce a
decrease of pain intensity and have a beneficial impact on cognition and quality
of life. This trial is a multi-center, randomized, controlled and single-blind
clinical study (NCT01602185). It includes 60 ketamine responder patients
suffering from neuropathic pain. They are randomly allocated to memantine,
dextromethorphan or placebo. After ketamine infusion, 60 patients received either
memantine (maximal dose 20 mg/day), or dextromethorphan (maximal dose 90 mg/day),
or placebo for 12 weeks. The primary endpoint is pain measured on a (0-10)
Numeric Rating Scale 1 month after inclusion. Secondary outcomes include
assessment of neuropathic pain, sleep, quality of life, anxiety/depression and
cognitive function at 2 and 3 months. Data analysis is performed using mixed
models and the tests are two-sided, with a type I error set at α=0.05. This study
will explore if oral memantine and/or dextromethorphan may be a beneficial relay
in ketamine responders and may diminish ketamine infusion frequency. Preservation
of cognitive function and quality of life is also a central issue that will be
analyzed in these vulnerable patients.

PMID: 24948402 [PubMed - indexed for MEDLINE]

171. Pharmacopsychiatry. 2014 Jul;47(4-5):141-4. doi: 10.1055/s-0034-1377042. Epub
2014 Jun 23.

Baseline vitamin B12 and folate levels do not predict improvement in depression
after a single infusion of ketamine.

Lundin NB(1), Niciu MJ(1), Luckenbaugh DA(1), Ionescu DF(1), Richards EM(1),
Vande Voort JL(1), Brutsche NE(1), Machado-Vieira R(1), Zarate CA Jr(1).

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, National Institute of
Mental Health, National Institutes of Health, Intramural Research Program,
Bethesda, MD.

INTRODUCTION: Deficiencies in both vitamin B12 and folate have been associated
with depression. Recently, higher baseline vitamin B12 levels were observed in
individuals with bipolar depression who responded to the antidepressant ketamine
at 7 days post-infusion. This study sought to -replicate this result by
correlating peripheral vitamin levels with ketamine's antidepressant efficacy in
bipolar depression and major depressive disorder (MDD).
METHODS: Baseline vitamin B12 and folate levels were obtained in 49 inpatients
with treatment-resistant MDD and 34 inpatients with treatment-resistant bipolar
depression currently experiencing a major depressive episode. All subjects
received a single intravenous ketamine infusion. Post-hoc Pearson correlations
were performed between baseline vitamin B12 and folate levels, as well as
antidepressant response assessed by percent change in Hamilton Depression Rating
Scale (HDRS) scores from baseline to 230 min, 1 day, and 7 days post-infusion.
RESULTS: No significant correlation was observed between baseline vitamin B12 or
folate and percent change in HDRS for any of the 3 time points in either MDD or
bipolar depression.
DISCUSSION: Ketamine's antidepressant efficacy may occur independently of
baseline peripheral vitamin levels.

PMCID: PMC4174587
PMID: 24955551 [PubMed - in process]

172. Psychosomatics. 2014 Jul-Aug;55(4):396-9. doi: 10.1016/j.psym.2013.12.002. Epub
2013 Dec 4.

Beneficial pre-ECT ketamine infusion in a patient with treatment-resistant
depression.

Sultan R(1), Riva-Posse P(1), Garlow SJ(1), Schwartz AC(2).

Author information:
(1)Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, Georgia. (2)Department of Psychiatry and Behavioral Sciences,
Emory University School of Medicine, Atlanta, Georgia. Electronic address:
aschwa2@emory.edu.

PMID: 24735865 [PubMed - in process]

182. J Clin Psychiatry. 2014 May;75(5):e417-23. doi: 10.4088/JCP.13m08698.

Clinical predictors of ketamine response in treatment-resistant major depression.

Niciu MJ(1), Luckenbaugh DA, Ionescu DF, Guevara S, Machado-Vieira R, Richards
EM, Brutsche NE, Nolan NM, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Intramural Research
Program (IRP), National Institute of Mental Health (NIMH), National Institutes of
Health (NIH), Bethesda, Maryland.

OBJECTIVE: The N-methyl-D-aspartate receptor antagonist ketamine has rapid
antidepressant effects in treatment-resistant major depressive disorder (MDD) and
bipolar depression. Clinical predictors may identify those more likely to benefit
from ketamine within clinically heterogeneous populations.
METHOD: Data were analyzed from 4 studies of treatment-resistant inpatients with
DSM-IV-TR-diagnosed MDD or bipolar I or II depression. Patients who were
currently experiencing a moderate-to-severe major depressive episode were
enrolled between November 2004 and March 2013. All subjects received a single
subanesthetic (0.5 mg/kg) ketamine infusion over 40 minutes. Patients were
analyzed at the 230-minute postinfusion time point (n = 108), at day 1 (n = 82),
and at day 7 (n = 71). Univariate Pearson correlations were performed for each
variable with percent change from baseline in the 17-item Hamilton Depression
Rating Scale (HDRS). Multivariate linear regression was then conducted for
statistically significant predictors (P ≤ .05, 2-tailed).
RESULTS: Higher body mass index correlated with greater HDRS improvement at 230
minutes (standardized β = -0.30, P = .004) and at day 1 (standardized β = -0.37,
P = .001), but not at day 7 (standardized β = -0.18, P = .10). Family history of
an alcohol use disorder in a first-degree relative was associated with greater
HDRS improvement at day 1 (standardized β = -0.27, P = .014) and day 7
(standardized β = -0.41, P < .001). No prior history of suicide attempt(s) was
associated with greater improvement only at day 7 (standardized β = 0.28, P =
.01). The overall statistical model explained 13%, 23%, and 36% of HDRS percent
change variance at 230 minutes, day 1, and day 7, respectively.
CONCLUSIONS: Despite its post hoc nature, this study identified several clinical
correlates of ketamine's rapid and durable antidepressant effects. Further
investigation of these relationships is critical for individualized treatment of
depression.

PMCID: PMC4310499
PMID: 24922494 [PubMed - indexed for MEDLINE]

183. Presse Med. 2014 May;43(5):492-500. doi: 10.1016/j.lpm.2013.11.013. Epub 2014 Mar
12.

[Ketamine in acute and severe major depressive disorder].

[Article in French]

Brittner M(1), Micoulaud-Franchi JA(2), Richieri R(2), Boyer L(3), Adida M(2),
Lancon C(2), Fond G(4).

Author information:
(1)CHU de Montpellier, université Montpellier 1, service universitaire de
psychiatrie, Inserm 1061, 34000 Montpellier, France. (2)Hôpital
Sainte-Marguerite, service hospitalo-universitaire de psychiatrie, 13009
Marseille, France. (3)Faculté de médecine, laboratoire de santé publique, EA
3279, 13385 Marseille cedex 05, France. (4)Groupe des hôpitaux universitaires de
Mondor, université Paris-Est-Créteil, pôle de psychiatrie, Eq psychiatrie
génétique, fondation FondaMental, fondation de coopération scientifique en santé
mentale, DHU Pepsy, Inserm U955, 40, rue de Mesly, 94010 Créteil, France.
Electronic address: guillaume.fond@gmail.com.

CONTEXT: Depression is a frequent, severe and expensive illness. Approximately
20% of depressive episodes are resistant to classic antidepressants.
Glutamatergic antagonists, in particular ketamine, established a new, rapid and
robust therapeutic approach in resistant depression.
RESULTS: The main results in the literature show a rapid and robust
antidepressant effect of ketamine, with infra-anesthesic posology (0.5mg/kg)
administered in intravenous way. Positive effects are observed on depressive
symptoms, suicidal thoughts, and there is a potential synergic action when used
in the induction of anesthesia for electroconvulsive therapy. However, effects
only last shortly. Side effects are mostly reversible and of mild intensity, no
severe consequences were reported.
LIMITS: Limits are the lack of power of the included studies, due to small sample
sizes, and the scarcity of studies. Misuse of ketamine is an important issue to
be taken into account, and few data about ketamine addiction potential and its
long-term effects are published at the moment.

PMID: 24630265 [PubMed - indexed for MEDLINE]

184. Psychopharmacology (Berl). 2014 May;231(9):2041-2. doi:
10.1007/s00213-014-3543-0. Epub 2014 Mar 26.

Rapid antidepressant effects and abuse liability of ketamine.

Yang C(1), Hashimoto K.

Author information:
(1)Division of Clinical Neuroscience, Chiba University Center for Forensic Mental
Health, 1-8-1 Inohana, Chiba, 260-8670, Japan.

Comment in
Psychopharmacology (Berl). 2014 May;231(9):2043-4.

PMID: 24668037 [PubMed - indexed for MEDLINE]

186. BMJ. 2014 Apr 3;348:g2576. doi: 10.1136/bmj.g2576.

Ketamine helps a third of patients with treatment resistant depression, finds
small UK study.

Torjesen I(1).

Author information:
(1)London.

PMID: 24699320 [PubMed - indexed for MEDLINE]

187. J Psychopharmacol. 2014 Apr 3;28(6):536-544. [Epub ahead of print]

Ketamine infusions for treatment resistant depression: a series of 28 patients
treated weekly or twice weekly in an ECT clinic.

Diamond PR(1), Farmery AD(2), Atkinson S(1), Haldar J(3), Williams N(4), Cowen
PJ(5), Geddes JR(5), McShane R(6).

Author information:
(1)Oxford Health NHS Foundation Trust, Oxford, UK. (2)Nuffield Department of
Anaesthetics, University of Oxford, Oxford, UK. (3)Oxford University Hospitals
NHS Trust, Oxford, UK. (4)Centre for Statistics in Medicine, University of
Oxford, Oxford, UK. (5)Department of Psychiatry, University of Oxford, Oxford,
UK. (6)Oxford Health NHS Foundation Trust, Oxford, UK Department of Psychiatry,
University of Oxford, Oxford, UK Rupert.mcshane@oxfordhealth.nhs.uk.

BACKGROUND: Ketamine has a rapid antidepressant effect in treatment-resistant
depression (TRD). The effects on cognitive function of multiple ketamine
infusions and of concurrent antidepressant medication on response rate and
duration are not known.
METHOD: Twenty-eight patients with uni- or bipolar TRD were treated over three
weeks with either three or six ketamine infusions (0.5 mg/kg over 40 minutes) in
the recovery room of a routine ECT clinic. Post-treatment memory assessments were
conducted on day 21 (4-7 days after the final infusion). Patients were followed
up for six months where possible, with severity of depression and side effects
monitored throughout.
RESULTS: Eight (29%) patients responded of whom four remitted. Only three (11%)
patients had responded within six hours after a single infusion, but in all
responders, the response had developed before the third infusion. The duration of
response from the final infusion was variable (median 70, range 25-168 days).
Discontinuations included two (7%) because of acute adverse reactions during the
infusion and five (18%) because of failure to benefit and increasing anxiety.
Ketamine was not associated with memory impairment. The ECT clinic was rated
suitable by patients and offered appropriate levels of monitoring.
CONCLUSION: This small, open label naturalistic study shows that up to six low
dose ketamine infusions can safely be given within an existing NHS clinical
structure to patients who continue their antidepressants. The response rate was
comparable to that found in RCTs of single doses of ketamine in
antidepressant-free patients but took slightly longer to develop.

PMID: 24699062 [PubMed - as supplied by publisher]

189. Clin Psychopharmacol Neurosci. 2014 Apr;12(1):72-3. doi:
10.9758/cpn.2014.12.1.72. Epub 2014 Apr 24.

The R-Stereoisomer of Ketamine as an Alternative for Ketamine for
Treatment-resistant Major Depression.

Hashimoto K(1).

Author information:
(1)Division of Clinical Neuroscience, Chiba University Center for Forensic Mental
Health, Chiba, Japan.

PMCID: PMC4022771
PMID: 24851126 [PubMed]

190. CNS Spectr. 2014 Apr;19(2):112-4. doi: 10.1017/S1092852914000029. Epub 2014 Feb
25.

Current drug development for antidepressants and ideas addressing downstream
glutamate: the ketamine example.

Potter WZ(1), Brady LS(1).

Author information:
(1)National Institute of Mental Health, Bethesda, Maryland, USA.

PMID: 24565466 [PubMed - indexed for MEDLINE]

191. Depress Anxiety. 2014 Apr;31(4):335-43. doi: 10.1002/da.22253. Epub 2014 Mar 25.

Effects of ketamine on explicit and implicit suicidal cognition: a randomized
controlled trial in treatment-resistant depression.

Price RB(1), Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ,
Soleimani L, Charney DS, Foulkes AL, Mathew SJ.

Author information:
(1)Department of Psychiatry, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania.

BACKGROUND: Preliminary evidence suggests intravenous ketamine has rapid effects
on suicidal cognition, making it an attractive candidate for depressed patients
at imminent risk of suicide. In the first randomized controlled trial of ketamine
using an anesthetic control condition, we tested ketamine's acute effects on
explicit suicidal cognition and a performance-based index of implicit suicidal
cognition (Implicit Association Test; IAT) previously linked to suicidal
behavior.
METHOD: Symptomatic patients with treatment-resistant unipolar major depression
(inadequate response to ≥3 antidepressants) were assessed using a composite index
of explicit suicidal ideation (Beck Scale for Suicidal Ideation,
Montgomery-Asberg Rating Scale suicide item, Quick Inventory of Depressive
Symptoms suicide item) and the IAT to assess suicidality implicitly. Measures
were taken at baseline and 24 hr following a single subanesthetic dose of
ketamine (n = 36) or midazolam (n = 21), a psychoactive placebo agent selected
for its similar, rapid anesthetic effects. Twenty four hours postinfusion,
explicit suicidal cognition was significantly reduced in the ketamine but not the
midazolam group.
RESULTS: Fifty three percent of ketamine-treated patients scored zero on all
three explicit suicide measures at 24 hr, compared with 24% of the midazolam
group (χ(2) = 4.6; P = .03). Implicit associations between self- and
escape-related words were reduced following ketamine (P = .01; d = .58) but not
midazolam (P = .68; d = .09). Ketamine-specific decreases in explicit suicidal
cognition were largest in patients with elevated suicidal cognition at baseline,
and were mediated by decreases in nonsuicide-related depressive symptoms.
CONCLUSIONS: Intravenous ketamine produces rapid reductions in suicidal cognition
over and above active placebo. Further study is warranted to test ketamine's
antisuicidal effects in higher-risk samples.

PMCID: PMC4112410
PMID: 24668760 [PubMed - indexed for MEDLINE]

192. J Affect Disord. 2014 Apr;159:56-61. doi: 10.1016/j.jad.2014.02.017. Epub 2014
Feb 18.

Do the dissociative side effects of ketamine mediate its antidepressant effects?

Luckenbaugh DA(1), Niciu MJ(1), Ionescu DF(1), Nolan NM(1), Richards EM(1),
Brutsche NE(1), Guevara S(1), Zarate CA(2).

Author information:
(1)Experimental Therapeutics & Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health (NIMH), National Institutes of
Health (NIH), Bethesda, MD USA. (2)Experimental Therapeutics & Pathophysiology
Branch, Intramural Research Program, National Institute of Mental Health (NIMH),
National Institutes of Health (NIH), Bethesda, MD USA. Electronic address:
zaratec@mail.nih.gov.

BACKGROUND: The N-methyl-d-aspartate receptor antagonist ketamine has rapid
antidepressant effects in major depression. Psychotomimetic symptoms,
dissociation and hemodynamic changes are known side effects of ketamine, but it
is unclear if these side effects relate to its antidepressant efficacy.
METHODS: Data from 108 treatment-resistant inpatients meeting criteria for major
depressive disorder and bipolar disorder who received a single subanesthetic
ketamine infusion were analyzed. Pearson correlations were performed to examine
potential associations between rapid changes in dissociation and psychotomimesis
with the Clinician-Administered Dissociative States Scale (CADSS) and Brief
Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania
Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item
Hamilton Depression Rating scale (HDRS) at 40 and 230min and Days 1 and 7.
RESULTS: Pearson correlations showed significant association between increased
CADSS score at 40min and percent improvement with ketamine in HDRS at 230min
(r=-0.35, p=0.007) and Day 7 (r=-0.41, p=0.01). Changes in YMRS or BPRS Positive
Symptom score at 40min were not significantly correlated with percent HDRS
improvement at any time point with ketamine. Changes in systolic blood pressure,
diastolic blood pressure, and pulse were also not significantly related to HDRS
change.
LIMITATIONS: Secondary data analysis, combined diagnostic groups, potential
unblinding.
CONCLUSIONS: Among the examined mediators of ketamine׳s antidepressant response,
only dissociative side effects predicted a more robust and sustained
antidepressant. Prospective, mechanistic investigations are critically needed to
understand why intra-infusion dissociation correlates with a more robust
antidepressant efficacy of ketamine.

Published by Elsevier B.V.

PMCID: PMC4065787
PMID: 24679390 [PubMed - indexed for MEDLINE]

193. J Clin Psychopharmacol. 2014 Apr;34(2):285-6. doi: 10.1097/JCP.0000000000000090.

Failed response to repeat intravenous ketamine infusions in geriatric patients
with major depressive disorder.

Szymkowicz SM(1), Finnegan N, Dale RM.

Author information:
(1)Department of Clinical and Health Psychology University of Florida
Gainesville, FL Behavioral Health Services, Lutheran Hospital Cleveland Clinic
Foundation Cleveland, OH Behavioral Health Services, Lutheran Hospital Cleveland
Clinic Foundation Cleveland, OH daler@ccf.org.

PMCID: PMC3941032
PMID: 24525638 [PubMed - indexed for MEDLINE]

194. Ther Adv Psychopharmacol. 2014 Apr;4(2):75-99. doi: 10.1177/2045125313507739.

Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions,
and a systematic review and meta-analysis of efficacy.

Caddy C(1), Giaroli G(2), White TP(1), Shergill SS(3), Tracy DK(4).

Author information:
(1)Cognition Schizophrenia and Imaging Laboratory, Department of Psychosis
Studies, the Institute of Psychiatry, King's College London, UK. (2)Cognition
Schizophrenia and Imaging Laboratory, Department of Psychosis Studies, the
Institute of Psychiatry, King's College London, UK and North East London NHS
Foundation Trust, London, UK. (3)Cognition Schizophrenia and Imaging Laboratory,
Department of Psychosis Studies, the Institute of Psychiatry, King's College
London, UK and South London and Maudsley NHS Foundation Trust, London, UK.
(4)Consultant Psychiatrist, Oxleas NHS Foundation Trust, Princess Royal
University Hospital, Orpington, BR6 8NY, UK and Cognition Schizophrenia and
Imaging Laboratory, Department of Psychosis Studies, the Institute of Psychiatry,
King's College London, UK.

The burden of depressive disorders and the frequent inadequacy of their current
pharmacological treatments are well established. The anaesthetic and
hallucinogenic drug ketamine has provoked much interest over the past decade or
so as an extremely rapidly acting antidepressant that does not modify 'classical'
monoaminergic receptors. Current evidence has shown several ways through which it
might exert therapeutic antidepressant actions: blockade of glutamatergic NMDA
receptors and relative upregulation of
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes may alter
cortical connectivity patterns; through intracellular changes in protein
expression, including the proteins mammalian target of rapamycin (mTOR) and
brain-derived neurotrophic factor (BDNF); and alteration of intracellular
signalling cascades. The clinical evidence demonstrates rapid improvements in
mood and suicidal thinking in most participants, although study numbers have
generally been small and many trials are unblinded and methodologically weak.
There is a small body of work to suggest ketamine might also augment
electroconvulsive therapy and potentially have a role as a surgical anaesthetic
in depressed patients. A major problem is that the effects of ketamine appear
temporary, disappearing after days to weeks (although longer benefits have been
sustained in some), and attempts to circumvent this through pharmacological
augmentation have been disappointing thus far. These exciting data are providing
new insights into neurobiological models of depression, and potentially opening
up a new class of antidepressants, but there are significant practical and
ethical issues about any future mainstream clinical role it might have.

PMCID: PMC3952483
PMID: 24688759 [PubMed]

196. Am J Psychiatry. 2014 Mar;171(3):262-4. doi: 10.1176/appi.ajp.2014.13101434.

A word to the wise about ketamine.

Schatzberg AF.

Comment in
Am J Psychiatry. 2014 Jul;171(7):796.

Comment on
Am J Psychiatry. 2013 Oct;170(10):1134-42.

PMID: 24585328 [PubMed - indexed for MEDLINE]

199. J Affect Disord. 2014 Mar;156:24-35. doi: 10.1016/j.jad.2013.11.014. Epub 2013
Dec 10.

A review of ketamine in affective disorders: current evidence of clinical
efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of
action.

Naughton M(1), Clarke G(2), O'Leary OF(3), Cryan JF(4), Dinan TG(5).

Author information:
(1)Department of Psychiatry, University College Cork, Western Road, Cork City,
Cork, Ireland. Electronic address: marienaughton@beaumont.ie. (2)Department of
Psychiatry, University College Cork, Western Road, Cork City, Cork, Ireland;
Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
Electronic address: g.clarke@ucc.ie. (3)Alimentary Pharmabiotic Centre,
University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience,
University College Cork, Cork, Ireland. Electronic address: o.oleary@ucc.ie.
(4)Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland;
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
Electronic address: j.cryan@ucc.ie. (5)Department of Psychiatry, University
College Cork, Western Road, Cork City, Cork, Ireland; Alimentary Pharmabiotic
Centre, University College Cork, Cork, Ireland. Electronic address:
t.dinan@ucc.ie.

INTRODUCTION: Recent research has seen low-dose ketamine emerge as a novel,
rapid-acting antidepressant. Ketamine, an N-methy-d-aspartate (NMDA) receptor
antagonist, leads to effects on the glutamatergic system and abnormalities in
this neurotransmittor system are present in depression. This article aims to (1)
review the clinical literature on low-dose ketamine as a rapid-acting
antidepressant in affective disorders, (2) provide a critical overview of the
limitations of ketamine and research attempts to overcome these (3) discuss the
proposed mechanisms of action of ketamine and (4) point towards future research
directions.
METHOD: The electronic database Pubmed, Web of Science and sciencedirect were
searched using the keywords: ketamine, N-methyl-d-aspartate receptor antagonist,
rapid-acting antidepressant, depression, treatment-resistant depression, bipolar
depression, suicidal ideation, electroconvulsive therapy, mechanism of action.
RESULT: The literature demonstrates evidence supporting a rapid-acting
antidepressant effect of low-dose intravenous ketamine in major depressive
disorder, in bipolar depression and in depression with suicidal ideation. There
are mixed results as to whether ketamine leads to a reduction in time to
remission in patients undergoing electroconvulsive therapy (ECT). Efforts to
unravel ketamine's therapeutic mechanism of action have implicated the mammalian
target of rapamycin (mTOR)-dependent synapse formation in the rat prefrontal
cortex, eukaryotic elongation factor 2 phosphorylation (p-eEF2) and glycogen
synthase kinase (GSK-3). Ketamine's limiting factors are the transient nature of
its antidepressant effect and concerns regarding abuse, and research efforts to
overcome these are reviewed.
CONCLUSION: Current and future research studies are using ketamine as a promising
tool to evaluate the glutamatergic neurotransmittor system to learn more about
the pathophysiology of depression and develop more specific rapid-acting
antidepressant treatments.

PMID: 24388038 [PubMed - indexed for MEDLINE]

200. J ECT. 2014 Mar;30(1):15-21. doi: 10.1097/YCT.0b013e3182a4b4c6.

Comparing effects of ketamine and thiopental administration during
electroconvulsive therapy in patients with major depressive disorder: a
randomized, double-blind study.

Yoosefi A(1), Sepehri AS, Kargar M, Akhondzadeh S, Sadeghi M, Rafei A, Alimadadi
A, Ghaeli P.

Author information:
(1)From the *Department of Anesthesiology, Amir Alam Hospital, †Department of
Clinical Pharmacy, Faculty of Pharmacy, ‡Research Center for Rational Use of
Drugs, Department of Clinical Pharmacy, §Psychiatric and Psychology Research
Centre, Roozbeh Hospital, ∥Department of Psychiatry, Roozbeh Hospital, and
¶Department of Statistics and Mathematics, Tehran University of Medical Sciences;
#Department of Psychology, University of Applied Science and Technology;
**Faculty of Pharmacy and Roozbeh Hospital, Tehran University of Medical
Sciences, Tehran, Iran.

OBJECTIVES: Recently, ketamine has attracted attention for induction of
anesthesia during electroconvulsive therapy (ECT). This study compared the
effects of thiopental and ketamine in patients undergoing this procedure.
METHOD: This randomized, double-blind clinical trial included inpatients, with
major depressive disorder, undergoing ECT. Subjects were randomly allocated to
receive either ketamine or thiopental. Mini-Mental State Examination and Hamilton
Depression Rating Scale were used to assess memory and depression, respectively,
before the first and second ECT sessions as well as a few days and 1 month after
the sixth session. The electrical charge, seizure duration, blood pressure, and
heart rate were also recorded.
RESULTS: Of the 31 patients, 17 met the criteria for the ketamine group but 2
dropped out of the study. Therefore, 15 patients received ketamine and 14
received thiopental. Each patient underwent 6 ECT sessions. At the end of the
study, depression improved significantly in both groups. However, a significant
difference in depression improvement was noted only before the second ECT with
ketamine compared with thiopental. Despite a significant decline in Mini-Mental
State Examination scores in both groups after the first ECT, cognitive function
improved afterward but was only significant in ketamine group. Seizure duration
was found to be significantly longer with ketamine. Stimulus intensity used for
each ECT increased gradually and linearly with a greater increase observed in
thiopental group.
CONCLUSIONS: Ketamine administration during ECT is well tolerated and patients
may experience earlier improvement in depressive symptoms, longer seizure
duration, and better cognitive performance when compared with thiopental.

PMID: 24091902 [PubMed - indexed for MEDLINE]

203. Psychiatry Res. 2014 Feb 28;215(2):355-61. doi: 10.1016/j.psychres.2013.12.008.
Epub 2013 Dec 13.

Rapid antidepressant effects of repeated doses of ketamine compared with
electroconvulsive therapy in hospitalized patients with major depressive
disorder.

Ghasemi M(1), Kazemi MH(2), Yoosefi A(3), Ghasemi A(4), Paragomi P(5), Amini
H(3), Afzali MH(6).

Author information:
(1)Department of Psychiatry, Roozbeh Psychiatric Hospital, Tehran University of
Medical Sciences, South Kargar Street, Tehran 13337-95914, Iran; Department of
Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
Department of Pharmacology, School of Medicine, Tehran University of Medical
Sciences, P.O. Box 13145-784, Tehran, Iran; NeurExpand Brain Center, 1205 York
Road, Lutherville, MD 21093, USA. Electronic address: m82.ghasemi@gmail.com.
(2)Department of Psychiatry, Roozbeh Psychiatric Hospital, Tehran University of
Medical Sciences, South Kargar Street, Tehran 13337-95914, Iran; Robert S. Boas
Center for Genomics and Human Genetics, The Feinstein Institute for Medical
Research (FIMR), Manhasset, NY, USA. (3)Department of Psychiatry, Roozbeh
Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar Street,
Tehran 13337-95914, Iran; Psychiatric Research Center, Roozbeh Psychiatric
Hospital, Tehran University of Medical Sciences, South Kargar Street, Tehran
13337, Iran. (4)Department of Pharmacology, School of Medicine, Tehran University
of Medical Sciences, P.O. Box 13145-784, Tehran, Iran. (5)Department of
Psychiatry, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences,
South Kargar Street, Tehran 13337-95914, Iran. (6)Department of Psychiatry,
Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar
Street, Tehran 13337-95914, Iran; Université de Toulouse-Le Mirail, Octogone, 5,
Allées Antonio Machado, 31058 Toulouse Cedex 9, France.

Comment in
Psychiatry Res. 2015 Jan 30;225(1-2):216.
Psychiatry Res. 2015 Jan 30;225(1-2):215.

Accumulating evidence suggests that N-methyl-d-aspartate receptor (NMDAR)
antagonists (e.g. ketamine) may exert rapid antidepressant effects in MDD
patients. In the present study, we evaluated the rapid antidepressant effects of
ketamine compared with the electroconvulsive therapy (ECT) in hospitalized
patients with MDD. In this blind, randomized study, 18 patients with DSM-IV MDD
were divided into two groups which received either three intravenous infusions of
ketamine hydrochloride (0.5 mg/kg over 45 min) or ECT on 3 test days (every 48
h). The primary outcome measure was the Beck Depression Inventory (BDI) and
Hamilton Depression Rating Scale (HDRS), which was used to rate overall
depressive symptoms at baseline, 24 h after each treatment, 72 h and one week
after the last (third) ketamine or ECT. Within 24 h, depressive symptoms
significantly improved in subjects receiving the first dose of ketamine compared
with ECT group. Compared to baseline level, this improvement remained significant
throughout the study. Depressive symptoms after the second dose ketamine was also
lower than the second ECT. This study showed that ketamine is as effective as ECT
in improving depressive symptoms in MDD patients and have more rapid
antidepressant effects compared with the ECT.

PMID: 24374115 [PubMed - indexed for MEDLINE]

206. Encephale. 2014 Feb;40(1):48-55. doi: 10.1016/j.encep.2013.09.002. Epub 2014 Jan
13.

[Ketamine's antidepressant effect: focus on ketamine mechanisms of action].

[Article in French]

De Maricourt P(1), Jay T(2), Goncalvès P(3), Lôo H(4), Gaillard R(5).

Author information:
(1)Service hospitalo-universitaire de santé mentale et de thérapeutique, hôpital
Sainte-Anne, université Paris Descartes, centre hospitalier Sainte-Anne, 1, rue
Cabanis, 75014 Paris, France; Inserm UMR 894, centre de psychiatrie et
neurosciences, université Paris Descartes, Sorbonne Paris Cité, 75014 Paris,
France. (2)Inserm UMR 894, centre de psychiatrie et neurosciences, université
Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France. (3)Clinique du Bois
Bondy, 93G11 EPS Ville Evrard, 93140 Bondy, France. (4)Service
hospitalo-universitaire de santé mentale et de thérapeutique, hôpital
Sainte-Anne, université Paris Descartes, centre hospitalier Sainte-Anne, 1, rue
Cabanis, 75014 Paris, France. (5)Service hospitalo-universitaire de santé mentale
et de thérapeutique, hôpital Sainte-Anne, université Paris Descartes, centre
hospitalier Sainte-Anne, 1, rue Cabanis, 75014 Paris, France; Inserm UMR 894,
centre de psychiatrie et neurosciences, université Paris Descartes, Sorbonne
Paris Cité, 75014 Paris, France. Electronic address:
raphael.gaillard@normalesup.org.

BACKGROUND: In recent years, discovery of ketamine's fast and powerful
antidepressant effects for treatment-resistant depression (TRD) has led to
rethinking of the pathophysiology of depression. Numerous studies in humans and
animals have focused on mechanisms of action underlying this effect, producing a
number of explanatory pathways.
METHOD: The aim of this article is to summarize the various hypotheses underlying
rapid antidepressant action of ketamine and therefore to better understand the
mechanisms underlying depression and antidepressant action.
RESULTS: Ketamine unique antidepressant properties have led to many studies on
its neurobiological grounds. Intracellular signaling pathways such as mTOR, GSK3
or eEF2 seem to play a key role and are associated with an increased synaptic
plasticity. Other hypotheses are discussed such as ketamine effects on
neuro-inflammation, the role of anterior cingulate cortex in brain changes
induced by ketamine, and the potential benefits of analgesic properties of
ketamine in depressive disorders.
CONCLUSION: Our review highlights the potential role of the glutamatergic system
in the pathophysiology and treatment of mood disorders. Understanding which
pathways underlie the fast antidepressant effect of ketamine paves the way for
the development of new antidepressants.

Copyright © 2013 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights
reserved.

PMID: 24434007 [PubMed - indexed for MEDLINE]

207. Int J Neuropsychopharmacol. 2014 Feb;17(2):331-6. doi: 10.1017/S1461145713001119.
Epub 2013 Oct 8.

Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in
treatment-resistant depression.

Haile CN(1), Murrough JW(2), Iosifescu DV(2), Chang LC(3), Al Jurdi RK(4),
Foulkes A(1), Iqbal S(1), Mahoney JJ 3rd(1), De La Garza R 2nd(1), Charney DS(2),
Newton TF(1), Mathew SJ(4).

Author information:
(1)Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of
Medicine, Houston, TX, USA. (2)Mood and Anxiety Disorders Program, Department of
Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
(3)Department of Anesthesiology, Baylor College of Medicine, New York, NY, USA.
(4)Michael E. DeBakey VA Medical Center, Houston, TX, USA.

Ketamine produces rapid antidepressant effects in treatment-resistant depression
(TRD), but the magnitude of response varies considerably between individual
patients. Brain-derived neurotrophic factor (BDNF) has been investigated as a
biomarker of treatment response in depression and has been implicated in the
mechanism of action of ketamine. We evaluated plasma BDNF and associations with
symptoms in 22 patients with TRD enrolled in a randomized controlled trial of
ketamine compared to an anaesthetic control (midazolam). Ketamine significantly
increased plasma BDNF levels in responders compared to non-responders 240 min
post-infusion, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were
negatively correlated with BDNF (r=-0.701, p = 0.008). Plasma BDNF levels at
240 min post-infusion were highly negatively associated with MADRS scores at
240 min (r = -0.897, p=.002), 24 h (r = -0.791, p = 0.038), 48 h (r = -0.944,
p = 0.001) and 72 h (r = -0.977, p = 0.010). No associations with BDNF were found
for patients receiving midazolam. These data support plasma BDNF as a peripheral
biomarker relevant to ketamine antidepressant response.

PMCID: PMC3992942
PMID: 24103211 [PubMed - indexed for MEDLINE]

208. J Affect Disord. 2014 Feb;155:123-9. doi: 10.1016/j.jad.2013.10.036. Epub 2013
Oct 29.

Augmentation of response and remission to serial intravenous subanesthetic
ketamine in treatment resistant depression.

Shiroma PR(1), Johns B(2), Kuskowski M(3), Wels J(4), Thuras P(3), Albott CS(3),
Lim KO(3).

Author information:
(1)Mental Health Service Line, Minneapolis VA Medical Center, Minneapolis, MN,
USA; Department of Psychiatry, University of Minnesota Medical School,
Minneapolis, MN, USA. Electronic address: paulo.shiroma@va.gov. (2)Department of
Psychiatry, North Memorial Medical Center, Minneapolis, MN, USA; Department of
Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA.
(3)Mental Health Service Line, Minneapolis VA Medical Center, Minneapolis, MN,
USA; Department of Psychiatry, University of Minnesota Medical School,
Minneapolis, MN, USA. (4)Department of Anesthesiology, Minneapolis VA Medical
Center, Minneapolis, MN, USA.

BACKGROUND: Ketamine has been showing high efficacy and rapid antidepressant
effect. However, studies of ketamine infusion wash subjects out from prior
antidepressants, which may be impractical in routine practice. In this study, we
determined antidepressant response and remission to six consecutive ketamine
infusions while maintaining stable doses of antidepressant regimen. We also
examined the trajectory of response and remission, and the time to relapse among
responders.
METHODS: TRD subjects had at least 2-month period of stable dose of
antidepressants. Subjects completed six IV infusions of 0.5mg/kg ketamine over
40min on a Monday-Wednesday-Friday schedule during a 12-day period participants
meeting response criteria were monitored for relapse for 4 weeks.
RESULTS: Fourteen subjects were enrolled. Out of twelve subjects who completed
all six infusions, eleven (91.6%) achieved response criterion while eight (66.6%)
remitted. After the first infusion, only three and one out of twelve subjects
responded and remitted, respectively. Four achieved response and six remitted
after 3 or more infusions. Five out of eleven subjects remain in response status
throughout the 4 weeks of follow-up. The mean time for six subjects who relapsed
was 16 days.
LIMITATIONS: Small sample and lack of a placebo group limits the interpretation
of efficacy.
CONCLUSIONS: Safety and efficacy of repeated ketamine infusions were attained
without medication-free state in patients with TRD. Repeated infusions achieved
superior antidepressant outcomes as compared to a single infusion with different
trajectories of response and remission. Future studies are needed to elucidate
neural circuits involved in treatment response to ketamine.

PMID: 24268616 [PubMed - indexed for MEDLINE]

211. Transl Psychiatry. 2014 Jan 7;4:e342. doi: 10.1038/tp.2013.112.

A possible mechanism of the nucleus accumbens and ventral pallidum 5-HT1B
receptors underlying the antidepressant action of ketamine: a PET study with
macaques.

Yamanaka H(1), Yokoyama C(1), Mizuma H(1), Kurai S(2), Finnema SJ(3), Halldin
C(3), Doi H(2), Onoe H(1).

Author information:
(1)Bio-Function Imaging Team, RIKEN Center for Life Science Technologies, 6-7-3
Minatojima-Minamimachi, Chuo-ku, Kobe, Japan. (2)Labelling Chemistry Team,
Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science
Technologies, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Japan. (3)Karolinska
Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research,
Karolinska University Hospital, Stockholm, Sweden.

Ketamine is a unique anesthetic reagent known to produce various psychotic
symptoms. Ketamine has recently been reported to elicit a long-lasting
antidepressant effect in patients with major depression. Although recent studies
provide insight into the molecular mechanisms of the effects of ketamine, the
antidepressant mechanism has not been fully elucidated. To understand the
involvement of the brain serotonergic system in the actions of ketamine, we
performed a positron emission tomography (PET) study on non-human primates. Four
rhesus monkeys underwent PET studies with two serotonin (5-HT)-related PET
radioligands, [(11)C]AZ10419369 and [(11)C]DASB, which are highly selective for
the 5-HT1B receptor and serotonin transporter (SERT), respectively. Voxel-based
analysis using standardized brain images revealed that ketamine administration
significantly increased 5-HT1B receptor binding in the nucleus accumbens and
ventral pallidum, whereas it significantly reduced SERT binding in these brain
regions. Fenfluramine, a 5-HT releaser, significantly decreased 5-HT1B receptor
binding, but no additional effect was observed when it was administered with
ketamine. Furthermore, pretreatment with
2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), a potent antagonist
of the glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)
receptor, blocked the action of ketamine on the 5-HT1B receptor but not SERT
binding. This indicates the involvement of AMPA receptor activation in
ketamine-induced alterations of 5-HT1B receptor binding. Because NBQX is known to
block the antidepressant effect of ketamine in rodents, alterations in the
serotonergic neurotransmission, particularly upregulation of postsynaptic 5-HT1B
receptors in the nucleus accumbens and ventral pallidum may be critically
involved in the antidepressant action of ketamine.

PMCID: PMC3905222
PMID: 24399045 [PubMed - indexed for MEDLINE]

212. Annu Rev Pharmacol Toxicol. 2014;54:119-39. doi:
10.1146/annurev-pharmtox-011613-135950.

Glutamate receptor antagonists as fast-acting therapeutic alternatives for the
treatment of depression: ketamine and other compounds.

Niciu MJ(1), Henter ID, Luckenbaugh DA, Zarate CA Jr, Charney DS.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Intramural Research
Program, National Institutes of Health/National Institute of Mental Health,
Bethesda, Maryland 20814-9692; email: mark.niciu@nih.gov.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent
antidepressant effects in treatment-resistant major depressive disorder and
bipolar depression. These effects are in direct contrast to the more modest
effects seen after weeks of treatment with classic monoaminergic antidepressants.
Numerous open-label and case studies similarly validate ketamine's antidepressant
properties. These clinical findings have been reverse-translated into preclinical
models in an effort to elucidate ketamine's antidepressant mechanism of action,
and three important targets have been identified: mammalian target of rapamycin
(mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3
(GSK-3). Current clinical and preclinical research is focused on (a)
prolonging/maintaining ketamine's antidepressant effects, (b) developing more
selective NMDA receptor antagonists free of ketamine's adverse effects, and (c)
identifying predictor, mediator/moderator, and treatment response biomarkers of
ketamine's antidepressant effects.

PMCID: PMC4089991
PMID: 24392693 [PubMed - indexed for MEDLINE]

213. Curr Neuropharmacol. 2014 Jan;12(1):57-70. doi: 10.2174/1570159X113119990043.

Ketamine as antidepressant? Current state and future perspectives.

Hasselmann HW(1).

Author information:
(1)Research Master Programme Cognitive and Clinical Neurosciences, Maastricht
University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.

Major depressive disorder (MDD) is a serious mental disorder that ranks among the
major causes of disease burden. Standard medical treatment targeting cerebral
monoamines often provides only insufficient symptom relief and fails in
approximately every fifth patient. The complexity of MDD therefore, reflects more
than monoaminergic dysregulation. Initial research argues the case for excessive
glutamate levels, suggesting that antiglutamatergic drugs might be useful in
treating MDD. Ketamine is a non-selective, high-affinity N-methyl-D-aspartate
receptor (NMDAR) antagonist most commonly used in pediatric and animal surgery.
In the past, ketamine has gained popularity because of its ability to rapidly
elevate mood, even in treatment-resistant and bipolar depression. However, there
are still many obstacles before widespread clinical approval of ketamine
treatment could become reality. In this review, ketamine's powerful
antidepressant effects are discussed and further research necessary for
therapeutic application is outlined. NMDAR antagonists provide an entirely new
way of treating the manifold appearances of depression that should not be left
unused.

PMCID: PMC3915350
PMID: 24533016 [PubMed]

214. Curr Pharm Des. 2014;20(23):3848-60.

Novel therapeutic strategies in major depression: focus on RNAi and ketamine.

Bortolozzi A, Celada P, Artigas F(1).

Author information:
(1)Dept. of Neurochemistry and Neuropharmacology, IIBB-CSIC (IDIBAPS), Rossello,
161, 6th floor, 08036 Barcelona, Spain. fapnqi@iibb.csic.es.

Major depression is a severe psychiatric syndrome with very high prevalence and -
socioeconomic impact. Despite extensive research, its pathophysiology is poorly
understood, yet several neurotransmitter systems and brain areas have been
implicated. The pharmacological treatment of major depression is mainly based on
drugs inhibiting serotonin (5-hydroxytryptamine, 5-HT) and/or noradrenaline (NA)
reuptake. These drugs evoke a series of neuronal adaptive mechanisms that limit
their full clinical action, making necessary for many patients the use of
augmentation strategies. In spite of such strategies, many depressed patients
show limited or no improvement, which worsens their quality of life and increases
the risk of suicide. Several novel observations in recent years have shaken the
antidepressant field, by showing that depressed patients with severe treatment
resistance can rapidly experience clinical remission. Hence, deep brain
stimulation (DBS) of ventral anterior cingulate cortex (Cg25) evokes rapid mood
improvements in treatment-resistant patients. Likewise, single doses of the
non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine evoke
rapid and long-lasting (up to 10 days) antidepressant responses in
treatment-resistant patients. On the other hand, new molecular strategies aimed
at modulating the expression of certain genes show great potential in the
antidepressant field. In particular, RNAi strategies have been used to evoke
antidepressant-like effects in laboratory animals by knocking-down the expression
of genes involved in antidepressant effects, such as the serotonin transporter
(SERT) or the 5-HT1A autoreceptor. Here we review these novel strategies due to
their potential impact in the identification of new targets and the further
development of new antidepressant drugs.

PMID: 24180396 [PubMed - indexed for MEDLINE]

215. Indian J Psychol Med. 2014 Jan;36(1):71-6. doi: 10.4103/0253-7176.127258.

Acute antidepressant effects of intramuscular versus intravenous ketamine.

Chilukuri H(1), Reddy NP(2), Pathapati RM(3), Manu AN(4), Jollu S(4), Shaik
AB(5).

Author information:
(1)Department of Psychiatry, Malla Reddy Institute of Medical Sciences,
Hyderabad, Andhra Pradesh, India. (2)Department of Anaesthesia, Narayana Medical
College, Nellore, Andhra Pradesh, India. (3)Department of Pharmacology, Narayana
Medical College, Nellore, Andhra Pradesh, India. (4)Department of Psychiatry,
Narayana Medical College, Nellore, Andhra Pradesh, India. (5)Department of
Statistics, Narayana Medical College, Nellore, Andhra Pradesh, India.

OBJECTIVE: Conventional antidepressants take two weeks before their therapeutic
action begins. Recent studies have reported on the rapid antidepressant effect of
ketamine when given as an intravenous (I.V.) infusion. Little is known about its
intramuscular (I.M.) use in depression. Hence this study was conducted to compare
the safety, tolerability and efficacy of I.M. versus. I.V. ketamine in Major
Depression (ICD-10).
MATERIALS AND METHODS: It was a randomized open label parallel group study in a
tertiary care teaching hospital. Study sample consisted of 27 subjects having
major depression divided randomly into three groups of nine subjects each.
Ketamine administered to each group in the dose of 0.5 mg/kg as an I.V. infusion,
as 0.5 mg/kg I.M. or 0.25 mg/kg I.M. respectively. Depression rated on the
Hamilton Depression Rating Scale (HAM-D) before the injection, two hours later,
the next day, and after three days. Data analyzed using the Statistical Package
for Social Sciences (SPSS).
RESULTS: Mean age of the sample was 36.81 years (SD 11.815). Two hours after the
injection, HAM-D fell by 58.86%, 60.29% & 57.36% in each group respectively. The
improvement was sustained for next three days. Adverse effects noticed were rare,
of mild nature and transient, lasting less than an hour.
CONCLUSIONS: Intramuscular ketamine in the dose of 0.25 mg/kg is as effective and
safe as 0.5 mg/kg given either I.M. or I.V., substantially alleviating depressive
symptoms within a few hours and sustained for 3 days.

PMCID: PMC3959024
PMID: 24701015 [PubMed]

219. Psychiatr Pol. 2014 Jan-Feb;48(1):49-58.

[Effectiveness of ketamine in depressed patients resistant to ECT or rTMS
therapy].

[Article in Polish]

Gosek P, Chojnacka M, Bieńkowski P, Swiecicki Ł.

OBJECTIVES: In the last decade several authors described a robust and clinically
relevant alleviation of depressive symptoms after infusions of the uncompetitive
N-methyl-D-aspartate (NMDA) glutamate receptor antagonist - ketamine. In the
majority of published reports ketamine was administrated to patients with
depression resistant to pharmacotherapy, but not to ECT. We present a series of 5
subjects suffering from multimodal treatment-resistant depression (including ECT
or rTMS and various medications) treated with intravenous infusions of ketamine
in a subanesthetic dose of 0.5 mg/kg in the naturalistic setting. To the best of
our knowledge it is the first report on ketamine infusion in patient resistant to
antidepressants and r
TMS METHODS: Two subjects have been diagnosed with MDD, one with BD, two with
severe depressive episode. The efficacy and possible adverse events were
monitored using psychometric scales. Basic life parameters and ECG were observed.
RESULTS: Ketamine's infusions showed transient antidepressant efficacy.
Improvement rate in our group was significant lower than in previously reported.
Ketamine was generally well tolerated. We noted transient BP variations and
appearance of mild and transient dissociative symptoms. Low early response rate
may be correlated with resistance to previous multimodal treatment, high rate of
somatization and anxiety comorbidity or heterogeneity of our group.
CONCLUSIONS: Our findings do not support the use of ketamine infusions as the
monotherapy in the subgroup of patients with multimodal treatment resistant
depression.

PMID: 24946434 [PubMed - indexed for MEDLINE]

221. Front Pharmacol. 2013 Dec 27;4:161. doi: 10.3389/fphar.2013.00161.

Antidepressant effects of ketamine: mechanisms underlying fast-acting novel
antidepressants.

Browne CA(1), Lucki I(2).

Author information:
(1)Department of Psychiatry, University of Pennsylvania Philadelphia, PA, USA.
(2)Department of Psychiatry, University of Pennsylvania Philadelphia, PA, USA ;
Department of Pharmacology, University of Pennsylvania Philadelphia, PA, USA.

Newer antidepressants are needed for the many individuals with major depressive
disorder (MDD) that do not respond adequately to treatment and because of a delay
of weeks before the emergence of therapeutic effects. Recent evidence from
clinical trials shows that the NMDA antagonist ketamine is a revolutionary novel
antidepressant because it acts rapidly and is effective for treatment-resistant
patients. A single infusion of ketamine alleviates depressive symptoms in
treatment-resistant depressed patients within hours and these effects may be
sustained for up to 2 weeks. Although the discovery of ketamine's effects has
reshaped drug discovery for antidepressants, the psychotomimetic properties of
this compound limit the use of this therapy to the most severely ill patients. In
order to develop additional antidepressants like ketamine, adequate preclinical
behavioral screening paradigms for fast-acting antidepressants need to be
established and used to identify the underlying neural mechanisms. This review
examines the preclinical literature attempting to model the antidepressant-like
effects of ketamine. Acute administration of ketamine has produced effects in
behavioral screens for antidepressants like the forced swim test, novelty
suppression of feeding and in rodent models for depression. Protracted behavioral
effects of ketamine have been reported to appear after a single treatment that
last for days. This temporal pattern is similar to its clinical effects and may
serve as a new animal paradigm for rapid antidepressant effects in humans. In
addition, protracted changes in molecules mediating synaptic plasticity have been
implicated in mediating the antidepressant-like behavioral effects of ketamine.
Current preclinical studies are examining compounds with more specific
pharmacological effects at glutamate receptors and synapses in order to develop
additional rapidly acting antidepressants without the hallucinogenic side effects
or abuse potential of ketamine.

PMCID: PMC3873522
PMID: 24409146 [PubMed]

223. Mol Psychiatry. 2013 Dec;18(12):1236-41. doi: 10.1038/mp.2013.87. Epub 2013 Jul
23.

Ketamine: synaptogenesis, immunomodulation and glycogen synthase kinase-3 as
underlying mechanisms of its antidepressant properties.

Zunszain PA(1), Horowitz MA, Cattaneo A, Lupi MM, Pariante CM.

Author information:
(1)Section of Stress, Psychiatry and Immunology, Department of Psychological
Medicine, Institute of Psychiatry, King's College London, London, UK.

Major depressive disorder is an extremely debilitating condition affecting
millions of people worldwide. Nevertheless, currently available antidepressant
medications still have important limitations, such as a low response rate and a
time lag for treatment response that represent a significant problem when dealing
with individuals who are vulnerable and prone to self-harm. Recent clinical
trials have shown that the N-methyl-D-aspartate receptor antagonist, ketamine,
can induce an antidepressant response within hours, which lasts up to 2 weeks,
and is effective even in treatment-resistant patients. Nonetheless, its use is
limited due to its psychotomimetic and addictive properties. Understanding the
molecular pathways through which ketamine exerts its antidepressant effects would
help in the developing of novel antidepressant agents that do not evoke the same
negative side effects of this drug. This review focuses specifically on the
effects of ketamine on three molecular mechanisms that are relevant to
depression: synaptogenesis, immunomodulation and regulation of glycogen synthase
kinase-3 activity.

PMCID: PMC3835937
PMID: 23877835 [PubMed - indexed for MEDLINE]

224. Biol Psychiatry. 2013 Nov 15;74(10):712-3. doi: 10.1016/j.biopsych.2013.08.011.

Scopolamine and ketamine: evidence of convergence?

Monteggia LM(1), Kavalali ET.

Author information:
(1)Department of Neuroscience, University of Texas Southwestern Medical Center,
Dallas, Texas. Electronic address: lisa.monteggia@utsouthwestern.edu.

Comment on
Biol Psychiatry. 2013 Nov 15;74(10):750-9.
Biol Psychiatry. 2012 Oct 1;72(7):537-47.

PMID: 24144324 [PubMed - indexed for MEDLINE]

231. Biol Psychiatry. 2013 Nov 1;74(9):e13-4. doi: 10.1016/j.biopsych.2013.04.019.
Epub 2013 May 23.

Transient resolution of treatment-resistant posttraumatic stress disorder
following ketamine infusion.

D'Andrea D(1), Andrew Sewell R.

Author information:
(1)Bayshore Community Hospital, Holmdel, New Jersey.

PMID: 23706680 [PubMed - indexed for MEDLINE]

232. Psychopharmacology (Berl). 2013 Nov;230(2):291-8. doi: 10.1007/s00213-013-3153-2.
Epub 2013 Jun 4.

Antidepressant effects of AMPA and ketamine combination: role of hippocampal
BDNF, synapsin, and mTOR.

Akinfiresoye L(1), Tizabi Y.

Author information:
(1)Department of Pharmacology, Howard University College of Medicine, 520 W
Street NW, Washington, DC, 20059, USA.

RATIONALE: A number of preclinical and clinical studies suggest that ketamine, a
glutamate N-methyl-D-aspartate receptor antagonist, has a rapid and lasting
antidepressant effect when administered either acutely or chronically. It has
been postulated that this effect is due to stimulation of
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.
OBJECTIVE: In this study, we tested whether AMPA alone has an antidepressant
effect and if the combination of AMPA and ketamine provides added benefit in
Wistar-Kyoto rats, a putative animal model of depression.
RESULTS: Chronic AMPA treatment resulted in a dose-dependent antidepressant
effect in both the forced swim test and sucrose preference test. Moreover,
chronic administration (10-11 days) of combinations of AMPA and ketamine, at
doses that were ineffective on their own, resulted in a significant
antidepressant effect. The behavioral effects were associated with increases in
hippocampal brain-derived neurotrophic factor, synapsin, and mammalian target of
rapamycin.
CONCLUSION: These findings are the first to provide evidence for an
antidepressant effect of AMPA and suggest the usefulness of AMPA-ketamine
combination in treatment of depression. Furthermore, these effects appear to be
associated with increases in markers of hippocampal neurogenesis and
synaptogenesis, suggesting a mechanism of their action.

PMCID: PMC3805670
PMID: 23732839 [PubMed - indexed for MEDLINE]

235. Am J Psychiatry. 2013 Oct;170(10):1079-81. doi: 10.1176/appi.ajp.2013.13081034.

Ketamine for treatment-resistant depression: ready or not for clinical use?

Rush AJ.

Comment on
Am J Psychiatry. 2013 Oct;170(10):1134-42.

PMID: 23982324 [PubMed - indexed for MEDLINE]

236. Am J Psychiatry. 2013 Oct;170(10):1134-42. doi: 10.1176/appi.ajp.2013.13030392.

Antidepressant efficacy of ketamine in treatment-resistant major depression: a
two-site randomized controlled trial.

Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S,
Pillemer S, Foulkes A, Shah A, Charney DS, Mathew SJ.

Comment in
Am J Psychiatry. 2013 Oct;170(10):1079-81.
Am J Psychiatry. 2014 Mar;171(3):262-4.

OBJECTIVE: Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist,
has shown rapid antidepressant effects, but small study groups and inadequate
control conditions in prior studies have precluded a definitive conclusion. The
authors evaluated the rapid antidepressant efficacy of ketamine in a large group
of patients with treatment-resistant major depression.
METHOD: This was a two-site, parallel-arm, randomized controlled trial of a
single infusion of ketamine compared to an active placebo control condition, the
anesthetic midazolam. Patients with treatment-resistant major depression
experiencing a major depressive episode were randomly assigned under double-blind
conditions to receive a single intravenous infusion of ketamine or midazolam in a
2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours
after drug administration, as assessed by the Montgomery-Åsberg Depression Rating
Scale (MADRS).
RESULTS: The ketamine group had greater improvement in the MADRS score than the
midazolam group 24 hours after treatment. After adjustment for baseline scores
and site, the MADRS score was lower in the ketamine group than in the midazolam
group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The
likelihood of response at 24 hours was greater with ketamine than with midazolam
(odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%,
respectively.
CONCLUSIONS: Ketamine demonstrated rapid antidepressant effects in an optimized
study design, further supporting NMDA receptor modulation as a novel mechanism
for accelerated improvement in severe and chronic forms of depression. More
information on response durability and safety is required before implementation
in clinical practice.

PMCID: PMC3992936
PMID: 23982301 [PubMed - indexed for MEDLINE]

237. Int J Neuropsychopharmacol. 2013 Oct;16(9):2111-7. doi:
10.1017/S1461145713000485. Epub 2013 May 20.

Antidepressant, mood stabilizing and procognitive effects of very low dose
sublingual ketamine in refractory unipolar and bipolar depression.

Lara DR(1), Bisol LW, Munari LR.

Author information:
(1)Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.

Intravenous ketamine (0.5 mg/kg) produces robust, rapid and long-lasting
antidepressant effects, but is unpractical. Sublingual administration of ketamine
renders better bioavailability (~30%) and less conversion to norketamine than
oral administration. We evaluated the therapeutic effects and tolerability of
very low dose sublingual (VLDS) racemic ketamine (10 mg from a 100 mg/ml solution
for 5 min and swallowed), repeatedly administered every 2-3 d or weekly, in 26
out-patients with refractory unipolar or bipolar depression. According to
patients' reports, VLDS ketamine produced rapid, clear and sustained effects,
improving mood level and stability, cognition and sleep in 20 patients (77%),
with only mild and transient light-headedness as a common side-effect (no
euphoria, psychotic or dissociative symptoms). Remission remained in some
patients after stopping ketamine. Thus, VLDS ketamine may have broad spectrum
effects beyond its antidepressant properties, with rapid onset of action, high
efficacy, good tolerability and low cost, allowing extended treatment as needed.

PMID: 23683309 [PubMed - indexed for MEDLINE]

238. Neuropsychopharmacology. 2013 Oct;38(11):2268-77. doi: 10.1038/npp.2013.128. Epub
2013 May 17.

GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of
subthreshold doses of ketamine.

Liu RJ(1), Fuchikami M, Dwyer JM, Lepack AE, Duman RS, Aghajanian GK.

Author information:
(1)Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University
School of Medicine, New Haven, CT, USA.

A single dose of the short-acting NMDA antagonist ketamine produces rapid and
prolonged antidepressant effects in treatment-resistant patients with major
depressive disorder (MDD), which are thought to occur via restoration of synaptic
connectivity. However, acute dissociative side effects and eventual fading of
antidepressant effects limit widespread clinical use of ketamine. Recent studies
in medial prefrontal cortex (mPFC) show that the synaptogenic and
antidepressant-like effects of a single standard dose of ketamine in rodents are
dependent upon activation of the mammalian target of rapamycin (mTOR) complex 1
(mTORC1) signaling pathway together with inhibitory phosphorylation of glycogen
synthase kinase-3 (GSK-3), which relieves its inhibitory in influence on mTOR.
Here, we found that the synaptogenic and antidepressant-like effects of a single
otherwise subthreshold dose of ketamine were potentiated when given together with
a single dose of lithium chloride (a nonselective GSK-3 inhibitor) or a
preferential GSK-3β inhibitor; these effects included rapid activation of the
mTORC1 signaling pathway, increased inhibitory phosphorylation of GSK-3β,
increased synaptic spine density/diameter, increased excitatory postsynaptic
currents in mPFC layer V pyramidal neurons, and antidepressant responses that
persist for up to 1 week in the forced-swim test model of depression. The results
demonstrate that low, subthreshold doses of ketamine combined with lithium or a
selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating
the pivotal role of the GSK-3 pathway in modulating the synaptogenic and
antidepressant responses to ketamine. The possible mitigation by GSK-3 inhibitors
of the eventual fading of ketamine's antidepressant effects remains to be
explored.

PMCID: PMC3773678
PMID: 23680942 [PubMed - indexed for MEDLINE]

241. Psychopharmacology (Berl). 2013 Sep 11. [Epub ahead of print]

Neurocognitive effects of ketamine in treatment-resistant major depression:
association with antidepressant response.

Murrough JW(1), Wan LB, Iacoviello B, Collins KA, Solon C, Glicksberg B, Perez
AM, Mathew SJ, Charney DS, Iosifescu DV, Burdick KE.

Author information:
(1)Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of
Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1230, New York, NY,
10029, USA, james.murrough@mssm.edu.

RATIONALE: The N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine
has demonstrated rapid antidepressant effects in patients with
treatment-resistant depression (TRD). Despite the promise of a novel and urgently
needed treatment for refractory depression, concerns regarding potential adverse
neurocognitive effects of ketamine remain.
OBJECTIVES: Although extensive research has been conducted in healthy volunteers,
there is a paucity of studies examining the neurocognitive effects of ketamine in
depressed patients. Therefore, the aims of the current study were to characterize
the relationship between baseline neurocognition and antidepressant response to
ketamine, measure the acute impact of ketamine on neurocognition, and investigate
the relationship between acute neurocognitive effects of ketamine and
antidepressant response.
METHODS: Neurocognitive functioning was assessed in 25 patients with TRD using a
comprehensive battery: estimated premorbid intelligence quotient (IQ), current
IQ, and tests from the MATRICS Consensus Cognitive Battery (MCCB). A subset of
the MCCB was repeated immediately following a 40-min intravenous infusion of
ketamine (0.5 mg/kg).
RESULTS: Patients who responded to ketamine 24 h following treatment had poorer
baseline neurocognitive performance relative to nonresponders and, in particular,
slower processing speed (F = 8.42; df = 23; p = 0.008). Ketamine was associated
with selective impairments in memory recall, and the degree of cognitive change
carried negative prognostic significance (e.g., negative cognitive effects
immediately after ketamine predicted lower response rate at 24 h; Fisher's exact
test two-sided p = 0.027).
CONCLUSIONS: Taken together, our findings suggest a potential baseline
neurocognitive predictor of ketamine response and an inverse relationship between
the cognitive effects of ketamine and antidepressant efficacy.

PMCID: PMC3952038
PMID: 24022236 [PubMed - as supplied by publisher]

242. Ugeskr Laeger. 2013 Sep 9;175(37):2090-3.

[Ketamine for treatment of acute depression].

[Article in Danish]

Hjerrild S(1), Bjerre J, Pedersen RH, Videbech P.

Author information:
(1)Center for Psykiatrisk Forskning, Aarhus Universitetshospital, Risskov,
Skovagervej 2, 8240 Risskov. simon@dadlnet.dk.

Comment in
Ugeskr Laeger. 2013 Sep 9;175(37):2089.

In clinical trials a single dose of the N-methyl-D-aspartate (NMDA) receptor
antagonist ketamine has shown a rapid antidepressant effect in patients with
treatment-resistant depression and bipolar depression. The implications of
glutaminergic mechanisms in depression and the rapid effect of a single dose of
ketamine could open new pathways to understand the pathophysiology of depression
and the development of novel rapid-acting antidepressant drugs.

PMID: 24011203 [PubMed - indexed for MEDLINE]

243. Ugeskr Laeger. 2013 Sep 9;175(37):2089.

[Ketamine for treatment of depression?].

[Article in Danish]

Vinberg M(1).

Author information:
(1)Region Hovedstadens Psykiatri, Psykiatrisk Center København, Kompetencecenter
for Affektive Lidelser, Blegdamsvej 9, 2100 København Ø. maj.vinberg@regionh.dk.

Comment on
Ugeskr Laeger. 2013 Sep 9;175(37):2090-3.

PMID: 24011202 [PubMed - indexed for MEDLINE]

244. Curr Psychiatry Rep. 2013 Sep;15(9):394. doi: 10.1007/s11920-013-0394-z.

Ketamine, sleep, and depression: current status and new questions.

Duncan WC Jr(1), Zarate CA Jr.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health,
Bethesda, MD, USA.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has well-described
rapid antidepressant effects in clinical studies of individuals with
treatment-resistant major depressive disorder (MDD). Preclinical studies
investigating the effects of ketamine on brain-derived neurotrophic factor (BDNF)
and on sleep slow wave activity (SWA) support its use as a prototype for
investigating the neuroplastic mechanisms presumably involved in the mechanism of
rapidly acting antidepressants. This review discusses human EEG slow wave sleep
parameters and plasma BDNF as central and peripheral surrogate markers of
plasticity, and their use in assessing ketamine's effects. Acutely, ketamine
elevates BDNF levels, as well as early night SWA and high-amplitude slow waves;
each of these measures correlates with change in mood in depressed patients who
respond to ketamine. The slow wave effects are limited to the first night
post-infusion, suggesting that their increase is part of an early cascade of
events triggering improved mood. Increased total sleep and decreased waking occur
during the first and second night post infusion, suggesting that these measures
are associated with the enduring treatment response observed with ketamine.

PMCID: PMC3827949
PMID: 23949569 [PubMed - indexed for MEDLINE]

246. J Clin Pharmacol. 2013 Sep;53(9):996-8. doi: 10.1002/jcph.122. Epub 2013 Jul 24.

Repeated S-ketamine infusions in therapy resistant depression: a case series.

Segmiller F(1), Rüther T, Linhardt A, Padberg F, Berger M, Pogarell O, Möller HJ,
Kohler C, Schüle C.

Author information:
(1)Department of Psychiatry and Psychotherapy, Ludwig Maximilian University,
Munich, Germany. felix.segmiller@med.uni-muenchen.deBrief Report

PMID: 23893490 [PubMed - indexed for MEDLINE]

250. Pharmacopsychiatry. 2013 Sep;46(6):227-8. doi: 10.1055/s-0033-1349861. Epub 2013
Jul 11.

Vitamin B12 level may be related to the efficacy of single ketamine infusion in
bipolar depression.

Permoda-Osip A(1), Dorszewska J, Bartkowska-Sniatkowska A, Chlopocka-Wozniak M,
Rybakowski JK.

Author information:
(1)Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan,
Poland.

The single infusion of ketamine, an N-methyl-d-aspartic acid (NMDA) glutamate
receptor antagonist, exerts a therapeutic effect in both unipolar and bipolar
depression. Homocysteine (HCY) acts agonistically on the NMDA receptor,
hyperhomocysteinemia is related to depression, and folic acid and vitamin B12 are
associated with HCY system. We estimated the serum levels of these substances in
20 bipolar depressed patients before ketamine infusion. 10 patients responded
favorably to this procedure, as their score on the Hamilton depression rating
scale, compared to baseline, was reduced by more than 50%, after 7 days. The
vitamin B12 level was significantly higher in "responders" compared to the
remaining patients. No differences between the 2 groups were found with regard to
HCY, folic acid levels and such clinical factors as age, duration of illness and
duration of current episode. These preliminary data suggest that the vitamin B12
level may be connected with the efficacy of ketamine infusion in bipolar
depression.

PMID: 23846402 [PubMed - indexed for MEDLINE]

251. BMJ Case Rep. 2013 Aug 19;2013. pii: bcr2013200370. doi: 10.1136/bcr-2013-200370.

Sustained antidepressant response to ketamine.

Atigari OV(1), Healy D.

Author information:
(1)Department of Psychiatry (Hergest Unit), Ysbyty Gwynedd Hospital, Bangor,
Wales, UK.

Case series outlining the treatment of three patients with ketamine, in which two
of the patients had a sustained antidepressant effect to ketamine without the
need for maintenance on antidepressants. These two responders have an established
diagnosis of bipolar affective disorder with a history of response to
electroconvulsive therapy and lithium, both of which have an influence on the
seizure threshold as has ketamine. The mechanism of action of ketamine is yet
unclear and although the current focus is on the N-methyl-d-aspartate and
alpha-amino-3-4-hydroxy-5methyl-4-isoxazoleproprionic acid receptors, we
additionally recommend that its impact on the seizure threshold should be
explored with a view to fully elucidating the mechanism of action.

PMCID: PMC3762430
PMID: 23960151 [PubMed - indexed for MEDLINE]

252. Biol Psychiatry. 2013 Aug 15;74(4):250-6. doi: 10.1016/j.biopsych.2012.06.022.
Epub 2012 Jul 27.

Rapid and longer-term antidepressant effects of repeated ketamine infusions in
treatment-resistant major depression.

Murrough JW(1), Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, Collins
KA, Mathew SJ, Charney DS, Iosifescu DV.

Author information:
(1)Mood and Anxiety Disorders Program, Department of Psychiatry, Mount Sinai
School of Medicine, New York, NY 10029, USA. james.murrough@mssm.edu

Comment in
Biol Psychiatry. 2013 Aug 15;74(4):238-9.

BACKGROUND: Ketamine is reported to have rapid antidepressant effects; however,
there is limited understanding of the time-course of ketamine effects beyond a
single infusion. A previous report including 10 participants with
treatment-resistant major depression (TRD) found that six ketamine infusions
resulted in a sustained antidepressant effect. In the current report, we examined
the pattern and durability of antidepressant effects of repeated ketamine
infusions in a larger sample, inclusive of the original.
METHODS: Participants with TRD (n = 24) underwent a washout of antidepressant
medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg)
administered open-label three times weekly over a 12-day period. Participants
meeting response criteria were monitored for relapse for up to 83 days from the
last infusion.
RESULTS: The overall response rate at study end was 70.8%. There was a large mean
decrease in Montgomery-Åsberg Depression Rating Scale score at 2 hours after the
first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely
sustained for the duration of the infusion period. Response at study end was
strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among
responders, median time to relapse after the last ketamine infusion was 18 days.
CONCLUSIONS: Ketamine was associated with a rapid antidepressant effect in TRD
that was predictive of a sustained effect. Future controlled studies will be
required to identify strategies to maintain an antidepressant response among
patients who benefit from a course of ketamine.

Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All
rights reserved.

PMCID: PMC3725185
PMID: 22840761 [PubMed - indexed for MEDLINE]

253. Aust N Z J Psychiatry. 2013 Aug;47(8):710-27. doi: 10.1177/0004867413486842. Epub
2013 May 9.

Ketamine as a new treatment for depression: a review of its efficacy and adverse
effects.

Katalinic N(1), Lai R, Somogyi A, Mitchell PB, Glue P, Loo CK.

Author information:
(1)School of Psychiatry, University of New South Wales, Sydney, Australia.

OBJECTIVE: Narrative review of the literature on the efficacy and safety of
subanaesthetic doses of ketamine for the treatment of depression.
METHOD: Medline and PubMed databases were searched up to October 2012 using
appropriate keywords.
RESULTS: The studies consistently report substantial efficacy with high response
and remission rates from 4 to 72 hours (averages 77% and 43%, respectively) from
single doses, though not all patients respond to ketamine. Early relapse is
common. While the usual procedure involves the administration of intravenous
ketamine at a dose of 0.5 mg/kg over 40 minutes, some preliminary evidence
suggests other dosing regimens and routes of administration may be useful or even
better. Repeated doses and maintenance pharmacological treatments have been
investigated in order to prolong the antidepressant effects, with only modest
success.
CONCLUSIONS: Current research on the antidepressant effects of ketamine has
consistently shown rapid and substantial improvement in mood in the majority of
patients. However, these effects have often been found to be short-lived. Future
research should focus on identifying predictors of response (e.g. clinical,
genetic, pharmacokinetic, environmental), examining different dosing regimens and
routes of administration, and strategies to maintain the antidepressant response.

PMID: 23661785 [PubMed - indexed for MEDLINE]

254. CNS Spectr. 2013 Aug;18(4):171-4. doi: 10.1017/S109285291300045X.

Mechanism of action of ketamine.

Stahl SM.

Ketamine induces rapid-onset and short-duration improvement in depressive and
suicidal symptoms in both treatment-resistant unipolar depression and bipolar
depression, and also reduces chronic pain after short intravenous infusions. In
order to develop long-acting oral agents with the same clinical effects, the
pharmacologic mechanism of action must be understood, and the leading hypotheses
are discussed here.

PMID: 23866089 [PubMed - indexed for MEDLINE]

257. Neuropsychopharmacology. 2013 Aug;38(9):1607-8. doi: 10.1038/npp.2013.140.

Conceptual confluence: the kynurenine pathway as a common target for ketamine and
the convergence of the inflammation and glutamate hypotheses of depression.

Miller AH(1).

Author information:
(1)Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, GA 30322, USA. amill02@emory.edu

Comment on
Neuropsychopharmacology. 2013 Aug;38(9):1609-16.

PMCID: PMC3717552
PMID: 23857540 [PubMed - indexed for MEDLINE]

261. J Psychiatr Res. 2013 Jul;47(7):955-65. doi: 10.1016/j.jpsychires.2013.02.015.
Epub 2013 Mar 26.

Ketamine, magnesium and major depression--from pharmacology to pathophysiology
and back.

Murck H(1).

Author information:
(1)Covance Inc., Princeton, USA. haraldmurck@yahoo.de

The glutamatergic mechanism of antidepressant treatments is now in the center of
research to overcome the limitations of monoamine-based approaches. There are
several unresolved issues. For the action of the model compound, ketamine,
NMDA-receptor block, AMPA-receptor activation and BDNF release appear to be
involved in a mechanism, which leads to synaptic sprouting and strengthened
synaptic connections. The link to the pathophysiology of depression is not clear.
An overlooked connection is the role of magnesium, which acts as physiological
NMDA-receptor antagonist: 1. There is overlap between the actions of ketamine
with that of high doses of magnesium in animal models, finally leading to
synaptic sprouting. 2. Magnesium and ketamine lead to synaptic strengthening, as
measured by an increase in slow wave sleep in humans. 3. Pathophysiological
mechanisms, which have been identified as risk factors for depression, lead to a
reduction of (intracellular) magnesium. These are neuroendocrine changes
(increased cortisol and aldosterone) and diabetes mellitus as well as Mg(2+)
deficiency. 4. Patients with therapy refractory depression appear to have lower
CNS Mg(2+) levels in comparison to health controls. 5. Experimental Mg(2+)
depletion leads to depression- and anxiety like behavior in animal models. 6.
Ketamine, directly or indirectly via non-NMDA glutamate receptor activation, acts
to increase brain Mg(2+) levels. Similar effects have been observed with other
classes of antidepressants. 7. Depressed patients with low Mg(2+) levels tend to
be therapy refractory. Accordingly, administration of Mg(2+) either alone or in
combination with standard antidepressants acts synergistically on depression like
behavior in animal models.CONCLUSION: On the basis of the potential
pathophysiological role of Mg(2+)-regulation, it may be possible to predict the
action of ketamine and of related compounds based on Mg(2+) levels. Furthermore,
screening for compounds to increase neuronal Mg(2+) concentration could be a
promising instrument to identify new classes of antidepressants. Overall, any
discussion of the glutamatergic system in affective disorders should consider the
role of Mg(2+).

PMID: 23541145 [PubMed - indexed for MEDLINE]

263. Nervenarzt. 2013 Jul;84(7):854-5. doi: 10.1007/s00115-012-3636-0.

[Ketamine for treatment of therapy-resistant depression: a case study].

[Article in German]

Segmiller F, Frisse D, Eser D, Möller HJ, Rüther T, Schüle C.

PMID: 23143117 [PubMed - indexed for MEDLINE]

266. Biol Psychiatry. 2013 Jun 15;73(12):1133-41. doi: 10.1016/j.biopsych.2013.03.026.

Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond.

Krystal JH(1), Sanacora G, Duman RS.

Author information:
(1)Department of Psychiatry, Yale University School of Medicine, New Haven,
Connecticut, USA. john.krystal@yale.edu

Traditional antidepressants require many weeks to reveal their therapeutic
effects. However, the widely replicated observation that a single subanesthetic
dose of the N-methyl-D-aspartate glutamate receptor antagonist ketamine produced
meaningful clinical improvement within hours, suggested that rapid-acting
antidepressants might be possible. The ketamine studies stimulated a new
generation of basic antidepressant research that identified new neural signaling
mechanisms in antidepressant response and provided a conceptual framework linking
a group of novel antidepressant mechanisms. This article presents the path that
led to the testing of ketamine, considers its promise as an antidepressant, and
reviews novel treatment mechanisms that are emerging from this line of research.

Published by Elsevier Inc.

PMCID: PMC3671489
PMID: 23726151 [PubMed - indexed for MEDLINE]

267. Biol Psychiatry. 2013 Jun 15;73(12):1213-21. doi: 10.1016/j.biopsych.2013.02.008.
Epub 2013 Mar 27.

Neural correlates of rapid antidepressant response to ketamine in
treatment-resistant unipolar depression: a preliminary positron emission
tomography study.

Carlson PJ(1), Diazgranados N, Nugent AC, Ibrahim L, Luckenbaugh DA, Brutsche N,
Herscovitch P, Manji HK, Zarate CA Jr, Drevets WC.

Author information:
(1)Salt Lake City Veterans Affairs Medical Center and Department of Psychiatry,
Salt Lake City, Utah, USA.

BACKGROUND: Multiple lines of evidence support a role for the glutamatergic
system in the pathophysiology of major depressive disorder (MDD). Ketamine, an
N-methyl-D-aspartate antagonist, rapidly improves depressive symptoms in
individuals with treatment-resistant depression. The neural mechanisms underlying
this effect remain unknown.
METHODS: In this preliminary study, 20 unmedicated participants with
treatment-resistant MDD underwent positron emission tomography to measure
regional cerebral glucose metabolism at baseline and following ketamine infusion
(single dose of .5mg/kg intravenous over 40minutes). Metabolic data were compared
between conditions using a combination of region-of-interest and voxelwise
analyses, and differences were correlated with the associated antidepressant
response.
RESULTS: Whole-brain metabolism did not change significantly following ketamine.
Regional metabolism decreased significantly under ketamine in the habenula,
insula, and ventrolateral and dorsolateral prefrontal cortices of the right
hemisphere. Metabolism increased postketamine in bilateral occipital, right
sensorimotor, left parahippocampal, and left inferior parietal cortices.
Improvement in depression ratings correlated directly with change in metabolism
in right superior and middle temporal gyri. Conversely, clinical improvement
correlated inversely with metabolic changes in right parahippocampal gyrus and
temporoparietal cortex.
CONCLUSIONS: Although preliminary, these results indicate that
treatment-resistant MDD subjects showed decreased metabolism in the right
habenula and the extended medial and orbital prefrontal networks in association
with rapid antidepressant response to ketamine. Conversely, metabolism increased
in sensory association cortices, conceivably related to the illusory phenomena
sometimes experienced with ketamine. Further studies are needed to elucidate how
these functional anatomical changes relate to the molecular mechanisms underlying
ketamine's rapid antidepressant effects.

Published by Elsevier Inc.

PMCID: PMC3672258
PMID: 23540908 [PubMed - indexed for MEDLINE]

270. CNS Neurosci Ther. 2013 Jun;19(6):428-36. doi: 10.1111/cns.12103. Epub 2013 Apr
12.

Ketamine as a fast acting antidepressant: current knowledge and open questions.

Salvadore G(1), Singh JB.

Author information:
(1)Janssen Pharmaceuticals LLC, Titusville, NJ 08560, USA. gsalvado@its.jnj.com

Several recent studies have shown that a single intravenous subanesthetic dose of
ketamine, a NMDA receptor antagonist, exerts rapid antidepressant effects in
patients with treatment refractory mood disorders and reduces suicidal ideation.
Those insights have fueled tremendous excitement in the efforts to elucidate the
mechanism underlying ketamine's antidepressant properties in animal models of
depression, as well as in humans through the use of brain imaging as well as
peripheral blood measurements. For example, there is emerging evidence that
ketamine's antidepressant properties rely on increasing AMPA signaling and
rapidly inducing synaptogenesis. While pilot clinical studies are promising, a
number of critical questions still remain unanswered. They relate to the safe and
effective use of ketamine in patients with mood disorders regarding the optimal
dose range, modality and method of administration for acute and long-term
maintenance of effect, and the biomarkers associated with response/nonresponse.
In this review article, we first summarize the clinical evidence about the use of
ketamine in mood disorders, as well as preclinical and humans studies which
investigated the mechanisms of action of ketamine, and predictors of
antidepressant response in clinical populations. We then provide a critical
overview of the knowledge gaps about the use of ketamine in depression and
suggest some future research directions for the investigation of ketamine as a
promising tool to develop novel more effective and fast acting antidepressants.

PMID: 23578128 [PubMed - indexed for MEDLINE]

276. J Affect Disord. 2013 May;147(1-3):416-20. doi: 10.1016/j.jad.2012.10.015. Epub
2012 Nov 22.

A 12-month naturalistic observation of three patients receiving repeat
intravenous ketamine infusions for their treatment-resistant depression.

Szymkowicz SM(1), Finnegan N, Dale RM.

Author information:
(1)Department of Clinical and Health Psychology, University of Florida,
Gainesville, FL 32610, USA.

BACKGROUND: Acute administration of subanesthestic doses of intravenous ketamine
have been shown to elicit a rapid antidepressant response in patients with
treatment-resistant depression. However, it remains to be seen if repeated doses
over a longer period of time will have the same effects. Here, we assess the
long-term efficacy of repeated intravenous ketamine infusions in three patients
with high treatment-resistant depression via a naturalistic observation study.
METHOD: Three patients consented to intravenous ketamine infusions as a therapy
for their treatment-resistant depression. Patients were administered ketamine at
0.5mg/kg of ideal body weight over 40 min followed by a saline flush until
discharge. Severity of depressive symptoms was rated with the Montgomery-Asberg
Depression Rating Scale.
RESULTS: All three patients responded to the ketamine infusions, but each went
through an individualized course of treatment based on their own response.
LIMITATIONS: This was an open-label naturalistic observation without blinding,
randomization, or a placebo control.
CONCLUSIONS: These cases add to the literature supporting the therapeutic effect
of low-dose repeated intravenous ketamine for patients with treatment-resistant
depression. Further study is needed to define the risks, benefits, indications,
and contraindications of this potential treatment.

PMCID: PMC3955270
PMID: 23182590 [PubMed - indexed for MEDLINE]

277. J Clin Psychiatry. 2013 May;74(5):516-7. doi: 10.4088/JCP.13ac08382.

Current status of ketamine and related compounds for depression.

Mathews DC(1), Zarate CA Jr.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health, and
Department of Health and Human Services, Bethesda, MD, USA.

PMCID: PMC3785314
PMID: 23759454 [PubMed - indexed for MEDLINE]

278. J Psychopharmacol. 2013 May;27(5):444-50. doi: 10.1177/0269881113478283. Epub
2013 Feb 20.

Serial infusions of low-dose ketamine for major depression.

Rasmussen KG(1), Lineberry TW, Galardy CW, Kung S, Lapid MI, Palmer BA, Ritter
MJ, Schak KM, Sola CL, Hanson AJ, Frye MA.

Author information:
(1)Department of Psychiatry and Psychology, Mayo Clinic, Rochester, USA.
rasmussen.keith@mayo.edu

BACKGROUND: Single infusions of ketamine have been used successfully to achieve
improvement in depressed patients. Side effects during the infusions have been
common. It is not known whether serial infusions or lower infusion rates result
in greater efficacy.
METHODS: Ten depressed patients were treated with twice weekly ketamine infusions
of ketamine 0.5 mg/kg administered over 100 min until either remission was
achieved or four infusions were given. Side effects were assessed with the Young
Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). Patients
were followed naturalistically at weekly intervals for four weeks after
completion of the infusions.
RESULTS: Five of 10 patients achieved remission status. There were no significant
increases on the BPRS or YMRS. Two of the remitting patients sustained their
improvement throughout the four week follow-up period.
CONCLUSIONS: Ketamine infusions at a lower rate than previously reported have
demonstrated similar efficacy and excellent tolerability and may be more
practically available for routine clinical care. Serial ketamine infusions appear
to be more effective than a single infusion. Further research to test relapse
prevention strategies with continuation ketamine infusions is indicated.

PMID: 23428794 [PubMed - indexed for MEDLINE]

282. Indian J Psychiatry. 2013 Apr;55(2):186-8. doi: 10.4103/0019-5545.111461.

Intramuscular ketamine in acute depression: A report on two cases.

Harihar C(1), Dasari P, Srinivas JS.

Author information:
(1)Department of Psychiatry, Narayana Medical College, Nellore, Andhra Pradesh,
India.

It takes about 2 weeks for the onset of antidepressant action of drugs while
electroconvulsive therapy though faster, is a cumbersome procedure requiring an
anaesthetist and at least a minor operation theatre. Recent studies have shown
that Ketamine, when given to severely depressed patients in the dose of 0.5 mg/kg
as a slow intravenous infusion over 40 minutes, brought about acute relief from
depression and amelioration of suicidal risk within a few hours. The improvement,
however, was transient and lasted for up to a week but could be sustained by
further weekly or biweekly injections. As the dose of ketamine administered was
found to be safe, it was now tried in the intramuscular route in two severely
depressed patients with similar rapid improvement. The cases are reported here
which pave way for an easier mode of treating acute depression.

PMCID: PMC3696246
PMID: 23825857 [PubMed]

283. J Clin Psychopharmacol. 2013 Apr;33(2):270-2. doi: 10.1097/JCP.0b013e3182856865.

Urgent ketamine infusion rapidly eliminated suicidal ideation for a patient with
major depressive disorder: a case report.

Zigman D, Blier P.

PMID: 23422387 [PubMed - indexed for MEDLINE]

287. Int J Neuropsychopharmacol. 2013 Mar;16(2):301-11. doi:
10.1017/S1461145712000545. Epub 2012 Jun 7.

Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity
in major depressive disorder.

Duncan WC(1), Sarasso S, Ferrarelli F, Selter J, Riedner BA, Hejazi NS, Yuan P,
Brutsche N, Manji HK, Tononi G, Zarate CA.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health,
Bethesda, MD, USA.

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid
antidepressant effects in treatment-resistant major depressive disorder (MDD). In
rats, ketamine selectively increased electroencephalogram (EEG) slow wave
activity (SWA) during non-rapid eye movement (REM) sleep and altered central
brain-derived neurotrophic factor (BDNF) expression. Taken together, these
findings suggest that higher SWA and BDNF levels may respectively represent
electrophysiological and molecular correlates of mood improvement following
ketamine treatment. This study investigated the acute effects of a single
ketamine infusion on depressive symptoms, EEG SWA, individual slow wave
parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a
peripheral marker of plasticity) in 30 patients with treatment-resistant MDD.
Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following
ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first
non-REM episode) increased after ketamine. The occurrence of high amplitude waves
increased during early sleep, accompanied by an increase in slow wave slope,
consistent with increased synaptic strength. Changes in BDNF levels were
proportional to changes in EEG parameters. Intriguingly, this link was present
only in patients who responded to ketamine treatment, suggesting that enhanced
synaptic plasticity - as reflected by increased SWA, individual slow wave
parameters and plasma BDNF - is part of the physiological mechanism underlying
the rapid antidepressant effects of NMDA antagonists. Further studies are
required to confirm the link found here between behavioural and synaptic changes,
as well as to test the reliability of these central and peripheral biomarkers of
rapid antidepressant response.

PMCID: PMC3510337
PMID: 22676966 [PubMed - indexed for MEDLINE]

288. J Psychiatry Neurosci. 2013 Mar;38(2):78-83. doi: 10.1503/jpn.120128.

Single treatments that have lasting effects: some thoughts on the antidepressant
effects of ketamine and botulinum toxin and the anxiolytic effect of psilocybin.

Young SN(1).

Author information:
(1)Department of Psychiatry, McGill University, Montréal, Que.
simon.young@mcgill.ca

Comment in
J Psychiatry Neurosci. 2013 Sep;38(5):E29.
J Psychiatry Neurosci. 2013 Sep;38(5):E29.

Recent clinical trials suggest that 3 single biological treatments have effects
that persist. Based on research showing that the muscles involved in facial
expressions can feed back to influence mood, a single trial diminishing glabella
frown lines with botulinum toxin demonstrated a significant antidepressant effect
for 16 weeks. Based primarily on research with animal models of depression
suggesting that glutamate may be involved in depression, the N-methyl-D-aspartate
antagonist ketamine has been tested in several trials. A single dose decreased
depression for up to a week. The reported effects of the use of mushrooms
containing psilocybin by a number of cultures around the world has stimulated
several trials showing beneficial effects of a single dose of psilocybin for over
a year in healthy people, and for up to 3 months in patients with anxiety
disorders who have advanced cancer. This article discusses these studies, their
rationale, their possible mechanisms of action, the future clinical research
required to establish these therapies and the basic research required to optimize
single treatments that have lasting effects.

PMCID: PMC3581595
PMID: 23171696 [PubMed - indexed for MEDLINE]

291. J Affect Disord. 2013 Feb 15;145(1):115-9. doi: 10.1016/j.jad.2012.05.042. Epub
2012 Aug 5.

Baseline delta sleep ratio predicts acute ketamine mood response in major
depressive disorder.

Duncan WC Jr(1), Selter J, Brutsche N, Sarasso S, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics & Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health,
Bethesda, MD, USA.

BACKGROUND: Electroencephalographic (EEG) sleep slow wave activity (SWA; EEG
power between 0.6 and 4Hz) has been proposed as a marker of central synaptic
plasticity. Decreased generation of sleep slow waves--a core feature of sleep in
depression--indicates underlying plasticity changes in the disease. Various
measures of SWA have previously been used to predict antidepressant treatment
response. This study examined the relationship between baseline patterns of SWA
in the first two NREM episodes and antidepressant response to an acute infusion
of the N-methyl-d-aspartate (NMDA) antagonist ketamine.
METHODS: Thirty patients (20M, 10F, 18-65) fulfilling DSM-IV criteria for
treatment-resistant major depressive disorder (MDD) who had been drug-free for
two weeks received a single open-label infusion of ketamine hydrochloride
(.5mg/kg) over 40 min. Depressive symptoms were assessed with the
Montgomery-Asberg Depression Rating Scale (MADRS) before and after ketamine
infusion. Sleep recordings were obtained the night before the infusion and were
visually scored. SWA was computed for individual artifact-free NREM sleep epochs,
and averaged for each NREM episode. Delta sleep ratio (DSR) was calculated as
SWA(NREM1)/SWA(NREM2).
RESULTS: A significant positive correlation was observed between baseline DSR and
reduced MADRS scores from baseline to Day 1 (r=.414, p=.02).
LIMITATIONS: The sample size was relatively small (N=30) and all subjects had
treatment-resistant MDD, which may limit the generalizability of the findings.
Further studies are needed to replicate and extend this observation to other
patient groups.
CONCLUSIONS: DSR may be a useful baseline predictor of ketamine response in
individuals with treatment-resistant MDD.

Published by Elsevier B.V.

PMCID: PMC3494813
PMID: 22871531 [PubMed - indexed for MEDLINE]

294. Rev Esp Anestesiol Reanim. 2013 Feb;60(2):110-3. doi:
10.1016/j.redar.2012.06.004. Epub 2012 Jul 19.

[Effect of sub-anaesthetic doses of ketamine in the postoperative period in a
patient with uncontrolled depression].

[Article in Spanish]

Cortiñas-Saenz M(1), Alonso-Menoyo MB, Errando-Oyonarte CL, Alférez-García I,
Carricondo-Martínez MA.

Author information:
(1)Servicio de Anestesiología y Reanimación, Hospital Torrecárdenas, Almería,
España. stl967523977@wanadoo.es

Recent studies indicate that the intravenous infusion of ketamine hydrochloride
(an N-methyl-D-aspartate receptor antagonist) leads to a rapid reduction in
depressive symptoms. A 42 year-old woman with breast cancer and major depression
resistant to medical treatment received a 90 minute intravenous infusion of 0.3
mg/kg ketamine for 5 consecutive days. A significant reduction from 22 to 13
(-41%) was observed in the symptoms assessed using the Hamilton scale, with the
effect maintained for 14 days. The possible therapeutic mechanism is discussed.

PMID: 22818586 [PubMed - indexed for MEDLINE]

297. J Psychosoc Nurs Ment Health Serv. 2013 Jan;51(1):11-4.

Ketamine for the treatment of depression.

Howland RH(1).

Author information:
(1)University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
HowlandRH@upmc.edu

Ketamine (Ketalar®) is an anesthetic agent derived from the hallucinogenic drug
phencyclidine (PCP). It is a high-affinity antagonist at N-methyl-D-aspartate
receptors and also binds to opioid mu and sigma receptors. Ketamine is being
intensively investigated as an antidepressant therapy. To date, five short-term
controlled studies and other open-label studies in patients with unipolar or
bipolar depression have demonstrated that intravenous ketamine is safe and has a
rapid and profound short-term effect on depressive symptoms, including suicidal
thoughts, even among patients considered treatment-resistant to standard
medications or electroconvulsive therapy. Before ketamine can be incorporated
into clinical practice, however, its long-term safety and effectiveness need to
be evaluated. Although the effectiveness of alternative routes of ketamine
administration (i.e., oral, intranasal, or intramuscular) needs to be determined,
intravenous ketamine could be conceptualized as a clinic-based procedural therapy
for treatment resistant forms of depression.

PMID: 23413455 [PubMed - indexed for MEDLINE]

298. Nat Med. 2013 Jan;19(1):8. doi: 10.1038/nm0113-8.

Rapid antidepressant effects of ketamine ignite drug discovery.

Dolgin E.

PMID: 23295995 [PubMed - indexed for MEDLINE]

304. Biol Psychiatry. 2012 Dec 1;72(11):e27-8. doi: 10.1016/j.biopsych.2012.05.031.
Epub 2012 Jul 6.

Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant
efficacy of ketamine in depressed patients.

Laje G, Lally N, Mathews D, Brutsche N, Chemerinski A, Akula N, Kelmendi B, Simen
A, McMahon FJ, Sanacora G, Zarate C Jr.

PMCID: PMC3786174
PMID: 22771240 [PubMed - indexed for MEDLINE]

306. Am J Psychiatry. 2012 Nov;169(11):1150-6.

Synaptic mechanisms underlying rapid antidepressant action of ketamine.

Kavalali ET(1), Monteggia LM.

Author information:
(1)Department of Neuroscience, University of Texas Southwestern Medical Center,
Dallas, USA. ege.kavalali@utsouthwestern.edu

Comment in
Am J Psychiatry. 2012 Nov;169(11):1137-40.

Recent clinical studies have demonstrated that a single subpsychotomimetic dose
of ketamine, an ionotropic glutamatergic N-methyl-D-aspartate (NMDA) receptor
antagonist, produces a rapid antidepressant response in patients with major
depressive disorder, with effects lasting up to 2 weeks. Despite enthusiasm about
this unexpected efficacy of ketamine, its widespread use as a fast-acting
antidepressant in routine clinical settings is curtailed by its abuse potential
as well as possible psychotomimetic effects. However, the ability of ketamine to
produce a rapid and long-lasting antidepressant response in patients with
depression provides a unique opportunity for investigation of mechanisms that
mediate these clinically relevant behavioral effects. From a mechanistic
perspective, it is easy to imagine how activation of NMDA receptors may trigger
cellular and behavioral responses; it is relatively more difficult, however, to
envision how transient blockade of one of the key pathways for neuronal
communication produces a persistent beneficial effect. The authors discuss recent
work linking ketamine's mechanism of action to homeostatic synaptic plasticity
processes activated after suppression of NMDA-mediated glutamatergic
neurotransmission. They focus on their recent work demonstrating that
ketamine-mediated blockade of NMDA receptors at rest deactivates eukaryotic
elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and
desuppression of rapid dendritic protein translation, including BDNF
(brain-derived neurotrophic factor), which then contributes to synaptic
plasticity mechanisms that mediate longterm effects of the drug. The authors also
explore possible molecular strategies to target spontaneous neurotransmitter
release selectively to help uncover novel presynaptic avenues for the development
of fast-acting antidepressants and possibly psychoactive compounds with
effectiveness against other neuropsychiatric disorders.

PMID: 23534055 [PubMed - indexed for MEDLINE]

308. Biol Psychiatry. 2012 Oct 1;72(7):537-47. doi: 10.1016/j.biopsych.2012.05.003.
Epub 2012 Jun 16.

Ketamine for depression: where do we go from here?

Aan Het Rot M(1), Zarate CA Jr, Charney DS, Mathew SJ.

Author information:
(1)Department of Psychology and School of Behavioral and Cognitive Neuroscience,
University of Groningen, The Netherlands. m.aan.het.rot@rug.nl

Comment in
Biol Psychiatry. 2013 Nov 15;74(10):712-3.

Since publication of the first randomized controlled trial describing rapid
antidepressant effects of ketamine, several reports have confirmed the potential
utility of this dissociative anesthetic medication for treatment of major
depressive episodes, including those associated with bipolar disorder and
resistant to other medications and electroconvulsive therapy. These reports have
generated several questions with respect to who might respond to ketamine, how,
and for how long. To start answering these questions. We used PubMed.gov and
ClinicalTrials.gov to perform a systematic review of all available published data
on the antidepressant effects of ketamine and of all recently completed, ongoing,
and planned studies. To date, 163 patients, primarily with treatment-resistant
depression, have participated in case studies, open-label investigations, or
controlled trials. All controlled trials have used a within-subject, crossover
design with an inactive placebo as the control. Ketamine administration has
usually involved an anaesthesiologist infusing a single, subanesthetic,
intravenous dose, and required hospitalization for at least 24 hours
postinfusion. Response rates in the open-label investigations and controlled
trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70%
at 72 hours postinfusion. Although adverse effects have generally been mild, some
patients have experienced brief changes in blood pressure, heart rate, or
respiratory rate. Risk-benefit analyses support further research of ketamine for
individuals with severe mood disorders. However, given the paucity of randomized
controlled trials, lack of an active placebo, limited data on long-term outcomes,
and potential risks, ketamine administration is not recommended outside of the
hospital setting.

Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All
rights reserved.

PMCID: PMC3438349
PMID: 22705040 [PubMed - indexed for MEDLINE]

309. Biol Psychiatry. 2012 Oct 1;72(7):555-61. doi: 10.1016/j.biopsych.2012.03.029.
Epub 2012 Apr 21.

Synaptic potentiation is critical for rapid antidepressant response to ketamine
in treatment-resistant major depression.

Cornwell BR(1), Salvadore G, Furey M, Marquardt CA, Brutsche NE, Grillon C,
Zarate CA Jr.

Author information:
(1)Section on Neurobiology of Fear and Anxiety, National Institute of Mental
Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
cornwellb@mail.nih.gov

BACKGROUND: Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate
receptor (NMDAR) antagonist, has therapeutic effects within hours in people
suffering from depression suggests that modulating glutamatergic
neurotransmission is a fundamental step in alleviating the debilitating symptoms
of mood disorders. Acutely, ketamine increases extracellular glutamate levels,
neuronal excitability, and spontaneous γ oscillations, but it is unknown whether
these effects are key to the mechanism of antidepressant action of ketamine.
METHODS: Twenty drug-free major depressive disorder patients received a single,
open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg).
Magnetoencephalographic recordings were made approximately 3 days before and
approximately 6.5 hours after the infusion, whereas patients passively received
tactile stimulation to the right and left index fingers and also while they
rested (eyes-closed). Antidepressant response was assessed by percentage change
in Montgomery-Åsberg Depression Rating Scale scores.
RESULTS: Patients with robust improvements in depressive symptoms 230 min after
infusion (responders) exhibited increased cortical excitability within this
antidepressant response window. Specifically, we found that stimulus-evoked
somatosensory cortical responses increase after infusion, relative to
pretreatment responses in responders but not in treatment nonresponders.
Spontaneous somatosensory cortical γ-band activity during rest did not change
within the same timeframe after ketamine in either responders or nonresponders.
CONCLUSIONS: These findings suggest NMDAR antagonism does not lead directly to
increased cortical excitability hours later and thus might not be sufficient for
therapeutic effects of ketamine to take hold. Rather, increased cortical
excitability as depressive symptoms improve is consistent with the hypothesis
that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic
potentiation is central to the antidepressant effect of ketamine.

Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All
rights reserved.

PMCID: PMC3408548
PMID: 22521148 [PubMed - indexed for MEDLINE]

310. Middle East J Anaesthesiol. 2012 Oct;21(6):871-3.

Ketamine infusion as a treatment for major depressive disorder: a new role for
anesthesiologists?

Dilley JD(1), Gentry WB, Golden KJ.

Author information:
(1)Department of Anesthesiology, University of Arkansas for Medical Sciences,
USA. joshuaddilley@gmail.com

PMID: 23634571 [PubMed - indexed for MEDLINE]

311. Int J Neuropsychopharmacol. 2012 Sep;15(8):1063-72. doi:
10.1017/S1461145711001593. Epub 2011 Nov 1.

An investigation of amino-acid neurotransmitters as potential predictors of
clinical improvement to ketamine in depression.

Salvadore G(1), van der Veen JW, Zhang Y, Marenco S, Machado-Vieira R, Baumann J,
Ibrahim LA, Luckenbaugh DA, Shen J, Drevets WC, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Division of Intramural
Research Program, National Institute of Mental Health, National Institutes of
Health, Bethesda, MD, USA.

Amino-acid neurotransmitter system dysfunction plays a major role in the
pathophysiology of major depressive disorder (MDD). We used proton magnetic
resonance spectroscopy (¹H-MRS) to investigate whether prefrontal levels of
amino-acid neurotransmitters predict antidepressant response to a single
intravenous infusion of the N-methyl-D-aspartate (NMDA) antagonist ketamine in
MDD patients. Fourteen drug-free patients with MDD were scanned 1-3 d before
receiving a single intravenous infusion of ketamine (0.5 mg/kg). We measured
gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate ratio (a surrogate
marker of glutamine) in the ventromedial prefrontal cortex (VM-PFC) and the
dorsomedial/dorsal anterolateral prefrontal cortex (DM/DA-PFC). Correlation
analyses were conducted to determine whether pretreatment GABA, glutamate, or
Glx/glutamate ratio predicted change in depressive and anxiety symptoms 230 min
after ketamine administration. Pretreatment GABA or glutamate did not correlate
with improved depressive symptoms in either of the two regions of interest
(p>0.1); pretreatment Glx/glutamate ratio in the DM/DA-PFC was negatively
correlated with improvement in depressive symptoms [r s(11)=-0.57, p<0.05].
Pretreatment glutamate levels in the VM-PFC were positively correlated with
improvement in anxiety symptoms [r s(11)=0.57, p<0.05]. The findings suggest an
association between lower Glx/glutamate ratio and greater improvement in response
to ketamine treatment. Because glutamine is mainly contained in glia, the
decreased Glx/glutamate ratio observed in this study may reflect the reduction in
glial cells found in the same regions in post-mortem studies of individuals with
MDD, and suggests that the presence of this neuropathological construct may be
associated with antidepressant responsiveness to ketamine.

PMCID: PMC3342437
PMID: 22040773 [PubMed - indexed for MEDLINE]

312. Int J Pharm Compd. 2012 Sep-Oct;16(5):364-8.

Compounded oral ketamine.

McNulty JP(1), Hahn K.

Author information:
(1)Hospice of St. Tammany, Covington, Louisiana, USA.

The nonnarcotic nonaddictive neuropathic pain reliever ketamine, which was
synthesized in the early 1960s by Parke-Davis, was first administered to human
patients in 1965. Used by the U. S. military as a field anesthetic during the
Vietnam War, it slowly became popular as both an induction and maintenance agent
for the general anesthesia required during brief surgical procedures. The use of
ketamine in the past has been limited primarily to intravenous administration in
hospitalized patients. Very recently, several published reports have described
the use of low-dose ketamine for the relief of pain, refractory depression, and
anxiety in patients with or without cancer. Because chronic pain, depression, and
anxiety often occur in hospice patients with or without cancer and in palliative
care patients who are not eligible for hospice, the discovery of new and
effective uses for an established drug to treat those conditions has excited
interest in the palliative care community. We support that interest with this
case report, which describes our experience in treating a 44-year-old male
hospice patient with severe constant anxiety, fear, and depression in addition to
multiple near-terminal comorbid physical conditions that produce chronic pain.
Prior treatments prescribed to resolve this patient's pain, anxiety, and
depression had proven ineffective. However, a single low-dose (0.5 mg/kg)
subcutaneous test injection of ketamine provided dramatic relief from those
symptoms for 80 hours, although the anesthetic effects of that drug are not of
long duration. This good outcome has been sustained to date by daily treatment
with a compounded flavored oral ketamine solution (40 mg/5 mL) that is not
commercially available. Flavoring the solution masks the bitter taste of ketamine
and renders the treatment palatable. We found ketamine to be a well-tolerated and
effective treatment for the triad of severe anxiety, chronic pain, and severe
depression in a hospice patient with multiple comorbid conditions. To our
knowledge, this report chronicles the first use of compounded oral ketamine for
home-based palliative or hospice care in Louisiana. A formulation for a flavored
oral ketamine solution is provided for easy reference.

PMID: 23072195 [PubMed - indexed for MEDLINE]

313. J ECT. 2012 Sep;28(3):157-61. doi: 10.1097/YCT.0b013e31824f8296.

Rapid antidepressant effect of ketamine in the electroconvulsive therapy setting.

Abdallah CG(1), Fasula M, Kelmendi B, Sanacora G, Ostroff R.

Author information:
(1)Department of Psychiatry and the Ribicoff Research Facilities, Yale University
School of Medicine, New Haven, CT, USA.

OBJECTIVES: Studies now provide strong evidence that the N-methyl-D-aspartate
receptor antagonist ketamine possesses rapidly acting antidepressant properties.
This study aimed to determine if a low dose of ketamine could be used to expedite
and augment the antidepressant effects of electroconvulsive therapy (ECT)
treatments in patients experiencing a severe depressive episode.
MATERIALS AND METHODS: Subjects with major depressive disorder or bipolar
disorder referred for ECT treatment of a major depressive episode were randomized
to receive thiopental alone or thiopental plus ketamine (0.5 mg/kg) for
anesthesia before each ECT session. The Hamilton Depression Rating Scale (HDRS)
was administered at baseline and at 24 to 72 hours after the first and sixth ECT
sessions.
RESULTS: Electroconvulsive therapy exerted a significant antidepressant effect in
both groups (F2,24 = 14.35, P < 0.001). However, there was no significant group
effect or group-by-time interaction on HDRS scores. In addition, post hoc
analyses of the time effect on HDRS showed no significant HDRS reduction after
the first ECT session for either group.
CONCLUSIONS: The results of this pilot study suggest that ketamine, at a dose of
0.5 mg/kg, given just before ECT, did not enhance the antidepressant effect of
ECT. Interestingly, the results further suggest that the coadministration of
ketamine with a barbiturate anesthetic and ECT may attenuate the immediate
antidepressant effects of the N-methyl-D-aspartate antagonist.

PMCID: PMC3426617
PMID: 22847373 [PubMed - indexed for MEDLINE]

314. Med Sci Monit. 2012 Sep;18(9):CR575-80.

315. Biol Psychiatry. 2012 Aug 15;72(4):e11-2. doi: 10.1016/j.biopsych.2012.02.039.
Epub 2012 Apr 12.

On the safety and benefits of repeated intravenous injections of ketamine for
depression.

Blier P, Zigman D, Blier J.

PMID: 22502989 [PubMed - indexed for MEDLINE]

319. Drugs Today (Barc). 2012 Jul;48(7):469-78. doi: 10.1358/dot.2012.48.7.1832873.

Glutamatergic approaches in major depressive disorder: focus on ketamine,
memantine and riluzole.

Owen RT(1).

Author information:
(1)scientific.prousjournals@thomsonreuters.com

The role of glutamate in modulating various mood states is being increasingly
recognized and researched. Existing antidepressants have been shown to exert
effects on various glutamatergic mechanisms, even if such agents are
traditionally classified as working via other mechanisms, such as selective
serotonin reuptake inhibitors. The NMDA receptor antagonist ketamine has been
investigated in various mood disorders, especially major depressive disorder
(MDD). It was found to produce a rapid, robust and persistent antidepressant
effect. Although it can produce cognitive, dissociative and perceptual
disturbances, these tend to be transient and do not outlast the antidepressant
effect. Trials with memantine and riluzole, agents with actions broadly similar
to and different from ketamine on the glutamatergic system, are also reviewed in
MDD and prospects for future research in the area are discussed. Although
preclinical studies are discussed, the main focus of the review is on clinical
outcomes.

PMID: 22844658 [PubMed - indexed for MEDLINE]

325. Neuropsychopharmacology. 2012 May;37(6):1526-33. doi: 10.1038/npp.2011.338. Epub
2012 Feb 1.

Course of improvement in depressive symptoms to a single intravenous infusion of
ketamine vs add-on riluzole: results from a 4-week, double-blind,
placebo-controlled study.

Ibrahim L(1), Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID, Kronstein
P, Moaddel R, Wainer I, Luckenbaugh DA, Manji HK, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Division of Intramural
Research Programs, National Institute of Mental Health-NIMH, National Institutes
of Health-NIH, Bethesda, MD, USA.

The N-methyl-D-aspartate antagonist ketamine has rapid antidepressant effects in
patients with treatment-resistant major depression (TRD); these effects have been
reported to last for 1 week in some patients. However, the extent and duration of
this antidepressant effect over longer periods has not been well characterized
under controlled conditions. Riluzole, a glutamatergic modulator with
antidepressant and synaptic plasticity-enhancing effects, could conceivably be
used to promote the antidepressant effects of ketamine. This study sought to
determine the extent and time course of antidepressant improvement to a
single-ketamine infusion over 4 weeks, comparing the addition of riluzole vs
placebo after the infusion. Forty-two subjects (18-65) with TRD and a
Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥ 22 received a single
intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion,
subjects were randomized to double-blind treatment with either riluzole
(100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were
rated daily. A significant improvement (P<0.001) in MADRS scores from baseline
was found. The effect size of improvement with ketamine was initially large and
remained moderate throughout the 28-day trial. Overall, 27% of ketamine
responders had not relapsed by 4 weeks following a single ketamine infusion. The
average time to relapse was 13.2 days (SE=2.2). However, the difference between
the riluzole and placebo treatment groups was not significant, suggesting that
the combination of riluzole with ketamine treatment did not significantly alter
the course of antidepressant response to ketamine alone.

PMCID: PMC3327857
PMID: 22298121 [PubMed - indexed for MEDLINE]

326. Indian J Psychol Med. 2012 Apr;34(2):170-5. doi: 10.4103/0253-7176.101793.

Rapid response with ketamine on suicidal cognition in resistant depression.

Thakurta RG(1), Das R, Bhattacharya AK, Saha D, Sen S, Singh OP, Bisui B.

Author information:
(1)Department of Psychiatry, Burdwan Medical College and Hospital, Burdwan, West
Bengal, India.

CONTEXT: Suicidal ideation in depressed patients is a serious and emergent
condition that requires urgent intervention. Intravenous ketamine, an
N-methyl-D-aspartate (NMDA) antagonist, has shown rapid antidepressant effects,
making it a potentially attractive candidate for depressed patients with suicidal
risk.
AIMS: In India few studies have corroborated such findings; the present study
aimed to assess the effectiveness and sustainability of antisuicidal effects of
ketamine in subjects with resistant depression.
SETTINGS AND DESIGN: Single-center, prospective, 4 weeks, open-label, single-arm
pilot study.
MATERIALS AND METHODS: Twenty-seven subjects with DSM-IV major depression
(treatment resistant) were recruited. The subjects were assessed on Scale for
Suicidal Ideation (SSI), 17-item Hamilton Depression Rating Scale (HDRS). After a
2-week drug-free period, subjects were given a single intravenous infusion of
ketamine hydrochloride (0.5 mg/kg) and were rated at baseline and at 40, 80, 120,
and 230 minutes and 1 and 2 days postinfusion.
RESULTS: The ketamine infusion was effective in reducing the SSI and HDRS scores,
the change remained significant from minute 40 to 230 at each time point.
CONCLUSIONS: The real strength of this study rests in documenting the rapid
albeit short-lasting effect of ketamine on suicidal ideation in depressed
patients.

PMCID: PMC3498782
PMID: 23162195 [PubMed]

329. CNS Drugs. 2012 Mar 1;26(3):189-204. doi: 10.2165/11599770-000000000-00000.

Ketamine for treatment-resistant unipolar depression: current evidence.

Mathew SJ(1), Shah A, Lapidus K, Clark C, Jarun N, Ostermeyer B, Murrough JW.

Author information:
(1)Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine,
Houston, TX, USA. sjmathew@bcm.edu

Currently available drugs for unipolar major depressive disorder (MDD), which
target monoaminergic systems, have a delayed onset of action and significant
limitations in efficacy. Antidepressants with primary pharmacological targets
outside the monoamine system may offer the potential for more rapid activity with
improved therapeutic benefit. The glutamate system has been scrutinized as a
target for antidepressant drug discovery. The purpose of this article is to
review emerging literature on the potential rapid-onset antidepressant properties
of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic
agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed,
followed by examples of its clinical application in chronic, refractory pain
conditions, which are commonly co-morbid with depression. The first generation of
studies in patients with treatment-resistant depression (TRD) reported the safety
and acute efficacy of a single subanaesthetic dose (0.5 mg/kg) of intravenous
ketamine. A second generation of ketamine studies is focused on testing alternate
routes of drug delivery, identifying methods to prevent relapse following
resolution of depressive symptoms and understanding the neural basis for the
putative antidepressant actions of ketamine. In addition to traditional
depression rating endpoints, ongoing research is examining the impact of ketamine
on neurocognition. Although the first clinical report in MDD was published in
2000, there is a paucity of adequately controlled double-blind trials, and
limited clinical experience outside of research settings. Given the potential
risks of ketamine, safety considerations will ultimately determine whether this
old drug is successfully repositioned as a new therapy for TRD.

PMCID: PMC3677048
PMID: 22303887 [PubMed - indexed for MEDLINE]

331. Psychiatr Pol. 2012 Mar-Apr;46(2):283-94.

[Antidepressant effect of ketamine, a N-methyl-D-aspartate (NMDA) glutamate
receptor antagonist, in the therapy of treatment-resistant depression].

[Article in Polish]

Gosek P(1), Chojnacka M, Bieńkowski P, Swiecicki Ł.

Author information:
(1)II Klinika Psychiatryczna IPiN w Warszawie.

Clinical practice and data from literature indicate that up to 30% of the
patients suffering from depression meet criteria for treatment-resistant
depression. In the past decade, interest in the use of NMDA receptor modulators
in the treatment of treatment-resistant depression is increasing. The use of
ketamine--an noncompetitive antagonist of the NMDA receptors, allows some
patients suffering from treatment resistant depression to achieve rapid and
significant improvement. The authors reviewed results of clinical studies, series
of cases and case reports on the use of ketamine. Most of the patient suffered
from the treatment-resistant major depression. Neurobiological basis of the
glutaminergic pathways and the postulated role of glutamate in mood modulation
have been described, as well as possible adverse events associated with ketamine
infusion. Concerns relate to the optimal dosage, frequency of administration,
long-term safety and efficacy of the therapy. Interesting results of the
published articles encourage further studies on therapeutic use of NMDA receptor
modulators in the treatment of treatment-resistant depression.

PMID: 23214398 [PubMed - indexed for MEDLINE]

335. Clin Pharmacol Ther. 2012 Feb;91(2):303-9. doi: 10.1038/clpt.2011.244. Epub 2011
Dec 28.

Ketamine as a novel antidepressant: from synapse to behavior.

Murrough JW(1).

Author information:
(1)Mood and Anxiety Disorders Program, Department of Psychiatry, Mount Sinai
School of Medicine, New York, New York, USA. james.murrough@mssm.edu

Recent reports of a rapid antidepressant effect of the glutamate
N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, even in
treatment-resistant populations, have spurred translational therapeutic and
neuroscience research aimed at elucidating ketamine's mechanism of action. This
article provides a concise overview of research findings that pertain to the
effects of low-dose ketamine at the cellular, neurocircuitry, and behavioral
levels and describes an integrated model of the action of ketamine in the
treatment of depression.

PMCID: PMC3673880
PMID: 22205190 [PubMed - indexed for MEDLINE]

336. Ann Pharmacother. 2012 Jan;46(1):117-23. doi: 10.1345/aph.1Q371. Epub 2011 Dec
20.

Intravenous ketamine for treatment-resistant major depressive disorder.

Covvey JR(1), Crawford AN, Lowe DK.

Author information:
(1)PGY1 Pharmacy Practice Resident, Virginia Commonwealth University Health
System, Richmond, VA, USA.

OBJECTIVE: To evaluate the literature regarding the efficacy and safety of
intravenous ketamine for treatment-resistant major depressive disorder (MDD).
DATA SOURCES: A MEDLINE search (1966-September 2011) was performed using the
terms treatment-resistant depression and ketamine. The search was restricted to
articles published in English and reporting on use of ketamine in humans.
STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified
from the data search were evaluated. Data were eligible for inclusion if they
were primary literature and evaluated the efficacy of ketamine for depressive
symptoms in treatment-resistant MDD. One case report, 3 case series, 3 open-label
trials, and 1 randomized crossover trial were included.
DATA SYNTHESIS: Several medications are available for treatment-resistant MDD;
however, they are often limited by a slow onset of therapeutic effect and
tolerability. It has been suggested that ketamine, a rapid-acting,
N-methyl-D-aspartate glutamate receptor antagonist, may have antidepressant
effects. Case reports, case series, and select trials evaluating ketamine use for
depressive symptoms in treatment-resistant MDD have demonstrated a rapid effect
for reductions of scores on a number of depression scales; however, its
sustainability effect remains unknown. Several studies reported a large or
moderate to large effect size for ketamine. Additionally, these studies showed
that ketamine use in this patient population is associated with relatively
well-tolerated adverse effects.
CONCLUSIONS: Ketamine for treatment-resistant MDD requires further evaluation
before it can be considered a viable treatment option.

PMID: 22190250 [PubMed - indexed for MEDLINE]

337. Indian J Psychol Med. 2012 Jan;34(1):56-60. doi: 10.4103/0253-7176.96161.

Rapid Antidepressant Response with Ketamine: Is it the Solution to Resistant
Depression?

Thakurta RG(1), Ray P, Kanji D, Das R, Bisui B, Singh OP.

Author information:
(1)Department of Psychiatry, Burdwan Medical College and Hospital, Burdwan, West
Bengal, India.

BACKGROUND: Treatment-resistant depression (TRD) is a relatively common
condition, challenging the clinician. There is an urgent need to develop
pharmacological treatments for TRD that exert rapid and sustained antidepressant
effects. Ketamine induces a rapid antidepressant effect.
AIMS: In India, very few studies have corroborated such findings, and the present
study aimed to assess the effectiveness and sustainability of antidepressant
effects of ketamine in subjects with TRD.
MATERIALS AND METHODS: The present study was a single-center, prospective,
4-week, open-label, single-arm pilot study. Twenty-two subjects with Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition major depression
(treatment resistant) were recruited. After a 2-week drug-free period, subjects
were given a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg)
and were rated at baseline and at 40, 80, 110, and 230 min and 1, 2, 3, 4, 7, and
14 days postinfusion. The main outcome measure was changes in scores on the
17-item Hamilton Depression Rating Scale (HDRS). Data were analyzed by using
Freidman's analysis of variance and a post hoc test.
RESULTS: The ketamine infusion was effective in reducing the HDRS scores, and the
change remained significant from minute 80 to day 3 postinfusion at each time
point. The change was not significant at any time after day 3.
CONCLUSION: The real strength of this study rests in documenting the rapid,
albeit short-lived, antidepressant effect of ketamine in TRD.

PMCID: PMC3361845
PMID: 22661809 [PubMed]

338. Neuropharmacology. 2012 Jan;62(1):35-41. doi: 10.1016/j.neuropharm.2011.08.044.
Epub 2011 Sep 2.

Signaling pathways underlying the rapid antidepressant actions of ketamine.

Duman RS(1), Li N, Liu RJ, Duric V, Aghajanian G.

Author information:
(1)Departments of Psychiatry and Neurobiology, Yale University School of
Medicine, 34 Park Street, New Haven, CT 06508, USA. ronald.duman@yale.edu

Currently available medications have significant limitations, most notably low
response rate and time lag for treatment response. Recent clinical studies have
demonstrated that ketamine, an NMDA receptor antagonist produces a rapid
antidepressant response (within hours) and is effective in treatment resistant
depressed patients. Molecular and cellular studies in rodent models demonstrate
that ketamine rapidly increases synaptogenesis, including increased density and
function of spine synapses, in the prefrontal cortex (PFC). Ketamine also
produces rapid antidepressant actions in behavioral models of depression, and
reverses the deficits in synapse number and behavior resulting from chronic
stress exposure. These effects of ketamine are accompanied by stimulation of the
mammalian target of rapamycin (mTOR), and increased levels of synaptic proteins.
Together these studies indicate that ketamine rapidly reverses the atrophy of
spines in the PFC and thereby causes a functional reconnection of neurons that
underlies the rapid behavioral responses. These findings identify new targets for
rapid acting antidepressants that are safer than ketamine. This article is part
of a Special Issue entitled 'Anxiety and Depression'.

PMCID: PMC3195863
PMID: 21907221 [PubMed - indexed for MEDLINE]

340. Neurotoxicology. 2012 Jan;33(1):70-7. doi: 10.1016/j.neuro.2011.11.001. Epub 2011
Dec 2.

Mapping the central effects of chronic ketamine administration in an adolescent
primate model by functional magnetic resonance imaging (fMRI).

Yu H(1), Li Q, Wang D, Shi L, Lu G, Sun L, Wang L, Zhu W, Mak YT, Wong N, Wang Y,
Pan F, Yew DT.

Author information:
(1)Department of Medical Psychology, Shandong University School of Medicine,
Jinan, Shandong 250012, PR China.

Ketamine, a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist,
is capable of triggering excessive glutamate release and subsequent cortical
excitation which may induce psychosis-like behavior and cognitive anomalies.
Growing evidence suggests that acute ketamine administration can provoke
dose-dependent positive and negative schizophrenia-like symptoms. While the acute
effects of ketamine are primarily linked to aberrant activation of the prefrontal
cortex and limbic structures with elevated glutamate and dopamine levels, the
long-term effects of ketamine on brain functions and neurochemical homeostasis
remain incompletely understood. In recent years, reports of ketamine abuse,
especially among young individuals, have surged rapidly, with profound
socioeconomic and health impacts. We herein investigated the chronic effects of
ketamine on brain function integrity in an animal model of adolescent cynomolgus
monkeys (Macaca fascicularis) by functional magnetic resonance imaging (fMRI).
Immunohistochemical study was also conducted to examine neurochemical changes in
the dopaminergic and cholinergic systems in the prefrontal cortex following
chronic ketamine administration. Our results suggest that repeated exposure to
ketamine markedly reduced neural activities in the ventral tegmental area,
substantia nigra in midbrain, posterior cingulate cortex, and visual cortex in
ketamine-challenged monkeys. In contrast, hyperfunction was observed in the
striatum and entorhinal cortex. In terms of neurochemical and locomotive changes,
chronically ketamine-challenged animals were found to have reduced tyrosine
hydroxylase (TH) but not choline acetyltransferase (ChAT) levels in the
prefrontal cortex, which was accompanied by diminished total movement compared
with the controls. Importantly, the mesolimbic, mesocortical and
entorhinal-striatal systems were found to be functionally vulnerable to
ketamine's chronic effects. Dysfunctions of these neural circuits have been
implicated in several neuropsychiatric disorders including depression,
schizophrenia and attention deficit disorder (ADD). Collectively, our results
support the proposition that repeated ketamine exposure can be exploited as a
pharmacological paradigm for studying the central effects of ketamine relevant to
neuropsychiatric disorders.

PMID: 22178134 [PubMed - indexed for MEDLINE]

341. PLoS One. 2012;7(9):e44799. doi: 10.1371/journal.pone.0044799. Epub 2012 Sep 24.

Ketamine decreases resting state functional network connectivity in healthy
subjects: implications for antidepressant drug action.

Scheidegger M(1), Walter M, Lehmann M, Metzger C, Grimm S, Boeker H, Boesiger P,
Henning A, Seifritz E.

Author information:
(1)Institute for Biomedical Engineering, University and ETH Zurich, Zurich,
Switzerland. scheidegger@biomed.ee.ethz.ch

Increasing preclinical and clinical evidence underscores the strong and rapid
antidepressant properties of the glutamate-modulating NMDA receptor antagonist
ketamine. Targeting the glutamatergic system might thus provide a novel molecular
strategy for antidepressant treatment. Since glutamate is the most abundant and
major excitatory neurotransmitter in the brain, pathophysiological changes in
glutamatergic signaling are likely to affect neurobehavioral plasticity,
information processing and large-scale changes in functional brain connectivity
underlying certain symptoms of major depressive disorder. Using resting state
functional magnetic resonance imaging (rsfMRI), the "dorsal nexus "(DN) was
recently identified as a bilateral dorsal medial prefrontal cortex region showing
dramatically increased depression-associated functional connectivity with large
portions of a cognitive control network (CCN), the default mode network (DMN),
and a rostral affective network (AN). Hence, Sheline and colleagues (2010)
proposed that reducing increased connectivity of the DN might play a critical
role in reducing depression symptomatology and thus represent a potential therapy
target for affective disorders. Here, using a randomized, placebo-controlled,
double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that
ketamine decreases functional connectivity of the DMN to the DN and to the
pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its
representative hub, the posterior cingulate cortex (PCC). These findings in
healthy subjects may serve as a model to elucidate potential biomechanisms that
are addressed by successful treatment of major depression. This notion is further
supported by the temporal overlap of our observation of subacute functional
network modulation after 24 hours with the peak of efficacy following an
intravenous ketamine administration in treatment-resistant depression.

PMCID: PMC3461985
PMID: 23049758 [PubMed - indexed for MEDLINE]

346. Expert Opin Ther Targets. 2011 Dec;15(12):1423-4. doi:
10.1517/14728222.2011.641380. Epub 2011 Nov 30.

Ketamine may exert antidepressant effects via mediating the kynurenine pathway.

Yang C, Zhou Z, Shi J, Yang J.

Comment on
Expert Opin Ther Targets. 2011 Apr;15(4):379-400.

PMID: 22126323 [PubMed - indexed for MEDLINE]

351. Anesthesiology. 2011 Oct;115(4):687-8. doi: 10.1097/ALN.0b013e31822ec185.

Depression and pain: does ketamine improve the quality of life of patients in
chronic pain by targeting their mood?

Romero-Sandoval EA.

Comment on
Anesthesiology. 2011 Oct;115(4):812-21.

PMID: 21841467 [PubMed - indexed for MEDLINE]

353. Int J Neuropsychopharmacol. 2011 Sep;14(8):1127-31. doi:
10.1017/S1461145711000629. Epub 2011 May 5.

A preliminary naturalistic study of low-dose ketamine for depression and suicide
ideation in the emergency department.

Larkin GL(1), Beautrais AL.

Author information:
(1)Department of Emergency Medicine, Yale University School of Medicine, New
Haven, CT, USA. gregor.larkin@gmail.com

We examined the preliminary feasibility, tolerability and efficacy of
single-dose, intravenous (i.v.) ketamine in depressed emergency department (ED)
patients with suicide ideation (SI). Fourteen depressed ED patients with SI
received a single i.v. bolus of ketamine (0.2 mg/kg) over 1-2 min. Patients were
monitored for 4 h, then re-contacted daily for 10 d. Treatment response and time
to remission were evaluated using the Montgomery-Asberg Depression Rating Scale
(MADRS) and Kaplan-Meier survival analysis, respectively. Mean MADRS scores fell
significantly from 40.4 (s.e.m.=1.8) at baseline to 11.5 (s.e.m.=2.2) at 240 min.
Median time to MADRS score ≤10 was 80 min (interquartile range 0.67-24 h). SI
scores (MADRS item 10) decreased significantly from 3.9 (s.e.m.=0.4) at baseline
to 0.6 (s.e.m. =0.2) after 40 min post-administration; SI improvements were
sustained over 10 d. These data provide preliminary, open-label support for the
feasibility and efficacy of ketamine as a rapid-onset antidepressant in the ED.

PMID: 21557878 [PubMed - indexed for MEDLINE]

355. Biol Psychiatry. 2011 Aug 15;70(4):e9-10; author reply e11-2. doi:
10.1016/j.biopsych.2010.11.031. Epub 2011 Apr 8.

Dose- and exposure-response to ketamine in depression.

Glue P, Gulati A, Le Nedelec M, Duffull S.

Comment on
Biol Psychiatry. 2010 Jan 15;67(2):139-45.

PMID: 21481846 [PubMed - indexed for MEDLINE]

366. J Clin Psychiatry. 2011 Mar;72(3):414-5. doi: 10.4088/JCP.10l06447blu.

A case of sustained remission following an acute course of ketamine in
treatment-resistant depression.

Murrough JW, Perez AM, Mathew SJ, Charney DS.

Comment in
J Clin Psychiatry. 2011 Mar;72(3):414.

PMID: 21450159 [PubMed - indexed for MEDLINE]

367. Psychiatry Res. 2011 Feb 28;191(2):122-7. doi: 10.1016/j.pscychresns.2010.10.009.
Epub 2011 Jan 12.

The antidepressant effect of ketamine is not associated with changes in occipital
amino acid neurotransmitter content as measured by [(1)H]-MRS.

Valentine GW(1), Mason GF, Gomez R, Fasula M, Watzl J, Pittman B, Krystal JH,
Sanacora G.

Author information:
(1)Department of Psychiatry, Yale University School of Medicine, New Haven, CT,
USA.

The NMDA receptor antagonist ketamine can induce a rapid improvement in
depressive symptoms that often endures for days after a single intravenous dose.
The pharmacodynamic basis for this effect is poorly understood. Using a proton
magnetic resonance spectroscopy ([(1)H]-MRS) method that previously detected a
normalization of amino acid neurotransmitter (AANt) content after chronic
treatment with conventional antidepressant treatments, we examined whether the
acute action of ketamine is associated with alterations in AANt content as well.
Ten subjects with major depressive disorder (MDD) received saline, then ketamine
in a fixed order, one week apart, under single-blind conditions. Each infusion
was associated with three [(1)H] MRS scans (baseline, 3h and 48 h post-infusion)
that measured glutamate, GABA and glutamine within the occipital cortex. Rating
scales were administered before, during and after each infusion. The rapid (1h)
and sustained (at least 7 days) antidepressant effect we observed after ketamine
infusion was not associated with either baseline measures of, or changes in,
occipital AANt content. Dissociative symptoms were not correlated with changes in
depression scores. While our results indicate that changes in occipital AANt
content are not a correlate of ketamine's antidepressant action, this may only
apply to the regional and temporal windows of our MRS measurements.

PMCID: PMC3061550
PMID: 21232924 [PubMed - indexed for MEDLINE]

369. Expert Rev Neurother. 2011 Jan;11(1):33-6. doi: 10.1586/ern.10.176.

Role of the mTOR signaling pathway in the rapid antidepressant action of
ketamine.

Hashimoto K(1).

Author information:
(1)Division of Clinical Neuroscience, Chiba University Center for Forensic Mental
Health, 1-8-1 Inohana, Chiba 260-8670, Japan. hashimoto@faculty.chiba-u.jp

Comment on
Science. 2010 Aug 20;329(5994):959-64.

Some patients with major depressive disorder remain resistant to antidepressant
medication. A randomized, placebo-controlled, double-blind trial demonstrated
that a single subanesthetic dose (0.5 mg/kg) of the N-methyl-D-aspartate receptor
antagonist ketamine caused a rapid antidepressant effect within hours in
treatment-resistant patients with major depressive disorder. However, the precise
cellular mechanisms underlying ketamine's rapid antidepressant actions were
unclear, although it is proposed that the
α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor might be involved
in these mechanisms. Recently, Li et al. reported the role of the mammalian
target of rapamycin (mTOR) signaling pathway, a ubiquitous protein kinase
involved in protein synthesis and synaptic plasticity, in ketamine's rapid
antidepressant effects. Here, these findings are put into context and their
significance is discussed.

PMID: 21158553 [PubMed]

373. Nat Med. 2010 Dec;16(12):1384-5. doi: 10.1038/nm1210-1384.

Cracking the moody brain: lifting the mood with ketamine.

Murrough JW(1), Charney DS.

Author information:
(1)Mood and Anxiety Disorders Program, Mount Sinai School of Medicine, New York,
New York, USA. james.murrough@mssm.edu

PMID: 21135850 [PubMed - indexed for MEDLINE]

375. Harv Ment Health Lett. 2010 Nov;27(5):6.

Research suggests new drug targets for depression. Pilot studies of ketamine
intrigue scientists, but risks of this anesthetic limit its clinical use.

[No authors listed]

PMID: 21218614 [PubMed - indexed for MEDLINE]

376. Behav Healthc. 2010 Oct;30(9):36-7.

Ketamine: a fast-acting antidepressant?

Glazer WM(1).

Author information:
(1)Glazer Medical Solutions, Key West, FL, USA.

PMID: 21077547 [PubMed - indexed for MEDLINE]

377. J Neuropsychiatry Clin Neurosci. 2010 Fall;22(4):442-4. doi:
10.1176/appi.neuropsych.22.4.442.

The use of a series of ketamine infusions in two patients with
treatment-resistant depression.

Messer M(1), Haller IV, Larson P, Pattison-Crisostomo J, Gessert CE.

Author information:
(1)Department of Behavioral Health, SMDC Health System, Duluth, Minnesota 55805,
USA.

Treatment-resistant depression often leads to increased morbidity and disability.
The authors report the use of ketamine, a selective N-methyl-D-aspartate (NMDA)
receptor antagonist, in two patients with treatment-resistant depression.
Multiple ketamine treatments may provide an effective rapid antidepressant effect
with prolonged benefit.

PMID: 21037130 [PubMed - indexed for MEDLINE]

380. Anesthesiology. 2010 Sep;113(3):678-84. doi: 10.1097/ALN.0b013e3181ed09a2.

Taming the ketamine tiger. 1965.

Domino EF(1).

Author information:
(1)Department of Pharmacology, University of Michigan, Ann Arbor, Michigan
48109-5632, USA. efdabcde@umich.edu

Comment in
Anesthesiology. 2011 Apr;114(4):1001-2; author reply 1002-3.

Pharmacologic actions of CI-581, a chemical derivative of phencyclidine, were
determined in 20 volunteers from a prison population. The results indicate that
this drug is an effective analgesic and anesthetic agent in doses of 1.0 to 2.0
mg per kilogram. With intravenous administration the onset of action is within 1
min and the effects last for about 5 to 10 min, depending on dosage level and
individual variation. No tachyphylaxis was evident on repeat doses. Respiratory
depression was slight and transient. Hypertension, tachycardia, and psychic
changes are undesirable characteristics of the drug. Whether these can be
modified by preanesthetic medication was not determined in this study. Recovery
from analgesia and coma usually took place within 10 min, although from
electroencephalographic evidence it may be assumed that subjects were not
completely normal until after 1 to 2 h. No evidence of liver or kidney toxicity
was obtained. CI-581 produces pharmacologic effects similar to those reported for
phencyclidine, but of shorter duration. The drug deserves further pharmacologic
and clinical trials. It is proposed that the words "dissociative anesthetic" be
used to describe the mental state produced by this drug.

PMID: 20693870 [PubMed - indexed for MEDLINE]

381. J ECT. 2010 Sep;26(3):223-7. doi: 10.1097/YCT.0b013e3181c3b0aa.

Rapid antidepressant effect of ketamine anesthesia during electroconvulsive
therapy of treatment-resistant depression: comparing ketamine and propofol
anesthesia.

Okamoto N(1), Nakai T, Sakamoto K, Nagafusa Y, Higuchi T, Nishikawa T.

Author information:
(1)Department of Psychiatry, National Center Hospital of Neurology and
Psychiatry, Kodaira City, Tokyo, Japan. okamoton@ncnp.go.jp

BACKGROUND: Reports of the superiority of the antidepressant effect of ketamine
during the conduct of electroconvulsive therapy (ECT) have been limited. We
conducted an open-label trial of ketamine to determine whether ketamine as the
anesthetic during ECT would provide a greater antidepressant effect than the
antidepressant effect obtained with propofol.
METHODS: Between April 2006 and April 2007, 31 inpatients with
treatment-resistant depression gave written consent for ECT and to participate in
this study. An anesthesiologist who was unaware of the mental symptoms of the
subjects assigned them to receive propofol or ketamine anesthetic according to
the preferences of the patients, and the patients underwent 8 ECT sessions for 4
weeks. The Hamilton Depression Rating Scale (HDRS) was valuated before ECT and
after the completion of the second, fourth, sixth, and eighth ECT sessions.
RESULTS: The HDRS scores improved earlier in the ketamine group, with decreases
in HDRS scores that were significantly greater in the ketamine group.
CONCLUSIONS: The results suggested that it is possible to improve symptoms of
depression earlier by using ketamine anesthesia.

PMID: 19935085 [PubMed - indexed for MEDLINE]

382. Psychol Med. 2010 Sep;40(9):1443-51. doi: 10.1017/S0033291709991619. Epub 2009
Dec 9.

Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy
volunteers: implications for antidepressant effect.

Horacek J(1), Brunovsky M, Novak T, Tislerova B, Palenicek T, Bubenikova-Valesova
V, Spaniel F, Koprivova J, Mohr P, Balikova M, Hoschl C.

Author information:
(1)Prague Psychiatric Centre, Prague, Czech Republic. horacek@pcp.lf3.cuni.cz

Comment in
Psychol Med. 2011 Aug;41(8):1787; author reply 1787-9.

BACKGROUND: Theta cordance is a novel quantitative electroencephalography (QEEG)
measure that correlates with cerebral perfusion. A series of clinical studies has
demonstrated that the prefrontal theta cordance value decreases after 1 week of
treatment in responders to antidepressants and that this effect precedes clinical
improvement. Ketamine, a non-competitive antagonist of N-methyl-D-aspartate
(NMDA) receptors, has a unique rapid antidepressant effect but its influence on
theta cordance is unknown.
METHOD: In a double-blind, cross-over, placebo-controlled experiment we studied
the acute effect of ketamine (0.54 mg/kg within 30 min) on theta cordance in a
group of 20 healthy volunteers.
RESULTS: Ketamine infusion induced a decrease in prefrontal theta cordance and an
increase in the central region theta cordance after 10 and 30 min. The change in
prefrontal theta cordance correlated with ketamine and norketamine blood levels
after 10 min of ketamine infusion.
CONCLUSIONS: Our data indicate that ketamine infusion immediately induces changes
similar to those that monoamineric-based antidepressants induce gradually. The
reduction in theta cordance could be a marker and a predictor of the fast-acting
antidepressant effect of ketamine, a hypothesis that could be tested in
depressive patients treated with ketamine.

PMID: 19995475 [PubMed - indexed for MEDLINE]

388. Neuropsychopharmacology. 2010 Jun;35(7):1415-22. doi: 10.1038/npp.2010.24. Epub
2010 Mar 10.

Anterior cingulate desynchronization and functional connectivity with the
amygdala during a working memory task predict rapid antidepressant response to
ketamine.

Salvadore G(1), Cornwell BR, Sambataro F, Latov D, Colon-Rosario V, Carver F,
Holroyd T, DiazGranados N, Machado-Vieira R, Grillon C, Drevets WC, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics, Mood and Anxiety Disorders Program, National
Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892,
USA. salvadoreg@mail.nih.gov

Comment in
Neuropsychopharmacology. 2010 Jun;35(7):1413-4.

Pregenual anterior cingulate cortex (pgACC) hyperactivity differentiates
treatment responders from non-responders to various pharmacological
antidepressant interventions, including ketamine, an N-methyl-D-aspartate
receptor antagonist. Evidence of pgACC hyperactivition during non-emotional
working memory tasks in patients with major depressive disorder (MDD) highlights
the importance of this region for processing both emotionally salient and
cognitive stimuli. However, it is unclear whether pgACC activity might serve as a
potential biomarker of antidepressant response during working memory tasks as
well, in line with previous research with emotionally arousing tasks. This study
tested the hypothesis that during the N-back task, a widely used working memory
paradigm, low pretreatment pgACC activity, as well as coherence between the pgACC
and the amygdala, would be correlated with the clinical improvement after
ketamine. Magnetoencephalography (MEG) recordings were obtained from 15 drug-free
patients with MDD during working memory performance 1 to 3 days before receiving
a single ketamine infusion. Functional activation patterns were analyzed using
advanced MEG source analysis. Source coherence analyses were conducted to
quantify the degree of long-range functional connectivity between the pgACC and
the amygdala. Patients who showed the least engagement of the pgACC in response
to increased working memory load showed the greatest symptomatic improvement
within 4 h of ketamine administration (r=0.82, p=0.0002, false discovery rate
(FDR) <0.05). Pretreatment functional connectivity between the pgACC and the left
amygdala was negatively correlated with antidepressant symptom change (r=-0.73,
p=0.0021, FDR <0.05).These data implicate the pgACC and its putative interaction
with the amygdala in predicting antidepressant response to ketamine in a working
memory task context.

PMCID: PMC2869391
PMID: 20393460 [PubMed - indexed for MEDLINE]

394. Indian J Psychiatry. 2010 Apr;52(2):97-9. doi: 10.4103/0019-5545.64573.

Innovative approaches to treatment - refractory depression: The ketamine story.

Rao TS(1), Andrade C.

Author information:
(1)Department of Psychiatry, JSS University, JSS Medical College Hospital, Mysore
- 570 004, India.

PMCID: PMC2927899
PMID: 20838494 [PubMed]

395. Ugeskr Laeger. 2010 Mar 15;172(11):899; author reply 899.

[Ketamine in melancholic depression].

[Article in Danish]

Hansen G, Jensen SB, Hilden T.

Comment on
Ugeskr Laeger. 2010 Feb 8;172(6):460-1.

PMID: 20568357 [PubMed - indexed for MEDLINE]

403. Biol Psychiatry. 2010 Jan 15;67(2):139-45. doi: 10.1016/j.biopsych.2009.08.038.

Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant
depression.

aan het Rot M(1), Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew
SJ.

Author information:
(1)Mood and Anxiety Disorders Program, Department of Psychiatry, Mount Sinai
School of Medicine, New York, New York. m.aan.het.rot@rug.nl

Comment in
Biol Psychiatry. 2011 Aug 15;70(4):e9-10; author reply e11-2.

BACKGROUND: A single subanesthetic (intravenous) IV dose of ketamine might have
rapid but transient antidepressant effects in patients with treatment-resistant
depression (TRD). Here we tested the tolerability, safety, and efficacy of
repeated-dose open-label IV ketamine (six infusions over 12 days) in 10
medication-free symptomatic patients with TRD who had previously shown a
meaningful antidepressant response to a single dose.
METHODS: On day 1, patients received a 40-min IV infusion of ketamine (.5 mg/kg)
in an inpatient setting with continuous vital-sign monitoring. Psychotomimetic
effects and adverse events were recorded repeatedly. The primary efficacy measure
was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS)
score. If patients showed a > or =50% reduction in MADRS scores on day 2, they
received five additional infusions on an outpatient basis (days 3, 5, 8, 10, and
12). Follow-up visits were conducted twice-weekly for > or =4 weeks or until
relapse.
RESULTS: Ketamine elicited minimal positive psychotic symptoms. Three patients
experienced significant but transient dissociative symptoms. Side effects during
and after each ketamine infusion were generally mild. The response criterion was
met by nine patients after the first infusion as well as after the sixth
infusion. The mean (SD) reduction in MADRS scores after the sixth infusion was
85% (12%). Postketamine, eight of nine patients relapsed, on average, 19 days
after the sixth infusion (range 6 days-45 days). One patient remained
antidepressant-free with minimal depressive symptoms for >3 months.
CONCLUSIONS: These pilot findings suggest feasibility of repeated-dose IV
ketamine for the acute treatment of TRD.

PMID: 19897179 [PubMed - indexed for MEDLINE]

406. Pharmacopsychiatry. 2010 Jan;43(1):33-5. doi: 10.1055/s-0029-1237375. Epub 2009
Dec 11.

Oral administration of the NMDA receptor antagonist S-ketamine as add-on therapy
of depression: a case series.

Paslakis G, Gilles M, Meyer-Lindenberg A, Deuschle M.

PMID: 20013614 [PubMed - indexed for MEDLINE]

408. Biol Psychiatry. 2009 Sep 1;66(5):522-6. doi: 10.1016/j.biopsych.2009.04.029.
Epub 2009 Jul 9.

Effects of intravenous ketamine on explicit and implicit measures of suicidality
in treatment-resistant depression.

Price RB(1), Nock MK, Charney DS, Mathew SJ.

Author information:
(1)Department of Psychiatry, Mount Sinai School of Medicine, New York, New York,
USA. rprice@eden.rutgers.edu

BACKGROUND: Intravenous ketamine has shown rapid antidepressant effects in early
trials, making it a potentially attractive candidate for depressed patients at
imminent risk of suicide. The Implicit Association Test (IAT), a
performance-based measure of association between concepts, may have utility in
suicide assessment.
METHODS: Twenty-six patients with treatment-resistant depression were assessed
using the suicidality item of the Montgomery-Asberg Depression Rating Scale
(MADRS-SI) 2 hours before and 24 hours following a single subanesthetic dose of
intravenous ketamine. Ten patients also completed IATs assessing implicit
suicidal associations at comparable time points. In a second study, nine patients
received thrice-weekly ketamine infusions over a 12-day period.
RESULTS: Twenty-four hours after a single infusion, MADRS-SI scores were reduced
on average by 2.08 points on a 0 to 6 scale (p < .001; d = 1.37), and 81% of
patients received a rating of 0 or 1 postinfusion. Implicit suicidal associations
were also reduced following ketamine (p = .003; d = 1.36), with reductions
correlated across implicit and explicit measures. MADRS-SI reductions were
sustained for 12 days by repeated-dose ketamine (p < .001; d = 2.42).
CONCLUSIONS: These preliminary findings support the premise that ketamine has
rapid beneficial effects on suicidal cognition and warrants further study.

PMCID: PMC2935847
PMID: 19545857 [PubMed - indexed for MEDLINE]

413. Pharmacol Ther. 2009 Aug;123(2):143-50. doi: 10.1016/j.pharmthera.2009.02.010.
Epub 2009 May 3.

Ketamine and the next generation of antidepressants with a rapid onset of action.

Machado-Vieira R(1), Salvadore G, Diazgranados N, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics Mood and Anxiety Disorders Program, National
Institute of Mental Health, Department of Health and Human Services, Bethesda,
Maryland, USA.

Existing treatments for major depressive disorder (MDD) usually take weeks to
months to achieve their antidepressant effects, and a significant number of
patients do not have adequate improvement even after months of treatment. In
addition, increased risk of suicide attempts is a major public health concern
during the first month of standard antidepressant therapy. Thus, improved
therapeutics that can exert their antidepressant effects within hours or a few
days of their administration are urgently needed, as is a better understanding of
the presumed mechanisms associated with these rapid antidepressant effects. In
this context, the N-methyl-D-aspartate (NMDA) antagonist ketamine has
consistently shown antidepressant effects within a few hours of its
administration. This makes it a valuable research tool to identify biomarkers of
response in order to develop the next generation of fast-acting antidepressants.
In this review, we describe clinical, electrophysiological, biochemical, and
imaging correlates as relevant targets in the study of the antidepressant
response associated with ketamine, and their implications for the development of
novel, fast-acting antidepressants. We also review evidence that
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA
throughput may represent a convergent mechanism for the rapid antidepressant
actions of ketamine. Overall, understanding the molecular basis of this work will
likely lead to the ultimate development of improved therapeutics for MDD.

PMCID: PMC2726824
PMID: 19397926 [PubMed - indexed for MEDLINE]

421. Biol Psychiatry. 2009 Feb 15;65(4):289-95. doi: 10.1016/j.biopsych.2008.08.014.
Epub 2008 Sep 25.

Increased anterior cingulate cortical activity in response to fearful faces: a
neurophysiological biomarker that predicts rapid antidepressant response to
ketamine.

Salvadore G(1), Cornwell BR, Colon-Rosario V, Coppola R, Grillon C, Zarate CA Jr,
Manji HK.

Author information:
(1)Mood and Anxiety Disorders Program, National Institute of Mental Health,
National Institutes of Health, Department of Health and Human Services, Bethesda,
Maryland, USA.

BACKGROUND: Most patients with major depressive disorder (MDD) experience a
period of lengthy trial and error when trying to find optimal antidepressant
treatment; identifying biomarkers that could predict response to antidepressant
treatment would be of enormous benefit. We tested the hypothesis that
pretreatment anterior cingulate cortex (ACC) activity could be a putative
biomarker of rapid antidepressant response to ketamine, in line with previous
findings that investigated the effects of conventional antidepressants. We also
investigated patterns of ACC activity to rapid presentation of fearful faces
compared with the normal habituation observed in healthy subjects.
METHODS: We elicited ACC activity in drug-free patients with MDD (n = 11) and
healthy control subjects (n = 11) by rapidly presenting fearful faces, a paradigm
known to activate rostral regions of the ACC. Spatial-filtering analyses were
performed on magnetoencephalographic (MEG) recordings, which offer the temporal
precision necessary to estimate ACC activity elicited by the rapid presentation
of stimuli. Magnetoencephalographic recordings were obtained only once for both
patients and control subjects. Patients were subsequently administered a single
ketamine infusion followed by assessment of depressive symptoms 4 hours later.
RESULTS: Although healthy subjects had decreased neuromagnetic activity in the
rostral ACC across repeated exposures, patients with MDD showed robust increases
in pretreatment ACC activity. Notably, this increase was positively correlated
with subsequent rapid antidepressant response to ketamine. Exploratory analyses
showed that pretreatment amygdala activity was negatively correlated with change
in depressive symptoms.
CONCLUSIONS: Pretreatment rostral ACC activation may be a useful biomarker that
identifies a subgroup of patients who will respond favorably to ketamine's
antidepressant effects.

PMCID: PMC2643469
PMID: 18822408 [PubMed - indexed for MEDLINE]

424. World J Biol Psychiatry. 2009;10(3):241-4. doi: 10.1080/15622970701714370.

Comparison of racemic ketamine and S-ketamine in treatment-resistant major
depression: report of two cases.

Paul R(1), Schaaff N, Padberg F, Möller HJ, Frodl T.

Author information:
(1)Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University,
Munich, Germany.

Recent studies with intravenous infusion of the NMDA receptor antagonist ketamine
showed robust and rapid antidepressant effects within hours after treatment.
Ketamine is a racemic mixture consisting of two enantiomers, R- and S-ketamine.
In contrast to ketamine, S-ketamine is reported to be less prone to psychomimetic
side effects, such as derealisation and hallucinations. In this report we
describe the effect of ketamine and S-ketamine infusion therapy, respectively, in
two patients with treatment-resistant major depression. Severity of depression
was rated using the Hamilton Depression Rating Scale (HAMD) and the Beck
Depression Inventory (BDI). While one patient did not respond to either
treatment, in the other patient intravenous administration of ketamine as well as
S-ketamine showed an antidepressant effect as assessed by a decrease in HAMD-21
and BDI at days 1 and 3 after infusion which faded until day 6. Both patients
experienced psychomimetic side effects during ketamine infusion which were absent
during treatment with S-ketamine. We conclude that S-ketamine might exert similar
antidepressant effects as ketamine in drug-resistant depression but may be better
tolerated by the patients.

PMID: 19224412 [PubMed - indexed for MEDLINE]

425. World J Biol Psychiatry. 2009;10(4 Pt 2):640-3.

Repeated intravenous ketamine therapy in a patient with treatment-resistant major
depression.

Liebrenz M(1), Stohler R, Borgeat A.

Author information:
(1)Psychiatric University Hospital, Research Group on Substance Use Disorders,
Zurich, Switzerland. Michael.Liebrenz@puk.zh.ch

BACKGROUND: The intravenous administration of ketamine, an N-methyl-D-aspartate
receptor antagonist, results in a great improvement of depression symptoms, but
it is not clear for how long. This single-case trial was conducted to explore the
duration of improvement and the effects of a second administration on the
clinical outcome.
METHODS: In an open label trial, a 55-year-old male patient with
treatment-resistant major depression and a co-occurring alcohol and
benzodiazepine dependence received two intravenous infusions of 0.5 mg/kg
ketamine over the course of 6 weeks. Depression severity was assessed by means of
a weekly clinical interview, the 21-item Hamilton Depression Rating Scale (HDRS),
and the 21-item Beck Depression Inventory (BDI).
RESULTS: The first ketamine infusion lead to a pronounced improvement of
symptoms, peaking on the second day post infusion (HDRS -56.6%, BDI -65.4%).
Positive effects started fading by day 7, reaching baseline by day 35. The second
infusion was less efficacious: HDRS and BDI were reduced by 43 and 35%,
respectively, and returned to baseline by day 7.
CONCLUSION: In this patient with a co-occurring substance use disorder, repeated
administrations of ketamine produced positive results. Since the second
application has been less efficacious, doses and schedule of administrations need
to be further investigated.

PMID: 17853274 [PubMed - indexed for MEDLINE]

440. Aust N Z J Psychiatry. 2008 Feb;42(2):170. doi: 10.1080/00048670701787628.

Ketamine followed by memantine for the treatment of major depression.

Kollmar R, Markovic K, Thürauf N, Schmitt H, Kornhuber J.

PMID: 18197514 [PubMed - indexed for MEDLINE]

445. Curr Psychiatry Rep. 2007 Dec;9(6):467-74.

The role of glutamate in mood disorders: results from the ketamine in major
depression study and the presumed cellular mechanism underlying its
antidepressant effects.

Maeng S, Zarate CA Jr.

In this article, we first review a study showing that the N-methyl-D-aspartate
(NMDA) receptor antagonist ketamine leads to rapid, robust, and relatively
sustained antidepressant effects in patients with treatment-resistant major
depression. We then discuss our hypothesis that the therapeutic effects of
monoaminergic antidepressants and ketamine may be mediated by increased
AMPA-to-NMDA glutamate receptor throughput in critical neuronal circuits. We
hypothesize that ketamine directly mediates this throughput, whereas
monoaminergic antidepressants work indirectly and gradually; this may explain, in
part, the lag of onset of several weeks to months that is observed with
traditional antidepressants.

PMID: 18221626 [PubMed - indexed for MEDLINE]

451. Swiss Med Wkly. 2007 Apr 21;137(15-16):234-6.

Intravenous ketamine therapy in a patient with a treatment-resistant major
depression.

Liebrenz M(1), Borgeat A, Leisinger R, Stohler R.

Author information:
(1)Psychiatric University Hospital, Research Group on Substance Use Disorders,
Zurich, Switzerland. Michael.Liebrenz@puk.zh.ch

BACKGROUND: Recently, reports from North America have indicated that the
intravenous infusion of ketamine hydrochloride (an N-methyl-d-aspartate receptor
antagonist) results in a sudden and robust improvement of depression symptoms.
OBJECTIVE: To corroborate antidepressant effectiveness of IV ketamine in a
patient with a co-occurring substance use disorder for the first time in a
European clinical setting.
DESIGN: Open label trial Methods: A 55-year-old male subject with a
treatment-resistant major depression and a co-occurring alcohol and
benzodiazepine dependence received an intravenous infusion of 0.5 mg/kg ketamine
over a period of 50 minutes. Effects were assessed by means of a clinical
interview, the 21-item Hamilton Depression Rating scale (HDRS), and the 21-item
Beck Depression Inventory (BDI) at baseline, 1 hour, 1 day, 2 days, and 7 days
after intervention.
RESULTS: Following the administration of ketamine the subject experienced a
significant improvement of his symptoms peaking on the 2nd day post infusion
(HDRS from 36 to 16; -56.6%, BDI from 26 to 9; -65.4%). The subject first
reported improvements 25 min. into the infusion and continued to describe
positive effects throughout the subsequent 7 days.
CONCLUSION: Ketamine not only seems to have strong antidepressant effects but
also to act very swiftly. These actions were unaffected by an alcohol or
benzodiazpine dependence.

PMID: 17525879 [PubMed - indexed for MEDLINE]

452. Swiss Med Wkly. 2007 Apr 21;137(15-16):215-6.

Ketamine and the potential role for rapid-acting antidepressant medications.

Krystal JH.

PMID: 17525875 [PubMed - indexed for MEDLINE]

455. J ECT. 2007 Mar;23(1):23-5.

Rapid relief of severe major depressive disorder by use of preoperative ketamine
and electroconvulsive therapy.

Goforth HW(1), Holsinger T.

Author information:
(1)Duke University Medical Center, and Consultation-Liaison Psychiatry Service,
Durham Veterans Affairs Medical Center, Durham, NC 27710, USA.
Harold.Goforth@duke.edu

Comment in
J ECT. 2007 Sep;23(3):208; author reply 209.

Major depressive disorder is a difficult-to-treat and recurrent debilitating
disorder. All approved somatic treatments for major depression to date require a
significant time lapse before demonstrating an antidepressant effect. However,
emerging evidence indicates a potential role for the use of ketamine to rapidly
relieve sy mptoms of major depression. We present a case of severe, recurrent
major depressive disorder that demonstrated marked improvement within 8 hours of
receiving a preoperative dose of ketamine and 1 treatment of electroconvulsive
therapy with bitemporal electrode placement. This case is supportive of a role of
ketamine in relieving symptoms of major depressive disorder rapidly and safely.

PMID: 17435569 [PubMed - indexed for MEDLINE]

466. Pain Med. 2006 Jan-Feb;7(1):92-5.

Two case studies of patients with major depressive disorder given low-dose
(subanesthetic) ketamine infusions.

Correll GE(1), Futter GE.

Author information:
(1)Mackay Base Hospital, MacKay, Queensland, Australia. correll2mackay.net.au

PMID: 16533209 [PubMed - indexed for MEDLINE]

Many of the more than 700 patients in Ketamine for Depression studies have been depressed bipolar patients.

How well Bipolar Depression responds compared to unipolar depression is not known.

Ketamine is not FDA approved for treatment of Depression or Bipolar Depression

Here are some recent studies of Ketamine for Bipolar

Parsaik 2015 Efficacy of Ketamine in Bipolar Depression: Systematic Review and Meta-analysis.

Hui Poon 2015 Pharmacological Approaches for Treatment-resistant Bipolar Disorder.

Best 2015 Ketamine and transcranial magnetic stimulation treatment for bipolar II disorder: a case report.

Lee 2015 Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysis.

Best 2014 Combined ketamine/transcranial magnetic stimulation treatment of severe depression in bipolar I disorder.

Here are some more references from MedLine regarding Ketamine and Bipolar

13. Cochrane Database Syst Rev. 2015 Sep 29;9:CD011611. doi:
10.1002/14651858.CD011611.pub2.

Ketamine and other glutamate receptor modulators for depression in bipolar
disorder in adults.

McCloud TL(1), Caddy C, Jochim J, Rendell JM, Diamond PR, Shuttleworth C, Brett
D, Amit BH, McShane R, Hamadi L, Hawton K, Cipriani A.

Author information:
(1)Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford,
UK.

BACKGROUND: There is emerging evidence that glutamatergic system dysfunction
might play an important role in the pathophysiology of bipolar depression. This
review focuses on the use of glutamate receptor modulators for depression in
bipolar disorder.
OBJECTIVES: 1. To assess the effects of ketamine and other glutamate receptor
modulators in alleviating the acute symptoms of depression in people with bipolar
disorder.2. To review the acceptability of ketamine and other glutamate receptor
modulators in people with bipolar disorder who are experiencing acute depression
symptoms.
SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review
Group's Specialised Register (CCDANCTR, to 9 January 2015). This register
includes relevant randomised controlled trials (RCTs) from: the Cochrane Library
(all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to
date). We cross-checked reference lists of relevant papers and systematic
reviews. We did not apply any restrictions to date, language or publication
status.
SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing ketamine,
memantine, or other glutamate receptor modulators with other active psychotropic
drugs or saline placebo in adults with bipolar depression.
DATA COLLECTION AND ANALYSIS: At least two review authors independently selected
studies for inclusion, assessed trial quality and extracted data. Primary
outcomes for this review were response rate and adverse events. Secondary
outcomes included remission rate, depression severity change scores, suicidality,
cognition, quality of life, and dropout rate. We contacted study authors for
additional information.
MAIN RESULTS: Five studies (329 participants) were included in this review. All
included studies were placebo-controlled and two-armed, and the glutamate
receptor modulators - ketamine (two trials), memantine (two trials), and cytidine
(one trial) - were used as add-on drugs to mood stabilisers. The treatment period
ranged from a single intravenous administration (all ketamine studies), to
repeated administration for memantine and cytidine (8 to 12 weeks, and 12 weeks,
respectively). Three of the studies took place in the USA, one in Taiwan, and in
one, the location was unclear. The majority (70.5%) of participants were from
Taiwan. All participants had a primary diagnosis of bipolar disorder, according
to the DSM-IV or DSM-IV-TR, and were in a current depressive phase. The severity
of depression was at least moderate in all but one study.Among all glutamate
receptor modulators included in this review, only ketamine appeared to be more
efficacious than placebo 24 hours after the infusion for the primary outcome,
response rate (odds ratio (OR) 11.61, 95% confidence interval (CI) 1.25 to
107.74; P = 0.03; I² = 0%, 2 studies, 33 participants). This evidence was rated
as low quality. The statistically significant difference disappeared at three
days, but the mean estimate still favoured ketamine (OR 8.24, 95% CI 0.84 to
80.61; 2 studies, 33 participants; very low quality evidence). We found no
difference in response between ketamine and placebo at one week (OR 4.00, 95% CI
0.33 to 48.66; P = 0.28, 1 study; 18 participants; very low quality
evidence).There was no significant difference between memantine and placebo in
response rate one week after treatment (OR 1.08, 95% CI 0.06 to 19.05; P = 0.96,
1 study, 29 participants), two weeks (OR 4.88, 95% CI 0.78 to 30.29; P = 0.09, 1
study, 29 participants), four weeks (OR 5.33, 95% CI 1.02 to 27.76; P = 0.05, 1
study, 29 participants), or at three months (OR, 1.66, 95% CI 0.69 to 4.03; P =
0.26, I² = 36%, 2 studies, 261 participants). These findings were based on very
low quality evidence.There was no significant difference between cytidine and
placebo in response rate at three months (OR, 1.13, 95% CI 0.30 to 4.24; P =
0.86, 1 study, 35 participants; very low quality evidence).For the secondary
outcome of remission, no significant differences were found between ketamine and
placebo, nor between memantine and placebo. For the secondary outcome of change
scores from baseline on depression scales, ketamine was more effective than
placebo at 24 hours (MD -11.81, 95% CI -20.01 to -3.61; P = 0.005, 2 studies, 32
participants) but not at one or two weeks after treatment. There was no
difference between memantine and placebo for this outcome.We found no significant
differences in terms of adverse events between placebo and ketamine, memantine,
or cytidine. There were no differences between ketamine and placebo, memantine
and placebo, or cytidine and placebo in total dropouts. No data were available on
dropouts due to adverse effects for ketamine or cytidine; but no difference was
found between memantine and placebo.
AUTHORS' CONCLUSIONS: Reliable conclusions from this review are severely limited
by the small amount of data usable for analysis. The body of evidence about
glutamate receptor modulators in bipolar disorder is even smaller than that which
is available for unipolar depression. Overall, we found limited evidence in
favour of a single intravenous dose of ketamine (as add-on therapy to mood
stabilisers) over placebo in terms of response rate up to 24 hours; ketamine did
not show any better efficacy in terms of remission in bipolar depression. Even
though ketamine has the potential to have a rapid and transient antidepressant
effect, the efficacy of a single intravenous dose may be limited. Ketamine's
psychotomimetic effects could compromise study blinding; this is a particular
issue for this review as no included study used an active comparator, and so we
cannot rule out the potential bias introduced by inadequate blinding
procedures.We did not find conclusive evidence on adverse events with ketamine.
To draw more robust conclusions, further RCTs (with adequate blinding) are needed
to explore different modes of administration of ketamine and to study different
methods of sustaining antidepressant response, such as repeated administrations.
There was not enough evidence to draw meaningful conclusions for the remaining
two glutamate receptor modulators (memantine and cytidine). This review is
limited not only by completeness of evidence, but also by the low to very low
quality of the available evidence.

PMID: 26415966 [PubMed - in process]

57. J Clin Psychiatry. 2015 Jun;76(6):737-8. doi: 10.4088/JCP.14l09527.

Single-dose ketamine followed by daily D-Cycloserine in treatment-resistant
bipolar depression.

Kantrowitz JT(1), Halberstam B, Gangwisch J.

Author information:
(1)jk3380@cumc.columbia.edu.

Comment in
J Clin Psychiatry. 2015 Jun;76(6):738-40.

PMID: 26132675 [PubMed - indexed for MEDLINE]

56. J Clin Psychiatry. 2015 Jun;76(6):738-40. doi: 10.4088/JCP.15com09904.

Maintaining the initial clinical response after ketamine in bipolar and unipolar
depression: an important next-step challenge.

Iosifescu DV(1).

Author information:
(1)One Gustave L. Levy Pl, Box 1230, New York, NY 10029 dan.iosifescu@mssm.edu.

Comment on
J Clin Psychiatry. 2015 Jun;76(6):737-8.

PMID: 26132676 [PubMed - indexed for MEDLINE]

54. Bipolar Disord. 2015 Jun;17(4):438-43. doi: 10.1111/bdi.12277. Epub 2014 Nov 14.

A single infusion of ketamine improves depression scores in patients with anxious
bipolar depression.

Ionescu DF(1,)(2), Luckenbaugh DA(3), Niciu MJ(3), Richards EM(3), Zarate CA
Jr(3).

Author information:
(1)Depression Clinical and Research Program, Massachusetts General Hospital,
Boston, MA, USA. (2)Harvard Medical School, Boston, MA, USA. (3)Experimental
Therapeutics and Pathophysiology Branch, Intramural Research Program, National
Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.

OBJECTIVE: Patents with anxious bipolar disorder have worse clinical outcomes and
are harder to treat with traditional medication regimens compared to those with
non-anxious bipolar disorder. Ketamine has been shown to rapidly and robustly
decrease symptoms of depression in depressed patients with bipolar disorder. We
sought to determine whether baseline anxiety status reduced ketamine's ability to
decrease symptoms of depression.
METHODS: Thirty-six patients with anxious (n = 21) and non-anxious (n = 15)
treatment-resistant bipolar depression (types I and II; concurrently treated with
either lithium or valproate) received a single infusion of ketamine (0.5 mg/kg)
over 40 min. Post-hoc analyses compared changes in the Montgomery-Åsberg
Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) in
anxious versus non-anxious depressed patients with bipolar disorder through 14
days post-infusion. Anxious bipolar depression was defined as DSM-IV bipolar
depression plus a HDRS Anxiety/Somatization Factor score of ≥ 7.
RESULTS: A linear mixed model revealed a significant effect of anxiety group on
the MADRS (p = 0.04) and HDRS (p = 0.04). Significant drug effects (all p <
0.001) suggested that both anxious and non-anxious groups had an antidepressant
response to ketamine. The drug-by-anxiety interactions were not significant (all
p > 0.28).
CONCLUSIONS: Both anxious and non-anxious patients with bipolar depression had
significant antidepressant responses to ketamine, although the anxious depressed
group did not show a clear antidepressant response disadvantage over the
non-anxious group. Given that anxiety has been shown to be a predictor of poor
treatment response in bipolar depression when traditional treatments are used,
our findings suggest a need for further investigations into ketamine's novel role
in the treatment of anxious bipolar depression.

Published 2014. This article is a U.S. Government work and is in the public
domain in the USA.

PMCID: PMC4431955 [Available on 2016-06-01]
PMID: 25400146 [PubMed - in process]

83. J Med Case Rep. 2015 Mar 31;9:73. doi: 10.1186/s13256-015-0520-0.

Ketamine and transcranial magnetic stimulation treatment for bipolar II disorder:
a case report.

Best SR(1), Griffin BP(2), Pavel DG(3).

Author information:
(1)The Neuroscience Center, 440 Lake Cook Road, Building 2, Deerfield, IL, 60015,
USA. srdbest@neuroscience.md. (2)Independent Practice, 333 East Ontario Suite
1203B, Chicago, IL, USA. blotdoc@aol.com. (3)PathFinder Brain SPECT, 440 Lake
Cook Road, Suite 3, Deerfield, IL, 60015, USA. danpavel@yahoo.com.

INTRODUCTION: To the best of our knowledge, this is the first case report of
successful treatment for bipolar II disorder using a combined ketamine and
transcranial magnetic stimulation treatment.
CASE PRESENTATION: A 43-year-old Caucasian unemployed man presented to us with
treatment-resistant bipolar II disorder, currently in a mixed state. A
psychometric assessment and brain single-photon emission computer tomography scan
were conducted at baseline. His psychometric assessment revealed severe
depressive and manic symptoms that were consistent with bipolar II disorder.
Findings from a brain single-photon emission computer tomography scan converged
with those from his psychometric assessment. The combined ketamine and
transcranial magnetic stimulation treatment was administered a total of 24 times
over five months, with his ketamine dosage increased from 50mg at the first
treatment to 600 mg by the last. Starting after the second treatment, he reported
substantial improvements in his symptoms. A follow-up psychometric assessment and
brain single-photon emission computer tomography scan five months later revealed
substantial blood flow increases in the previously deficient areas.
CONCLUSIONS: We provide preliminary evidence for a treatment method that
magnifies the therapeutic benefits of infused ketamine along with transcranial
magnetic stimulation. We postulate that this may be based on an interaction at
the level of the relevant cortico-thalamo-cortical circuit(s).

PMCID: PMC4391108
PMID: 25890258 [PubMed - in process]

87. Gen Hosp Psychiatry. 2015 Mar-Apr;37(2):178-84. doi:
10.1016/j.genhosppsych.2015.01.003. Epub 2015 Jan 15.

Ketamine as a novel treatment for major depressive disorder and bipolar
depression: a systematic review and quantitative meta-analysis.

Lee EE(1), Della Selva MP(1), Liu A(1), Himelhoch S(1).

Author information:
(1)Department of Psychiatry, University of Maryland School of Medicine,
Baltimore, MD.

OBJECTIVE: Given the significant disability, morbidity and mortality associated
with depression, the promising recent trials of ketamine highlight a novel
intervention. A meta-analysis was conducted to assess the efficacy of ketamine in
comparison with placebo for the reduction of depressive symptoms in patients who
meet criteria for a major depressive episode.
METHOD: Two electronic databases were searched in September 2013 for
English-language studies that were randomized placebo-controlled trials of
ketamine treatment for patients with major depressive disorder or bipolar
depression and utilized a standardized rating scale. Studies including
participants receiving electroconvulsive therapy and adolescent/child
participants were excluded. Five studies were included in the quantitative
meta-analysis.
RESULTS: The quantitative meta-analysis showed that ketamine significantly
reduced depressive symptoms. The overall effect size at day 1 was large and
statistically significant with an overall standardized mean difference of 1.01
(95% confidence interval 0.69-1.34) (P<.001), with the effects sustained at 7
days postinfusion. The heterogeneity of the studies was low and not statistically
significant, and the funnel plot showed no publication bias.
CONCLUSIONS: The large and statistically significant effect of ketamine on
depressive symptoms supports a promising, new and effective pharmacotherapy with
rapid onset, high efficacy and good tolerability.

PMID: 25698228 [PubMed - in process]

94. Pharmacopsychiatry. 2015 Mar;48(2):78-9. doi: 10.1055/s-0034-1394399. Epub 2014
Oct 27.

Single ketamine infusion and neurocognitive performance in bipolar depression.

Permoda-Osip A(1), Kisielewski J(1), Bartkowska-Sniatkowska A(2), Rybakowski
JK(1).

Author information:
(1)Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan,
Poland. (2)Department of Pediatric Anaesthesiology and Intensive Therapy, Poznan
University of Medical Sciences, Poznan, Poland.

We estimated neurocognitive performance using the trail making test (TMT) and the
Stroop color-word interference test before, and on the 3(rd) day after a single
infusion of ketamine, in 18 bipolar depressed patients receiving mood-stabilizing
drugs. The performance on all tests significantly improved on the 3(rd) day after
ketamine infusion which correlated positively with baseline intensity of
neuropsychological impairment and was not associated either with baseline
intensity of depression or reduction of depressive symptoms after 3 or 7 days.
The results suggest that in such population of patients, single ketamine infusion
may improve neuropsychological performance independently of antidepressant
effect.

PMID: 25347227 [PubMed - in process]

127. J ECT. 2014 Dec;30(4):e50-1. doi: 10.1097/YCT.0000000000000167.

Combined ketamine/transcranial magnetic stimulation treatment of severe
depression in bipolar I disorder.

Best SR(1).

Author information:
(1)The Neuroscience Center Deerfield, IL srdbest@neuroscience.md.

PMID: 25054363 [PubMed - indexed for MEDLINE]

139. J Affect Disord. 2014 Oct 16;172C:307-311. doi: 10.1016/j.jad.2014.09.015. [Epub
ahead of print]

Shank3 as a potential biomarker of antidepressant response to ketamine and its
neural correlates in bipolar depression.

Ortiz R(1), Niciu MJ(1), Lukkahati N(2), Saligan LN(3), Nugent AC(1), Luckenbaugh
DA(1), Machado-Vieira R(1), Zarate CA Jr(4).

Author information:
(1)National Institutes of Health/National Institute of Mental Health,
Experimental Therapeutics & Pathophysiology Branch, Building 10/Clinical Research
Center (CRC), 10 Center Dr., Room 7-5342, Bethesda, MD 20892, USA. (2)National
Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA;
School of Nursing, University of Nevada at Las Vegas, Las Vegas, NV, USA.
(3)National Institute of Nursing Research, National Institutes of Health,
Bethesda, MD, USA. (4)National Institutes of Health/National Institute of Mental
Health, Experimental Therapeutics & Pathophysiology Branch, Building 10/Clinical
Research Center (CRC), 10 Center Dr., Room 7-5342, Bethesda, MD 20892, USA.
Electronic address: zaratec@mail.nih.gov.

BACKGROUND: Shank3, a post-synaptic density protein involved in
N-methyl-d-aspartate (NMDA) receptor tethering and dendritic spine rearrangement,
is implicated in the pathophysiology of bipolar disorder. We hypothesized that
elevated baseline plasma Shank3 levels might predict antidepressant response to
the NMDA receptor antagonist ketamine.
METHODS: Twenty-nine subjects with bipolar depression received a double-blind,
randomized, subanesthetic dose (.5mg/kg) ketamine infusion. Of the patients for
whom Shank3 levels were collected, 15 completed baseline 3-Tesla MRI and 17
completed post-ketamine [(18)F]-FDG PET.
RESULTS: Higher baseline Shank3 levels predicted antidepressant response at Days
1 (r=-.39, p=.047), 2 (r=-.45, p=.02), and 3 (r=-.42, p=.03) and were associated
with larger average (r=.58, p=.02) and right amygdala volume (r=.65, p=.009).
Greater baseline Shank3 also predicted increased glucose metabolism in the
hippocampus (r=.51, p=.04) and amygdala (r=.58, p=.02).
LIMITATIONS: Limitations include the small sample size, inability to assess the
source of peripheral Shank3, and the lack of a placebo group for baseline Shank3
levels and comparative structural/functional neuroimaging.
CONCLUSIONS: Shank3 is a potential biomarker of antidepressant response to
ketamine that correlates with baseline amygdala volume and increased glucose
metabolism in the amygdala and hippocampus.

Published by Elsevier B.V.

PMCID: PMC4400209 [Available on 2016-04-16]
PMID: 25451430 [PubMed - as supplied by publisher]

140. Transl Psychiatry. 2014 Oct 14;4:e469. doi: 10.1038/tp.2014.105.

Anti-anhedonic effect of ketamine and its neural correlates in
treatment-resistant bipolar depression.

Lally N(1), Nugent AC(2), Luckenbaugh DA(2), Ameli R(2), Roiser JP(3), Zarate
CA(2).

Author information:
(1)1] Experimental Therapeutics and Pathophysiology Branch, National Institute of
Mental Health, National Institutes of Health, Bethesda, MD, USA [2] Institute of
Cognitive Neuroscience, University College London, London, UK. (2)Experimental
Therapeutics and Pathophysiology Branch, National Institute of Mental Health,
National Institutes of Health, Bethesda, MD, USA. (3)Institute of Cognitive
Neuroscience, University College London, London, UK.

Anhedonia--which is defined as diminished pleasure from, or interest in,
previously rewarding activities-is one of two cardinal symptoms of a major
depressive episode. However, evidence suggests that standard treatments for
depression do little to alleviate the symptoms of anhedonia and may cause reward
blunting. Indeed, no therapeutics are currently approved for the treatment of
anhedonia. Notably, over half of patients diagnosed with bipolar disorder
experience significant levels of anhedonia during a depressive episode. Recent
research into novel and rapid-acting therapeutics for depression, particularly
the noncompetitive N-Methyl-D-aspartate receptor antagonist ketamine, has
highlighted the role of the glutamatergic system in the treatment of depression;
however, it is unknown whether ketamine specifically improves anhedonic symptoms.
The present study used a randomized, placebo-controlled, double-blind crossover
design to examine whether a single ketamine infusion could reduce anhedonia
levels in 36 patients with treatment-resistant bipolar depression. The study also
used positron emission tomography imaging in a subset of patients to explore the
neurobiological mechanisms underpinning ketamine's anti-anhedonic effects. We
found that ketamine rapidly reduced the levels of anhedonia. Furthermore, this
reduction occurred independently from reductions in general depressive symptoms.
Anti-anhedonic effects were specifically related to increased glucose metabolism
in the dorsal anterior cingulate cortex and putamen. Our study emphasizes the
importance of the glutamatergic system in treatment-refractory bipolar
depression, particularly in the treatment of symptoms such as anhedonia.

PMCID: PMC4350513
PMID: 25313512 [PubMed - in process]

188. Br J Pharmacol. 2014 Apr;171(8):2230-42. doi: 10.1111/bph.12494.

A pilot study of plasma metabolomic patterns from patients treated with ketamine
for bipolar depression: evidence for a response-related difference in
mitochondrial networks.

Villaseñor A(1), Ramamoorthy A, Silva dos Santos M, Lorenzo MP, Laje G, Zarate C
Jr, Barbas C, Wainer IW.

Author information:
(1)Center for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia,
Universidad CEU San Pablo, Madrid, Spain.

BACKGROUND AND PURPOSE: (R,S)-ketamine produces rapid and significant
antidepressant effects in approximately 65% of patients suffering from
treatment-resistant bipolar depression (BD). The genetic, pharmacological and
biochemical differences between ketamine responders and non-responders have not
been identified. The purpose of this study was to employ a metabolomics approach,
a global, non-targeted determination of endogenous metabolic patterns, to
identify potential markers of ketamine response and non-response.
EXPERIMENTAL APPROACH: Plasma samples from 22 BD patients were analyzed to
produce metabolomic patterns. The patients had received ketamine in a
placebo-controlled crossover study and the samples were obtained 230 min
post-administration at which time the patients were categorized as responders or
non-responders. Matching plasma samples from the placebo arm of the study were
also analysed. During the study, the patients were maintained on either lithium
or valproate.
KEY RESULTS: The metabolomic patterns were significantly different between the
patients maintained on lithium and those maintained on valproate, irrespective of
response to ketamine. In the patients maintained on lithium, 18 biomarkers were
identified. In responders, lysophosphatidylethanolamines (4) and
lysophosphatidylcholines (9) were increased relative to non-responders.
CONCLUSIONS AND IMPLICATIONS: The results indicate that the differences between
patients who respond to ketamine and those who do not are due to alterations in
the mitochondrial β-oxidation of fatty acids. These differences were not produced
by ketamine administration. The data indicate that pretreatment metabolomics
screening may be a guide to the prediction of response and a potential approach
to the individualization of ketamine therapy.

PMCID: PMC3976632
PMID: 24684390 [PubMed - indexed for MEDLINE]

197. Bipolar Disord. 2014 Mar;16(2):119-28. doi: 10.1111/bdi.12118. Epub 2013 Sep 18.

Neural correlates of rapid antidepressant response to ketamine in bipolar
disorder.

Nugent AC(1), Diazgranados N, Carlson PJ, Ibrahim L, Luckenbaugh DA, Brutsche N,
Herscovitch P, Drevets WC, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, NIMH, NIH, Bethesda, MD,
USA.

OBJECTIVES: Ketamine, an N-methyl d-aspartate (NMDA) antagonist, has rapid
antidepressant effects in depressed subjects with bipolar disorder (BD). Evidence
supports a role for the glutamatergic system in the pathophysiology of BD. This
double-blind, randomized, cross-over study sought to determine cerebral metabolic
correlates of antidepressant response to ketamine.
METHODS: Twenty-one subjects with BD currently in a depressed state underwent
[(18) F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging
after receiving a placebo infusion as well as after receiving a ketamine
infusion. Metabolism was compared between ketamine and placebo infusions, and
correlated with clinical response. Regional metabolic rate of glucose (rMRGlu) in
regions of interest (ROIs) and Montgomery-Åsberg Depression Rating Scale (MADRS)
scores were the main outcome measures.
RESULTS: The study found that change in metabolism between sessions was
significantly correlated with percentage change in MADRS scores in the right
ventral striatum; subjects who showed the greatest improvement had the largest
metabolic increase after ketamine infusion compared to placebo. In a voxel-wise
analysis, subjects with BD had significantly lower glucose metabolism in the left
hippocampus following the ketamine infusion than following the placebo infusion.
In addition, metabolism in the subgenual anterior cingulate cortex (ACC)
following the placebo infusion was positively correlated with percentage
improvement in MADRS score following the ketamine infusion.
CONCLUSIONS: Taken together, the results suggest that higher activity in the
subgenual ACC may predict antidepressant response to ketamine. Ketamine
administration altered glucose metabolism in areas known to be involved in mood
disorders; these alterations may partially underlie ketamine's mechanism of
action.

Published 2013. This article is a U.S. Government work and is in the public
domain in the USA.

PMCID: PMC3949142
PMID: 24103187 [PubMed - indexed for MEDLINE]

220. Psychiatr Pol. 2014 Jan-Feb;48(1):35-47.

[Factors connected with efficacy of single ketamine infusion in bipolar
depression].

[Article in Polish]

Permoda-Osip A, Skibińska M, Bartkowska-Sniatkowska A, Kliwicki S,
Chłopocka-Woźniak M, Rybakowski JK.

AIM: The aim of this study was to evaluate the efficacy of single ketamine
infusion and clinical and biochemical factors connected with such efficacy, in
patients with bipolar depression, which had not improved on antidepressant
treatment.
METHODS: The study included 42 patients (32 women, 10 men), aged 22-67 years,
with bipolar depression. They received > or = 1 mood-stabilizing medications of
first and/or second generation. After discontinuation of antidepressants (> or =
7 days), intravenous infusion of ketamine (0.5 mg/kg body weight) was performed.
The assessment of depression by the 17-item Hamilton Depression Rating Scale was
made before, and after 1, 3, 7 and 14 days following administration of ketamine.
The assumed criterion for clinical improvement was the reduction of > or = 50%
score on the Hamilton scale after 7 days. In a subgroup of 20 patients, prior to
administration of ketamine, serum concentrations of homocysteine, vitamin B12,
folic acid, neurotrophins and inflammatory proteins were measured.
RESULTS: In the whole group, the severity of depression on the Hamilton scale
decreased significantly 24 hours after administration of ketamine from 22.6 +/-
5.1 to 15.6 +/- 7.4 points. After 7 days it was 13 +/- 7 and after 14 days - 11.8
+/- 7.8 points. Patients showing clinical improvement (n = 22) had significantly
higher frequency of alcohol addiction and family history of alcoholism.
Biochemical tests in the subset of 20 patients demonstrated that those with
clinical improvement (n = 10) had higher serum concentrations of vitamin B12 and
receptor-1 Vascular Endothelial Growth Factor before administration of ketamine.
Ketamine infusion was well tolerated.
CONCLUSIONS: The results confirm a rapid antidepressant effect of ketamine
infusion maintaining for 2 weeks, in a considerable proportion of patients with
bipolar depression, and good clinical tolerance of such procedure. Also, some
clinical and biochemical factors associated with ketamine efficacy were shown.

PMID: 24946433 [PubMed - indexed for MEDLINE]

237. Int J Neuropsychopharmacol. 2013 Oct;16(9):2111-7. doi:
10.1017/S1461145713000485. Epub 2013 May 20.

Antidepressant, mood stabilizing and procognitive effects of very low dose
sublingual ketamine in refractory unipolar and bipolar depression.

Lara DR(1), Bisol LW, Munari LR.

Author information:
(1)Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.

Intravenous ketamine (0.5 mg/kg) produces robust, rapid and long-lasting
antidepressant effects, but is unpractical. Sublingual administration of ketamine
renders better bioavailability (~30%) and less conversion to norketamine than
oral administration. We evaluated the therapeutic effects and tolerability of
very low dose sublingual (VLDS) racemic ketamine (10 mg from a 100 mg/ml solution
for 5 min and swallowed), repeatedly administered every 2-3 d or weekly, in 26
out-patients with refractory unipolar or bipolar depression. According to
patients' reports, VLDS ketamine produced rapid, clear and sustained effects,
improving mood level and stability, cognition and sleep in 20 patients (77%),
with only mild and transient light-headedness as a common side-effect (no
euphoria, psychotic or dissociative symptoms). Remission remained in some
patients after stopping ketamine. Thus, VLDS ketamine may have broad spectrum
effects beyond its antidepressant properties, with rapid onset of action, high
efficacy, good tolerability and low cost, allowing extended treatment as needed.

PMID: 23683309 [PubMed - indexed for MEDLINE]

275. J Affect Disord. 2013 May;147(1-3):431-6. doi: 10.1016/j.jad.2012.08.040. Epub
2012 Nov 30.

Clinical experience using intranasal ketamine in the treatment of pediatric
bipolar disorder/fear of harm phenotype.

Papolos DF(1), Teicher MH, Faedda GL, Murphy P, Mattis S.

Author information:
(1)Juvenile Bipolar Research Foundation, Maplewood, NJ, USA.
demitri@optonline.net

OBJECTIVES: Intravenous ketamine, a glutamate N-methyl-d-aspartate (NMDA)
receptor antagonist, has been shown to exert a rapid antidepressant effect in
adults with treatment resistant depression. Children with bipolar disorder (BD)
often respond poorly to pharmacotherapy, including polypharmacy. A
pediatric-onset Fear of Harm (FOH) phenotype has been described, and is
characterized by severe clinical features and resistance to accepted treatments
for BD. The potential efficacy and safety of intranasal ketamine in children with
BD with FOH-phenotype were assessed by a systematic retrospective chart review of
a case series from the private practice of one of the authors, including cases
with clear refractoriness to mood stabilizers, antipsychotics and
benzodiazepines.
METHODS: A comparison was made between routinely collected symptom measures 1-2
weeks prior to and after the administration of ketamine, in 12
treatment-refractory youth, 10 males 2 females ages 6-19years.
RESULTS: Ketamine administration was associated with a substantial reduction in
measures of mania, fear of harm and aggression. Significant improvement was
observed in mood, anxiety and behavioral symptoms, attention/executive functions,
insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated.
CONCLUSIONS: Intranasal ketamine administration in treatment-resistant youth with
BD-FOH produced marked improvement in all symptomatic dimensions. A rapid,
substantial therapeutic response, with only minimal side effects was observed.
Formal clinical trials to assess safety and efficacy are warranted.

PMID: 23200737 [PubMed - indexed for MEDLINE]

295. Hum Psychopharmacol. 2013 Jan;28(1):87-90. doi: 10.1002/hup.2271. Epub 2012 Nov
5.

Single ketamine infusion in bipolar depression resistant to antidepressants: are
neurotrophins involved?

Rybakowski JK(1), Permoda-Osip A, Skibinska M, Adamski R, Bartkowska-Sniatkowska
A.

Author information:
(1)Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan,
Poland. rybakows@wlkp.top.pl

OBJECTIVES: We investigated serum brain-derived neurotrophin factor (BDNF), nerve
growth factor (NGF), neurotrophin-3 (NTF3), neurotrophin-4 (NTF4) and the
glial-derived neurotrophic factor (GDNF), in relation to ketamine efficacy, in
bipolar depressed patients resistant to treatment with antidepressants.
METHODS: Twenty-five patients (4 male, 21 female), aged 27-67 years, with bipolar
depression, receiving mood-stabilizing medications, were studied. Antidepressants
were discontinued for at least 7 days before single intravenous ketamine infusion
(0.5 mg/kg body weight). Response to ketamine was defined as ≥ 50% reduction on
17-item Hamilton Depression Rating Scale (HDRS) after 1 week, and remission as
HDRS score ≤ 7. Serum BDNF, NGF, NTF3, NTF4 and GDNF levels were estimated by
enzyme-linked immunosorbent assay.
RESULTS: There were 13 ketamine responders and 12 non-responders. The remission
was obtained in eight and 12 patients after seven and 14 days, respectively. At
baseline, there were no differences between responders and non-responders in any
of the neurotrophins. Serum BDNF was significantly reduced after 7 days in
non-responders. Serum NGF, NT3, NT4 and GDNF did not significantly change.
CONCLUSIONS: The results confirm an antidepressant effect of ketamine infusion as
an add-on to mood-stabilizing drugs in bipolar depression resistant to
antidepressant treatment. They may also suggest a possible involvement of BDNF in
this effect.

PMID: 23124710 [PubMed - indexed for MEDLINE]

318. Br J Clin Pharmacol. 2012 Aug;74(2):304-14. doi:
10.1111/j.1365-2125.2012.04198.x.

Simultaneous population pharmacokinetic modelling of ketamine and three major
metabolites in patients with treatment-resistant bipolar depression.

Zhao X(1), Venkata SL, Moaddel R, Luckenbaugh DA, Brutsche NE, Ibrahim L, Zarate
CA Jr, Mager DE, Wainer IW.

Author information:
(1)Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo,
NY, USA.

AIM: To construct a population pharmacokinetic (popPK) model for ketamine (Ket),
norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine
(2S,6S;2R,6R)-HNK) and hydroxyketamine (HK) in patients with treatment-resistant
bipolar depression.
METHOD: Plasma samples were collected at 40, 80, 110, 230 min on day 1, 2 and 3
in nine patients following a 40 min infusion of (R,S)-Ket (0.5 mg kg⁻¹) and
analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)-HNK,
(2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK. A compartmental popPK model was
constructed that included all quantified analytes, and unknown parameters were
estimated with an iterative two-stage algorithm in ADAPT5.
RESULTS: Ket, norKet, DHNK and (2S,6S;2R,6R)-HNK were present during the first
230 min post infusion and significant concentrations (>5 ng ml⁻¹) were observed
on day 1. Plasma concentrations of (2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK were
below the limit of quantification. The average (S) : (R) plasma concentrations
for Ket and DHNK were <1.0 while no significant enantioselectivity was observed
for norKet. There were large inter-patient variations in terminal half-lives and
relative metabolite concentrations; at 230 min (R,S)-DHNK was the major
metabolite in four out of nine patients, (R,S)-norKet in three out of nine
patients and (2S,6S;2R,6R)-HNK in two out of nine patients. The final PK model
included three compartments for (R,S)-Ket, two compartments for (R,S)-norKet and
single compartments for DHNK and HNK. All PK profiles were well described, and
parameters for (R,S)-Ket and (R,S)-norKet were in agreement with prior estimates.
CONCLUSION: This represents the first PK analysis of (2S,6S;2R,6R)-HNK and
(R,S)-DHNK. The results demonstrate that while norKet is the initial metabolite,
it is not the main metabolite suggesting that future Ket studies should include
the analysis of the major metabolites.

Published 2012. This article is a U.S. Government work and is in the public
domain in the USA.

PMCID: PMC3630750

400. Ugeskr Laeger. 2010 Feb 8;172(6):460-1.

[Ketamine in melancholic depression].

[Article in Danish]

Bjerre J(1), Fontenay C.

Author information:
(1)Psykiatrien i Region Syddanmark, Esbjerg, Denmark. johannesbjerre@hotmail.com

Comment in
Ugeskr Laeger. 2010 Mar 15;172(11):899; author reply 899.

A 35-year-old male known with bipolar disorder was admitted after a suicide
attempt with cuts in both wrists. The patient had a major depression with
melancholic symptoms and nihilistic delusions. To relieve the patient's agony in
the days before electroconvulsive therapy and to reduce the risk of suicide, the
patient was treated with S-ketamine 0,5 mg/kg. The patient's symptoms were
reduced two hours after treatment and the effect was measurable for five days.

PMID: 20146912 [PubMed - indexed for MEDLINE]

Ketamine & Bipolar

1. J Psychiatr Res. 2015 Oct;69:67-71. doi: 10.1016/j.jpsychires.2015.07.023. Epub
2015 Jul 23.

Comparison of plasma MicroRNA levels in drug naive, first episode depressed
patients and healthy controls.

Camkurt MA(1), Acar Ş(2), Coşkun S(3), Güneş M(4), Güneş S(5), Yılmaz MF(6),
Görür A(7), Tamer L(7).

Author information:
(1)Afşin State Hospital, Psychiatry Clinic, Kahramanmaraş, Turkey. Electronic
address: dr.akif@gmail.com. (2)Mersin University, Teaching Hospital, Psychiatry
Department, Mersin, Turkey. (3)Dicle University, Faculty of Medicine, Department
of Medical Genetics, Diyarbakır, Turkey. (4)Dicle University, Faculty of
Medicine, Psychiatry Department, Diyarbakır, Turkey. (5)Mersin University,
Teaching Hospital Child and Adolescent Psychiatry Department, Mersin, Turkey.
(6)Kahramanmaraş State Hospital, Kahramanmaraş, Turkey. (7)Mersin University,
Teaching Hospital, Clinical Biochemistry Department, Mersin, Turkey.

Major depression is the most common psychiatric disorder. The diagnosis of
depression depends on a patient's subjective complaints, and the nature of the
heterogeneous disorder. Thus, there is no known biomarker for depression to date.
Previous research has indicated that microRNAs are dysregulated in bipolar
disorder and schizophrenia. We aimed to investigate microRNA dysregulation in
plasma samples of patients with major depression. Venous blood samples of 50
depressed patients and 41 healthy controls were collected and the quantification
of microRNAs was established using qRT-PCR. We found miR-320a significantly
downregulated and miR-451a significantly upregulated in depressed patients. We
also found miR-17-5p and miR-223-3p upregulated, but not as significantly as
miR-451a. Merging our results with previous published data shows that the blood
miR-320 family may be a potential microRNA family dysregulated in major
depression. Research should be performed on miR-320-related pathways and their
relationship to depression. Additionally, miR-451a could serve as a candidate
biomarker for depression based on the acting mechanism of ketamine. Studies
targeting miR-451a levels before and after treatment could be helpful.

PMID: 26343596 [PubMed - in process]

2. Cochrane Database Syst Rev. 2015 Sep 29;9:CD011611. doi:
10.1002/14651858.CD011611.pub2.

Ketamine and other glutamate receptor modulators for depression in bipolar
disorder in adults.

McCloud TL(1), Caddy C, Jochim J, Rendell JM, Diamond PR, Shuttleworth C, Brett
D, Amit BH, McShane R, Hamadi L, Hawton K, Cipriani A.

Author information:
(1)Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford,
UK.

BACKGROUND: There is emerging evidence that glutamatergic system dysfunction
might play an important role in the pathophysiology of bipolar depression. This
review focuses on the use of glutamate receptor modulators for depression in
bipolar disorder.
OBJECTIVES: 1. To assess the effects of ketamine and other glutamate receptor
modulators in alleviating the acute symptoms of depression in people with bipolar
disorder.2. To review the acceptability of ketamine and other glutamate receptor
modulators in people with bipolar disorder who are experiencing acute depression
symptoms.
SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review
Group's Specialised Register (CCDANCTR, to 9 January 2015). This register
includes relevant randomised controlled trials (RCTs) from: the Cochrane Library
(all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to
date). We cross-checked reference lists of relevant papers and systematic
reviews. We did not apply any restrictions to date, language or publication
status.
SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing ketamine,
memantine, or other glutamate receptor modulators with other active psychotropic
drugs or saline placebo in adults with bipolar depression.
DATA COLLECTION AND ANALYSIS: At least two review authors independently selected
studies for inclusion, assessed trial quality and extracted data. Primary
outcomes for this review were response rate and adverse events. Secondary
outcomes included remission rate, depression severity change scores, suicidality,
cognition, quality of life, and dropout rate. We contacted study authors for
additional information.
MAIN RESULTS: Five studies (329 participants) were included in this review. All
included studies were placebo-controlled and two-armed, and the glutamate
receptor modulators - ketamine (two trials), memantine (two trials), and cytidine
(one trial) - were used as add-on drugs to mood stabilisers. The treatment period
ranged from a single intravenous administration (all ketamine studies), to
repeated administration for memantine and cytidine (8 to 12 weeks, and 12 weeks,
respectively). Three of the studies took place in the USA, one in Taiwan, and in
one, the location was unclear. The majority (70.5%) of participants were from
Taiwan. All participants had a primary diagnosis of bipolar disorder, according
to the DSM-IV or DSM-IV-TR, and were in a current depressive phase. The severity
of depression was at least moderate in all but one study.Among all glutamate
receptor modulators included in this review, only ketamine appeared to be more
efficacious than placebo 24 hours after the infusion for the primary outcome,
response rate (odds ratio (OR) 11.61, 95% confidence interval (CI) 1.25 to
107.74; P = 0.03; I² = 0%, 2 studies, 33 participants). This evidence was rated
as low quality. The statistically significant difference disappeared at three
days, but the mean estimate still favoured ketamine (OR 8.24, 95% CI 0.84 to
80.61; 2 studies, 33 participants; very low quality evidence). We found no
difference in response between ketamine and placebo at one week (OR 4.00, 95% CI
0.33 to 48.66; P = 0.28, 1 study; 18 participants; very low quality
evidence).There was no significant difference between memantine and placebo in
response rate one week after treatment (OR 1.08, 95% CI 0.06 to 19.05; P = 0.96,
1 study, 29 participants), two weeks (OR 4.88, 95% CI 0.78 to 30.29; P = 0.09, 1
study, 29 participants), four weeks (OR 5.33, 95% CI 1.02 to 27.76; P = 0.05, 1
study, 29 participants), or at three months (OR, 1.66, 95% CI 0.69 to 4.03; P =
0.26, I² = 36%, 2 studies, 261 participants). These findings were based on very
low quality evidence.There was no significant difference between cytidine and
placebo in response rate at three months (OR, 1.13, 95% CI 0.30 to 4.24; P =
0.86, 1 study, 35 participants; very low quality evidence).For the secondary
outcome of remission, no significant differences were found between ketamine and
placebo, nor between memantine and placebo. For the secondary outcome of change
scores from baseline on depression scales, ketamine was more effective than
placebo at 24 hours (MD -11.81, 95% CI -20.01 to -3.61; P = 0.005, 2 studies, 32
participants) but not at one or two weeks after treatment. There was no
difference between memantine and placebo for this outcome.We found no significant
differences in terms of adverse events between placebo and ketamine, memantine,
or cytidine. There were no differences between ketamine and placebo, memantine
and placebo, or cytidine and placebo in total dropouts. No data were available on
dropouts due to adverse effects for ketamine or cytidine; but no difference was
found between memantine and placebo.
AUTHORS' CONCLUSIONS: Reliable conclusions from this review are severely limited
by the small amount of data usable for analysis. The body of evidence about
glutamate receptor modulators in bipolar disorder is even smaller than that which
is available for unipolar depression. Overall, we found limited evidence in
favour of a single intravenous dose of ketamine (as add-on therapy to mood
stabilisers) over placebo in terms of response rate up to 24 hours; ketamine did
not show any better efficacy in terms of remission in bipolar depression. Even
though ketamine has the potential to have a rapid and transient antidepressant
effect, the efficacy of a single intravenous dose may be limited. Ketamine's
psychotomimetic effects could compromise study blinding; this is a particular
issue for this review as no included study used an active comparator, and so we
cannot rule out the potential bias introduced by inadequate blinding
procedures.We did not find conclusive evidence on adverse events with ketamine.
To draw more robust conclusions, further RCTs (with adequate blinding) are needed
to explore different modes of administration of ketamine and to study different
methods of sustaining antidepressant response, such as repeated administrations.
There was not enough evidence to draw meaningful conclusions for the remaining
two glutamate receptor modulators (memantine and cytidine). This review is
limited not only by completeness of evidence, but also by the low to very low
quality of the available evidence.

PMID: 26415966 [PubMed - in process]

3. World J Psychiatry. 2015 Sep 22;5(3):330-41. doi: 10.5498/wjp.v5.i3.330.

Pharmacologic approaches to treatment resistant depression: Evidences and
personal experience.

Tundo A(1), de Filippis R(1), Proietti L(1).

Author information:
(1)Antonio Tundo, Rocco de Filippis, Luca Proietti, Istituto di Psicopatologia,
Private Outpatients Clinic, 00196 Roma, Italy.

AIM: To review evidence supporting pharmacological treatments for
treatment-resistant depression (TRD) and to discuss them according to personal
clinical experience.
METHODS: Original studies, clinical trials, systematic reviews, and meta-analyses
addressing pharmacological treatment for TRD in adult patients published from
1990 to 2013 were identified by data base queries (PubMed, Google Scholar e
Quertle Searches) using terms: "treatment resistant depression", "treatment
refractory depression", "partial response depression", "non responder
depression", "optimization strategy", "switching strategy", "combination
strategy", "augmentation strategy", selective serotonin reuptake inhibitors
antidepressants (SSRI), tricyclic antidepressants (TCA), serotonin norepinephrine
reuptake inhibitors antidepressants, mirtazapine, mianserine, bupropione,
monoamine oxidase inhibitor antidepressant (MAOI), lithium, thyroid hormones,
second generation antipsychotics (SGA), dopamine agonists, lamotrigine,
psychostimulants, dextromethorphan, dextrorphan, ketamine, omega-3 fatty acids,
S-adenosil-L-metionine, methylfolat, pindolol, sex steroids, glucocorticoid
agents. Other citations of interest were further identified from references
reported in the accessed articles. Selected publications were grouped by
treatment strategy: (1) switching from an ineffective antidepressant (AD) to a
new AD from a similar or different class; (2) combining the current AD regimen
with a second AD from a different class; and (3) augmenting the current AD
regimen with a second agent not thought to be an antidepressant itself.
RESULTS: Switching from a TCA to another TCA provides only a modest advantage
(response rate 9%-27%), while switching from a SSRI to another SSRI is more
advantageous (response rate up to 75%). Evidence supports the usefulness of
switching from SSRI to venlafaxine (5 positive trials out 6), TCA (2 positive
trials out 3), and MAOI (2 positive trials out 2) but not from SSRI to
bupropione, duloxetine and mirtazapine. Three reviews demonstrated that the
benefits of intra- and cross-class switch do not significantly differ. Data on
combination strategy are controversial regarding TCA-SSRI combination (positive
results in old studies, negative in more recent study) and bupropion-SSRI
combination (three open series studies but not three controlled trails support
the useful of this combination) and positive regard mirtazapine (or its analogue
mianserine) combination with ADs of different classes. As regards the
augmentation strategy, available evidences supported the efficacy of TCA
augmentation with lithium salts and thyroid hormone (T3), but are conflicting
regard the SSRI augmentation with these two drugs (1 positive trial out of 4 for
lithium and 3 out of 5 for thyroid hormone). Double-blind controlled studies
showed the efficacy of AD augmentation with aripiprazole (5 positive trials out
5), quetiapine (3 positive trials out 3) and, at less extent, of fluoxetine
augmentation with olanzapine (3 positive trials out 6), so these drugs received
the FDA indication for the acute treatment of TRD. Results on AD augmentation
with risperidone are conflicting (2 short term positive trials, 1 short-term and
1 long-term negative trials). Case series and open-label trials showed that AD
augmentation with pramipexole or ropinirole, two dopamine agonists, could be an
effective treatment for TRD (response rate to pramipexole 48%-74%, to ropinirole
40%-44%) although one recent double-blind placebo-controlled study does not
support the superiority of pramipexole over placebo. Evidences do not justify the
use of psychostimulants, omega-3 fatty acids, S-adenosil-L-metionine,
methylfolate, pindolol, lamotrigine, and sex hormone as AD augmentation for TRD.
Combining the available evidences with our experience we suggest treating
non-responders to one SSRI bupropion or mirtazapine trial by switching to
venlafaxine, and non-responders to one venlafaxine trial by switching to a TCA
or, if TCA are not tolerated, combining mirtazapine with SSRI or venlafaxine. In
non-responders to two or more ADs (including at least one TCA if tolerated)
current AD regimen could be augmented with lithium salts (mainly in patients with
bipolar depression or suicidality), SGAs (mostly aripiprazole) or DA-agonists
(mostly pramipexole). In patients with severe TRD, i.e., non-responders to
combination and augmentation strategies as well as to electroconvulsive therapy
if workable, we suggest to try a combination plus augmentation strategy.
CONCLUSION: Our study identifies alternative effective treatment strategies for
TRD. Further studies are needed to compare the efficacy of different strategies
in more homogeneous subpopulations.

PMCID: PMC4582308
PMID: 26425446 [PubMed]

4. Physiol Rep. 2015 Sep;3(9). pii: e12554. doi: 10.14814/phy2.12554.

Effects of leptin on sympathetic nerve activity in conscious mice.

Morgan DA(1), Despas F(2), Rahmouni K(3).

Author information:
(1)Department of Pharmacology, University of Iowa Carver College of Medicine,
Iowa City, Iowa. (2)Department of Internal Medicine, University of Iowa Carver
College of Medicine, Iowa City, Iowa. (3)Department of Pharmacology, University
of Iowa Carver College of Medicine, Iowa City, Iowa Department of Internal
Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
kamal-rahmouni@uiowa.edu.

The adipocyte-derived hormone, leptin, has emerged as an important regulator of
regional sympathetic nerve activity (SNA) with pathophysiological implications in
obesity. Genetically engineered mice are useful to understand the molecular
pathways underlying the SNA responses evoked by leptin. However, so far the
effect of leptin on direct SNA in mice has been studied under general anesthesia.
Here, we examined the sympathetic responses evoked by leptin in conscious mice.
Mice were instrumented, under ketamine/xylazine anesthesia, with renal or lumbar
SNA recordings using a thin (40 gauge) bipolar platinum-iridium wire. The
electrodes were exteriorized at the nape of the neck and mice were allowed (5 h)
to recover from anesthesia. Interestingly, the reflex increases in renal and
lumbar SNA caused by sodium nitroprusside (SNP)-induced hypotension was higher in
the conscious phase versus the anesthetized state, whereas the increase in both
renal and lumbar SNA evoked by leptin did not differ between anesthetized or
conscious mice. Next, we assessed whether isoflurane anesthesia would yield a
better outcome. Again, the SNP-induced increase in renal SNA and
baroreceptor-renal SNA reflex were significantly elevated in the conscious states
relative to isoflurane-anesthetized phase, but the renal SNA response induced by
leptin in the conscious states were qualitatively comparable to those evoked
above. Thus, despite improvement in sympathetic reflexes in conscious mice the
sympathetic responses evoked by leptin mimic those induced during anesthesia.

© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on
behalf of the American Physiological Society and The Physiological Society.

PMCID: PMC4600394
PMID: 26381017 [PubMed]

5. Mol Psychiatry. 2015 Aug 18. doi: 10.1038/mp.2015.112. [Epub ahead of print]

Understanding and predicting suicidality using a combined genomic and clinical
risk assessment approach.

Niculescu AB(1), Levey DF(2), Phalen PL(3), Le-Niculescu H(4), Dainton HD(4),
Jain N(4), Belanger E(3), James A(3), George S(3), Weber H(3), Graham DL(4),
Schweitzer R(4), Ladd TB(4), Learman R(4), Niculescu EM(4), Vanipenta NP(4), Khan
FN(4), Mullen J(5), Shankar G(5), Cook S(6), Humbert C(6), Ballew A(6), Yard
M(7), Gelbart T(8), Shekhar A(4), Schork NJ(9), Kurian SM(8), Sandusky GE(7),
Salomon DR(8).

Author information:
(1)1] Department of Psychiatry, Indiana University School of Medicine,
Indianapolis, IN, USA [2] Stark Neuroscience Research Institute, Indiana
University School of Medicine, Indianapolis, IN, USA [3] Indianapolis VA Medical
Center, Indianapolis, IN, USA. (2)1] Department of Psychiatry, Indiana University
School of Medicine, Indianapolis, IN, USA [2] Stark Neuroscience Research
Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
(3)Indianapolis VA Medical Center, Indianapolis, IN, USA. (4)Department of
Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
(5)Advanced Biomedical IT Core, Indiana University School of Medicine,
Indianapolis, IN, USA. (6)Marion County Coroner's Office, Indianapolis, IN, USA.
(7)INBRAIN, Indiana University School of Medicine, Indianapolis, IN, USA.
(8)Department of Molecular and Experimental Medicine, The Scripps Research
Institute, La Jolla, CA, USA. (9)J. Craig Venter Institute, La Jolla, CA, USA.

Worldwide, one person dies every 40 seconds by suicide, a potentially preventable
tragedy. A limiting step in our ability to intervene is the lack of objective,
reliable predictors. We have previously provided proof of principle for the use
of blood gene expression biomarkers to predict future hospitalizations due to
suicidality, in male bipolar disorder participants. We now generalize the
discovery, prioritization, validation, and testing of such markers across major
psychiatric disorders (bipolar disorder, major depressive disorder,
schizoaffective disorder, and schizophrenia) in male participants, to understand
commonalities and differences. We used a powerful within-participant discovery
approach to identify genes that change in expression between no suicidal ideation
and high suicidal ideation states (n=37 participants out of a cohort of 217
psychiatric participants followed longitudinally). We then used a convergent
functional genomics (CFG) approach with existing prior evidence in the field to
prioritize the candidate biomarkers identified in the discovery step. Next, we
validated the top biomarkers from the prioritization step for relevance to
suicidal behavior, in a demographically matched cohort of suicide completers from
the coroner's office (n=26). The biomarkers for suicidal ideation only are
enriched for genes involved in neuronal connectivity and schizophrenia, the
biomarkers also validated for suicidal behavior are enriched for genes involved
in neuronal activity and mood. The 76 biomarkers that survived Bonferroni
correction after validation for suicidal behavior map to biological pathways
involved in immune and inflammatory response, mTOR signaling and growth factor
regulation. mTOR signaling is necessary for the effects of the rapid-acting
antidepressant agent ketamine, providing a novel biological rationale for its
possible use in treating acute suicidality. Similarly, MAOB, a target of
antidepressant inhibitors, was one of the increased biomarkers for suicidality.
We also identified other potential therapeutic targets or biomarkers for drugs
known to mitigate suicidality, such as omega-3 fatty acids, lithium and
clozapine. Overall, 14% of the top candidate biomarkers also had evidence for
involvement in psychological stress response, and 19% for involvement in
programmed cell death/cellular suicide (apoptosis). It may be that in the face of
adversity (stress), death mechanisms are turned on at a cellular (apoptosis) and
organismal level. Finally, we tested the top increased and decreased biomarkers
from the discovery for suicidal ideation (CADM1, CLIP4, DTNA, KIF2C),
prioritization with CFG for prior evidence (SAT1, SKA2, SLC4A4), and validation
for behavior in suicide completers (IL6, MBP, JUN, KLHDC3) steps in a completely
independent test cohort of psychiatric participants for prediction of suicidal
ideation (n=108), and in a future follow-up cohort of psychiatric participants
(n=157) for prediction of psychiatric hospitalizations due to suicidality. The
best individual biomarker across psychiatric diagnoses for predicting suicidal
ideation was SLC4A4, with a receiver operating characteristic (ROC) area under
the curve (AUC) of 72%. For bipolar disorder in particular, SLC4A4 predicted
suicidal ideation with an AUC of 93%, and future hospitalizations with an AUC of
70%. SLC4A4 is involved in brain extracellular space pH regulation. Brain pH has
been implicated in the pathophysiology of acute panic attacks. We also describe
two new clinical information apps, one for affective state (simplified affective
state scale, SASS) and one for suicide risk factors (Convergent Functional
Information for Suicide, CFI-S), and how well they predict suicidal ideation
across psychiatric diagnoses (AUC of 85% for SASS, AUC of 89% for CFI-S). We
hypothesized a priori, based on our previous work, that the integration of the
top biomarkers and the clinical information into a universal predictive measure
(UP-Suicide) would show broad-spectrum predictive ability across psychiatric
diagnoses. Indeed, the UP-Suicide was able to predict suicidal ideation across
psychiatric diagnoses with an AUC of 92%. For bipolar disorder, it predicted
suicidal ideation with an AUC of 98%, and future hospitalizations with an AUC of
94%. Of note, both types of tests we developed (blood biomarkers and clinical
information apps) do not require asking the individual assessed if they have
thoughts of suicide, as individuals who are truly suicidal often do not share
that information with clinicians. We propose that the widespread use of such risk
prediction tests as part of routine or targeted healthcare assessments will lead
to early disease interception followed by preventive lifestyle modifications and
proactive treatment.Molecular Psychiatry advance online publication, 18 August
2015; doi:10.1038/mp.2015.112.

PMID: 26283638 [PubMed - as supplied by publisher]

6. Biol Psychiatry. 2015 Jul 29. pii: S0006-3223(15)00608-3. doi:
10.1016/j.biopsych.2015.07.014. [Epub ahead of print]

Interaction of Ketamine and Cannabis in Bipolar Disorder.

Hasselmann H(1).

Author information:
(1)Clinic for Psychiatry and Psychotherapy and NeuroCure Clinical Research
Center, Charité Universitätsmedizin Berlin, Berlin, Germany. Electronic address:
helge.hasselmann@charite.de.

PMID: 26382597 [PubMed - as supplied by publisher]

7. Biol Psychiatry. 2015 Jul 7. pii: S0006-3223(15)00572-7. doi:
10.1016/j.biopsych.2015.07.003. [Epub ahead of print]

Possible Affective Switch Associated with Intravenous Ketamine Treatment in a
Patient with Bipolar I Disorder.

Alison McInnes L(1), James-Myers MB(2), Turner MS(2).

Author information:
(1)Department of Psychiatry, Kaiser Permanente, San Francisco, California.
Electronic address: Alison.mcinnes@kp.org. (2)Department of Psychiatry, Kaiser
Permanente, San Francisco, California.

PMID: 26229040 [PubMed - as supplied by publisher]

8. Indian J Pharmacol. 2015 Jul-Aug;47(4):454-5. doi: 10.4103/0253-7613.161277.

Ketamine-induced affective switch in a patient with treatment-resistant
depression.

Banwari G(1), Desai P(1), Patidar P(1).

Author information:
(1)Department of Psychiatry, Smt. N. H. L. Municipal Medical College and Sheth V.
S. General Hospital, Ahmedabad, Gujarat, India.

There is growing evidence to support the rapid, albeit short-lived antidepressant
effect of subanesthetic dose of ketamine, a noncompetitive glutamate
N-methyl-D-aspartate receptor antagonist in treatment-resistant unipolar and
bipolar depression. Ketamine is known to cause transient mood elevation or
euphoria, psychotomimetic effects, and dissociative symptoms, but its use in
unipolar or bipolar depression has not been reported to induce an affective
switch amounting to persistent or prolonged hypomania/mania or manic-like
syndrome. We report the case of a 52-year-old male with first episode,
continuous, nonpsychotic, treatment-resistant, unipolar major depression of 10
years duration, who manifested a switch from depression to mania while being
treated with subanesthetic dose of ketamine, given intramuscularly. This case
suggests that polarity switch should be considered as a potential side effect
while using ketamine for treatment-resistant depression.

PMCID: PMC4527073
PMID: 26288483 [PubMed - in process]

9. Neurochem Res. 2015 Jul;40(7):1421-30. doi: 10.1007/s11064-015-1610-5. Epub 2015
May 22.

Preventive Effect of Cecropia pachystachya Against Ketamine-Induced Manic
Behavior and Oxidative Stress in Rats.

Gazal M(1), Kaufmann FN, Acosta BA, Oliveira PS, Valente MR, Ortmann CF,
Sturbelle R, Lencina CL, Stefanello FM, Kaster MP, Reginatto FH, Ghisleni G.

Author information:
(1)Programa de Pós-Graduação em Saúde e Comportamento, Centro de Ciências da Vida
e da Saúde, Universidade Católica de Pelotas, Rua Gonçalves Chaves 373, Pelotas,
RS, 96015560, Brazil.

Cecropia species are widely used in traditional medicine by its anti-diabetic,
anti-hypertensive and anti-inflammatory properties. In the present study, we
investigated the neuroprotective and antioxidant effects of the crude aqueous
extract from Cecropia pachystachya leaves in a rat model of mania induced by
ketamine. The results indicated that ketamine treatment (25 mg/kg i.p., for
8 days) induced hyperlocomotion in the open-field test and oxidative damage in
prefrontal cortex and hippocampus, evaluated by increased lipid peroxidation,
carbonyl protein formation and decreased total thiol content. Moreover, ketamine
treatment reduced the activity of the antioxidant enzymes superoxide dismutase
and catalase in hippocampus. Pretreatment of rats with C. pachystachya aqueous
extract (200 and 400 mg/kg p.o., for 14 days) or with lithium chloride (45 mg/kg
p.o., for 14 days, used as a positive control) prevented both behavioral and
pro-oxidant effects of ketamine. These findings suggest that C. pachystachya
might be a useful tool for preventive intervention in bipolar disorder, reducing
the episode relapse and the oxidative damage associated with the manic phase of
this disorder .

PMID: 25998886 [PubMed - in process]

10. Peptides. 2015 Jul;69:66-76. doi: 10.1016/j.peptides.2015.04.003. Epub 2015 Apr
13.

Ketamine modulates TRH and TRH-like peptide turnover in brain and peripheral
tissues of male rats.

Pekary AE(1), Sattin A(2), Lloyd RL(3).

Author information:
(1)Research Services, VA Greater Los Angeles Healthcare System, University of
California, Los Angeles, CA 90073, United States; Center for Ulcer Research and
Education, VA Greater Los Angeles Healthcare System, University of California,
Los Angeles, CA 90073, United States; Department of Medicine, University of
California, Los Angeles, CA 90073, United States. Electronic address:
Albert.Pekary@va.gov. (2)Research Services, VA Greater Los Angeles Healthcare
System, University of California, Los Angeles, CA 90073, United States;
Psychiatry Services, VA Greater Los Angeles Healthcare System, University of
California, Los Angeles, CA 90073, United States; Departments of Psychiatry &
Biobehavioral Sciences, University of California, Los Angeles, CA 90073, United
States; Brain Research Institute, University of California, Los Angeles, CA
90073, United States. (3)Department of Psychology, University of Minnesota, 332
Bohannon Hall, 10 University Drive, Duluth, MN 55812-2494, United States.

Major depression is the largest single healthcare burden with treatments of slow
onset and often limited efficacy. Ketamine, a NMDA antagonist used extensively as
a pediatric and veterinary anesthetic, has recently been shown to be a rapid
acting antidepressant, making it a potential lifesaver for suicidal patients.
Side effects and risk of abuse limit the chronic use of ketamine. More complete
understanding of the neurobiochemical mechanisms of ketamine should lead to safer
alternatives. Some of the physiological and pharmacological actions of ketamine
are consistent with increased synthesis and release of TRH (pGlu-His-Pro-NH2),
and TRH-like peptides (pGlu-X-Pro-NH2) where "X" can be any amino acid residue.
Moreover, TRH-like peptides are themselves potential therapeutic agents for the
treatment of major depression, anxiety, bipolar disorder, epilepsy, Alzheimer's
and Parkinson's diseases. For these reasons, male Sprague-Dawley rats were
anesthetized with 162 mg/kg ip ketamine and then infused intranasally with 20 μl
of sterile saline containing either 0 or 5 mg/ml Glu-TRH. One, 2 or 4h later, the
brain levels of TRH and TRH-like peptides were measured in various brain regions
and peripheral tissues. At 1h in brain following ketamine only, the levels of TRH
and TRH-like peptides were significantly increased in 52 instances (due to
increased biosynthesis and/or decreased release) or decreased in five instances.
These changes, listed by brain region in order of decreasing number of
significant increases (↑) and/or decreases (↓), were: hypothalamus (9↑); piriform
cortex (8↑); entorhinal cortex (7↑); nucleus accumbens (7↑); posterior cingulate
(5↑); striatum (4↑); frontal cortex (2↑,3↓); amygdala (3↑); medulla oblongata
(1↑,2↓); cerebellum (2↑); hippocampus (2↑); anterior cingulate (2↑). The
corresponding changes in peripheral tissues were: adrenals (8↑); epididymis (4↑);
testis (1↑,3↓); pancreas (1↑); prostate (1↑). We conclude that TRH and TRH-like
peptides may be downstream mediators of the rapid antidepressant actions of
ketamine.

Published by Elsevier Inc.

PMID: 25882008 [PubMed - in process]

11. Int J Neuropsychopharmacol. 2015 Jun 2;18(11). pii: pyv063. doi:
10.1093/ijnp/pyv063.

Restoration of Sp4 in Forebrain GABAergic Neurons Rescues Hypersensitivity to
Ketamine in Sp4 Hypomorphic Mice.

Higa KK(1), Ji B(1), Buell MR(1), Risbrough VB(1), Powell SB(1), Young JW(1),
Geyer MA(1), Zhou X(2).

Author information:
(1)Department of Psychiatry, University of California San Diego, La Jolla, CA (Ms
Higa, Drs Ji, Risbrough, Powell, Young, Geyer, and Zhou, and Ms Buell); Research
Service, VA San Diego Healthcare System, La Jolla, CA (Drs Risbrough, Powell,
Young, Geyer, and Zhou, and Ms Buell); Neurosciences Graduate Program, University
of California San Diego, La Jolla, CA (Ms Higa). (2)Department of Psychiatry,
University of California San Diego, La Jolla, CA (Ms Higa, Drs Ji, Risbrough,
Powell, Young, Geyer, and Zhou, and Ms Buell); Research Service, VA San Diego
Healthcare System, La Jolla, CA (Drs Risbrough, Powell, Young, Geyer, and Zhou,
and Ms Buell); Neurosciences Graduate Program, University of California San
Diego, La Jolla, CA (Ms Higa). xzhou@ucsd.edu.

BACKGROUND: Ketamine produces schizophrenia-like behavioral phenotypes in healthy
people. Prolonged ketamine effects and exacerbation of symptoms after the
administration of ketamine have been observed in patients with schizophrenia.
More recently, ketamine has been used as a potent antidepressant to treat
patients with major depression. The genes and neurons that regulate behavioral
responses to ketamine, however, remain poorly understood. Sp4 is a transcription
factor for which gene expression is restricted to neuronal cells in the brain.
Our previous studies demonstrated that Sp4 hypomorphic mice display several
behavioral phenotypes relevant to psychiatric disorders, consistent with human
SP4 gene associations with schizophrenia, bipolar disorder, and major depression.
Among those behavioral phenotypes, hypersensitivity to ketamine-induced
hyperlocomotion has been observed in Sp4 hypomorphic mice.
METHODS: In the present study, we used the Cre-LoxP system to restore Sp4 gene
expression, specifically in either forebrain excitatory or GABAergic inhibitory
neurons in Sp4 hypomorphic mice. Mouse behavioral phenotypes related to
psychiatric disorders were examined in these distinct rescue mice.
RESULTS: Restoration of Sp4 in forebrain excitatory neurons did not rescue
deficient sensorimotor gating nor ketamine-induced hyperlocomotion. Restoration
of Sp4 in forebrain GABAergic neurons, however, rescued ketamine-induced
hyperlocomotion, but did not rescue deficient sensorimotor gating.
CONCLUSIONS: Our studies suggest that the Sp4 gene in forebrain GABAergic neurons
regulates ketamine-induced hyperlocomotion.

PMID: 26037489 [PubMed - in process]

12. Bipolar Disord. 2015 Jun;17(4):438-43. doi: 10.1111/bdi.12277. Epub 2014 Nov 14.

A single infusion of ketamine improves depression scores in patients with anxious
bipolar depression.

Ionescu DF(1,)(2), Luckenbaugh DA(3), Niciu MJ(3), Richards EM(3), Zarate CA
Jr(3).

Author information:
(1)Depression Clinical and Research Program, Massachusetts General Hospital,
Boston, MA, USA. (2)Harvard Medical School, Boston, MA, USA. (3)Experimental
Therapeutics and Pathophysiology Branch, Intramural Research Program, National
Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.

OBJECTIVE: Patents with anxious bipolar disorder have worse clinical outcomes and
are harder to treat with traditional medication regimens compared to those with
non-anxious bipolar disorder. Ketamine has been shown to rapidly and robustly
decrease symptoms of depression in depressed patients with bipolar disorder. We
sought to determine whether baseline anxiety status reduced ketamine's ability to
decrease symptoms of depression.
METHODS: Thirty-six patients with anxious (n = 21) and non-anxious (n = 15)
treatment-resistant bipolar depression (types I and II; concurrently treated with
either lithium or valproate) received a single infusion of ketamine (0.5 mg/kg)
over 40 min. Post-hoc analyses compared changes in the Montgomery-Åsberg
Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) in
anxious versus non-anxious depressed patients with bipolar disorder through 14
days post-infusion. Anxious bipolar depression was defined as DSM-IV bipolar
depression plus a HDRS Anxiety/Somatization Factor score of ≥ 7.
RESULTS: A linear mixed model revealed a significant effect of anxiety group on
the MADRS (p = 0.04) and HDRS (p = 0.04). Significant drug effects (all p <
0.001) suggested that both anxious and non-anxious groups had an antidepressant
response to ketamine. The drug-by-anxiety interactions were not significant (all
p > 0.28).
CONCLUSIONS: Both anxious and non-anxious patients with bipolar depression had
significant antidepressant responses to ketamine, although the anxious depressed
group did not show a clear antidepressant response disadvantage over the
non-anxious group. Given that anxiety has been shown to be a predictor of poor
treatment response in bipolar depression when traditional treatments are used,
our findings suggest a need for further investigations into ketamine's novel role
in the treatment of anxious bipolar depression.

Published 2014. This article is a U.S. Government work and is in the public
domain in the USA.

PMCID: PMC4431955 [Available on 2016-06-01]
PMID: 25400146 [PubMed - in process]

13. J Clin Psychiatry. 2015 Jun;76(6):738-40. doi: 10.4088/JCP.15com09904.

Maintaining the initial clinical response after ketamine in bipolar and unipolar
depression: an important next-step challenge.

Iosifescu DV(1).

Author information:
(1)One Gustave L. Levy Pl, Box 1230, New York, NY 10029 dan.iosifescu@mssm.edu.

Comment on
J Clin Psychiatry. 2015 Jun;76(6):737-8.

PMID: 26132676 [PubMed - indexed for MEDLINE]

14. J Clin Psychiatry. 2015 Jun;76(6):737-8. doi: 10.4088/JCP.14l09527.

Single-dose ketamine followed by daily D-Cycloserine in treatment-resistant
bipolar depression.

Kantrowitz JT(1), Halberstam B, Gangwisch J.

Author information:
(1)jk3380@cumc.columbia.edu.

Comment in
J Clin Psychiatry. 2015 Jun;76(6):738-40.

PMID: 26132675 [PubMed - indexed for MEDLINE]

15. Aust N Z J Psychiatry. 2015 May 26. pii: 0004867415586601. [Epub ahead of print]

Changes in cortical N-methyl-d-aspartate receptors and post-synaptic density
protein 95 in schizophrenia, mood disorders and suicide.

Dean B(1), Gibbons AS(1), Boer S(2), Uezato A(3), Meador-Woodruff J(4), Scarr
E(1), McCullumsmith RE(5).

Author information:
(1)Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and
Mental Health, Parkville, VIC, Australia Psychiatric Neuropathology Laboratory,
Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia.
(2)Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and
Mental Health, Parkville, VIC, Australia. (3)Department of Psychiatry and
Behavioral Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
(4)Department of Psychiatry, University of Alabama Birmingham, Birmingham, AL,
USA. (5)Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA.

OBJECTIVES: In humans, depending on dose, blocking the N-methyl-d-aspartate
receptor (NMDAR) with ketamine can cause psychomimetic or antidepressant effects.
The overall outcome for drugs such as ketamine depends on dose and the number of
its available binding sites in the central nervous system, and to understand
something of the latter variable we measure NMDAR in the frontal pole,
dorsolateral prefrontal, anterior cingulate and parietal cortices from people
with schizophrenia, bipolar disorder, major depressive disorders and age/sex
matched controls.
METHOD: We measured levels of NMDARs (using [(3)H]MK-801 binding) and NMDAR
sub-unit mRNAs (GRINs: using in situ hybridisation) as well as post-synaptic
density protein 95 (anterior cingulate cortex only; not major depressive
disorders: an NMDAR post-synaptic associated protein) in bipolar disorder,
schizophrenia and controls.
RESULTS: Compared to controls, levels of NMDAR were lower in the outer laminae of
the dorsolateral prefrontal cortex (-17%, p = 0.01) in people with schizophrenia.
In bipolar disorder, levels of NMDAR binding (laminae IV-VI; -19%, p < 0.01) and
GRIN2C mRNA (laminae I-VI; -27%, p < 0.05) were lower in the anterior cingulate
cortex and NMDAR binding was lower in the outer lamina IV of the dorsolateral
prefrontal cortex (-19%, p < 0.01). In major depressive disorders, levels of
GRIN2D mRNA were higher in frontal pole (+22%, p < 0.05). In suicide completers,
levels of GRIN2B mRNA were higher in parietal cortex (+20%, p < 0.01) but lower
(-35%, p = 0.02) in dorsolateral prefrontal cortex while post-synaptic density
protein 95 was higher (+26%, p < 0.05) in anterior cingulate cortex.
CONCLUSION: These data suggest that differences in cortical NMDAR expression and
post-synaptic density protein 95 are present in psychiatric disorders and suicide
completion and may contribute to different responses to ketamine.

PMID: 26013316 [PubMed - as supplied by publisher]

16. Ann N Y Acad Sci. 2015 May;1345:47-58. doi: 10.1111/nyas.12646. Epub 2015 Feb 3.

The promise of ketamine for treatment-resistant depression: current evidence and
future directions.

DeWilde KE(1), Levitch CF(1), Murrough JW(1), Mathew SJ(2), Iosifescu DV(1).

Author information:
(1)Mood and Anxiety Disorders Program, Icahn School of Medicine at Mount Sinai,
New York, New York. (2)Menninger Department of Psychiatry and Behavioral
Sciences, Baylor College of Medicine, Houston, Texas.

Major depressive disorder (MDD) is one of the most disabling diseases worldwide
and is becoming a significant public health threat. Current treatments for MDD
primarily consist of monoamine-targeting agents and have limited efficacy.
However, the glutamate neurotransmitter system has recently come into focus as a
promising alternative for novel antidepressant treatments. We review the current
data on the glutamate NMDA receptor antagonist ketamine, which has been shown in
clinical trials to act as a rapid antidepressant in MDD. We also examine ketamine
efficacy on dimensions of psychopathology, including anhedonia, cognition, and
suicidality, consistent with the NIMH Research Domain Criteria initiative. Other
aspects of ketamine reviewed in this paper include safety and efficacy, different
administration methods, and the risks of misuse of ketamine outside of medical
settings. Finally, we conclude with a discussion of glutamatergic agents other
than ketamine currently being tested as novel antidepressants.

PMCID: PMC4447578 [Available on 2016-05-01]
PMID: 25649308 [PubMed - indexed for MEDLINE]

17. Hum Psychopharmacol. 2015 May;30(3):152-63. doi: 10.1002/hup.2475. Epub 2015 Apr
7.

The use of ketamine as an antidepressant: a systematic review and meta-analysis.

Coyle CM(1), Laws KR.

Author information:
(1)School of Life and Medical Sciences, University of Hertfordshire, Hatfield,
UK.

OBJECTIVE: The current meta-analysis examines the effects of ketamine infusion on
depressive symptoms over time in major depressive disorder (MDD) and bipolar
disorder (BD).
METHODS: Following a systematic review of the literature, data were extracted
from 21 studies (n = 437 receiving ketamine) and analysed at four post-infusion
time points (4 h, 24 h, 7 days and 12-14 days). The moderating effects of several
factors were assessed including: repeat/single infusion, diagnosis,
open-label/participant-blind infusion, pre-post/placebo-controlled design and the
sex of patients.
RESULTS: Effect sizes were significantly larger for repeat than single infusion
at 4 h, 24 h and 7 days. For single infusion studies, effect sizes were large and
significant at 4 h, 24 h and 7 days. The percentage of males was a predictor of
antidepressant response at 7 days. Effect sizes for open-label and
participant-blind infusions were not significantly different at any time point.
CONCLUSIONS: Single ketamine infusions elicit a significant antidepressant effect
from 4 h to 7 days; the small number of studies at 12-14 days post infusion
failed to reach significance. Results suggest a discrepancy in peak response time
depending upon primary diagnosis - 24 h for MDD and 7 days for BD. The majority
of published studies have used pre-post comparison; further placebo-controlled
studies would help to clarify the effect of ketamine over time.

PMID: 25847818 [PubMed - in process]

18. Ther Adv Chronic Dis. 2015 May;6(3):97-114. doi: 10.1177/2040622315579059.

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of
depression: a perspective review.

Iadarola ND(1), Niciu MJ(1), Richards EM(1), Vande Voort JL(1), Ballard ED(1),
Lundin NB(1), Nugent AC(1), Machado-Vieira R(1), Zarate CA Jr(2).

Author information:
(1)National Institutes of Health/National Institute of Mental Health,
Experimental Therapeutics and Pathophysiology Branch, Bethesda, MD, USA.
(2)National Institutes of Health/National Institute of Mental Health,
Experimental Therapeutics and Pathophysiology Branch, 10 Center Dr., Building
10/CRC, Room 7-5545, Bethesda, MD 20892, USA.

Current pharmacotherapies for major depressive disorder (MDD) and bipolar
depression (BDep) have a distinct lag of onset that can generate great distress
and impairment in patients. Furthermore, as demonstrated by several real-world
effectiveness trials, their efficacy is limited. All approved antidepressant
medications for MDD primarily act through monoaminergic mechanisms, agonists or
antagonists with varying affinities for serotonin, norepinephrine and dopamine.
The glutamate system has received much attention in recent years as an avenue for
developing novel therapeutics. A single subanesthetic dose infusion of the
noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been
shown to have rapid and potent antidepressant effects in treatment-resistant MDD
and BDep. In a reverse translational framework, ketamine's clinical efficacy has
inspired many preclinical studies to explore glutamatergic mechanisms of
antidepressant action. These studies have revealed enhanced synaptic
plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release
of local translational inhibition of brain-derived neurotrophic factor and
secretion from dendritic spines, mammalian target of rapamycin activation and
glycogen synthase kinase-3 inhibition. Current efforts are focused on extending
ketamine's antidepressant efficacy, uncovering the neurobiological mechanisms
responsible for ketamine's antidepressant activity in biologically enriched
subgroups, and identifying treatment response biomarkers to personalize
antidepressant selection. Other NMDA receptor antagonists have been studied both
preclinically and clinically, which have revealed relatively modest
antidepressant effects compared with ketamine but potentially other favorable
characteristics, for example, decreased dissociative or psychotomimetic effects;
therefore, there is great interest in developing novel glutamatergic
antidepressants with greater target specificity and/or decreased adverse effects.

PMCID: PMC4416968
PMID: 25954495 [PubMed]

19. J Med Case Rep. 2015 Mar 31;9:73. doi: 10.1186/s13256-015-0520-0.

Ketamine and transcranial magnetic stimulation treatment for bipolar II disorder:
a case report.

Best SR(1), Griffin BP(2), Pavel DG(3).

Author information:
(1)The Neuroscience Center, 440 Lake Cook Road, Building 2, Deerfield, IL, 60015,
USA. srdbest@neuroscience.md. (2)Independent Practice, 333 East Ontario Suite
1203B, Chicago, IL, USA. blotdoc@aol.com. (3)PathFinder Brain SPECT, 440 Lake
Cook Road, Suite 3, Deerfield, IL, 60015, USA. danpavel@yahoo.com.

INTRODUCTION: To the best of our knowledge, this is the first case report of
successful treatment for bipolar II disorder using a combined ketamine and
transcranial magnetic stimulation treatment.
CASE PRESENTATION: A 43-year-old Caucasian unemployed man presented to us with
treatment-resistant bipolar II disorder, currently in a mixed state. A
psychometric assessment and brain single-photon emission computer tomography scan
were conducted at baseline. His psychometric assessment revealed severe
depressive and manic symptoms that were consistent with bipolar II disorder.
Findings from a brain single-photon emission computer tomography scan converged
with those from his psychometric assessment. The combined ketamine and
transcranial magnetic stimulation treatment was administered a total of 24 times
over five months, with his ketamine dosage increased from 50mg at the first
treatment to 600 mg by the last. Starting after the second treatment, he reported
substantial improvements in his symptoms. A follow-up psychometric assessment and
brain single-photon emission computer tomography scan five months later revealed
substantial blood flow increases in the previously deficient areas.
CONCLUSIONS: We provide preliminary evidence for a treatment method that
magnifies the therapeutic benefits of infused ketamine along with transcranial
magnetic stimulation. We postulate that this may be based on an interaction at
the level of the relevant cortico-thalamo-cortical circuit(s).

PMCID: PMC4391108
PMID: 25890258 [PubMed - in process]

20. CNS Drugs. 2015 Mar;29(3):181-8. doi: 10.1007/s40263-015-0232-4.

Does ketamine have anti-suicidal properties? Current status and future
directions.

Price RB(1), Mathew SJ.

Author information:
(1)Department of Psychiatry, University of Pittsburgh School of Medicine, 3811
O'Hara St., Pittsburgh, PA, 15213, USA, rebecca.price@stanfordalumni.org.

Ketamine, a widely used anesthetic agent, is currently being investigated as a
novel therapeutic for depression and suicidality. Ketamine has garnered
substantial attention from researchers, clinicians, media outlets, and patients
alike, but numerous questions remain. One of the compelling features of ketamine
is the rapidity of its antidepressant effects, which peak just 24 h after
infusion, setting it apart from other existing treatments. Ketamine's rapid time
course has inspired research efforts to explore its potential as a life-saving
therapy for patients at imminent risk of suicide. In this article, we review
current evidence supporting the rapid effects of ketamine on suicidal ideation in
the context of unipolar and bipolar depression. We then discuss several future
directions that are necessary before ketamine can be considered a viable
treatment option for suicidality in clinical settings. These include: testing for
a specific anti-suicidal effect-separate from overall antidepressant effects-to
ascertain whether ketamine might hold promise for a broader class of suicidal
patients; ensuring that acute benefits of ketamine can be prolonged over a
clinically meaningful timeframe; and developing a better understanding of the
mechanisms by which ketamine might reduce suicide risk. Such efforts will enable
the field to more accurately assess the potential of ketamine, as well as its
limitations, allowing for appropriate placement within the context of
comprehensive clinical care for suicide prevention.

PMCID: PMC4380583 [Available on 2016-03-01]
PMID: 25715884 [PubMed - in process]

21. Gen Hosp Psychiatry. 2015 Mar-Apr;37(2):178-84. doi:
10.1016/j.genhosppsych.2015.01.003. Epub 2015 Jan 15.

Ketamine as a novel treatment for major depressive disorder and bipolar
depression: a systematic review and quantitative meta-analysis.

Lee EE(1), Della Selva MP(1), Liu A(1), Himelhoch S(1).

Author information:
(1)Department of Psychiatry, University of Maryland School of Medicine,
Baltimore, MD.

OBJECTIVE: Given the significant disability, morbidity and mortality associated
with depression, the promising recent trials of ketamine highlight a novel
intervention. A meta-analysis was conducted to assess the efficacy of ketamine in
comparison with placebo for the reduction of depressive symptoms in patients who
meet criteria for a major depressive episode.
METHOD: Two electronic databases were searched in September 2013 for
English-language studies that were randomized placebo-controlled trials of
ketamine treatment for patients with major depressive disorder or bipolar
depression and utilized a standardized rating scale. Studies including
participants receiving electroconvulsive therapy and adolescent/child
participants were excluded. Five studies were included in the quantitative
meta-analysis.
RESULTS: The quantitative meta-analysis showed that ketamine significantly
reduced depressive symptoms. The overall effect size at day 1 was large and
statistically significant with an overall standardized mean difference of 1.01
(95% confidence interval 0.69-1.34) (P<.001), with the effects sustained at 7
days postinfusion. The heterogeneity of the studies was low and not statistically
significant, and the funnel plot showed no publication bias.
CONCLUSIONS: The large and statistically significant effect of ketamine on
depressive symptoms supports a promising, new and effective pharmacotherapy with
rapid onset, high efficacy and good tolerability.

PMID: 25698228 [PubMed - in process]

22. J Psychiatr Res. 2015 Mar;62:23-30. doi: 10.1016/j.jpsychires.2015.01.003. Epub
2015 Jan 26.

A systematic review and meta-analysis of randomized controlled trials of
adjunctive ketamine in electroconvulsive therapy: efficacy and tolerability.

McGirr A(1), Berlim MT(2), Bond DJ(3), Neufeld NH(4), Chan PY(5), Yatham LN(6),
Lam RW(7).

Author information:
(1)Department of Psychiatry, University of British Columbia, Vancouver, BC,
Canada. Electronic address: alexander.mcgirr@alumni.ubc.ca. (2)Neuromodulation
Research Clinic, Douglas Mental Health University Institute and McGill
University, Montréal, Québec, Canada; Depressive Disorders Program, Douglas
Mental Health University Institute and McGill University, Montréal, Québec,
Canada. (3)Department of Psychiatry, University of Minnesota, Minneapolis, MN,
USA. (4)Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
(5)Department of Psychiatry, University of British Columbia, Vancouver, BC,
Canada; Neurostimulation Service, Vancouver General Hospital, Vancouver, BC,
Canada. (6)Mood Disorders Centre of Excellence, University of British Columbia,
Vancouver, BC, Canada. (7)Department of Psychiatry, University of British
Columbia, Vancouver, BC, Canada; Mood Disorders Centre of Excellence, University
of British Columbia, Vancouver, BC, Canada.

Comment in
J Psychiatr Res. 2015 Sep;68:283-4.
J Psychiatr Res. 2015 Sep;68:226-7.

BACKGROUND: Electroconvulsive therapy (ECT) remains one of the most effective
tools in the psychiatric treatment armamentarium, particularly for refractory
depression. Yet, there remains a subset of patients who do not respond to ECT or
for whom clinically adequate seizures cannot be elicited, for whom ketamine has
emerged as a putative augmentation agent.
METHODS: We searched EMBASE, PsycINFO, CENTRAL, and MEDLINE from 1962 to April
2014 to identify randomized controlled trials evaluating ketamine in ECT
(PROSPERO #CRD42014009035). Clinical remission, response, and change in
depressive symptom scores were extracted by two independent raters. Adverse
events were recorded. Drop-outs were assessed as a proxy for acceptability.
Meta-analyses employed a random effects model.
RESULTS: Data were synthesized from 5 RCTs, representing a total of 182 patients
with major depressive episodes (n = 165 Major Depressive Disorder, n = 17 Bipolar
Disorder). ECT with ketamine augmentation was not associated with higher rates of
clinical remission (Risk Difference (RD) = 0.00; 95%CI = -0.08 to 0.10), response
(RD = -0.01; 95%CI = -0.11 to 0.08), or improvements in depressive symptoms (SMD
= 0.38; 95%CI = -0.41 to 1.17). Ketamine augmentation was associated with higher
rates of confusion/disorientation/prolonged delirium (OR = 6.59, 95%CI:
1.28-33.82, NNH = 3), but not agitation, hypertension or affective switches.
CONCLUSION: Our meta-analysis of randomized controlled trials of ketamine
augmentation in the ECT setting suggests a lack of clinical efficacy, and an
increased likelihood of confusion. Individuals for whom adequate seizures or
therapeutic response cannot be obtained have not been studied using randomized
controlled designs. Additional research is required to address the role of
ketamine in this population.

PMID: 25684151 [PubMed - in process]

23. Pharmacopsychiatry. 2015 Mar;48(2):78-9. doi: 10.1055/s-0034-1394399. Epub 2014
Oct 27.

Single ketamine infusion and neurocognitive performance in bipolar depression.

Permoda-Osip A(1), Kisielewski J(1), Bartkowska-Sniatkowska A(2), Rybakowski
JK(1).

Author information:
(1)Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan,
Poland. (2)Department of Pediatric Anaesthesiology and Intensive Therapy, Poznan
University of Medical Sciences, Poznan, Poland.

We estimated neurocognitive performance using the trail making test (TMT) and the
Stroop color-word interference test before, and on the 3(rd) day after a single
infusion of ketamine, in 18 bipolar depressed patients receiving mood-stabilizing
drugs. The performance on all tests significantly improved on the 3(rd) day after
ketamine infusion which correlated positively with baseline intensity of
neuropsychological impairment and was not associated either with baseline
intensity of depression or reduction of depressive symptoms after 3 or 7 days.
The results suggest that in such population of patients, single ketamine infusion
may improve neuropsychological performance independently of antidepressant
effect.

PMID: 25347227 [PubMed - in process]

24. Psychol Med. 2015 Mar;45(4):693-704. doi: 10.1017/S0033291714001603. Epub 2014
Jul 10.

A systematic review and meta-analysis of randomized, double-blind,
placebo-controlled trials of ketamine in the rapid treatment of major depressive
episodes.

McGirr A(1), Berlim MT(2), Bond DJ(3), Fleck MP(4), Yatham LN(1), Lam RW(1).

Author information:
(1)Department of Psychiatry,University of British Columbia,Vancouver, BC,Canada.
(2)Neuromodulation Research Clinic,Douglas Mental Health University Institute and
McGill University,Montréal, Québec,Canada. (3)Department of Psychiatry,University
of Minnesota,Minneapolis, MN,USA. (4)Depressive Disorders Program, Douglas Mental
Health University Institute and McGill University,Montréal, Québec,Canada.

BACKGROUND: There is growing interest in glutamatergic agents in depression,
particularly ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor
antagonist. We aimed to assess the efficacy of ketamine in major depressive
episodes.
METHOD: We searched EMBASE, PsycINFO, CENTRAL, and Medline from 1962 to January
2014 to identify double-blind, randomized controlled trials with allocation
concealment evaluating ketamine in major depressive episodes. Clinical remission,
response and depressive symptoms were extracted by two independent raters. The
primary outcome measure was clinical remission at 24 h, 3 days and 7 days
post-treatment. Analyses employed a random-effects model.
RESULTS: Data were synthesized from seven RCTs employing an intravenous infusion
and one RCT employing intranasal ketamine, representing 73 subjects in parallel
arms and 110 subjects in cross-over designs [n = 34 with bipolar disorder (BD), n
= 149 with major depressive disorder (MDD)]. Ketamine was associated with higher
rates of clinical remission relative to comparator (saline or midazolam) at 24 h
[OR 7.06, number needed to treat (NNT) = 5], 3 days (OR 3.86, NNT = 6), and 7
days (OR 4.00, NNT = 6), as well as higher rates of clinical response at 24 h (OR
9.10, NNT = 3), 3 days (OR 6.77, NNT = 3), and 7 days (OR 4.87, NNT = 4). A
standardized mean difference of 0.90 in favor of ketamine was observed at 24 h
based on depression rating scale scores, with group comparisons revealing greater
efficacy in unipolar depression compared to bipolar depression (1.07 v. 0.68).
Ketamine was associated with transient psychotomimetic effects, but no persistent
psychosis or affective switches.
CONCLUSION: Our meta-analysis suggests that single administrations ketamine are
efficacious in the rapid treatment of unipolar and bipolar depression. Additional
research is required to determine optimal dosing schedules, route, treatment
schedules, and the potential efficacy of other glutamatergic agents.

PMID: 25010396 [PubMed - in process]

25. Eur Neuropsychopharmacol. 2015 Feb;25(2):231-47. doi:
10.1016/j.euroneuro.2014.12.004. Epub 2015 Jan 19.

Cognition as a target in major depression: new developments.

Solé B(1), Jiménez E(1), Martinez-Aran A(1), Vieta E(2).

Author information:
(1)Barcelona Bipolar Disorders Program, Institute of Neurosciences, University of
Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain. (2)Barcelona Bipolar
Disorders Program, Institute of Neurosciences, University of Barcelona, IDIBAPS,
CIBERSAM, Barcelona, Catalonia, Spain. Electronic address: evieta@clinic.ub.es.

Major depressive disorder (MDD) is a highly prevalent and disabling psychiatric
illness often accompanied of cognitive dysfunction which may persist even when
patients achieve clinical remission. Currently, cognitive deficits emerge as a
potential target because they compromise the functional outcome of depressed
patients. The aim of this study was to review data for several potential
pharmacological treatments targeting cognition in MDD, resulting from monotherapy
or adjunctive treatment. An extensive and systematic Pubmed/Medline search of the
published literature until March 2014 was conducted using a variety of search
term to find relevant articles. Bibliographies of retrieved papers were further
examined for publications of interest. Searches were limited to articles
available in English language. We describe studies using modafinil,
lisdexamfetamine, ketamine, lanicemine, memantine, galantamine, donepezil,
vortioxetine, intranasal oxytocin, omega-3, s-adenosyl-methionine, scopolamine
and erythropoietin. From these articles, we determined that there are a number of
promising new therapies, pharmacological agents or complementary medicines, but
data are just emerging. Drugs and therapies targeting cognitive dysfunction in
MDD should prove effective in improving specific cognitive domains and
functioning, while ruling out pseudospecificity.

PMID: 25640673 [PubMed - in process]

26. J Psychiatr Res. 2015 Feb;61:40-5. doi: 10.1016/j.jpsychires.2014.12.015. Epub
2014 Dec 27.

Rating depression over brief time intervals with the Hamilton Depression Rating
Scale: standard vs. abbreviated scales.

Luckenbaugh DA(1), Ameli R(2), Brutsche NE(3), Zarate CA Jr(4).

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health, and
Department of Health and Human Services, Bethesda, MD, USA. Electronic address:
dave.luckenbaugh@nih.gov. (2)Experimental Therapeutics and Pathophysiology
Branch, Intramural Research Program, National Institute of Mental Health,
National Institutes of Health, and Department of Health and Human Services,
Bethesda, MD, USA. Electronic address: rezvan.ameli@nih.gov. (3)Experimental
Therapeutics and Pathophysiology Branch, Intramural Research Program, National
Institute of Mental Health, National Institutes of Health, and Department of
Health and Human Services, Bethesda, MD, USA. Electronic address:
nancy.brutsche@nih.gov. (4)Experimental Therapeutics and Pathophysiology Branch,
Intramural Research Program, National Institute of Mental Health, National
Institutes of Health, and Department of Health and Human Services, Bethesda, MD,
USA. Electronic address: zaratec@mail.nih.gov.

Although antidepressant trials typically use weekly ratings to examine changes in
symptoms over six to 12 weeks, antidepressant treatments may improve symptoms
more quickly. Thus, rating scales must be adapted to capture changes over shorter
intervals. We examined the use of the 17-item Hamilton Depression Rating Scale
(HDRS) to evaluate more rapid changes. Data were examined from 58 patients with
major depressive disorder or bipolar disorder enrolled in double-blind,
placebo-controlled, crossover studies who received a single infusion of ketamine
(0.5 mg/kg) or placebo over 40 min then crossed over to the other condition. HDRS
subscales, a single HDRS Depressed mood item, and a visual analogue scale were
used at baseline, after a brief interval (230 min), and one week post-infusion.
Effect sizes for the ketamine-placebo difference were moderate (d > 0.50), but
one and two-item HDRS subscales had the smallest effects. Response rates on
active drug were lowest for the complete HDRS (43%); the remaining scales had
higher response rates to active drug, but the shortest subscales had higher
response rates to placebo. Correlations between the changes from baseline to 230
min post-ketamine across scores were similar for most subscales (r = 0.82-0.97),
but correlations using the single items were lower (r < 0.74). Overall, effect
sizes for drug-placebo differences and correlations between changes were lower
for one- and two-item measures. Response rates were lower with the full HDRS
scale. The data suggest that, to best identify rapid antidepressant effects, a
scale should have more than two items, but fewer items than a full scale.

Published by Elsevier Ltd.

PMCID: PMC4308518 [Available on 2016-02-01]
PMID: 25592045 [PubMed - indexed for MEDLINE]

27. Am J Addict. 2015 Jan;24(1):7-9. doi: 10.1111/ajad.12153.

Intensive ketamine use for multiple years: A case report.

Liu JX(1), Zerbo E, Ross S.

Author information:
(1)New York University School of Medicine, New York, New York.

Ketamine is known within the medical field for its anesthetic properties, yet its
unique psychedelic and antidepressant properties are being increasingly
recognized. We document the case of a patient with bipolar I disorder and an
extensive history of substance dependence who used large doses of ketamine (1-3
g) on a daily basis over a period of 5 years, and described acute antidepressant
effects as well as diminished cravings for alcohol. While his use was untenable
and ultimately led to an inpatient admission, it is notable that he did not
experience a withdrawal syndrome nor did he have any observable cognitive
deficits upon cessation of use. Such a unique drug profile suggests that further
exploration of its risks and therapeutic potential in treating mood and addiction
disorders is warranted.

PMID: 25823629 [PubMed - in process]

28. Curr Mol Med. 2015;15(3):206-21.

Glutamate Signaling in Synaptogenesis and NMDA Receptors as Potential Therapeutic
Targets for Psychiatric Disorders.

Ohgi Y, Futamura T, Hashimoto K(1).

Author information:
(1)Division of Clinical Neuroscience, Chiba University Center for Forensic Mental
Health, 1- 8-1 Inohana, Chiba 260-8670, Japan. hashimoto@faculty.chiba-u.jp.

Glutamate, a major excitatory neurotransmitter, plays important roles in synaptic
plasticity, such as long-term potentiation (LTP) and new synapse formation.
Growing evidence suggests that glutamate signaling is involved in the
neurobiology of psychiatric disorders, including schizophrenia, major depressive
disorder (MDD) and bipolar disorder (BP). Postmortem brain studies demonstrated
altered spine density in brains from patients with these psychiatric disorders,
indicating that remodeled neuronal circuits may contribute to the pathobiology of
these psychiatric diseases. Drugs targeting the glutamate system have typically
attracted attention as they show efficacy in animal studies and potential
therapeutic effects in the clinical setting. In particular, the Nmethyl-
D-aspartate (NMDA) receptor antagonist, ketamine exerts a rapid and robust
antidepressant effect in treatment-resistant patients with MDD and BP, whereas
conventional antidepressants require several weeks for therapeutic onset. Animal
studies showed that ketamine induced rapid synaptogenesis, suggestive of synaptic
plasticity via NMDA receptor signaling being an essential event in the treatment
of depression. Therefore, drugs modulating glutamate signaling could also be
potential therapeutic drugs for psychiatric disorders. First, we summarize the
role of glutamate signaling on dendritic spine formation, maintenance and
remodeling. Then, we discuss the abnormalities identified in dendritic spine and
glutamate signaling from postmortem brain studies and animal models of
psychiatric disorders. Finally, we review the potential benefits of drugs acting
on the NMDA receptor in clinical and animal models of psychiatric disorders.

PMID: 25817855 [PubMed - in process]

29. Curr Neuropharmacol. 2015;13(5):592-604.

Pharmacological Approaches for Treatment-resistant Bipolar Disorder.

Hui Poon S, Sim K, Baldessarini RJ(1).

Author information:
(1)Department of General Psychiatry, Institute of Mental Health, 10, Buangkok
View, Singapore 539747.

Bipolar disorder is prevalent, with high risks of disability, substance abuse and
premature mortality. Treatment responses typically are incomplete, especially for
depressive components, so that many cases can be considered "treatment
resistant." We reviewed reports on experimental treatments for such patients:
there is a striking paucity of such research, mainly involving small incompletely
controlled trials of add-on treatment, and findings remain preliminary.
Encouraging results have been reported by adding aripiprazole, bupropion,
clozapine, ketamine, memantine, pramipexole, pregabalin, and perhaps
tri-iodothyronine in resistant manic or depressive phases. The urgency of
incomplete responses in such a severe illness underscores the need for more
systematic, simpler, and better controlled studies in more homogeneous samples of
patients.

PMID: 26467409 [PubMed - in process]

30. Neural Plast. 2015;2015:858251. doi: 10.1155/2015/858251. Epub 2015 Jun 7.

Lithium and Valproate Levels Do Not Correlate with Ketamine's Antidepressant
Efficacy in Treatment-Resistant Bipolar Depression.

Xu AJ(1), Niciu MJ(2), Lundin NB(2), Luckenbaugh DA(2), Ionescu DF(3), Richards
EM(2), Vande Voort JL(4), Ballard ED(2), Brutsche NE(2), Machado-Vieira R(2),
Zarate CA Jr(2).

Author information:
(1)New York Medical College, 40 Sunshine Cottage Road, Valhalla, NY 10595, USA.
(2)National Institute of Mental Health, National Institutes of Health,
Experimental Therapeutics and Pathophysiology Branch, 10 Center Drive, Building
10/CRC, Bethesda, MD 20892, USA. (3)Massachusetts General Hospital, Depression
Clinical & Research Program, 1 Bowdoin Square, 6th Floor, Boston, MA 02114, USA.
(4)Department of Psychiatry & Psychological Services, Mayo Clinic, 200 First
Street SW, Rochester, MN 55905, USA.

Ketamine and lithium both inhibit glycogen synthase kinase 3. In addition,
lithium and ketamine have synergistic antidepressant-like effects at individually
subeffective doses in rodents. We hypothesized that ketamine's antidepressant
effects would be improved by therapeutic doses of lithium versus valproate and
that serum lithium levels would positively correlate with ketamine's
antidepressant efficacy. Thirty-six patients with treatment-resistant bipolar
depression maintained on therapeutic-dose lithium (n = 23, 0.79 ± 0.15 mEq/L) or
valproate (n = 13, 79.6 ± 12.4 mg/mL) received 0.5 mg/kg ketamine infusion in a
randomized, double-blind, placebo-controlled, crossover trial. The primary
depression outcome measure-the Montgomery-Åsberg Depression Rating Scale
(MADRS)-was assessed before infusion and at numerous postinfusion time points.
Both lithium (F 1,118 = 152.08, p < 0.001, and d = 2.27) and valproate (F 1,128 =
20.12, p < 0.001, and d = 0.79) significantly improved depressive symptoms, but
no statistically significant difference was observed between mood stabilizer
groups (F 1,28 = 2.51, p = 0.12, and d = 0.60). Serum lithium and valproate
levels did not correlate with ketamine's antidepressant efficacy. Although the
study was potentially underpowered, our results suggest that lithium may not
potentiate ketamine's antidepressant efficacy in treatment-resistant bipolar
depression.

PMCID: PMC4475570
PMID: 26137324 [PubMed - in process]

31. J ECT. 2014 Dec;30(4):e50-1. doi: 10.1097/YCT.0000000000000167.

Combined ketamine/transcranial magnetic stimulation treatment of severe
depression in bipolar I disorder.

Best SR(1).

Author information:
(1)The Neuroscience Center Deerfield, IL srdbest@neuroscience.md.

PMID: 25054363 [PubMed - indexed for MEDLINE]

32. J Psychiatr Res. 2014 Nov;58:161-6. doi: 10.1016/j.jpsychires.2014.07.027. Epub
2014 Aug 12.

Improvement in suicidal ideation after ketamine infusion: relationship to
reductions in depression and anxiety.

Ballard ED(1), Ionescu DF(2), Vande Voort JL(2), Niciu MJ(2), Richards EM(2),
Luckenbaugh DA(2), Brutsché NE(2), Ameli R(2), Furey ML(2), Zarate CA Jr(2).

Author information:
(1)Experimental Therapeutics & Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health,
Bethesda, MD 20892, USA. Electronic address: Elizabeth.Ballard@nih.gov.
(2)Experimental Therapeutics & Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health,
Bethesda, MD 20892, USA.

OBJECTIVE: Suicide is a psychiatric emergency. Currently, there are no approved
pharmacologic treatments for suicidal ideation. Ketamine is an
N-methyl-D-aspartate (NMDA) receptor antagonist that rapidly reduces suicidal
ideation as well as depression and anxiety, but the dynamic between these
symptoms is not known. The aim of this analysis was to evaluate whether ketamine
has an impact on suicidal thoughts, independent of depressive and anxiety
symptoms.
METHODS: 133 patients with treatment-resistant depression (major depressive
disorder or bipolar I/II disorder) received a single subanesthetic infusion of
ketamine (0.5 mg/kg over 40 min). Post-hoc correlations and linear mixed models
evaluated the relationship between suicidal ideation and depression and anxiety
symptoms using the Hamilton Depression Rating Scale (HAMD), Scale for Suicidal
Ideation (SSI), Beck Depression Inventory (BDI), and Hamilton Anxiety Rating
Scale (HAMA) focusing on 230 min post-infusion.
RESULTS: At 230 min post-infusion, correlations between changes in suicidal
ideation and depression ranged from 0.23 to 0.44 (p < .05), accounting for up to
19% in the variance of ideation change. Correlations with anxiety ranged from
0.23 to 0.40 (p < .05), accounting for similar levels of variance. Ketamine
infusion was associated with significant reductions in suicidal ideation compared
to placebo, when controlling for the effects of ketamine on depression (F1,587 =
10.31, p = .001) and anxiety (F1,567 = 8.54, p = .004).
CONCLUSIONS: Improvements in suicidal ideation after ketamine infusion are
related to, but not completely driven by, improvements in depression and anxiety.
Investigation of the specific effects of ketamine on suicidal thoughts is
warranted.

Published by Elsevier Ltd.

PMCID: PMC4163501 [Available on 2015-11-01]
PMID: 25169854 [PubMed - in process]

33. Neurosci Biobehav Rev. 2014 Nov;47:336-58. doi: 10.1016/j.neubiorev.2014.08.017.
Epub 2014 Sep 16.

The role of NMDA receptors in the pathophysiology and treatment of mood
disorders.

Ghasemi M(1), Phillips C(2), Trillo L(3), De Miguel Z(4), Das D(5), Salehi A(5).

Author information:
(1)Department of Neurology, Johns Hopkins University School of Medicine,
Baltimore, MD, USA; Department of Neurology, University of Massachusetts Medical
School, Worcester, MA, USA. Electronic address: m82.ghasemi@gmail.com.
(2)Department of Physical Therapy, Arkansas State University, Jonesboro, AR, USA.
(3)Department of Psychiatry, Washington University, St. Louis, MO, USA.
(4)Department of Biological Sciences, Stanford University, Stanford, CA, USA.
(5)VA Palo Alto Health Care System, Palo Alto, CA, USA; Department of Psychiatry
and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA,
USA.

Mood disorders such as major depressive disorder and bipolar disorder are chronic
and recurrent illnesses that cause significant disability and affect
approximately 350 million people worldwide. Currently available biogenic amine
treatments provide relief for many and yet fail to ameliorate symptoms for
others, highlighting the need to diversify the search for new therapeutic
strategies. Here we present recent evidence implicating the role of
N-methyl-D-aspartate receptor (NMDAR) signaling in the pathophysiology of mood
disorders. The possible role of NMDARs in mood disorders has been supported by
evidence demonstrating that: (i) both BPD and MDD are characterized by altered
levels of central excitatory neurotransmitters; (ii) NMDAR expression,
distribution, and function are atypical in patients with mood disorders; (iii)
NMDAR modulators show positive therapeutic effects in BPD and MDD patients; and
(iv) conventional antidepressants/mood stabilizers can modulate NMDAR function.
Taken together, this evidence suggests the NMDAR system holds considerable
promise as a therapeutic target for developing next generation drugs that may
provide more rapid onset relief of symptoms. Identifying the subcircuits involved
in mood and elucidating the role of NMDARs subtypes in specific brain circuits
would constitute an important step toward the development of more effective
therapies with fewer side effects.

PMID: 25218759 [PubMed - indexed for MEDLINE]

34. Psychopharmacology (Berl). 2014 Nov;231(22):4417-8. doi:
10.1007/s00213-014-3773-1. Epub 2014 Oct 15.

Ketamine's effectiveness in unipolar versus bipolar depression.

Fond G(1), Boyer L.

Author information:
(1)Pôle de psychiatrie des hôpitaux universitaires H Mondor, DHU Pe-Psy INSERM
U955, Eq Psychiatrie Génétique, Fondation FondaMental Fondation de coopération
scientifique en santé mentale, Université Paris Est-Créteil, Créteil, France,
guillaume.fond@gmail.com.

Comment on
Psychopharmacology (Berl). 2014 Oct;231(19):3907-8.

PMID: 25315362 [PubMed - indexed for MEDLINE]

35. J Affect Disord. 2014 Oct 16;172C:307-311. doi: 10.1016/j.jad.2014.09.015. [Epub
ahead of print]

Shank3 as a potential biomarker of antidepressant response to ketamine and its
neural correlates in bipolar depression.

Ortiz R(1), Niciu MJ(1), Lukkahati N(2), Saligan LN(3), Nugent AC(1), Luckenbaugh
DA(1), Machado-Vieira R(1), Zarate CA Jr(4).

Author information:
(1)National Institutes of Health/National Institute of Mental Health,
Experimental Therapeutics & Pathophysiology Branch, Building 10/Clinical Research
Center (CRC), 10 Center Dr., Room 7-5342, Bethesda, MD 20892, USA. (2)National
Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA;
School of Nursing, University of Nevada at Las Vegas, Las Vegas, NV, USA.
(3)National Institute of Nursing Research, National Institutes of Health,
Bethesda, MD, USA. (4)National Institutes of Health/National Institute of Mental
Health, Experimental Therapeutics & Pathophysiology Branch, Building 10/Clinical
Research Center (CRC), 10 Center Dr., Room 7-5342, Bethesda, MD 20892, USA.
Electronic address: zaratec@mail.nih.gov.

BACKGROUND: Shank3, a post-synaptic density protein involved in
N-methyl-d-aspartate (NMDA) receptor tethering and dendritic spine rearrangement,
is implicated in the pathophysiology of bipolar disorder. We hypothesized that
elevated baseline plasma Shank3 levels might predict antidepressant response to
the NMDA receptor antagonist ketamine.
METHODS: Twenty-nine subjects with bipolar depression received a double-blind,
randomized, subanesthetic dose (.5mg/kg) ketamine infusion. Of the patients for
whom Shank3 levels were collected, 15 completed baseline 3-Tesla MRI and 17
completed post-ketamine [(18)F]-FDG PET.
RESULTS: Higher baseline Shank3 levels predicted antidepressant response at Days
1 (r=-.39, p=.047), 2 (r=-.45, p=.02), and 3 (r=-.42, p=.03) and were associated
with larger average (r=.58, p=.02) and right amygdala volume (r=.65, p=.009).
Greater baseline Shank3 also predicted increased glucose metabolism in the
hippocampus (r=.51, p=.04) and amygdala (r=.58, p=.02).
LIMITATIONS: Limitations include the small sample size, inability to assess the
source of peripheral Shank3, and the lack of a placebo group for baseline Shank3
levels and comparative structural/functional neuroimaging.
CONCLUSIONS: Shank3 is a potential biomarker of antidepressant response to
ketamine that correlates with baseline amygdala volume and increased glucose
metabolism in the amygdala and hippocampus.

Published by Elsevier B.V.

PMCID: PMC4400209 [Available on 2016-04-16]
PMID: 25451430 [PubMed - as supplied by publisher]

36. Am J Addict. 2014 Oct 15. doi: 10.1002/AJAD.12153.x. [Epub ahead of print]

Intensive ketamine use for multiple years: A case report.

Liu JX(1), Zerbo E, Ross S.

Author information:
(1)New York University School of Medicine, New York, New York.

Ketamine is known within the medical field for its anesthetic properties, yet its
unique psychedelic and antidepressant properties are being increasingly
recognized. We document the case of a patient with bipolar I disorder and an
extensive history of substance dependence who used large doses of ketamine
(1-3 g) on a daily basis over a period of 5 years, and described acute
antidepressant effects as well as diminished cravings for alcohol. While his use
was untenable and ultimately led to an inpatient admission, it is notable that he
did not experience a withdrawal syndrome nor did he have any observable cognitive
deficits upon cessation of use. Such a unique drug profile suggests that further
exploration of its risks and therapeutic potential in treating mood and addiction
disorders is warranted. (Am J Addict 2014;XX:1-3).

PMID: 25318850 [PubMed - as supplied by publisher]

37. Transl Psychiatry. 2014 Oct 14;4:e469. doi: 10.1038/tp.2014.105.

Anti-anhedonic effect of ketamine and its neural correlates in
treatment-resistant bipolar depression.

Lally N(1), Nugent AC(2), Luckenbaugh DA(2), Ameli R(2), Roiser JP(3), Zarate
CA(2).

Author information:
(1)1] Experimental Therapeutics and Pathophysiology Branch, National Institute of
Mental Health, National Institutes of Health, Bethesda, MD, USA [2] Institute of
Cognitive Neuroscience, University College London, London, UK. (2)Experimental
Therapeutics and Pathophysiology Branch, National Institute of Mental Health,
National Institutes of Health, Bethesda, MD, USA. (3)Institute of Cognitive
Neuroscience, University College London, London, UK.

Anhedonia--which is defined as diminished pleasure from, or interest in,
previously rewarding activities-is one of two cardinal symptoms of a major
depressive episode. However, evidence suggests that standard treatments for
depression do little to alleviate the symptoms of anhedonia and may cause reward
blunting. Indeed, no therapeutics are currently approved for the treatment of
anhedonia. Notably, over half of patients diagnosed with bipolar disorder
experience significant levels of anhedonia during a depressive episode. Recent
research into novel and rapid-acting therapeutics for depression, particularly
the noncompetitive N-Methyl-D-aspartate receptor antagonist ketamine, has
highlighted the role of the glutamatergic system in the treatment of depression;
however, it is unknown whether ketamine specifically improves anhedonic symptoms.
The present study used a randomized, placebo-controlled, double-blind crossover
design to examine whether a single ketamine infusion could reduce anhedonia
levels in 36 patients with treatment-resistant bipolar depression. The study also
used positron emission tomography imaging in a subset of patients to explore the
neurobiological mechanisms underpinning ketamine's anti-anhedonic effects. We
found that ketamine rapidly reduced the levels of anhedonia. Furthermore, this
reduction occurred independently from reductions in general depressive symptoms.
Anti-anhedonic effects were specifically related to increased glucose metabolism
in the dorsal anterior cingulate cortex and putamen. Our study emphasizes the
importance of the glutamatergic system in treatment-refractory bipolar
depression, particularly in the treatment of symptoms such as anhedonia.

PMCID: PMC4350513
PMID: 25313512 [PubMed - in process]

38. Acta Neuropsychiatr. 2014 Oct;26(5):307-14. doi: 10.1017/neu.2014.17. Epub 2014
Jul 30.

Effects of single and combined gabapentin use in elevated plus maze and forced
swimming tests.

Kilic FS(1), Ismailoglu S(1), Kaygisiz B(1), Oner S(2).

Author information:
(1)1Department of Pharmacology, Medical Faculty,Eskisehir Osmangazi
University,Eskisehir,Turkey. (2)2Department of Biostatistics, Medical
Faculty,Eskisehir Osmangazi University,Eskisehir,Turkey.

BACKGROUND: Gabapentin, a third-generation antiepileptic drug, is a structural
analogue of γ-aminobutyric acid, which is an important mediator of central
nervous system. There is clinical data indicating its effectiveness in the
treatment of psychiatric illnesses such as bipolar disorder and anxiety
disorders.
OBJECTIVES: We aimed to investigate the antidepressant and anxiolytic-like
effects and mechanisms of gabapentin in rats.
MATERIAL AND METHODS: Female Spraque-Dawley rats weighing 250±20 g were used. A
total of 13 groups were formed, each containing 8 rats: gabapentin (5, 10, 20, 40
mg/kg), amitriptyline (10 mg/kg), sertraline (5 mg/kg), diazepam (5 mg/kg),
ketamine (10 mg/kg), gabapentin 20 mg/kg was also combined with amitriptyline (10
mg/kg), sertraline (5 mg/kg), diazepam (5 mg/kg) and ketamine (10 mg/kg). All the
drugs were used intraperitoneally as single dose. Saline was administered to the
control group. Elevated plus maze and forced swimming tests were used as
experimental models of anxiety and depression, respectively.
RESULTS: It was observed that gabapentin showed an anxiolytic-like and
antidepressant-like effect in all doses in rats. Its antidepressant effect was
found to be the same as the antidepressant effects of amitriptyline and
sertraline. There was no change in the antidepressant effect when gabapentin was
combined with amitriptyline and ketamine, but there was an increase when combined
with sertraline and diazepam. Gabapentin and amitriptyline showed similar
anxiolytic effect, whereas ketamine and diazepam had more potent anxiolytic
effect compared with them.
CONCLUSIONS: These data suggest that gabapentin may possess antidepressant- and
anxiolytic-like effects.

PMID: 25076169 [PubMed - indexed for MEDLINE]

39. Psychopharmacology (Berl). 2014 Oct;231(19):3907-8. doi:
10.1007/s00213-014-3731-y. Epub 2014 Sep 2.

A comment on Fond and colleagues' systematic review and meta-analysis of ketamine
in the treatment of depressive disorders (Psychopharmacology 2014; Jul 20 [Epub
ahead of print]).

McGirr A(1), Berlim MT.

Author information:
(1)Department of Psychiatry, University of British Columbia, 11th Floor, 2775
Laurel Street, Vancouver, BC, V5Z 1M9, Canada, alexander.mcgirr@alumni.ubc.ca.

Comment in
Psychopharmacology (Berl). 2014 Nov;231(22):4417-8.

Comment on
Psychopharmacology (Berl). 2014 Sep;231(18):3663-76.

PMID: 25176174 [PubMed - indexed for MEDLINE]

40. Psychopharmacology (Berl). 2014 Sep;231(18):3663-76. doi:
10.1007/s00213-014-3664-5. Epub 2014 Jul 20.

Ketamine administration in depressive disorders: a systematic review and
meta-analysis.

Fond G(1), Loundou A, Rabu C, Macgregor A, Lançon C, Brittner M,
Micoulaud-Franchi JA, Richieri R, Courtet P, Abbar M, Roger M, Leboyer M, Boyer
L.

Author information:
(1)Pôle de psychiatrie des hôpitaux universitaires H Mondor, Université Paris
Est-Créteil, INSERM U955, Eq Psychiatrie Génétique, Fondation FondaMental
Fondation de coopération scientifique en santé mentale, 40, rue de Mesly, 94010,
Créteil, France, guillaume.fond@gmail.com.

Comment in
Psychopharmacology (Berl). 2014 Oct;231(19):3907-8.

INTRODUCTION: Ketamine's efficacy in depressive disorders has been established in
several controlled trials. The aim of the present study was to determine whether
or not ketamine administration significantly improves depressive symptomatology
in depression and more specifically in major depressive disorder (MDD), bipolar
depression, resistant depression (non-ECT studies), and as an anesthetic agent in
electroconvulsive therapy (ECT) for resistant depression (ECT studies). Secondary
outcomes were the duration of ketamine's effect, the efficacy on suicidal
ideations, the existence of a dose effect, and the safety/tolerance of the
treatment.
METHODS: Studies were included if they met the following criteria (without any
language or date restriction): design: randomized controlled trials,
intervention: ketamine administration, participants: diagnosis of depression, and
evaluation of severity based on a validated scale. We calculated standardized
mean differences (SMDs) with 95 % confidence intervals (CIs) for each study. We
used fixed and random effects models. Heterogeneity was assessed using the I2
statistic.
RESULTS: We included nine non-ECT studies in our quantitative analysis (192
patients with major depressive disorder and 34 patients with bipolar depression).
Overall, depression scores were significantly decreased in the ketamine groups
compared to those in the control groups (SMD = -0.99; 95 % CI -1.23, -0.75;
p < 0.01). Ketamine's efficacy was confirmed in MDD (resistant to previous
pharmacological treatments or not) (SMD = -0.91; 95 % CI -1.19,-0.64; p < 0.01),
in bipolar depression (SMD = -1.34; 95 % CI -1.94, -0.75), and in drug-free
patients as well as patients under medication. Four ECT trials (118 patients)
were included in our quantitative analysis. One hundred and three patients were
diagnosed with major depressive disorder and 15 with bipolar depression. Overall,
depression scores were significantly improved in the 58 patients receiving
ketamine in ECT anesthesia induction compared to the 60 patients (SMD = -0.56; 95
% CI -1.10, -0.02; p = 0.04; I2 = 52.4 %). The duration of ketamine's effects was
assessed in only two non-ECT studies and seemed to persist for 2-3 days; this
result needs to be confirmed. Three of four studies found significant decrease of
suicidal thoughts and one found no difference between groups, but suicidal
ideations were only studied by the suicide item of the depressive scales. It was
not possible to determine a dose effect; 0.5 mg/kg was used in the majority of
the studies. Some cardiovascular events were described (mostly transient blood
pressure elevation that may require treatment), and ketamine's use should remain
cautious in patients with a cardiovascular history.
CONCLUSION: The present meta-analysis confirms ketamine's efficacy in depressive
disorders in non-ECT studies, as well as in ECT studies. The results of this
first meta-analysis are encouraging, and further studies are warranted to detail
efficacy in bipolar disorders and other specific depressed populations. Middle-
and long-term efficacy and safety have yet to be explored. Extrapolation should
be cautious: Patients included had no history of psychotic episodes and no
history of alcohol or substance use disorders, which is not representative of all
the depressed patients that may benefit from this therapy.

PMID: 25038867 [PubMed - indexed for MEDLINE]

41. Pharmacopsychiatry. 2014 Jul;47(4-5):141-4. doi: 10.1055/s-0034-1377042. Epub
2014 Jun 23.

Baseline vitamin B12 and folate levels do not predict improvement in depression
after a single infusion of ketamine.

Lundin NB(1), Niciu MJ(1), Luckenbaugh DA(1), Ionescu DF(1), Richards EM(1),
Vande Voort JL(1), Brutsche NE(1), Machado-Vieira R(1), Zarate CA Jr(1).

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, National Institute of
Mental Health, National Institutes of Health, Intramural Research Program,
Bethesda, MD.

INTRODUCTION: Deficiencies in both vitamin B12 and folate have been associated
with depression. Recently, higher baseline vitamin B12 levels were observed in
individuals with bipolar depression who responded to the antidepressant ketamine
at 7 days post-infusion. This study sought to -replicate this result by
correlating peripheral vitamin levels with ketamine's antidepressant efficacy in
bipolar depression and major depressive disorder (MDD).
METHODS: Baseline vitamin B12 and folate levels were obtained in 49 inpatients
with treatment-resistant MDD and 34 inpatients with treatment-resistant bipolar
depression currently experiencing a major depressive episode. All subjects
received a single intravenous ketamine infusion. Post-hoc Pearson correlations
were performed between baseline vitamin B12 and folate levels, as well as
antidepressant response assessed by percent change in Hamilton Depression Rating
Scale (HDRS) scores from baseline to 230 min, 1 day, and 7 days post-infusion.
RESULTS: No significant correlation was observed between baseline vitamin B12 or
folate and percent change in HDRS for any of the 3 time points in either MDD or
bipolar depression.
DISCUSSION: Ketamine's antidepressant efficacy may occur independently of
baseline peripheral vitamin levels.

PMCID: PMC4174587
PMID: 24955551 [PubMed - in process]

42. Psychopharmacology (Berl). 2014 Jul;231(13):2705-16. doi:
10.1007/s00213-014-3451-3. Epub 2014 Feb 13.

Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and
MK-801 on intracranial self-stimulation in rats.

Hillhouse TM(1), Porter JH, Negus SS.

Author information:
(1)Department of Psychology, Virginia Commonwealth University, PO Box 842018, 806
West Franklin Street, Richmond, 23284, VA, USA.

RATIONALE: The noncompetitive NMDA antagonist ketamine produces rapid
antidepressant effects in treatment-resistant patients suffering from major
depressive and bipolar disorders. However, abuse liability is a concern.
OBJECTIVES: This study examined abuse-related effects of ketamine using
intracranial self-stimulation (ICSS) in rats. The higher-affinity NMDA antagonist
MK-801 and the monoamine reuptake inhibitor cocaine were examined for comparison.
METHODS: Male Sprague Dawley rats were implanted with electrodes targeting the
medial forebrain bundle and trained to respond to brain stimulation under a
frequency-rate ICSS procedure. The first experiment compared the potency and time
course of ketamine (3.2-10.0 mg/kg) and MK-801 (0.032-0.32 mg/kg). The second
experiment examined effects of repeated dosing with ketamine (3.2-20.0 mg/kg/day)
and acute cocaine (10.0 mg/kg).
RESULTS: Following acute administration, ketamine (3.2-10 mg/kg) produced only
dose- and time-dependent depressions of ICSS and failed to produce an
abuse-related facilitation of ICSS at any dose or pretreatment time. In contrast,
MK-801 (0.032-0.32 mg/kg) produced a mixed profile of rate-increasing and
rate-decreasing effects; ICSS facilitation was especially prominent at an
intermediate dose of 0.18 mg/kg. Repeated dosing with ketamine produced
dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and
18.0 mg/kg) but failed to unmask expression of ICSS facilitation. Termination of
ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As
reported previously, 10.0 mg/kg cocaine facilitated ICSS.
CONCLUSIONS: The dissociable effects of ketamine and MK-801 suggest differences
in the pharmacology of these nominally similar NMDA antagonists. Failure of
ketamine to facilitate ICSS contrasts with other evidence for the abuse liability
of ketamine.

PMCID: PMC4058412
PMID: 24522331 [PubMed - indexed for MEDLINE]

43. J Clin Psychiatry. 2014 May;75(5):e417-23. doi: 10.4088/JCP.13m08698.

Clinical predictors of ketamine response in treatment-resistant major depression.

Niciu MJ(1), Luckenbaugh DA, Ionescu DF, Guevara S, Machado-Vieira R, Richards
EM, Brutsche NE, Nolan NM, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Intramural Research
Program (IRP), National Institute of Mental Health (NIMH), National Institutes of
Health (NIH), Bethesda, Maryland.

OBJECTIVE: The N-methyl-D-aspartate receptor antagonist ketamine has rapid
antidepressant effects in treatment-resistant major depressive disorder (MDD) and
bipolar depression. Clinical predictors may identify those more likely to benefit
from ketamine within clinically heterogeneous populations.
METHOD: Data were analyzed from 4 studies of treatment-resistant inpatients with
DSM-IV-TR-diagnosed MDD or bipolar I or II depression. Patients who were
currently experiencing a moderate-to-severe major depressive episode were
enrolled between November 2004 and March 2013. All subjects received a single
subanesthetic (0.5 mg/kg) ketamine infusion over 40 minutes. Patients were
analyzed at the 230-minute postinfusion time point (n = 108), at day 1 (n = 82),
and at day 7 (n = 71). Univariate Pearson correlations were performed for each
variable with percent change from baseline in the 17-item Hamilton Depression
Rating Scale (HDRS). Multivariate linear regression was then conducted for
statistically significant predictors (P ≤ .05, 2-tailed).
RESULTS: Higher body mass index correlated with greater HDRS improvement at 230
minutes (standardized β = -0.30, P = .004) and at day 1 (standardized β = -0.37,
P = .001), but not at day 7 (standardized β = -0.18, P = .10). Family history of
an alcohol use disorder in a first-degree relative was associated with greater
HDRS improvement at day 1 (standardized β = -0.27, P = .014) and day 7
(standardized β = -0.41, P < .001). No prior history of suicide attempt(s) was
associated with greater improvement only at day 7 (standardized β = 0.28, P =
.01). The overall statistical model explained 13%, 23%, and 36% of HDRS percent
change variance at 230 minutes, day 1, and day 7, respectively.
CONCLUSIONS: Despite its post hoc nature, this study identified several clinical
correlates of ketamine's rapid and durable antidepressant effects. Further
investigation of these relationships is critical for individualized treatment of
depression.

PMCID: PMC4310499
PMID: 24922494 [PubMed - indexed for MEDLINE]

44. Med Hypotheses. 2014 May;82(5):581-8. doi: 10.1016/j.mehy.2014.02.015. Epub 2014
Feb 22.

Delayed mood transitions in major depressive disorder.

Korf J(1).

Author information:
(1)University of Groningen, Centre of Psychiatry, Groningen, The Netherlands.
Electronic address: j.korf@umcg.nl.

The hypothesis defended here is that the process of mood-normalizing transitions
fails in a significant proportion of patients suffering from major depressive
disorder. Such a failure is largely unrelated to the psychological content.
Evidence for the hypothesis is provided by the highly variable and unpredictable
time-courses of the depressive episodes. The main supporting observations are:
(1) mood transitions within minutes or days have been reported during deep brain
stimulation, naps after sleep deprivation and bipolar mood disorders; (2) sleep
deprivation, electroconvulsive treatment and experimental drugs (e.g., ketamine)
may facilitate mood transitions in major depressive disorder within hours or a
few days; (3) epidemiological and clinical studies show that the time-to-recovery
from major depressive disorder can be described with decay models implying very
short depressive episodes; (4) lack of relationship between the length of
depression and recovery episodes in recurrent depression; (5) mood fluctuations
predict later therapeutic success in major depressive disorder. We discuss some
recent models aimed to describe random mood transitions. The observations
together suggest that the mood transitions have a wide variety of apparently
unrelated causes. We suggest that the mechanism of mood transition is compromised
in major depressive disorder, which has to be recognized in diagnostic systems.

PMID: 24613736 [PubMed - indexed for MEDLINE]

45. J Psychopharmacol. 2014 Apr 3;28(6):536-544. [Epub ahead of print]

Ketamine infusions for treatment resistant depression: a series of 28 patients
treated weekly or twice weekly in an ECT clinic.

Diamond PR(1), Farmery AD(2), Atkinson S(1), Haldar J(3), Williams N(4), Cowen
PJ(5), Geddes JR(5), McShane R(6).

Author information:
(1)Oxford Health NHS Foundation Trust, Oxford, UK. (2)Nuffield Department of
Anaesthetics, University of Oxford, Oxford, UK. (3)Oxford University Hospitals
NHS Trust, Oxford, UK. (4)Centre for Statistics in Medicine, University of
Oxford, Oxford, UK. (5)Department of Psychiatry, University of Oxford, Oxford,
UK. (6)Oxford Health NHS Foundation Trust, Oxford, UK Department of Psychiatry,
University of Oxford, Oxford, UK Rupert.mcshane@oxfordhealth.nhs.uk.

BACKGROUND: Ketamine has a rapid antidepressant effect in treatment-resistant
depression (TRD). The effects on cognitive function of multiple ketamine
infusions and of concurrent antidepressant medication on response rate and
duration are not known.
METHOD: Twenty-eight patients with uni- or bipolar TRD were treated over three
weeks with either three or six ketamine infusions (0.5 mg/kg over 40 minutes) in
the recovery room of a routine ECT clinic. Post-treatment memory assessments were
conducted on day 21 (4-7 days after the final infusion). Patients were followed
up for six months where possible, with severity of depression and side effects
monitored throughout.
RESULTS: Eight (29%) patients responded of whom four remitted. Only three (11%)
patients had responded within six hours after a single infusion, but in all
responders, the response had developed before the third infusion. The duration of
response from the final infusion was variable (median 70, range 25-168 days).
Discontinuations included two (7%) because of acute adverse reactions during the
infusion and five (18%) because of failure to benefit and increasing anxiety.
Ketamine was not associated with memory impairment. The ECT clinic was rated
suitable by patients and offered appropriate levels of monitoring.
CONCLUSION: This small, open label naturalistic study shows that up to six low
dose ketamine infusions can safely be given within an existing NHS clinical
structure to patients who continue their antidepressants. The response rate was
comparable to that found in RCTs of single doses of ketamine in
antidepressant-free patients but took slightly longer to develop.

PMID: 24699062 [PubMed - as supplied by publisher]

46. Br J Pharmacol. 2014 Apr;171(8):2230-42. doi: 10.1111/bph.12494.

A pilot study of plasma metabolomic patterns from patients treated with ketamine
for bipolar depression: evidence for a response-related difference in
mitochondrial networks.

Villaseñor A(1), Ramamoorthy A, Silva dos Santos M, Lorenzo MP, Laje G, Zarate C
Jr, Barbas C, Wainer IW.

Author information:
(1)Center for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia,
Universidad CEU San Pablo, Madrid, Spain.

BACKGROUND AND PURPOSE: (R,S)-ketamine produces rapid and significant
antidepressant effects in approximately 65% of patients suffering from
treatment-resistant bipolar depression (BD). The genetic, pharmacological and
biochemical differences between ketamine responders and non-responders have not
been identified. The purpose of this study was to employ a metabolomics approach,
a global, non-targeted determination of endogenous metabolic patterns, to
identify potential markers of ketamine response and non-response.
EXPERIMENTAL APPROACH: Plasma samples from 22 BD patients were analyzed to
produce metabolomic patterns. The patients had received ketamine in a
placebo-controlled crossover study and the samples were obtained 230 min
post-administration at which time the patients were categorized as responders or
non-responders. Matching plasma samples from the placebo arm of the study were
also analysed. During the study, the patients were maintained on either lithium
or valproate.
KEY RESULTS: The metabolomic patterns were significantly different between the
patients maintained on lithium and those maintained on valproate, irrespective of
response to ketamine. In the patients maintained on lithium, 18 biomarkers were
identified. In responders, lysophosphatidylethanolamines (4) and
lysophosphatidylcholines (9) were increased relative to non-responders.
CONCLUSIONS AND IMPLICATIONS: The results indicate that the differences between
patients who respond to ketamine and those who do not are due to alterations in
the mitochondrial β-oxidation of fatty acids. These differences were not produced
by ketamine administration. The data indicate that pretreatment metabolomics
screening may be a guide to the prediction of response and a potential approach
to the individualization of ketamine therapy.

PMCID: PMC3976632
PMID: 24684390 [PubMed - indexed for MEDLINE]

47. Depress Anxiety. 2014 Apr;31(4):297-307. doi: 10.1002/da.22224. Epub 2013 Dec 18.

Developing biomarkers in mood disorders research through the use of rapid-acting
antidepressants.

Niciu MJ(1), Mathews DC, Nugent AC, Ionescu DF, Furey ML, Richards EM,
Machado-Vieira R, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics & Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health, and
Department of Health and Human Services, Bethesda, Maryland.

An impediment to progress in mood disorders research is the lack of analytically
valid and qualified diagnostic and treatment biomarkers. Consistent with the
National Institute of Mental Health (NIMH)'s Research Domain Criteria (RDoC)
initiative, the lack of diagnostic biomarkers has precluded us from moving away
from a purely subjective (symptom-based) toward a more objective diagnostic
system. In addition, treatment response biomarkers in mood disorders would
facilitate drug development and move beyond trial-and-error toward more
personalized treatments. As such, biomarkers identified early in the
pathophysiological process are proximal biomarkers (target engagement), while
those occurring later in the disease process are distal (disease pathway
components). One strategy to achieve this goal in biomarker development is to
increase efforts at the initial phases of biomarker development (i.e. exploration
and validation) at single sites with the capability of integrating multimodal
approaches across a biological systems level. Subsequently, resultant putative
biomarkers could then undergo characterization and surrogacy as these latter
phases require multisite collaborative efforts. We have used multimodal
approaches - genetics, proteomics/metabolomics, peripheral measures, multimodal
neuroimaging, neuropsychopharmacological challenge paradigms and clinical
predictors - to explore potential predictor and mediator/moderator biomarkers of
the rapid-acting antidepressants ketamine and scopolamine. These exploratory
biomarkers may then be used for a priori stratification in larger multisite
controlled studies during the validation and characterization phases with the
ultimate goal of surrogacy. In sum, the combination of target engagement and
well-qualified disease-related measures are crucial to improve our
pathophysiological understanding, personalize treatment selection, and expand our
armamentarium of novel therapeutics.

PMCID: PMC3984598
PMID: 24353110 [PubMed - indexed for MEDLINE]

48. J Affect Disord. 2014 Apr;159:56-61. doi: 10.1016/j.jad.2014.02.017. Epub 2014
Feb 18.

Do the dissociative side effects of ketamine mediate its antidepressant effects?

Luckenbaugh DA(1), Niciu MJ(1), Ionescu DF(1), Nolan NM(1), Richards EM(1),
Brutsche NE(1), Guevara S(1), Zarate CA(2).

Author information:
(1)Experimental Therapeutics & Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health (NIMH), National Institutes of
Health (NIH), Bethesda, MD USA. (2)Experimental Therapeutics & Pathophysiology
Branch, Intramural Research Program, National Institute of Mental Health (NIMH),
National Institutes of Health (NIH), Bethesda, MD USA. Electronic address:
zaratec@mail.nih.gov.

BACKGROUND: The N-methyl-d-aspartate receptor antagonist ketamine has rapid
antidepressant effects in major depression. Psychotomimetic symptoms,
dissociation and hemodynamic changes are known side effects of ketamine, but it
is unclear if these side effects relate to its antidepressant efficacy.
METHODS: Data from 108 treatment-resistant inpatients meeting criteria for major
depressive disorder and bipolar disorder who received a single subanesthetic
ketamine infusion were analyzed. Pearson correlations were performed to examine
potential associations between rapid changes in dissociation and psychotomimesis
with the Clinician-Administered Dissociative States Scale (CADSS) and Brief
Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania
Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item
Hamilton Depression Rating scale (HDRS) at 40 and 230min and Days 1 and 7.
RESULTS: Pearson correlations showed significant association between increased
CADSS score at 40min and percent improvement with ketamine in HDRS at 230min
(r=-0.35, p=0.007) and Day 7 (r=-0.41, p=0.01). Changes in YMRS or BPRS Positive
Symptom score at 40min were not significantly correlated with percent HDRS
improvement at any time point with ketamine. Changes in systolic blood pressure,
diastolic blood pressure, and pulse were also not significantly related to HDRS
change.
LIMITATIONS: Secondary data analysis, combined diagnostic groups, potential
unblinding.
CONCLUSIONS: Among the examined mediators of ketamine׳s antidepressant response,
only dissociative side effects predicted a more robust and sustained
antidepressant. Prospective, mechanistic investigations are critically needed to
understand why intra-infusion dissociation correlates with a more robust
antidepressant efficacy of ketamine.

Published by Elsevier B.V.

PMCID: PMC4065787
PMID: 24679390 [PubMed - indexed for MEDLINE]

49. Bipolar Disord. 2014 Mar;16(2):119-28. doi: 10.1111/bdi.12118. Epub 2013 Sep 18.

Neural correlates of rapid antidepressant response to ketamine in bipolar
disorder.

Nugent AC(1), Diazgranados N, Carlson PJ, Ibrahim L, Luckenbaugh DA, Brutsche N,
Herscovitch P, Drevets WC, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, NIMH, NIH, Bethesda, MD,
USA.

OBJECTIVES: Ketamine, an N-methyl d-aspartate (NMDA) antagonist, has rapid
antidepressant effects in depressed subjects with bipolar disorder (BD). Evidence
supports a role for the glutamatergic system in the pathophysiology of BD. This
double-blind, randomized, cross-over study sought to determine cerebral metabolic
correlates of antidepressant response to ketamine.
METHODS: Twenty-one subjects with BD currently in a depressed state underwent
[(18) F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging
after receiving a placebo infusion as well as after receiving a ketamine
infusion. Metabolism was compared between ketamine and placebo infusions, and
correlated with clinical response. Regional metabolic rate of glucose (rMRGlu) in
regions of interest (ROIs) and Montgomery-Åsberg Depression Rating Scale (MADRS)
scores were the main outcome measures.
RESULTS: The study found that change in metabolism between sessions was
significantly correlated with percentage change in MADRS scores in the right
ventral striatum; subjects who showed the greatest improvement had the largest
metabolic increase after ketamine infusion compared to placebo. In a voxel-wise
analysis, subjects with BD had significantly lower glucose metabolism in the left
hippocampus following the ketamine infusion than following the placebo infusion.
In addition, metabolism in the subgenual anterior cingulate cortex (ACC)
following the placebo infusion was positively correlated with percentage
improvement in MADRS score following the ketamine infusion.
CONCLUSIONS: Taken together, the results suggest that higher activity in the
subgenual ACC may predict antidepressant response to ketamine. Ketamine
administration altered glucose metabolism in areas known to be involved in mood
disorders; these alterations may partially underlie ketamine's mechanism of
action.

Published 2013. This article is a U.S. Government work and is in the public
domain in the USA.

PMCID: PMC3949142
PMID: 24103187 [PubMed - indexed for MEDLINE]

50. J Affect Disord. 2014 Mar;156:24-35. doi: 10.1016/j.jad.2013.11.014. Epub 2013
Dec 10.

A review of ketamine in affective disorders: current evidence of clinical
efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of
action.

Naughton M(1), Clarke G(2), O'Leary OF(3), Cryan JF(4), Dinan TG(5).

Author information:
(1)Department of Psychiatry, University College Cork, Western Road, Cork City,
Cork, Ireland. Electronic address: marienaughton@beaumont.ie. (2)Department of
Psychiatry, University College Cork, Western Road, Cork City, Cork, Ireland;
Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
Electronic address: g.clarke@ucc.ie. (3)Alimentary Pharmabiotic Centre,
University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience,
University College Cork, Cork, Ireland. Electronic address: o.oleary@ucc.ie.
(4)Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland;
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
Electronic address: j.cryan@ucc.ie. (5)Department of Psychiatry, University
College Cork, Western Road, Cork City, Cork, Ireland; Alimentary Pharmabiotic
Centre, University College Cork, Cork, Ireland. Electronic address:
t.dinan@ucc.ie.

INTRODUCTION: Recent research has seen low-dose ketamine emerge as a novel,
rapid-acting antidepressant. Ketamine, an N-methy-d-aspartate (NMDA) receptor
antagonist, leads to effects on the glutamatergic system and abnormalities in
this neurotransmittor system are present in depression. This article aims to (1)
review the clinical literature on low-dose ketamine as a rapid-acting
antidepressant in affective disorders, (2) provide a critical overview of the
limitations of ketamine and research attempts to overcome these (3) discuss the
proposed mechanisms of action of ketamine and (4) point towards future research
directions.
METHOD: The electronic database Pubmed, Web of Science and sciencedirect were
searched using the keywords: ketamine, N-methyl-d-aspartate receptor antagonist,
rapid-acting antidepressant, depression, treatment-resistant depression, bipolar
depression, suicidal ideation, electroconvulsive therapy, mechanism of action.
RESULT: The literature demonstrates evidence supporting a rapid-acting
antidepressant effect of low-dose intravenous ketamine in major depressive
disorder, in bipolar depression and in depression with suicidal ideation. There
are mixed results as to whether ketamine leads to a reduction in time to
remission in patients undergoing electroconvulsive therapy (ECT). Efforts to
unravel ketamine's therapeutic mechanism of action have implicated the mammalian
target of rapamycin (mTOR)-dependent synapse formation in the rat prefrontal
cortex, eukaryotic elongation factor 2 phosphorylation (p-eEF2) and glycogen
synthase kinase (GSK-3). Ketamine's limiting factors are the transient nature of
its antidepressant effect and concerns regarding abuse, and research efforts to
overcome these are reviewed.
CONCLUSION: Current and future research studies are using ketamine as a promising
tool to evaluate the glutamatergic neurotransmittor system to learn more about
the pathophysiology of depression and develop more specific rapid-acting
antidepressant treatments.

PMID: 24388038 [PubMed - indexed for MEDLINE]

51. Eur J Pharmacol. 2014 Feb 5;724:132-9. doi: 10.1016/j.ejphar.2013.12.028. Epub
2013 Dec 30.

Neuroprotective and antioxidant effects of curcumin in a ketamine-induced model
of mania in rats.

Gazal M(1), Valente MR(1), Acosta BA(1), Kaufmann FN(1), Braganhol E(2), Lencina
CL(2), Stefanello FM(2), Ghisleni G(3), Kaster MP(1).

Author information:
(1)Programa de Pós-Graduação em Saúde e Comportamento, Universidade Católica de
Pelotas, Pelotas, Rio Grande do Sul, Brazil. (2)Centro de Ciências Químicas,
Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, Rio
Grande do Sul, Brazil. (3)Programa de Pós-Graduação em Saúde e Comportamento,
Universidade Católica de Pelotas, Pelotas, Rio Grande do Sul, Brazil. Electronic
address: ghisleni.g@gmail.com.

Bipolar disorder (BD) is a chronic and debilitating illness characterized by
recurrent manic and depressive episodes. Our research investigates the protective
effects of curcumin, the main curcuminoid of the Indian spice turmeric, in a
model of mania induced by ketamine administration in rats. Our results indicated
that ketamine treatment (25 mg/kg, for 8 days) induced hyperlocomotion in the
open-field test and oxidative damage in prefrontal cortex (PFC) and hippocampus
(HP), evaluated by increased lipid peroxidation and decreased total thiol
content. Moreover, ketamine treatment reduced the activity of the antioxidant
enzymes superoxide dismutase and catalase in the HP. Pretreatment of rats with
curcumin (20 and 50 mg/kg, for 14 days) or with lithium chloride (45 mg/kg,
positive control) prevented behavioral and pro-oxidant effects induced by
ketamine. These findings suggest that curcumin might be a good compound for
preventive intervention in BD, reducing the episode relapse and the oxidative
damage associated with the manic phase of this disorder.

PMID: 24384407 [PubMed - indexed for MEDLINE]

52. Curr Psychiatry Rep. 2014 Feb;16(2):431. doi: 10.1007/s11920-013-0431-y.

Options for pharmacological treatment of refractory bipolar depression.

Tondo L(1), Vázquez GH, Baldessarini RJ.

Author information:
(1)International Consortium for Bipolar and Psychotic Disorder Research, McLean
Hospital, Belmont, MA, USA, ltondo@mclean.harvard.edu.

Bipolar disorders of types I and II, even when treated by currently standard
options, show a marked excess of depressive morbidity. Treated, type I patients
in mid-course or from the onset of illness are ill, overall, 50 % of weeks of
follow-up, and 75 % of that unresolved morbidity is depressive. Currently widely
held impressions are that bipolar depression typically is poorly responsive to
antidepressants, that treatment-resistant depression (TRD) is characteristic of
the disorder, and that risk of mania with antidepressant treatment is very high.
However, none of these views is supported consistently by available research. TRD
may be more prevalent in bipolar than unipolar mood disorders. Relatively intense
research attention is directed toward characteristics and treatments of TRD in
unipolar depression, but studies of bipolar TRD are uncommon. We found only five
controlled trials, plus 10 uncontrolled trials, providing data on a total of 13
drug treatments, all of which involved one or two trials, in 87 % as add-ons to
complex, uncontrolled regimens. In two controlled trials, ketamine was superior
to placebo but it is short-acting and not orally active; pramipexole was weakly
superior to placebo in one controlled trial; three other drugs failed to
outperform controls. Other pharmacotherapies are inadequately evaluated and
nonpharmacological options are virtually untested in bipolar TRD. The available
research supports the view that antidepressants may be effective in bipolar
depression provided that currently agitated patients are excluded, that risk of
mania with antidepressants is only moderately greater than risk of spontaneous
mania, and that bipolar TRD is not necessarily resistant to all treatments.

PMID: 24425269 [PubMed - indexed for MEDLINE]

53. Encephale. 2014 Feb;40(1):15-23. doi: 10.1016/j.encep.2013.09.001. Epub 2014 Jan
14.

[Ketamine's antidepressant effect: literature review on clinical use].

[Article in French]

De Maricourt P(1), Jay T(2), Goncalvès P(3), Lôo H(4), Gaillard R(5).

Author information:
(1)Service hospitalo-universitaire de santé mentale et de thérapeutique, centre
hospitalier Sainte-Anne, université Paris-Descartes, 1, rue Cabanis, 75014 Paris,
France; Inserm UMR 894, centre de psychiatrie et neurosciences, université
Paris-Descartes, Sorbonne, Paris Cité, Paris, France. Electronic address:
pdemaricourt@gmail.com. (2)Inserm UMR 894, centre de psychiatrie et
neurosciences, université Paris-Descartes, Sorbonne, Paris Cité, Paris, France.
(3)Service du Dr. Zagury, clinique du Bois Bondy, 93G11 EPS Ville Evrard, France.
(4)Service hospitalo-universitaire de santé mentale et de thérapeutique, centre
hospitalier Sainte-Anne, université Paris-Descartes, 1, rue Cabanis, 75014 Paris,
France. (5)Service hospitalo-universitaire de santé mentale et de thérapeutique,
centre hospitalier Sainte-Anne, université Paris-Descartes, 1, rue Cabanis, 75014
Paris, France; Inserm UMR 894, centre de psychiatrie et neurosciences, université
Paris-Descartes, Sorbonne, Paris Cité, Paris, France.

BACKGROUND: Depressive disorders have a major impact on public health. They are
prevalent and disabling, with high economic burden for society. Antidepressants
have a delayed action and at least one third of patients do not achieve adequate
response. The recent discovery of ketamine's unique antidepressant properties,
with rapid onset of response and high rate of responders opens new perspectives
for treatment-resistant depression (TRD).
METHOD: The aim of this article is to summarize preclinical trials and clinical
trials demonstrating ketamine antidepressant properties and to review the
different modalities of use.
RESULTS: Most clinical studies used ketamine with a single subanesthetic
intravenous administration in patients with treatment-resistant depression,
demonstrating a rapid but transient antidepressant response with high response
rates. To prevent relapse and maintain the initial benefits, few studies have
shown the interest of serial infusions of ketamine, while others combined
ketamine and electroconvulsive therapy using the former as an anesthetic. So far,
relay treatments with glutamatergic agents such as riluzole are disappointing.
Although most studies were conducted in patients with TRD in recurrent depression
or bipolar disorder, efficacy in acutely suicidal patients is promising.
CONCLUSION: Our review highlights the increasing interest in the use of ketamine
in the treatment of treatment-resistant depression. Although a widespread use of
ketamine as an antidepressant in routine clinical settings seems limited by
psychotomimetic effects and the lack of strategy to maintain initial benefits,
ketamine or related drugs might be used to target specific conditions, such as
bipolar depression or high suicide risk.

Copyright © 2013 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights
reserved.

PMID: 24434008 [PubMed - indexed for MEDLINE]

54. World J Biol Psychiatry. 2014 Feb;15(2):84-95. doi: 10.3109/15622975.2013.830775.
Epub 2013 Sep 2.

Multiple levels of impaired neural plasticity and cellular resilience in bipolar
disorder: developing treatments using an integrated translational approach.

Machado-Vieira R(1), Soeiro-De-Souza MG, Richards EM, Teixeira AL, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, National Institute of
Mental Health, NIH , Bethesda, MD , USA.

OBJECTIVES: This paper reviews the neurobiology of bipolar disorder (BD),
particularly findings associated with impaired cellular resilience and
plasticity.
METHODS: PubMed/Medline articles and book chapters published over the last 20
years were identified using the following keyword combinations: BD, calcium,
cytokines, endoplasmic reticulum (ER), genetics, glucocorticoids, glutamate,
imaging, ketamine, lithium, mania, mitochondria, neuroplasticity,
neuroprotection, neurotrophic, oxidative stress, plasticity, resilience, and
valproate.
RESULTS: BD is associated with impaired cellular resilience and synaptic
dysfunction at multiple levels, associated with impaired cellular resilience and
plasticity. These findings were partially prevented or even reversed with the use
of mood stabilizers, but longitudinal studies associated with clinical outcome
remain scarce.
CONCLUSIONS: Evidence consistently suggests that BD involves impaired neural
plasticity and cellular resilience at multiple levels. This includes the genetic
and intra- and intercellular signalling levels, their impact on brain structure
and function, as well as the final translation into behaviour/cognitive changes.
Future studies are expected to adopt integrated translational approaches using a
variety of methods (e.g., microarray approaches, neuroimaging, genetics,
electrophysiology, and the new generation of -omics techniques). These studies
will likely focus on more precise diagnoses and a personalized medicine paradigm
in order to develop better treatments for those who need them most.

PMCID: PMC4180367
PMID: 23998912 [PubMed - indexed for MEDLINE]

55. Annu Rev Pharmacol Toxicol. 2014;54:119-39. doi:
10.1146/annurev-pharmtox-011613-135950.

Glutamate receptor antagonists as fast-acting therapeutic alternatives for the
treatment of depression: ketamine and other compounds.

Niciu MJ(1), Henter ID, Luckenbaugh DA, Zarate CA Jr, Charney DS.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Intramural Research
Program, National Institutes of Health/National Institute of Mental Health,
Bethesda, Maryland 20814-9692; email: mark.niciu@nih.gov.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent
antidepressant effects in treatment-resistant major depressive disorder and
bipolar depression. These effects are in direct contrast to the more modest
effects seen after weeks of treatment with classic monoaminergic antidepressants.
Numerous open-label and case studies similarly validate ketamine's antidepressant
properties. These clinical findings have been reverse-translated into preclinical
models in an effort to elucidate ketamine's antidepressant mechanism of action,
and three important targets have been identified: mammalian target of rapamycin
(mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3
(GSK-3). Current clinical and preclinical research is focused on (a)
prolonging/maintaining ketamine's antidepressant effects, (b) developing more
selective NMDA receptor antagonists free of ketamine's adverse effects, and (c)
identifying predictor, mediator/moderator, and treatment response biomarkers of
ketamine's antidepressant effects.

PMCID: PMC4089991
PMID: 24392693 [PubMed - indexed for MEDLINE]

56. Curr Neuropharmacol. 2014 Jan;12(1):57-70. doi: 10.2174/1570159X113119990043.

Ketamine as antidepressant? Current state and future perspectives.

Hasselmann HW(1).

Author information:
(1)Research Master Programme Cognitive and Clinical Neurosciences, Maastricht
University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.

Major depressive disorder (MDD) is a serious mental disorder that ranks among the
major causes of disease burden. Standard medical treatment targeting cerebral
monoamines often provides only insufficient symptom relief and fails in
approximately every fifth patient. The complexity of MDD therefore, reflects more
than monoaminergic dysregulation. Initial research argues the case for excessive
glutamate levels, suggesting that antiglutamatergic drugs might be useful in
treating MDD. Ketamine is a non-selective, high-affinity N-methyl-D-aspartate
receptor (NMDAR) antagonist most commonly used in pediatric and animal surgery.
In the past, ketamine has gained popularity because of its ability to rapidly
elevate mood, even in treatment-resistant and bipolar depression. However, there
are still many obstacles before widespread clinical approval of ketamine
treatment could become reality. In this review, ketamine's powerful
antidepressant effects are discussed and further research necessary for
therapeutic application is outlined. NMDAR antagonists provide an entirely new
way of treating the manifold appearances of depression that should not be left
unused.

PMCID: PMC3915350
PMID: 24533016 [PubMed]

57. Curr Pharm Des. 2014;20(32):5151-9.

Targeting of NMDA receptors in the treatment of major depression.

Dang YH, Ma XC, Zhang JC, Ren Q, Wu J, Gao CG, Hashimoto K(1).

Author information:
(1)Division of Clinical Neuroscience, Chiba University Center for Forensic Mental
Health, Chiba 260-8670, Japan. hashimoto@faculty.chiba-u.jp.

Major depressive disorder (MDD) is a common, recurrent mental illness that
affects millions of people worldwide. Accumulating evidence suggests that the
N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, plays an
important role in the neurobiology and treatment of this disease. Currently, the
non-competitive NMDA receptor antagonist ketamine is considered as one of the
most attractive candidate drugs in therapy of treatment-resistant depression. A
recent study demonstrated ketamine's rapid antidepressant activity in patients
with treatment-resistant MDD and bipolar disorder. The response rate for ketamine
ranged from 25% to 85% at 24 hours post-infusion and from 14% to 70% at 72 hours
post-infusion, with generally mild adverse effects. Based on the role of the NMDA
receptor in depression, a number of therapeutic drugs which interact with this
receptor have been developed. In this article, we reviewed recent findings
concerning the role of glutamatergic signaling in the neurobiology of MDD and
potential, novel therapeutic drugs, such as ketamine, memantine, AZD6765,
traxoprodil, MK-0657, GLYX-13, NRX-1047, D-cycloserine, sarcosine, all of which
target this system.

PMID: 24410564 [PubMed - in process]

58. Front Behav Neurosci. 2014 Nov 5;8:388. doi: 10.3389/fnbeh.2014.00388.
eCollection 2014.

Addiction and reward-related genes show altered expression in the postpartum
nucleus accumbens.

Zhao C(1), Eisinger BE(1), Driessen TM(1), Gammie SC(2).

Author information:
(1)Department of Zoology, University of Wisconsin-Madison Madison, WI, USA.
(2)Department of Zoology, University of Wisconsin-Madison Madison, WI, USA ;
Neuroscience Training Program, University of Wisconsin-Madison Madison, WI, USA.

Motherhood involves a switch in natural rewards, whereby offspring become highly
rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and
addictions, but to date no study has evaluated on a large scale the events in NAC
that underlie the maternal change in natural rewards. In this study we utilized
microarray and bioinformatics approaches to evaluate postpartum NAC gene
expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated
that postpartum (relative to virgin) NAC gene expression profile was
significantly enriched for genes related to addiction and reward in five of five
independently curated databases (e.g., Malacards, Phenopedia). Over 100
addiction/reward related genes were identified and these included: Per1, Per2,
Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1,
Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC
expression profile to be significantly enriched for genes related to the drug
action of nicotine, ketamine, and dronabinol. Pathway analysis indicated
postpartum NAC as enriched for RNA processing, CNS development/differentiation,
and transcriptional regulation. Weighted Gene Coexpression Network Analysis
(WGCNA) identified possible networks for transcription factors, including Nr1d1,
Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for
mental health disorders and MSET analysis indicated postpartum NAC to be enriched
for genes related to depression, bipolar disorder (BPD), and schizophrenia.
Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed
via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study
indicates for the first time that postpartum NAC involves large scale gene
expression alterations linked to addiction and reward. Because the postpartum
state also involves decreased response to drugs, the findings could provide
insights into how to mitigate addictions.

PMCID: PMC4220701
PMID: 25414651 [PubMed]

59. J Affect Disord. 2014;167:333-5. doi: 10.1016/j.jad.2014.05.050. Epub 2014 Jun 2.

The utility of the combination of dextromethorphan and quinidine in the treatment
of bipolar II and bipolar NOS.

Kelly TF(1), Lieberman DZ(2).

Author information:
(1)Depression & Bipolar Clinic of Colorado, 315 West Oak Street, 5th Floor, Fort
Collins, CO 80521, United States; Department of Psychiatry and Behavioral
Science, George Washington University School of Medicine and Health Sciences,
Washington DC, United States. Electronic address: TamKelly@comcast.net.
(2)Department of Psychiatry and Behavioral Science, George Washington University
School of Medicine and Health Sciences, Washington DC, United States.

BACKGROUND: Dextromethorphan is an over-the-counter antitussive agent that may be
a rapidly acting treatment for bipolar depression. Like ketamine, it is an NMDA
receptor antagonist.
METHODS: We conducted a retrospective chart review of depressed patients with
treatment resistant bipolar II or bipolar NOS disorder who were treated with the
combination of dextromethorphan 20 mg and quinidine 10 mg (DMQ). One pill of DMQ
taken once or twice a day was added to participants׳ drug regimen. No changes
were made to the pre-existing drug regimen during the course of treatment with
DMQ. The primary outcome measure was the Clinical Global Impression-Improvement
(CGI-I) score after 90 days of treatment.
RESULTS: Seventy-seven participants met the inclusion criteria. All had been
experiencing depressive symptoms for at least two years, and the mean number of
failed medication trials was 21.2. The average CGI-I score at day 90 was 1.66
(1=slightly improved, 2=much improved). Some patients reported improvement within
1-2 days of starting DMQ. Nineteen patients discontinued treatment due to adverse
effects, chiefly nausea.
LIMITATIONS: Because this was a retrospective chart review with no control group,
conclusions about causation cannot be made. Nevertheless, the duration of
depressive symptoms prior to starting DMQ makes spontaneous recovery less likely.
CONCLUSIONS: DMQ, an NMDA antagonist, may be effective in the treatment of
bipolar depression. Because its putative mechanism does not depend on the
monoaminergic system, it may be appropriate for patients who have not responded
to other medications. Unlike ketamine, DMQ does not require i.v. administration.

PMID: 25016490 [PubMed - indexed for MEDLINE]

60. J Mol Neurosci. 2014;54(2):211-8. doi: 10.1007/s12031-014-0277-8. Epub 2014 Mar
16.

Downregulation of neuregulin 1-ErbB4 signaling in parvalbumin interneurons in the
rat brain may contribute to the antidepressant properties of ketamine.

Wang N(1), Zhang GF, Liu XY, Sun HL, Wang XM, Qiu LL, Yang C, Yang JJ.

Author information:
(1)Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing
University, Nanjing, 210002, China.

Comment in
J Mol Neurosci. 2015 Feb;55(2):372-3.

Increasing evidence underscores the strong, rapid, and sustained antidepressant
properties of ketamine with a good tolerability profile in patients with
depression; however, the underlying mechanisms are not fully elucidated.
Neuregulin 1 (NRG1) is a bipolar disorder susceptibility gene and a biomarker of
major depressive disorder, which regulates pyramidal neuron activity via ErbB4 in
parvalbumin interneurons. Moreover, NRG1-ErbB4 signaling is reported to play a
key role in the modulation of synaptic plasticity through regulating the
neurotransmission. We therefore hypothesized that hypofunction of NRG1-ErbB4
signaling in parvalbumin interneurons is involved in the process of ketamine
exerting rapid antidepressant actions in rats subjected to the forced swimming
test (FST). The results showed that ketamine reduced the immobility time and
latency to feed of rats receiving the FST, downregulated the levels of NRG1,
phosphorylated ErbB4 (p-ErbB4), parvalbumin, 67-kDA isoform of glutamic acid
decarboxylase (GAD67), gamma-aminobutyric acid (GABA), and upregulated the levels
of glutamate in the rat prefrontal cortex and hippocampus. Pretreatment with NRG1
abolished both ketamine's antidepressant effects and ketamine-induced reduction
in p-ErbB4, parvalbumin, GAD67, and GABA levels and increase in glutamate levels.
These results suggest that the downregulation of NRG1-ErbB4 signaling in
parvalbumin interneurons in the rat brain may be a mechanism underlying
ketamine's antidepressant properties.

PMID: 24633675 [PubMed - indexed for MEDLINE]

61. Psychiatr Pol. 2014 Jan-Feb;48(1):35-47.

[Factors connected with efficacy of single ketamine infusion in bipolar
depression].

[Article in Polish]

Permoda-Osip A, Skibińska M, Bartkowska-Sniatkowska A, Kliwicki S,
Chłopocka-Woźniak M, Rybakowski JK.

AIM: The aim of this study was to evaluate the efficacy of single ketamine
infusion and clinical and biochemical factors connected with such efficacy, in
patients with bipolar depression, which had not improved on antidepressant
treatment.
METHODS: The study included 42 patients (32 women, 10 men), aged 22-67 years,
with bipolar depression. They received > or = 1 mood-stabilizing medications of
first and/or second generation. After discontinuation of antidepressants (> or =
7 days), intravenous infusion of ketamine (0.5 mg/kg body weight) was performed.
The assessment of depression by the 17-item Hamilton Depression Rating Scale was
made before, and after 1, 3, 7 and 14 days following administration of ketamine.
The assumed criterion for clinical improvement was the reduction of > or = 50%
score on the Hamilton scale after 7 days. In a subgroup of 20 patients, prior to
administration of ketamine, serum concentrations of homocysteine, vitamin B12,
folic acid, neurotrophins and inflammatory proteins were measured.
RESULTS: In the whole group, the severity of depression on the Hamilton scale
decreased significantly 24 hours after administration of ketamine from 22.6 +/-
5.1 to 15.6 +/- 7.4 points. After 7 days it was 13 +/- 7 and after 14 days - 11.8
+/- 7.8 points. Patients showing clinical improvement (n = 22) had significantly
higher frequency of alcohol addiction and family history of alcoholism.
Biochemical tests in the subset of 20 patients demonstrated that those with
clinical improvement (n = 10) had higher serum concentrations of vitamin B12 and
receptor-1 Vascular Endothelial Growth Factor before administration of ketamine.
Ketamine infusion was well tolerated.
CONCLUSIONS: The results confirm a rapid antidepressant effect of ketamine
infusion maintaining for 2 weeks, in a considerable proportion of patients with
bipolar depression, and good clinical tolerance of such procedure. Also, some
clinical and biochemical factors associated with ketamine efficacy were shown.

PMID: 24946433 [PubMed - indexed for MEDLINE]

62. Rev Psiquiatr Clin. 2014;41(5):131-134.

Biomarkers in mood disorders research: developing new and improved therapeutics.

Niciu MJ(1), Mathews DC(1), Ionescu DF(1), Richards EM(1), Furey ML(1), Yuan
P(1), Nugent AC(1), Henter ID(1), Machado-Vieira R(1), Zarate CA Jr(1).

Author information:
(1)Experimental Therapeutics & Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health,
Bethesda, Maryland.

BACKGROUND: Recently, surrogate neurobiological biomarkers that correlate with
target engagement and therapeutic response have been developed and tested in
early phase studies of mood disorders.
OBJECTIVE: The identification of biomarkers could help develop personalized
psychiatric treatments that may impact public health.
METHODS: These biomarkers, which are associated with clinical response
post-treatment, can be directly validated using multimodal approaches including
genetic tools, proteomics/metabolomics, peripheral measures, neuroimaging,
biostatistical predictors, and clinical predictors.
RESULTS: To date, early phase biomarker studies have sought to identify measures
that can serve as "biosignatures", or biological patterns of clinical response.
These studies have also sought to identify clinical predictors and surrogate
outcomes associated with pathophysiological domains consistently described in the
National Institute of Mental Health's (NIMH) new Research Domain Criteria (RDoC).
Using the N-methyl-D-aspartate (NMDA) antagonist ketamine as an example, we
identified changes in several domains (clinical, cognitive, and
neurophysiological) that predicted ketamine's rapid and sustained antidepressant
effects in individuals with treatment-resistant major depressive disorder (MDD)
or bipolar depression.
DISCUSSION: These approaches may ultimately provide clues into the neurobiology
of psychiatric disorders and may have enormous impact Backon the development of
novel therapeutics.

PMCID: PMC4465361
PMID: 26082563 [PubMed]

63. Front Psychiatry. 2013 Dec 24;4:169. doi: 10.3389/fpsyt.2013.00169.

Connectivity, pharmacology, and computation: toward a mechanistic understanding
of neural system dysfunction in schizophrenia.

Anticevic A(1), Cole MW(2), Repovs G(3), Savic A(4), Driesen NR(5), Yang G(6),
Cho YT(5), Murray JD(7), Glahn DC(8), Wang XJ(7), Krystal JH(9).

Author information:
(1)Department of Psychiatry, Yale University School of Medicine , New Haven, CT ,
USA ; NIAAA Center for the Translational Neuroscience of Alcoholism , New Haven,
CT , USA ; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center
, New Haven, CT , USA ; Interdepartmental Neuroscience Program, Yale University ,
New Haven, CT , USA ; Olin Neuropsychiatry Research Center, Institute of Living,
Hartford Hospital , Hartford, CT , USA ; Department of Psychology, Yale
University , New Haven, CT , USA. (2)Department of Psychology, Washington
University in St. Louis , St. Louis, MO , USA. (3)Department of Psychology,
University of Ljubljana , Ljubljana , Slovenia. (4)Department of Psychiatry,
University of Zagreb School of Medicine , Zagreb , Croatia. (5)Department of
Psychiatry, Yale University School of Medicine , New Haven, CT , USA.
(6)Department of Psychiatry, Yale University School of Medicine , New Haven, CT ,
USA ; Interdepartmental Neuroscience Program, Yale University , New Haven, CT ,
USA. (7)Center for Neural Science, New York University , New York, NY , USA.
(8)Department of Psychiatry, Yale University School of Medicine , New Haven, CT ,
USA ; Olin Neuropsychiatry Research Center, Institute of Living, Hartford
Hospital , Hartford, CT , USA. (9)Department of Psychiatry, Yale University
School of Medicine , New Haven, CT , USA ; NIAAA Center for the Translational
Neuroscience of Alcoholism , New Haven, CT , USA ; Abraham Ribicoff Research
Facilities, Connecticut Mental Health Center , New Haven, CT , USA ; Department
of Neurobiology, Yale University School of Medicine , New Haven, CT , USA.

Neuropsychiatric diseases such as schizophrenia and bipolar illness alter the
structure and function of distributed neural networks. Functional neuroimaging
tools have evolved sufficiently to reliably detect system-level disturbances in
neural networks. This review focuses on recent findings in schizophrenia and
bipolar illness using resting-state neuroimaging, an advantageous approach for
biomarker development given its ease of data collection and lack of task-based
confounds. These benefits notwithstanding, neuroimaging does not yet allow the
evaluation of individual neurons within local circuits, where pharmacological
treatments ultimately exert their effects. This limitation constitutes an
important obstacle in translating findings from animal research to humans and
from healthy humans to patient populations. Integrating new neuroscientific tools
may help to bridge some of these gaps. We specifically discuss two complementary
approaches. The first is pharmacological manipulations in healthy volunteers,
which transiently mimic some cardinal features of psychiatric conditions. We
specifically focus on recent neuroimaging studies using the NMDA receptor
antagonist, ketamine, to probe glutamate synaptic dysfunction associated with
schizophrenia. Second, we discuss the combination of human pharmacological
imaging with biophysically informed computational models developed to guide the
interpretation of functional imaging studies and to inform the development of
pathophysiologic hypotheses. To illustrate this approach, we review clinical
investigations in addition to recent findings of how computational modeling has
guided inferences drawn from our studies involving ketamine administration to
healthy subjects. Thus, this review asserts that linking experimental studies in
humans with computational models will advance to effort to bridge cellular,
systems, and clinical neuroscience approaches to psychiatric disorders.

PMCID: PMC3871997
PMID: 24399974 [PubMed]

64. CNS Spectr. 2013 Dec;18 Suppl 1:4-20; quiz 21. doi: 10.1017/S1092852913000746.
Epub 2013 Nov 15.

A review of FDA-approved treatment options in bipolar depression.

McIntyre RS(1), Cha DS(2), Kim RD(2), Mansur RB(2).

Author information:
(1)1 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
(2)3 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto,
Ontario, Canada.

OBJECTIVES/INTRODUCTION: Herein we review the evidence supporting Food and Drug
Administration (FDA) approved and emerging treatments for bipolar
depression.METHODS: A PubMed search of all English-language articles published up
to July 2013 was conducted. The search terms were quetiapine,
olanzapine-fluoxetine, olanzapine, lurasidone, ketamine, modafinil/armodafinil,
and lamotrigine. The search was augmented with a manual review of relevant
article reference lists, as well as posters presented at national and
international meetings. Articles selected for review were based on the adequacy
of sample size, the use of standardized diagnostic instruments, validated
assessment measures, and overall manuscript quality.
RESULTS: Olanzapine-fluoxetine combination (OFC), quetiapine, and lurasidone are
FDA-approved for the acute treatment of bipolar depression. Lurasidone is the
most recently approved agent for bipolar depression. Olanzapine-fluoxetine
combination and quetiapine are approved as single modality therapies while
lurasidone is approved as a monotherapy and as an adjunct to lithium or
divalproex. The overall effect size of the 3 treatments in mitigating depressive
symptoms is similar. Clinically significant weight gain and metabolic disruption
as well as sedation are significant limitations of OFC and quetiapine. The
minimal propensity for weight gain as well as the metabolic neutrality of
lurasidone in the bipolar population is a clinically significant advantage.
Evidence also supports lamotrigine with compelling evidence as an adjunct to
lithium and in recurrence prevention paradigm; suggested evidence also exists for
ketamine and modafinil/armodafinil; notwithstanding, these treatments remain
investigational.
CONCLUSION: Relatively few agents are FDA-approved for bipolar depression. The
selection and sequencing of agents in bipolar depression should give primacy to
those agents that are FDA-approved. Further refinement of the selection process
will need to pay careful attention to the relative hazards of weight gain and
metabolic disruption in this highly susceptible population. Other agents with
differential mechanisms (eg, ketamine) offer a promising alternative in bipolar
depression.

PMID: 24237641 [PubMed - indexed for MEDLINE]

65. Psychiatry Investig. 2013 Dec;10(4):421-4. doi: 10.4306/pi.2013.10.4.421. Epub
2013 Dec 16.

A 10-week memantine treatment in bipolar depression: a case report. Focus on
depressive symptomatology, cognitive parameters and quality of life.

Strzelecki D(1), Tabaszewska A(2), Barszcz Z(2), Józefowicz O(1), Kropiwnicki
P(3), Rabe-Jabłońska J(1).

Author information:
(1)Department of Affective and Psychotic Disorders, Medical University of Łódź,
Łódź, Poland. (2)Central Clinical Hospital, Łódź, Poland. (3)Department of
Adolescent Psychiatry, Medical University of Łódź, Łódź, Poland.

Memantine and other glutamatergic agents have been currently investigated in some
off-label indications due to glutamatergic involvement in several
psychoneurological disorders. We assumed that memantine similarly to ketamine may
positively influence mood, moreover having a potential to improve cognition and
general quality of life. We report a case of a 49-year-old male hospitalized
during a manic and a subsequent moderate depressive episode. After an ineffective
use of lithium, olanzapine and antidepressive treatment with mianserin, memantine
was added up to 20 mg per day for 10 weeks. The mental state was assessed using
the Hamilton Depression Rating Scale, the Young Mania Rating Scale, the Hamilton
Anxiety Scale, the Clinical Global Inventory, the World Health Organization
Quality of Life Scale and psychological tests. After 10 weeks the patient
achieved a partial symptomatic improvement in mood, anxiety and quality of sleep,
but his activity remained insufficient. We also observed an improvement in the
parameters of cognitive functioning and quality of life. There was neither
significant mood variations during the memantine use nor mood changes after its
termination. No significant side effects were noted during the memantine
treatment. We conclude that using memantine in bipolar depression may improve
mood, cognitive functioning and quality of life.

PMCID: PMC3902162
PMID: 24474993 [PubMed]

66. Biol Psychiatry. 2013 Nov 15;74(10):e23-4. doi: 10.1016/j.biopsych.2013.01.038.
Epub 2013 May 28.

Subanesthetic dose ketamine does not induce an affective switch in three
independent samples of treatment-resistant major depression.

Niciu MJ(1), Luckenbaugh DA, Ionescu DF, Mathews DC, Richards EM, Zarate CA Jr.

Author information:
(1)National Institutes of Health/National Institute of Mental Health,
Experimental Therapeutics and Pathophysiology Branch, Intramural Research
Program, Bethesda, Maryland.

Comment in
Biol Psychiatry. 2013 Nov 15;74(10):e25.

Comment on
Biol Psychiatry. 2011 Aug 15;70(4):e13-4.

PMCID: PMC3805682
PMID: 23726512 [PubMed - indexed for MEDLINE]

67. Biol Psychiatry. 2013 Nov 15;74(10):e25. doi: 10.1016/j.biopsych.2013.03.019.
Epub 2013 May 28.

Reply to: Subanesthetic dose ketamine does not induce an affective switch in
three independent samples of treatment-resistant major depression.

Altinay M(1), Anand A.

Author information:
(1)Center for Behavioral Health, Cleveland Clinic Foundation, Cleveland, Ohio.

Comment on
Biol Psychiatry. 2013 Nov 15;74(10):e23-4.
Biol Psychiatry. 2011 Aug 15;70(4):e13-4.

PMID: 23726510 [PubMed - indexed for MEDLINE]

68. Int J Neuropsychopharmacol. 2013 Oct;16(9):2111-7. doi:
10.1017/S1461145713000485. Epub 2013 May 20.

Antidepressant, mood stabilizing and procognitive effects of very low dose
sublingual ketamine in refractory unipolar and bipolar depression.

Lara DR(1), Bisol LW, Munari LR.

Author information:
(1)Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.

Intravenous ketamine (0.5 mg/kg) produces robust, rapid and long-lasting
antidepressant effects, but is unpractical. Sublingual administration of ketamine
renders better bioavailability (~30%) and less conversion to norketamine than
oral administration. We evaluated the therapeutic effects and tolerability of
very low dose sublingual (VLDS) racemic ketamine (10 mg from a 100 mg/ml solution
for 5 min and swallowed), repeatedly administered every 2-3 d or weekly, in 26
out-patients with refractory unipolar or bipolar depression. According to
patients' reports, VLDS ketamine produced rapid, clear and sustained effects,
improving mood level and stability, cognition and sleep in 20 patients (77%),
with only mild and transient light-headedness as a common side-effect (no
euphoria, psychotic or dissociative symptoms). Remission remained in some
patients after stopping ketamine. Thus, VLDS ketamine may have broad spectrum
effects beyond its antidepressant properties, with rapid onset of action, high
efficacy, good tolerability and low cost, allowing extended treatment as needed.

PMID: 23683309 [PubMed - indexed for MEDLINE]

69. Ugeskr Laeger. 2013 Sep 9;175(37):2090-3.

[Ketamine for treatment of acute depression].

[Article in Danish]

Hjerrild S(1), Bjerre J, Pedersen RH, Videbech P.

Author information:
(1)Center for Psykiatrisk Forskning, Aarhus Universitetshospital, Risskov,
Skovagervej 2, 8240 Risskov. simon@dadlnet.dk.

Comment in
Ugeskr Laeger. 2013 Sep 9;175(37):2089.

In clinical trials a single dose of the N-methyl-D-aspartate (NMDA) receptor
antagonist ketamine has shown a rapid antidepressant effect in patients with
treatment-resistant depression and bipolar depression. The implications of
glutaminergic mechanisms in depression and the rapid effect of a single dose of
ketamine could open new pathways to understand the pathophysiology of depression
and the development of novel rapid-acting antidepressant drugs.

PMID: 24011203 [PubMed - indexed for MEDLINE]

70. Pharmacopsychiatry. 2013 Sep;46(6):227-8. doi: 10.1055/s-0033-1349861. Epub 2013
Jul 11.

Vitamin B12 level may be related to the efficacy of single ketamine infusion in
bipolar depression.

Permoda-Osip A(1), Dorszewska J, Bartkowska-Sniatkowska A, Chlopocka-Wozniak M,
Rybakowski JK.

Author information:
(1)Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan,
Poland.

The single infusion of ketamine, an N-methyl-d-aspartic acid (NMDA) glutamate
receptor antagonist, exerts a therapeutic effect in both unipolar and bipolar
depression. Homocysteine (HCY) acts agonistically on the NMDA receptor,
hyperhomocysteinemia is related to depression, and folic acid and vitamin B12 are
associated with HCY system. We estimated the serum levels of these substances in
20 bipolar depressed patients before ketamine infusion. 10 patients responded
favorably to this procedure, as their score on the Hamilton depression rating
scale, compared to baseline, was reduced by more than 50%, after 7 days. The
vitamin B12 level was significantly higher in "responders" compared to the
remaining patients. No differences between the 2 groups were found with regard to
HCY, folic acid levels and such clinical factors as age, duration of illness and
duration of current episode. These preliminary data suggest that the vitamin B12
level may be connected with the efficacy of ketamine infusion in bipolar
depression.

PMID: 23846402 [PubMed - indexed for MEDLINE]

71. BMJ Case Rep. 2013 Aug 19;2013. pii: bcr2013200370. doi: 10.1136/bcr-2013-200370.

Sustained antidepressant response to ketamine.

Atigari OV(1), Healy D.

Author information:
(1)Department of Psychiatry (Hergest Unit), Ysbyty Gwynedd Hospital, Bangor,
Wales, UK.

Case series outlining the treatment of three patients with ketamine, in which two
of the patients had a sustained antidepressant effect to ketamine without the
need for maintenance on antidepressants. These two responders have an established
diagnosis of bipolar affective disorder with a history of response to
electroconvulsive therapy and lithium, both of which have an influence on the
seizure threshold as has ketamine. The mechanism of action of ketamine is yet
unclear and although the current focus is on the N-methyl-d-aspartate and
alpha-amino-3-4-hydroxy-5methyl-4-isoxazoleproprionic acid receptors, we
additionally recommend that its impact on the seizure threshold should be
explored with a view to fully elucidating the mechanism of action.

PMCID: PMC3762430
PMID: 23960151 [PubMed - indexed for MEDLINE]

72. CNS Spectr. 2013 Aug;18(4):171-4. doi: 10.1017/S109285291300045X.

Mechanism of action of ketamine.

Stahl SM.

Ketamine induces rapid-onset and short-duration improvement in depressive and
suicidal symptoms in both treatment-resistant unipolar depression and bipolar
depression, and also reduces chronic pain after short intravenous infusions. In
order to develop long-acting oral agents with the same clinical effects, the
pharmacologic mechanism of action must be understood, and the leading hypotheses
are discussed here.

PMID: 23866089 [PubMed - indexed for MEDLINE]

73. CNS Spectr. 2013 Aug;18(4):188-98. doi: 10.1017/S1092852912000971. Epub 2013 Feb
1.

Glutamate system as target for development of novel antidepressants.

Catena-Dell'Osso M(1), Fagiolini A, Rotella F, Baroni S, Marazziti D.

Author information:
(1)1 Department of Psychiatry, Neurobiology, Farmacology and Biotecnology,
University of Pisa, Pisa, Italy.

Depression is a common psychiatric condition characterized by affective,
cognitive, psychomotor, and neurovegetative symptoms that interfere with a
person's ability to work, study, deal with interpersonal relationships, and enjoy
once-pleasurable activities. After the serendipitous discovery of the first
antidepressants, for years the only pharmacodynamic mechanisms explored in the
search of novel antidepressants were those related to the 3 main monoamines:
serotonin, norepinephrine, and dopamine. New-generation monoaminergic
antidepressants, such as selective-serotonin and dual-acting
serotonin/norepinephrine reuptake inhibitors, improved treatment and quality of
life of depressed patients. Nevertheless, there are still important clinical
limitations: the long latency of onset of the antidepressant action; side
effects, which can lead to early discontinuation; low rate of response; and high
rate of relapse/recurrence. Therefore, in the last several years, the focus of
research has moved from monoamines toward other molecular mechanisms, including
glutamatergic (Glu) neurotransmission. This review provides a comprehensive
overview of the current knowledge on the Glu system and on its relationships with
mood disorders. Up to now, N-methyl-D-aspartate (NMDA) receptor antagonists, in
particular ketamine, provided the most promising results in preclinical studies
and produced a consistent and rapid, although transient, antidepressant effect
with a good tolerability profile in humans. Although data are encouraging, more
double-blind, randomized, placebo-controlled trials are needed to clarify the
real potentiality of ketamine, and of the other Glu modulators, in the treatment
of unipolar and bipolar depression.

PMID: 23369807 [PubMed - indexed for MEDLINE]

74. CNS Drugs. 2013 Jul;27(7):515-29. doi: 10.1007/s40263-013-0073-y.

Pharmacological management of bipolar depression: acute treatment, maintenance,
and prophylaxis.

Vieta E(1), Valentí M.

Author information:
(1)Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS,
CIBERSAM, 170 Villarroel St, 08036 Barcelona, Catalonia, Spain.
evieta@clinic.ub.es

Although the most distinctive clinical feature of bipolar disorder is the
pathologically elevated mood, it does not usually constitute the prevalent mood
state of bipolar illness. The majority of patients with bipolar disorder spend
much more time in depressive episodes, including subsyndromal depressive
symptoms, and bipolar depression accounts for the largest part of the morbidity
and mortality of the illness. The pharmacological treatment of bipolar depression
mostly consists of combinations of at least two drugs, including mood stabilizers
(lithium and anticonvulsants), atypical antipsychotics, and antidepressants.
Antidepressants are the most frequently prescribed drugs, but recommendations
from evidence-based guidelines are not conclusive and do not overtly support
their use. Among antidepressants, best evidence exists for fluoxetine, but in
combination with olanzapine. Although some guidelines recommend the use of
selective serotonin reuptake inhibitors or bupropion in combination with
antimanic agents as first-choice treatment, others do not, based on the available
evidence. Among anticonvulsants, the use of lamotrigine is overall recommended as
a first-line choice, but acute monotherapy studies have failed. Valproate is
generally mentioned as a second-line treatment. Lithium monotherapy is also
suggested by most guidelines as a first-line treatment, but its efficacy in acute
use is not totally clear. Amongst atypical antipsychotics, quetiapine, in
monotherapy or as adjunctive treatment, is recommended by most guidelines as a
first-line choice. Olanzapine monotherapy is also suggested by some guidelines
and is approved in Japan. Armodafinil, pramipexole, ketamine, and lurasidone are
recent proposals. Long-term treatment in bipolar disorder is strongly
recommended, but guidelines do not recommend the use of antidepressants as a
maintenance treatment. Lithium, lamotrigine, valproate, olanzapine, quetiapine,
and aripiprazole are the recommended first-line maintenance options.

PMID: 23749421 [PubMed - indexed for MEDLINE]

75. J Psychopharmacol. 2013 Jul;27(7):651-4. doi: 10.1177/0269881113486718. Epub 2013
May 15.

Two cases of delayed-onset suicidal ideation, dysphoria and anxiety after
ketamine infusion in patients with obsessive-compulsive disorder and a history of
major depressive disorder.

Niciu MJ(1), Grunschel BD, Corlett PR, Pittenger C, Bloch MH.

Author information:
(1)Yale University, Department of Psychiatry/Connecticut Mental Health Center
(CMHC), Clinical Neuroscience Research Unit (CNRU), New Haven, Connecticut, USA.
mark.niciu@nih.gov

Ketamine is a non-competitive N-methyl-D-aspartate receptor antagonist that is
Food and Drug Administration-approved in the United States for anesthesia due to
its sedative effects with low risk of severe respiratory depression.
Subanesthetic dose intravenous ketamine has rapidly acting antidepressant effects
in treatment-resistant unipolar and bipolar depression. We recently reported an
open-label trial of ketamine in 10 subjects with treatment-refractory
obsessive-compulsive disorder, seven of whom had active comorbid depression.
Although ketamine had no sustained anti-obsessive effect, four of the seven
subjects with comorbid depression experienced an acute antidepressant effect.
However, we unexpectedly observed delayed-onset dysphoria, worsening anxiety and
suicidal thinking in two of the three subjects with obsessive-compulsive disorder
and extensive psychiatric comorbidity but minimal depressive symptoms at the
start of infusion. The implications of these adverse neuropsychiatric effects in
two patients with similar psychiatric comorbidity are discussed. We conclude that
there remains insufficient data on therapeutic ketamine in the presence of
comorbid psychiatric disorders to promote its off-label use in a non-research
milieu.

PMID: 23676198 [PubMed - indexed for MEDLINE]

76. Biol Psychiatry. 2013 Jun 15;73(12):1142-55. doi: 10.1016/j.biopsych.2012.11.031.
Epub 2013 Jan 29.

Human biomarkers of rapid antidepressant effects.

Zarate CA Jr(1), Mathews DC, Furey ML.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health,
Department of Health and Human Services, Bethesda, Maryland, USA.
zaratec@mail.nih.gov

Mood disorders such as major depressive disorder and bipolar disorder--and their
consequent effects on the individual and society--are among the most disabling
and costly of all medical illnesses. Although a number of antidepressant
treatments are available in clinical practice, many patients still undergo
multiple and lengthy medication trials before experiencing relief of symptoms.
Therefore a tremendous need exists to improve current treatment options and to
facilitate more rapid, successful treatment in patients suffering from the
deleterious neurobiological effects of ongoing depression. Toward that end,
ongoing research is exploring the identification of biomarkers that might be
involved in prevention, diagnosis, treatment response, severity, or prognosis of
depression. Biomarkers evaluating treatment response will be the focus of this
review, given the importance of providing relief to patients in a more expedient
and systematic manner. A novel approach to developing such biomarkers of response
would incorporate interventions with a rapid onset of action--such as sleep
deprivation or intravenous drugs (e.g., ketamine or scopolamine). This
alternative translational model for new treatments in psychiatry would facilitate
shorter studies, improve feasibility, and increase higher compound throughput
testing for these devastating disorders.

Published by Elsevier Inc.

PMCID: PMC3672383
PMID: 23374639 [PubMed - indexed for MEDLINE]

77. J Affect Disord. 2013 May;147(1-3):431-6. doi: 10.1016/j.jad.2012.08.040. Epub
2012 Nov 30.

Clinical experience using intranasal ketamine in the treatment of pediatric
bipolar disorder/fear of harm phenotype.

Papolos DF(1), Teicher MH, Faedda GL, Murphy P, Mattis S.

Author information:
(1)Juvenile Bipolar Research Foundation, Maplewood, NJ, USA.
demitri@optonline.net

OBJECTIVES: Intravenous ketamine, a glutamate N-methyl-d-aspartate (NMDA)
receptor antagonist, has been shown to exert a rapid antidepressant effect in
adults with treatment resistant depression. Children with bipolar disorder (BD)
often respond poorly to pharmacotherapy, including polypharmacy. A
pediatric-onset Fear of Harm (FOH) phenotype has been described, and is
characterized by severe clinical features and resistance to accepted treatments
for BD. The potential efficacy and safety of intranasal ketamine in children with
BD with FOH-phenotype were assessed by a systematic retrospective chart review of
a case series from the private practice of one of the authors, including cases
with clear refractoriness to mood stabilizers, antipsychotics and
benzodiazepines.
METHODS: A comparison was made between routinely collected symptom measures 1-2
weeks prior to and after the administration of ketamine, in 12
treatment-refractory youth, 10 males 2 females ages 6-19years.
RESULTS: Ketamine administration was associated with a substantial reduction in
measures of mania, fear of harm and aggression. Significant improvement was
observed in mood, anxiety and behavioral symptoms, attention/executive functions,
insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated.
CONCLUSIONS: Intranasal ketamine administration in treatment-resistant youth with
BD-FOH produced marked improvement in all symptomatic dimensions. A rapid,
substantial therapeutic response, with only minimal side effects was observed.
Formal clinical trials to assess safety and efficacy are warranted.

PMID: 23200737 [PubMed - indexed for MEDLINE]

78. J Clin Psychiatry. 2013 May;74(5):516-7. doi: 10.4088/JCP.13ac08382.

Current status of ketamine and related compounds for depression.

Mathews DC(1), Zarate CA Jr.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health, and
Department of Health and Human Services, Bethesda, MD, USA.

PMCID: PMC3785314
PMID: 23759454 [PubMed - indexed for MEDLINE]

79. Anesthesiology. 2013 Feb;118(2):308-17. doi: 10.1097/ALN.0b013e318279fb21.

Effects of propofol, sevoflurane, remifentanil, and (S)-ketamine in subanesthetic
concentrations on visceral and somatosensory pain-evoked potentials.

Untergehrer G(1), Jordan D, Eyl S, Schneider G.

Author information:
(1)Department of Anesthesiology, Helios Clinic Wuppertal, Witten/Herdecke
University, Wuppertal, Germany.

BACKGROUND: Although electroencephalographic parameters and auditory evoked
potentials (AEP) reflect the hypnotic component of anesthesia, there is currently
no specific and mechanism-based monitoring tool for anesthesia-induced blockade
of nociceptive inputs. The aim of this study was to assess visceral pain-evoked
potentials (VPEP) and contact heat-evoked potentials (CHEP) as
electroencephalographic indicators of drug-induced changes of visceral and
somatosensory pain. Additionally, AEP and electroencephalographic permutation
entropy were used to evaluate sedative components of the applied drugs.
METHODS: In a study enrolling 60 volunteers, VPEP, CHEP (amplitude N2-P1), and
AEP (latency Nb, amplitude Pa-Nb) were recorded without drug application and at
two subanesthetic concentration levels of propofol, sevoflurane, remifentanil, or
(s)-ketamine. Drug-induced changes of evoked potentials were analyzed. VPEP were
generated by electric stimuli using bipolar electrodes positioned in the distal
esophagus. For CHEP, heat pulses were given to the medial aspect of the right
forearm using a CHEP stimulator. In addition to AEP, electroencephalographic
permutation entropy was used to indicate level of sedation.
RESULTS: With increasing concentrations of propofol, sevoflurane, remifentanil,
and (s)-ketamine, VPEP and CHEP N2-P1 amplitudes decreased. AEP and
electroencephalographic permutation entropy showed neither clinically relevant
nor statistically significant suppression of cortical activity during drug
application.
CONCLUSIONS: Decreasing VPEP and CHEP amplitudes under subanesthetic
concentrations of propofol, sevoflurane, remifentanil, and (s)-ketamine indicate
suppressive drug effects. These effects seem to be specific for analgesia.

PMID: 23254146 [PubMed - indexed for MEDLINE]

80. Bipolar Disord. 2013 Feb;15(1):61-9. doi: 10.1111/bdi.12026. Epub 2012 Nov 27.

Evidence-based treatment strategies for treatment-resistant bipolar depression: a
systematic review.

Sienaert P(1), Lambrichts L, Dols A, De Fruyt J.

Author information:
(1)Department of Mood Disorders, University Psychiatric Center, Catholic
University Leuven, Campus Kortenberg, Kortenberg, Belgium.
pascal.sienaert@uc-kortenberg.be

OBJECTIVES: Treatment resistance in bipolar depression is a common clinical
problem that constitutes a major challenge for the treating clinician as there is
a paucity of treatment options. The objective of this paper was to review the
evidence for treatment options in treatment-resistant bipolar depression, as
found in randomized controlled trials and with special attention to the
definition and assessment of treatment resistance.
METHODS: A Medline search (from database inception to May 2012) was performed
using the search terms treatment resistance or treatment refractory, and bipolar
depression or bipolar disorder, supplemented with 43 separate searches using the
various pharmacologic agents or technical interventions as search terms.
RESULTS: Only seven studies met our inclusion criteria. These studies examined
the effects of ketamine (n = 1), (ar)modafinil (n = 2), pramipexole (n = 1),
lamotrigine (n = 1), inositol (n = 1), risperidone (n = 1), and electroconvulsive
therapy (ECT) (n = 2).
CONCLUSIONS: The available level I evidence for treatment strategies in resistant
bipolar depression is extremely scarce, and although the response rates reported
are reassuring, most of the strategies remain experimental. There is an urgent
need for further study in homogeneous patient samples using a clear concept of
treatment resistance.

PMID: 23190379 [PubMed - indexed for MEDLINE]

81. Graefes Arch Clin Exp Ophthalmol. 2013 Feb;251(2):529-35. doi:
10.1007/s00417-012-2212-4. Epub 2012 Nov 24.

Electroretinography in streptozotocin diabetic rats following acute intraocular
pressure elevation.

Kohzaki K(1), Vingrys AJ, Armitage JA, Bui BV.

Author information:
(1)Department of Ophthalmology, Jikei University, 3-25-8, Nishi-Shimbashi,
Minato-ku, Tokyo, 105-8461, Japan.

BACKGROUND: We consider whether pre-existing streptozotocin induced hyperglycemia
in rats affects the ability of the eye to cope with a single episode of acute
intraocular pressure (IOP) elevation.
METHODS: Electroretinogram (ERG) responses were measured (-6.08 to 1.92 log
cd.s.m(-2)) in anaesthetized (60:5 mg/kg ketamine:xylazine) dark-adapted (>12 h)
adult Sprague-Dawley rats 1 week after a single acute IOP elevation to 70 mmHg
for 60 min. This was undertaken in rats treated 11 weeks earlier with
streptozotocin (STZ, n = 12, 50 mg/kg at 6 weeks of age) or citrate buffer (n =
12). ERG responses were analyzed to derive an index of photoreceptor (a-wave),
ON-bipolar (b-wave), amacrine (oscillatory potentials) and inner retinal
(positive scotopic threshold response, pSTR) function.
RESULTS: One week following acute IOP elevation there was a significant reduction
of the ganglion cell pSTR (-35 ± 11 %, P = 0.0161) in STZ-injected animals. In
contrast the pSTR in citrate-injected animals was not significant changed (+16 ±
14 %). The negative component of the STR was unaffected by IOP elevation in
either citrate or STZ-treated groups. Photoreceptoral (a-wave, citrate-control +4
± 3 %, STZ +4 ± 5 %) and ON-bipolar cell (b-wave, control +4 ± 3 %, STZ +4 ± 5 %)
mediated responses were not significantly affected by IOP elevation in either
citrate- or STZ-injected rats. Finally, oscillatory potentials (citrate-control
+8 ± 23 %, STZ +1 ± 17 %) were not reduced 1 week after IOP challenge.
CONCLUSIONS: The ganglion cell dominated pSTR was reduced following a single
episode of IOP elevation in STZ diabetic, but not control rats. These data
indicate that hyperglycemia renders the inner retina more susceptible to IOP
elevation.

PMID: 23180237 [PubMed - indexed for MEDLINE]

82. Hum Psychopharmacol. 2013 Jan;28(1):87-90. doi: 10.1002/hup.2271. Epub 2012 Nov
5.

Single ketamine infusion in bipolar depression resistant to antidepressants: are
neurotrophins involved?

Rybakowski JK(1), Permoda-Osip A, Skibinska M, Adamski R, Bartkowska-Sniatkowska
A.

Author information:
(1)Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan,
Poland. rybakows@wlkp.top.pl

OBJECTIVES: We investigated serum brain-derived neurotrophin factor (BDNF), nerve
growth factor (NGF), neurotrophin-3 (NTF3), neurotrophin-4 (NTF4) and the
glial-derived neurotrophic factor (GDNF), in relation to ketamine efficacy, in
bipolar depressed patients resistant to treatment with antidepressants.
METHODS: Twenty-five patients (4 male, 21 female), aged 27-67 years, with bipolar
depression, receiving mood-stabilizing medications, were studied. Antidepressants
were discontinued for at least 7 days before single intravenous ketamine infusion
(0.5 mg/kg body weight). Response to ketamine was defined as ≥ 50% reduction on
17-item Hamilton Depression Rating Scale (HDRS) after 1 week, and remission as
HDRS score ≤ 7. Serum BDNF, NGF, NTF3, NTF4 and GDNF levels were estimated by
enzyme-linked immunosorbent assay.
RESULTS: There were 13 ketamine responders and 12 non-responders. The remission
was obtained in eight and 12 patients after seven and 14 days, respectively. At
baseline, there were no differences between responders and non-responders in any
of the neurotrophins. Serum BDNF was significantly reduced after 7 days in
non-responders. Serum NGF, NT3, NT4 and GDNF did not significantly change.
CONCLUSIONS: The results confirm an antidepressant effect of ketamine infusion as
an add-on to mood-stabilizing drugs in bipolar depression resistant to
antidepressant treatment. They may also suggest a possible involvement of BDNF in
this effect.

PMID: 23124710 [PubMed - indexed for MEDLINE]

83. J Psychosoc Nurs Ment Health Serv. 2013 Jan;51(1):11-4.

Ketamine for the treatment of depression.

Howland RH(1).

Author information:
(1)University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
HowlandRH@upmc.edu

Ketamine (Ketalar®) is an anesthetic agent derived from the hallucinogenic drug
phencyclidine (PCP). It is a high-affinity antagonist at N-methyl-D-aspartate
receptors and also binds to opioid mu and sigma receptors. Ketamine is being
intensively investigated as an antidepressant therapy. To date, five short-term
controlled studies and other open-label studies in patients with unipolar or
bipolar depression have demonstrated that intravenous ketamine is safe and has a
rapid and profound short-term effect on depressive symptoms, including suicidal
thoughts, even among patients considered treatment-resistant to standard
medications or electroconvulsive therapy. Before ketamine can be incorporated
into clinical practice, however, its long-term safety and effectiveness need to
be evaluated. Although the effectiveness of alternative routes of ketamine
administration (i.e., oral, intranasal, or intramuscular) needs to be determined,
intravenous ketamine could be conceptualized as a clinic-based procedural therapy
for treatment resistant forms of depression.

PMID: 23413455 [PubMed - indexed for MEDLINE]

84. Perspect Psychiatr Care. 2013 Jan;49(1):2-4. doi: 10.1111/ppc.12006. Epub 2012
Dec 30.

Ketamine as an alternative treatment for treatment-resistant depression.

Dowben JS(1), Grant JS, Keltner NL.

Author information:
(1)nkeltner@uab.edu

PMID: 23293991 [PubMed - indexed for MEDLINE]

85. PLoS One. 2013;8(2):e56053. doi: 10.1371/journal.pone.0056053. Epub 2013 Feb 4.

Long-lasting antidepressant action of ketamine, but not glycogen synthase
kinase-3 inhibitor SB216763, in the chronic mild stress model of mice.

Ma XC(1), Dang YH, Jia M, Ma R, Wang F, Wu J, Gao CG, Hashimoto K.

Author information:
(1)Department of Psychiatry, First Affiliated Hospital of Medical College of
Xi'an Jiaotong University, Xian, China.

BACKGROUND: Clinical studies demonstrate that the N-methyl-D-aspartate (NMDA)
receptor antagonist, ketamine, induces rapid antidepressant effects in patients
with refractive major depressive disorder and bipolar depression. This rapid
onset of action makes ketamine a highly attractive drug for patients,
particularly those who do not typically respond to therapy. A recent study
suggested that glycogen synthase kinase (GSK)-3 may underlie the rapid
antidepressant action of ketamine, although the precise mechanisms are unclear.
In this study, we examined the effects of ketamine and GSK-3 inhibitor SB216763
in the unpredictable, chronic mild stress (CMS) mouse model of mice.
METHODOLOGY/PRINCIPAL FINDINGS: Adult C57/B6 male mice were divided into 2
groups, a non-stressed control group and the unpredictable CMS (35 days) group.
Then, either vehicle, ketamine (10 mg/kg), or the established GSK-3 inhibitor,
SB216763 (10 mg/kg), were administered into mice in the CMS group, while vehicle
was administered to controls. In the open field test, there was no difference
between the four groups (control+vehicle, CMS+vehicle, CMS+ketamine,
CMS+SB216763). In the sucrose intake test, a 1% sucrose intake drop, seen in CMS
mice, was significantly attenuated after a single dose of ketamine, but not
SB216763. In the tail suspension test (TST) and forced swimming test (FST), the
increased immobility time seen in CMS mice was significantly attenuated by a
single dose of ketamine, but not SB216763. Interestingly, the ketamine-induced
increase in the sucrose intake test persisted for 8 days after a single dose of
ketamine. Furthermore, a single administration of ketamine, but not SB216763,
significantly attenuated the immobility time of the TST and FST in the control
(non-stressed) mice.
CONCLUSIONS/SIGNIFICANCE: These findings suggest that a single administration of
ketamine, but not GSK-3 inhibitor SB216763, produces a long-lasting
antidepressant action in CMS model mice.

PMCID: PMC3563541
PMID: 23390559 [PubMed - indexed for MEDLINE]

86. J Affect Disord. 2012 Dec 15;142(1-3):233-40. doi: 10.1016/j.jad.2012.04.032.
Epub 2012 Aug 2.

Neuropsychological and mood effects of ketamine in electroconvulsive therapy: a
randomised controlled trial.

Loo CK(1), Katalinic N, Garfield JB, Sainsbury K, Hadzi-Pavlovic D, Mac-Pherson
R.

Author information:
(1)School of Psychiatry, University of New South Wales, Sydney, NSW 2031,
Australia. colleen.loo@unsw.edu.au

BACKGROUND: Preliminary evidence suggests that the use of ketamine during
electroconvulsive therapy (ECT) may be neuroprotective against cognitive
impairment and have synergistic antidepressant effects. This study tested whether
the addition of ketamine reduced cognitive impairment and enhanced efficacy over
a course of ECT, in a randomised, placebo-controlled, double-blind study.
METHODS: Fifty-one depressed patients treated with ultrabrief pulse-width right
unilateral ECT were randomised to receive either ketamine (0.5mg/kg) or placebo
(saline) in addition to thiopentone during anaesthesia for ECT.
Neuropsychological outcomes (measured before ECT, after six treatments, and after
the final ECT treatment) and mood outcomes (measured before ECT, and weekly after
every three ECT treatments) were measured by a rater blinded to treatment
condition.
RESULTS: Neuropsychological outcomes did not differ between groups. The
ECT-ketamine group had a slightly greater improvement in depressive symptoms over
the first week of treatment and at one-week follow up, though there was no
overall difference in efficacy at the end of the ECT course. No psychomimetic
effects were detected.
LIMITATIONS: The study was conducted in a clinical setting, so not all aspects of
ECT treatment were fully controlled. Thiopentone doses differed slightly between
groups, in order to accommodate the addition of ketamine to the anaesthetic.
CONCLUSIONS: The addition of ketamine did not decrease cognitive impairment in
patients having ultrabrief pulse-width right unilateral ECT, but was safe and
slightly improved efficacy in the first week of treatment and at one-week follow
up.
CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov ID: NCT00680433. Ketamine as an
anaesthetic agent in electroconvulsive therapy (ECT). www.clinicaltrials.gov.

PMID: 22858219 [PubMed - indexed for MEDLINE]

87. Bipolar Disord. 2012 Dec;14(8):880-7. doi: 10.1111/bdi.12003. Epub 2012 Sep 14.

Family history of alcohol dependence and antidepressant response to an
N-methyl-D-aspartate antagonist in bipolar depression.

Luckenbaugh DA(1), Ibrahim L, Brutsche N, Franco-Chaves J, Mathews D, Marquardt
CA, Cassarly C, Zarate CA Jr.

Author information:
(1)Experimental Therapeutics and Pathophysiology Branch, Division of Intramural
Research Program, Department of Health and Human Services, National Institute of
Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.

OBJECTIVES: Both ketamine and ethanol are N-methyl-d-aspartate (NMDA) receptor
antagonists. Ketamine has rapid antidepressant properties in major depressive
disorder (MDD) as well as bipolar depression. In individuals with MDD, a positive
family history of alcohol dependence (FHP) was associated with greater
improvement in depressive symptoms after ketamine administration compared to
individuals whose family history of alcohol dependence was negative (FHN). This
study investigated whether FHP influences ketamine's antidepressant and
perceptual effects in individuals with bipolar depression.
METHODS: A post hoc analysis was conducted on 33 subjects with DSM-IV bipolar
disorder (BD) type I or II depression pooled from two previously published
studies. All subjects had undergone a double-blind, randomized, crossover trial
of a single intravenous infusion of ketamine (0.5 mg/kg) combined with lithium or
valproate therapy. Subjects were rated at baseline; at 40, 80, 120, and 230 min;
and at days 1, 2, 3, 7, 10, and 14 post-infusion. The primary outcome measure was
Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Patients were
categorized as FHP when they reported at least one first-degree relative with
alcohol dependence. Measures of psychosis, dissociation, and dysphoria were also
collected.
RESULTS: After ketamine infusion, subjects with FHP showed significantly greater
improvement on MADRS scores than FHN subjects. In addition, patients with FHP had
attenuated psychotomimetic and dissociative scores compared to FHN patients.
CONCLUSIONS: FHP appears to predict a more sustained antidepressant response to
ketamine in individuals with BD. Family history of alcoholism may be an important
consideration in the development of glutamatergic-based therapies for depression.

Published 2012. This article is a U.S. Government work and is in the public
domain in the USA.

PMCID: PMC3504126
PMID: 22978511 [PubMed - indexed for MEDLINE]

88. J Psychiatr Res. 2012 Dec;46(12):1569-75. doi: 10.1016/j.jpsychires.2012.08.010.
Epub 2012 Sep 19.

Evaluation of behavioral and neurochemical changes induced by ketamine in rats:
implications as an animal model of mania.

Ghedim FV(1), Fraga Dde B, Deroza PF, Oliveira MB, Valvassori SS, Steckert AV,
Budni J, Dal-Pizzol F, Quevedo J, Zugno AI.

Author information:
(1)Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia
Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências
Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da
Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul
Catarinense, 88806-000 Criciúma, SC, Brazil.

Bipolar disorder (BD) is a chronic, prevalent, and highly debilitating
psychiatric illness characterized by recurrent manic and depressive episodes.
Mood stabilizing agents such as lithium and valproate are two primary drugs used
to treat BD. To develop a novel animal model of mania (hallmark of BD), it is
important to assess the therapeutic and prophylactic effect of these mood
stabilizers on the new candidate target animal model. The present work
investigates the therapeutic and prophylactic value of lithium and valproate in a
novel preclinical animal model of mania, induced by ketamine. In the prevention
protocol, wistar rats were pretreated with lithium (47.5 mg/kg, i.p., twice a
day), valproate (200 mg/kg, i.p., twice a day), or saline (i.p., twice a day) for
14 days. Between days 8 and 14, the rats were treated with ketamine (25 mg/kg,
i.p.) or saline. In the reversal protocol, rats first received ketamine (25
mg/kg, i.p.) or saline. After, the administration of lithium, valproate, or
saline was carried out for seven days. Our results indicated that lithium and
valproate reversed and prevented ketamine-induced hyperlocomotion. Moreover,
lithium and valproate reversed (prefrontal cortex, hippocampus, and striatum) and
prevented (prefrontal cortex, hippocampus, striatum, and amygdala) the increase
of the TBARS level induced by ketamine. The protein carbonyl formation, induced
by ketamine, was reversed by lithium and valproate in the prefrontal cortex,
hippocampus, and striatum, and prevented only in the amygdala. These findings
support the notion that the administration of ketamine might be a promising
pharmacological animal model of mania, which could play a role in the
pathophysiology of BD.

PMID: 22998743 [PubMed - indexed for MEDLINE]

89. Biol Psychiatry. 2012 Oct 1;72(7):537-47. doi: 10.1016/j.biopsych.2012.05.003.
Epub 2012 Jun 16.

Ketamine for depression: where do we go from here?

Aan Het Rot M(1), Zarate CA Jr, Charney DS, Mathew SJ.

Author information:
(1)Department of Psychology and School of Behavioral and Cognitive Neuroscience,
University of Groningen, The Netherlands. m.aan.het.rot@rug.nl

Comment in
Biol Psychiatry. 2013 Nov 15;74(10):712-3.

Since publication of the first randomized controlled trial describing rapid
antidepressant effects of ketamine, several reports have confirmed the potential
utility of this dissociative anesthetic medication for treatment of major
depressive episodes, including those associated with bipolar disorder and
resistant to other medications and electroconvulsive therapy. These reports have
generated several questions with respect to who might respond to ketamine, how,
and for how long. To start answering these questions. We used PubMed.gov and
ClinicalTrials.gov to perform a systematic review of all available published data
on the antidepressant effects of ketamine and of all recently completed, ongoing,
and planned studies. To date, 163 patients, primarily with treatment-resistant
depression, have participated in case studies, open-label investigations, or
controlled trials. All controlled trials have used a within-subject, crossover
design with an inactive placebo as the control. Ketamine administration has
usually involved an anaesthesiologist infusing a single, subanesthetic,
intravenous dose, and required hospitalization for at least 24 hours
postinfusion. Response rates in the open-label investigations and controlled
trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70%
at 72 hours postinfusion. Although adverse effects have generally been mild, some
patients have experienced brief changes in blood pressure, heart rate, or
respiratory rate. Risk-benefit analyses support further research of ketamine for
individuals with severe mood disorders. However, given the paucity of randomized
controlled trials, lack of an active placebo, limited data on long-term outcomes,
and potential risks, ketamine administration is not recommended outside of the
hospital setting.

PMCID: PMC3438349
PMID: 22705040 [PubMed - indexed for MEDLINE]

90. Med Hypotheses. 2012 Oct;79(4):504-7. doi: 10.1016/j.mehy.2012.07.002. Epub 2012
Jul 21.

Methoxetamine: from drug of abuse to rapid-acting antidepressant.

Coppola M(1), Mondola R.

Author information:
(1)Department of Addiction, ASL CN2, Viale Coppino 46, 12051 Alba (CN), Italy.
coppolamail@alice.it

Methoxetamine is a dissociative anaesthetic showing pharmacodynamic similarities
with its analogue ketamine, a medication with demonstrated rapid-acting
antidepressant effects. Like ketamine and other arylcyclohexylamine compounds,
methoxetamine is thought to be both a noncompetitive NMDA receptor antagonist and
a dopamine reuptake inhibitor. Furthermore, it acts as an agonist at dopamine D2,
serotonin 5HT2, muscarinic cholinergic, sigma-1, opioid mu and k receptors. The
hypothesis is that methoxetamine can produce rapid antidepressant effects in
patients with resistant and non-resistant unipolar and bipolar depression.

PMID: 22819129 [PubMed - indexed for MEDLINE]

91. J ECT. 2012 Sep;28(3):157-61. doi: 10.1097/YCT.0b013e31824f8296.

Rapid antidepressant effect of ketamine in the electroconvulsive therapy setting.

Abdallah CG(1), Fasula M, Kelmendi B, Sanacora G, Ostroff R.

Author information:
(1)Department of Psychiatry and the Ribicoff Research Facilities, Yale University
School of Medicine, New Haven, CT, USA.

OBJECTIVES: Studies now provide strong evidence that the N-methyl-D-aspartate
receptor antagonist ketamine possesses rapidly acting antidepressant properties.
This study aimed to determine if a low dose of ketamine could be used to expedite
and augment the antidepressant effects of electroconvulsive therapy (ECT)
treatments in patients experiencing a severe depressive episode.
MATERIALS AND METHODS: Subjects with major depressive disorder or bipolar
disorder referred for ECT treatment of a major depressive episode were randomized
to receive thiopental alone or thiopental plus ketamine (0.5 mg/kg) for
anesthesia before each ECT session. The Hamilton Depression Rating Scale (HDRS)
was administered at baseline and at 24 to 72 hours after the first and sixth ECT
sessions.
RESULTS: Electroconvulsive therapy exerted a significant antidepressant effect in
both groups (F2,24 = 14.35, P < 0.001). However, there was no significant group
effect or group-by-time interaction on HDRS scores. In addition, post hoc
analyses of the time effect on HDRS showed no significant HDRS reduction after
the first ECT session for either group.
CONCLUSIONS: The results of this pilot study suggest that ketamine, at a dose of
0.5 mg/kg, given just before ECT, did not enhance the antidepressant effect of
ECT. Interestingly, the results further suggest that the coadministration of
ketamine with a barbiturate anesthetic and ECT may attenuate the immediate
antidepressant effects of the N-methyl-D-aspartate antagonist.

PMCID: PMC3426617
PMID: 22847373 [PubMed - indexed for MEDLINE]

92. Biol Psychiatry. 2012 Aug 15;72(4):331-8. doi: 10.1016/j.biopsych.2012.03.004.
Epub 2012 Apr 18.

Relationship of ketamine's plasma metabolites with response, diagnosis, and side
effects in major depression.

Zarate CA Jr(1), Brutsche N, Laje G, Luckenbaugh DA, Venkata SL, Ramamoorthy A,
Moaddel R, Wainer IW.

Author information:
(1)Experimental Therapeutics & Pathophysiology Branch, Division of Intramural
Research Programs, National Institute of Mental Health, National Institutes of
Health, Bethesda, MD 20892, USA. zaratec@mail.nih.gov

BACKGROUND: Ketamine has rapid antidepressant effects lasting as long as 1 week
in patients with major depressive disorder (MDD) and bipolar depression (BD).
Ketamine is extensively metabolized. This study examined the relationship between
ketamine metabolites and response, diagnosis, and psychotomimetic symptoms in MDD
and BD patients.
METHODS: Following a 40-minute ketamine infusion (.5 mg/kg), plasma samples were
collected at 40, 80, 110, and 230 minutes and day 1 postinfusion in 67 patients
currently experiencing a major depressive episode (MDD, n = 45; BD, n = 22).
Concentrations of ketamine, norketamine (NK), dehydronorketamine (DHNK), six
hydroxynorketamine metabolites (HNK), and hydroxyketamine (HK) were measured.
Plasma concentrations were analyzed by diagnostic group and correlated with
patients' depressive, psychotic, and dissociative symptoms. The relationship
between cytochrome P450 gene polymorphisms and metabolites, response, and
diagnosis was also examined.
RESULTS: Ketamine, NK, DHNK, four of six HNKs, and HK were present during the
first 230 minutes postinfusion. Patients with BD had higher plasma concentrations
of DHNK, (2S,6S;2R,6R)-HNK, (2S,6R;2R,6S)-HNK, and (2S,5S;2R,5R)-HNK than
patients with MDD, who, in turn, had higher concentrations of (2S,6S;2R,6R)-HK.
Higher (2S,5S;2R,5R)-HNK concentrations were associated with nonresponse to
ketamine in BD patients. Dehydronorketamine, HNK4c, and HNK4f levels were
significantly negatively correlated with psychotic and dissociative symptoms at
40 minutes. No relationship was found between cytochrome P450 genes and any of
the parameters examined.
CONCLUSIONS: A diagnostic difference was observed in the metabolism and
disposition of ketamine. Concentrations of (2S,5S;2R,5R)-HNK were related to
nonresponse to ketamine in BD. Some hydroxylated metabolites of ketamine
correlated with psychotic and dissociative symptoms.

PMCID: PMC3442255
PMID: 22516044 [PubMed - indexed for MEDLINE]

93. Am J Psychiatry. 2012 Aug;169(8):868-9. doi: 10.1176/appi.ajp.2012.12020219.

Long-term maintenance with intramuscular ketamine for treatment-resistant bipolar
II depression.

Cusin C, Hilton GQ, Nierenberg AA, Fava M.

PMID: 22854933 [PubMed - indexed for MEDLINE]

94. Br J Clin Pharmacol. 2012 Aug;74(2):304-14. doi:
10.1111/j.1365-2125.2012.04198.x.

Simultaneous population pharmacokinetic modelling of ketamine and three major
metabolites in patients with treatment-resistant bipolar depression.

Zhao X(1), Venkata SL, Moaddel R, Luckenbaugh DA, Brutsche NE, Ibrahim L, Zarate
CA Jr, Mager DE, Wainer IW.

Author information:
(1)Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo,
NY, USA.

AIM: To construct a population pharmacokinetic (popPK) model for ketamine (Ket),
norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine
(2S,6S;2R,6R)-HNK) and hydroxyketamine (HK) in patients with treatment-resistant
bipolar depression.
METHOD: Plasma samples were collected at 40, 80, 110, 230 min on day 1, 2 and 3
in nine patients following a 40 min infusion of (R,S)-Ket (0.5 mg kg⁻¹) and
analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)-HNK,
(2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK. A compartmental popPK model was
constructed that included all quantified analytes, and unknown parameters were
estimated with an iterative two-stage algorithm in ADAPT5.
RESULTS: Ket, norKet, DHNK and (2S,6S;2R,6R)-HNK were present during the first
230 min post infusion and significant concentrations (>5 ng ml⁻¹) were observed
on day 1. Plasma concentrations of (2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK were
below the limit of quantification. The average (S) : (R) plasma concentrations
for Ket and DHNK were <1.0 while no significant enantioselectivity was observed
for norKet. There were large inter-patient variations in terminal half-lives and
relative metabolite concentrations; at 230 min (R,S)-DHNK was the major
metabolite in four out of nine patients, (R,S)-norKet in three out of nine
patients and (2S,6S;2R,6R)-HNK in two out of nine patients. The final PK model
included three compartments for (R,S)-Ket, two compartments for (R,S)-norKet and
single compartments for DHNK and HNK. All PK profiles were well described, and
parameters for (R,S)-Ket and (R,S)-norKet were in agreement with prior estimates.
CONCLUSION: This represents the first PK analysis of (2S,6S;2R,6R)-HNK and
(R,S)-DHNK. The results demonstrate that while norKet is the initial metabolite,
it is not the main metabolite suggesting that future Ket studies should include
the analysis of the major metabolites.

Published 2012. This article is a U.S. Government work and is in the public
domain in the USA.

PMCID: PMC3630750
PMID: 22295895 [PubMed - indexed for MEDLINE]

95. Biol Psychiatry. 2012 Jun 1;71(11):939-46. doi: 10.1016/j.biopsych.2011.12.010.
Epub 2012 Jan 31.

Replication of ketamine's antidepressant efficacy in bipolar depression: a
randomized controlled add-on trial.

Zarate CA Jr(1), Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N,
Cravchik A, Selter J, Marquardt CA, Liberty V, Luckenbaugh DA.

Author information:
(1)Experimental Therapeutics & Pathophysiology Branch, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health, and
Department of Health and Human Services, Bethesda, Maryland, USA.
zaratec@mail.nih.gov

BACKGROUND: Currently, no pharmacological treatments for bipolar depression exist
that exert rapid (within hours) antidepressant or antisuicidal effects. We
previously reported that intravenous administration of the N-methyl-D-aspartate
antagonist ketamine produced rapid antidepressant effects in patients with
treatment-resistant bipolar depression. The present study sought to replicate
this finding in an independent sample.
METHODS: In this double-blind, randomized, crossover, placebo-controlled study,
15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic
levels of lithium or valproate received a single intravenous infusion of either
ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The
primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which
was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230
minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion.
RESULTS: Within 40 minutes, depressive symptoms, as well as suicidal ideation,
significantly improved in subjects receiving ketamine compared with placebo (d =
.89, 95% confidence interval = .61-1.16, and .98, 95% confidence interval =
.64-1.33, respectively); this improvement remained significant through day 3.
Seventy-nine percent of subjects responded to ketamine and 0% responded to
placebo at some point during the trial. The most common side effect was
dissociative symptoms, which occurred only at the 40-minute time point.
CONCLUSIONS: This study replicated our previous finding that patients with
bipolar depression who received a single ketamine infusion experienced a rapid
and robust antidepressant response. In addition, we found that ketamine rapidly
improved suicidal ideation in these patients.

PMCID: PMC3343177
PMID: 22297150 [PubMed - indexed for MEDLINE]

96. Pharmacopsychiatry. 2012 May;45(3):122-4. doi: 10.1055/s-0031-1291349. Epub 2011
Nov 15.

Venlafaxin-associated post-ictal asystole during electroconvulsive therapy.

Kranaster L, Janke C, Hausner L, Frölich L, Sartorius A.

While post-stimulus asystoles occur quite often during electroconvulsive therapy
(ECT) post-ictal or post-seizure sinus bradycardias or even asystoles are rare
events. We report the case of an 82-year-old female patient with a current major
depressive episode, who developed the rare event of a post-ictal asystole of 6 s
and 4 ventricular escape beats during ECT. In the past this patient with a
bipolar disorder and mild Alzheimer's disease had already been frequently treated
with ECT with good success and no adverse events. Relevant comedication was
venlafaxin, quetiapine, donepezil and clonidine, anesthesia was performed with
ketamine and succinylcholine. Concurrent medication was completely unchanged
compared to previous ECT sessions with the exception of venlafaxine, presumably
at high serum levels. In summary, in line with some already existing reports, we
expect the noradrenergic action of venlafaxin to have contributed substantially
to the post-ictal asystole and want to indicate that the combination of ECT and
venlafaxin might be harmful--especially in the elderly population.

PMID: 22086742 [PubMed - indexed for MEDLINE]

97. Brain Nerve. 2012 Feb;64(2):119-29.

[Recent progress in mood disorder research].

[Article in Japanese]

Kato T(1).

Author information:
(1)Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science
Institute, Saitama, Japan.

When papers published in highly-prestigious journals in 2010 and 2011 were
categorized, the number of papers on genestic studies was found to be the
largest, followed by papers on brain imaging, postmortem brain studies, and
animal model studies. Follow-up studies of the findings of initial genome-wide
association analyses constitute a major part of genetic studies. Recent brain
imaging studies were found to integrate previous findings that indicated altered
responces of prefrontal cortex to cognitive stimuli and enhanced responces of
amygdala to emotional faces. Reduced size of the hippocampus is reportedly not a
result of stress but perhaps a vulnerability factor. Among animal model studies,
molecular mechanisms underlying rapid anti-depressive effects of ketamine are
drawing attention. The role of neurogenesis in fear memory and depression is
complex, and a link between psychopathology and neuroscience may be needed to
understand the roles of neurogenesis. Postmortem brain analyses are currently
used to investigate several pathophysiological hypotheses related to the roles of
monoamine, neuroplasticity, and neuroinflammation in depression, as well as the
roles of GABAergic neurons and mitochondria in bipolar disorder. Several studies
are integrating postmortem brain analysis and animal model studies. Genetic and
neuroimaging studies of mood disorders have advanced, and neurobiological basis
of the findings of these studies should be further elucidated in animal models
and postmortem brains.

PMID: 22308257 [PubMed - indexed for MEDLINE]

98. PLoS One. 2012;7(2):e31104. doi: 10.1371/journal.pone.0031104. Epub 2012 Feb 16.

Blood pressure modifies retinal susceptibility to intraocular pressure elevation.

He Z(1), Nguyen CT, Armitage JA, Vingrys AJ, Bui BV.

Author information:
(1)Department of Optometry and Vision Sciences, University of Melbourne,
Parkville, Victoria, Australia.

Primary open angle glaucoma affects more than 67 million people. Elevated
intraocular pressure (IOP) is a risk factor for glaucoma and may reduce nutrient
availability by decreasing ocular perfusion pressure (OPP). An interaction
between arterial blood pressure and IOP determines OPP; but the exact
contribution that these factors have for retinal function is not fully
understood. Here we sought to determine how acute modifications of arterial
pressure will affect the susceptibility of neuronal function and blood flow to
IOP challenge. Anaesthetized (ketamine:xylazine) Long-Evan rats with low (∼60
mmHg, sodium nitroprusside infusion), moderate (∼100 mmHg, saline), or high
levels (∼160 mmHg, angiotensin II) of mean arterial pressure (MAP, n = 5-10 per
group) were subjected to IOP challenge (10-120 mmHg, 5 mmHg steps every 3
minutes). Electroretinograms were measured at each IOP step to assess bipolar
cell (b-wave) and inner retinal function (scotopic threshold response or STR).
Ocular blood flow was measured using laser-Doppler flowmetry in groups with
similar MAP level and the same IOP challenge protocol. Both b-wave and STR
amplitudes decreased with IOP elevation. Retinal function was less susceptible to
IOP challenge when MAP was high, whereas the converse was true for low MAP.
Consistent with the effects on retinal function, higher IOP was needed to
attenuated ocular blood flow in animals with higher MAP. The susceptibility of
retinal function to IOP challenge can be ameliorated by acute high BP, and
exacerbated by low BP. This is partially mediated by modifications in ocular
blood flow.

PMCID: PMC3281054
PMID: 22359566 [PubMed - indexed for MEDLINE]

99. Biol Psychiatry. 2011 Aug 15;70(4):e13-4. doi: 10.1016/j.biopsych.2011.02.030.
Epub 2011 May 6.

Induction of prolonged mania during ketamine therapy for reflex sympathetic
dystrophy.

Ricke AK, Snook RJ, Anand A.

Comment in
Biol Psychiatry. 2013 Nov 15;74(10):e25.
Biol Psychiatry. 2013 Nov 15;74(10):e23-4.

PMCID: PMC3465663
PMID: 21529780 [PubMed - indexed for MEDLINE]

100. J Neuroinflammation. 2011 Aug 10;8:94. doi: 10.1186/1742-2094-8-94.

Severe depression is associated with increased microglial quinolinic acid in
subregions of the anterior cingulate gyrus: evidence for an immune-modulated
glutamatergic neurotransmission?

Steiner J(1), Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, Mawrin C,
Brisch R, Bielau H, Meyer zu Schwabedissen L, Bogerts B, Myint AM.

Author information:
(1)Department of Psychiatry, University of Magdeburg, Magdeburg, Germany.
johann.steiner@med.ovgu.de

Erratum in
J Neuroinflammation. 2013;10:34.

BACKGROUND: Immune dysfunction, including monocytosis and increased blood levels
of interleukin-1, interleukin-6 and tumour necrosis factor α has been observed
during acute episodes of major depression. These peripheral immune processes may
be accompanied by microglial activation in subregions of the anterior cingulate
cortex where depression-associated alterations of glutamatergic neurotransmission
have been described.
METHODS: Microglial immunoreactivity of the N-methyl-D-aspartate (NMDA) glutamate
receptor agonist quinolinic acid (QUIN) in the subgenual anterior cingulate
cortex (sACC), anterior midcingulate cortex (aMCC) and pregenual anterior
cingulate cortex (pACC) of 12 acutely depressed suicidal patients (major
depressive disorder/MDD, n = 7; bipolar disorder/BD, n = 5) was analyzed using
immunohistochemistry and compared with its expression in 10 healthy control
subjects.
RESULTS: Depressed patients had a significantly increased density of
QUIN-positive cells in the sACC (P = 0.003) and the aMCC (P = 0.015) compared to
controls. In contrast, counts of QUIN-positive cells in the pACC did not differ
between the groups (P = 0.558). Post-hoc tests showed that significant findings
were attributed to MDD and were absent in BD.
CONCLUSIONS: These results add a novel link to the immune hypothesis of
depression by providing evidence for an upregulation of microglial QUIN in brain
regions known to be responsive to infusion of NMDA antagonists such as ketamine.
Further work in this area could lead to a greater understanding of the
pathophysiology of depressive disorders and pave the way for novel NMDA receptor
therapies or immune-modulating strategies.

PMCID: PMC3177898
PMID: 21831269 [PubMed - indexed for MEDLINE]

101. J Psychopharmacol. 2011 Jun;25(6):808-21. doi: 10.1177/0269881110362126. Epub
2010 Apr 22.

Differential effects produced by ketamine on oscillatory activity recorded in the
rat hippocampus, dorsal striatum and nucleus accumbens.

Hunt MJ(1), Falinska M, Łeski S, Wójcik DK, Kasicki S.

Author information:
(1)Laboratory of the Limbic System, Nencki Institute of Experimental Biology,
Warsaw, Poland. mhunt@nencki.gov.pl

Previously, we showed that NMDA antagonists enhance high-frequency oscillations
(130-180 Hz) in the nucleus accumbens. However, whether NMDA antagonists can
enhance high-frequency oscillations in other brain regions remains unclear. Here,
we used monopolar, bipolar and inverse current source density techniques to
examine oscillatory activity in the hippocampus, a region known to generate
spontaneous ripples (∼200 Hz), its surrounding tissue, and the dorsal striatum,
neuroanatomically related to the nucleus accumbens. In monopolar recordings,
ketamine-induced increases in the power of high-frequency oscillations were
detected in all structures, although the power was always substantially larger in
the nucleus accumbens. In bipolar recordings, considered to remove common-mode
input, high-frequency oscillations associated with ketamine injection were not
present in the regions we investigated outside the nucleus accumbens. In line
with this, inverse current source density showed the greatest changes in current
to occur in the vicinity of the nucleus accumbens and a monopolar structure of
the generator. We found little spatial localisation of ketamine high-frequency
oscillations in other areas. In contrast, sharp-wave ripples, which were well
localized to the hippocampus, occurred less frequently after ketamine. Notably,
we also found ketamine produced small, but significant, changes in the power of
30-90 Hz gamma oscillations (an increase in the hippocampus and a decrease in the
nucleus accumbens).

PMID: 20413405 [PubMed - indexed for MEDLINE]

102. Med Hypotheses. 2011 May;76(5):717-9. doi: 10.1016/j.mehy.2011.02.003. Epub 2011
Mar 1.

Dextromethorphan as a potential rapid-acting antidepressant.

Lauterbach EC(1).

Author information:
(1)Department of Psychiatry and Behavioral Sciences, Mercer University School of
Medicine, 1550 College Street, Macon, GA 31201, USA. eclbgnp@earthlink.net

Comment in
Med Hypotheses. 2011 Aug;77(2):309-10.

Dextromethorphan shares pharmacological properties in common with antidepressants
and, in particular, ketamine, a drug with demonstrated rapid-acting
antidepressant activity. Pharmacodynamic similarities include actions on NMDA, μ
opiate, sigma-1, calcium channel, serotonin transporter, and muscarinic sites.
Additional unique properties potentially contributory to an antidepressant effect
include actions at ß, alpha-2, and serotonin 1b/d receptors. It is therefore,
hypothesized that dextromethorphan may have antidepressant efficacy in bipolar,
unipolar, major depression, psychotic, and treatment-resistant depressive
disorders, and may display rapid-onset of antidepressant response. An
antidepressant response may be associated with a positive family history of
alcoholism, prediction of ketamine response, increased AMPA-to-NMDA receptor
activity ratio, antidepressant properties in animal models of depression, reward
system activation, enhanced erythrocyte magnesium concentration, and correlation
with frontal μ receptor binding potential. Clinical trials of dextromethorphan in
depressive disorders, especially treatment-resistant depression, now seem
warranted.

PMID: 21367535 [PubMed - indexed for MEDLINE]

103. Arch Gen Psychiatry. 2010 Nov;67(11):1110-1. doi:
10.1001/archgenpsychiatry.2010.138.

N-methyl-D-aspartate glutamate receptor antagonists and the promise of
rapid-acting antidepressants.

Krystal JH(1).

Author information:
(1)Department of Psychiatry, Yale University School of Medicine, Ste 901, 300
George St, New Haven, CT 06511, USA. john.krystal@yale.edu

Comment on
Arch Gen Psychiatry. 2010 Aug;67(8):793-802.

PMID: 21041611 [PubMed - indexed for MEDLINE]

104. Harv Ment Health Lett. 2010 Nov;27(5):6.

Research suggests new drug targets for depression. Pilot studies of ketamine
intrigue scientists, but risks of this anesthetic limit its clinical use.

[No authors listed]

PMID: 21218614 [PubMed - indexed for MEDLINE]

105. Int Urogynecol J. 2010 Oct;21(10):1279-84. doi: 10.1007/s00192-010-1189-y. Epub
2010 Jun 2.

Effects of periurethral neuromuscular electrical stimulation on the voiding
frequency in rats.

Zhang Y(1), Bicek AD, Wang G, Timm GW.

Author information:
(1)Department of Urologic Surgery, University of Minnesota, 748 Mayo Memorial
Building, 420 Delaware Street S.E, Minneapolis, MN 55455, USA. zhang320@umn.edu

INTRODUCTION AND HYPOTHESIS: This study aims to test the hypothesis that a
urethra-to-bladder inhibitory pathway exists through which periurethral
neuromuscular electrical stimulation (NMES) inhibits overactive bladder
contractions in rats.
METHODS: Bladder overactivity was induced in 22 female Sprague Dawley rats by
injection of ketamine/xylazine/acepromizine (K/X/A). A bipolar electrode was
placed surgically in the periurethral region to deliver NMES. Intravesical
pressure, bladder inter-contraction interval (ICI) and voided volume (VV) were
monitored while the bladder was continuously infused with saline.
RESULTS: K/X/A induced more frequent bladder contractions (ICI = 48.6 +/- 20.1 s,
before cutting the pubo-symphasis) compared to a 10-min ICI induced by urethane.
NMES significantly increased ICI (63.1 +/- 31.3 s before vs. 97.2 +/- 42.9 s
after NMES, p < 0.001) and VV (0.063 = 0.041 ml before vs. 0.088 = 0.044 ml after
NMES, p < 0.02).
CONCLUSIONS: Injection of K/X/A may potentially be used as a model of bladder
overactivity. NMES inhibits bladder contractions in rats with bladder
overactivity, which supports the existence of a urethra-to-bladder inhibitory
pathway.

PMID: 20532871 [PubMed - indexed for MEDLINE]

106. Harv Rev Psychiatry. 2010 Sep-Oct;18(5):293-303. doi:
10.3109/10673229.2010.511059.

Glutamatergic modulators: the future of treating mood disorders?

Zarate C Jr(1), Machado-Vieira R, Henter I, Ibrahim L, Diazgranados N, Salvadore
G.

Author information:
(1)Experimental Therapeutics & Pathophysiology Branch, Division of Intramural
Research Programs, National Institute of Mental Health, National Institutes of
Health, Department of Health & Human Services, Bethesda, MD 20892, USA.
zaratec@mail.nih.gov

Mood disorders such as bipolar disorder and major depressive disorder are common,
chronic, and recurrent conditions affecting millions of individuals worldwide.
Existing antidepressants and mood stabilizers used to treat these disorders are
insufficient for many. Patients continue to have low remission rates, delayed
onset of action, residual subsyndromal symptoms, and relapses. New therapeutic
agents able to exert faster and sustained antidepressant or mood-stabilizing
effects are urgently needed to treat these disorders. In this context, the
glutamatergic system has been implicated in the pathophysiology of mood disorders
in unique clinical and neurobiological ways. In addition to evidence confirming
the role of the glutamatergic modulators riluzole and ketamine as
proof-of-concept agents in this system, trials with diverse glutamatergic
modulators are under way. Overall, this system holds considerable promise for
developing the next generation of novel therapeutics for the treatment of bipolar
disorder and major depressive disorder.

PMCID: PMC3000412
PMID: 20825266 [PubMed - indexed for MEDLINE]

107. Arch Gen Psychiatry. 2010 Aug;67(8):793-802. doi:
10.1001/archgenpsychiatry.2010.90.

A randomized add-on trial of an N-methyl-D-aspartate antagonist in
treatment-resistant bipolar depression.

Diazgranados N(1), Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S,
Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK,
Zarate CA Jr.

Author information:
(1)Experimental Therapeutics, Mood and Anxiety Disorders Program, National
Institute of Mental Health, National Institutes of Health, Department of Health
and Human Services, Bethesda, Maryland, USA.

Comment in
Arch Gen Psychiatry. 2010 Nov;67(11):1110-1.

CONTEXT: Existing therapies for bipolar depression have a considerable lag of
onset of action. Pharmacological strategies that produce rapid antidepressant
effects-for instance, within a few hours or days-would have an enormous impact on
patient care and public health.
OBJECTIVE: To determine whether an N-methyl-D-aspartate-receptor antagonist
produces rapid antidepressant effects in subjects with bipolar depression.
DESIGN: A randomized, placebo-controlled, double-blind, crossover, add-on study
conducted from October 2006 to June 2009.
SETTING: Mood Disorders Research Unit at the National Institute of Mental Health,
Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression
(treatment-resistant).
INTERVENTIONS: Subjects maintained at therapeutic levels of lithium or valproate
received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or
placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating
Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes
and on days 1, 2, 3, 7, 10, and 14 postinfusion.
MAIN OUTCOME MEASURES: Change in Montgomery-Asberg Depression Rating Scale
primary efficacy measure scores.
RESULTS: Within 40 minutes, depressive symptoms significantly improved in
subjects receiving ketamine compared with placebo (d = 0.52, 95% confidence
interval [CI], 0.28-0.76); this improvement remained significant through day 3.
The drug difference effect size was largest at day 2 (d = 0.80, 95% CI,
0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6%
responded to placebo at some point during the trial. One subject receiving
ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally
well tolerated; the most common adverse effect was dissociative symptoms, only at
the 40-minute point.
CONCLUSION: In patients with treatment-resistant bipolar depression, robust and
rapid antidepressant effects resulted from a single intravenous dose of an
N-methyl-D-aspartate antagonist.

PMCID: PMC3000408
PMID: 20679587 [PubMed - indexed for MEDLINE]

108. Epilepsy Behav. 2010 Jul;18(3):171-8. doi: 10.1016/j.yebeh.2010.04.002. Epub 2010
Jun 3.

Voltage-dependent calcium channel and NMDA receptor antagonists augment
anticonvulsant effects of lithium chloride on pentylenetetrazole-induced clonic
seizures in mice.

Ghasemi M(1), Shafaroodi H, Nazarbeiki S, Meskar H, Heydarpour P, Ghasemi A,
Talab SS, Ziai P, Bahremand A, Dehpour AR.

Author information:
(1)Department of Pharmacology, School of Medicine, Tehran University of Medical
Sciences, P.O. Box 13145-784, Tehran, Iran. mghasem2@jhmi.edu

Although lithium is still a mainstay in the treatment of bipolar disorder, its
underlying mechanisms of action have not been completely elucidated. Several
studies have shown that lithium can also modulate seizure susceptibility in a
variety of models. In the present study, using a model of clonic seizures induced
with pentylenetetrazole (PTZ) in male Swiss mice, we investigated whether there
is any interaction between lithium and either calcium channel blockers (CCBs:
nifedipine, verapamil, and diltiazem) or N-methyl-D-aspartate (NMDA) receptor
antagonists (ketamine and MK-801) in modulating seizure threshold. Acute lithium
administration (5-100mg/kg, ip) significantly (P<0.01) increased seizure
threshold. CCBs and NMDA receptor antagonists also exerted dose-dependent
anticonvulsant effects on PTZ-induced seizures. Noneffective doses of CCBs
(5mg/kg, ip), when combined with a noneffective dose of lithium (5mg/kg, ip),
exerted significant anticonvulsant effects. Moreover, co-administration of a
noneffective dose of either MK-801 (0.05mg/kg, ip) or ketamine (5mg/kg, ip) with
a noneffective dose of lithium (5mg/kg, ip) significantly increased seizure
threshold. Our findings demonstrate that lithium increases the clonic seizure
threshold induced by PTZ in mice and interacts with either CCBs or NMDA receptor
antagonists in exerting this effect, suggesting a role for Ca(2+) signaling in
the anticonvulsant effects of lithium in the PTZ model of clonic seizures in
mice.

PMID: 20605531 [PubMed - indexed for MEDLINE]

109. Ugeskr Laeger. 2010 Feb 8;172(6):460-1.

[Ketamine in melancholic depression].

[Article in Danish]

Bjerre J(1), Fontenay C.

Author information:
(1)Psykiatrien i Region Syddanmark, Esbjerg, Denmark. johannesbjerre@hotmail.com

Comment in
Ugeskr Laeger. 2010 Mar 15;172(11):899; author reply 899.

A 35-year-old male known with bipolar disorder was admitted after a suicide
attempt with cuts in both wrists. The patient had a major depression with
melancholic symptoms and nihilistic delusions. To relieve the patient's agony in
the days before electroconvulsive therapy and to reduce the risk of suicide, the
patient was treated with S-ketamine 0,5 mg/kg. The patient's symptoms were
reduced two hours after treatment and the effect was measurable for five days.

PMID: 20146912 [PubMed - indexed for MEDLINE]

110. Neuroscientist. 2009 Oct;15(5):525-39. doi: 10.1177/1073858409336093. Epub 2009
May 26.

The role of the tripartite glutamatergic synapse in the pathophysiology and
therapeutics of mood disorders.

Machado-Vieira R(1), Manji HK, Zarate CA.

Author information:
(1)Experimental Therapeutics, Mood and Anxiety Disorders Research Program,
NIMH-NIH, Bethesda, Maryland 20892, USA.

Erratum in
Neuroscientist. 2010 Apr;16(2):199.

Bipolar disorder and major depressive disorder are common, chronic, and recurrent
mood disorders that affect the lives of millions of individuals worldwide.
Growing evidence suggests that glutamatergic system dysfunction is directly
involved in mood disorders. This article describes the role of the "tripartite
glutamatergic synapse," comprising presynaptic and postsynaptic neurons and glial
cells, in the pathophysiology and therapeutics of mood disorders. Glutamatergic
neurons and glia directly control synaptic and extrasynaptic glutamate levels/
release through integrative effects that target glutamate excitatory amino acid
transporters, postsynaptic density proteins, ionotropic receptors
(alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA],
N-methyl-D-aspartate [NMDA], and kainate), and metabotropic receptors. This
article also explores the glutamatergic modulators riluzole and ketamine, which
are considered valuable proof-of-concept agents for developing the next
generation of antidepressants and mood stabilizers. In therapeutically relevant
paradigms, ketamine preferentially targets postsynaptic AMPA/NMDA receptors, and
riluzole preferentially targets presynaptic voltage-operated channels and glia.

PMCID: PMC2762009
PMID: 19471044 [PubMed - indexed for MEDLINE]

111. Schizophr Bull. 2009 Jul;35(4):748-59. doi: 10.1093/schbul/sbn006. Epub 2008 Feb
16.

Neuroleptic drugs revert the contextual fear conditioning deficit presented by
spontaneously hypertensive rats: a potential animal model of emotional context
processing in schizophrenia?

Calzavara MB(1), Medrano WA, Levin R, Kameda SR, Andersen ML, Tufik S, Silva RH,
Frussa-Filho R, Abílio VC.

Author information:
(1)Department of Pharmacology, Universidade Federal de São Paulo, Rua Botucatu,
862 Ed. Leal Prado, CEP 04023-062, São Paulo, Brazil.

Schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder
(ADHD) present abnormalities in emotion processing. A previous study showed that
the spontaneously hypertensive rats (SHR), a putative animal model of ADHD,
present reduced contextual fear conditioning (CFC). The aim of the present study
was to characterize the deficit in CFC presented by SHR. Adult male normotensive
Wistar rats and SHR were submitted to the CFC task. Sensitivity of the animals to
the shock and the CFC performance after repeated exposure to the task were
investigated. Pharmacological characterization consisted in the evaluation of the
effects of the following drugs administered previously to the acquisition of the
CFC: pentylenetetrazole (anxiogenic) and chlordiazepoxide (anxiolytic);
methylphenidate and amphetamine (used for ADHD); lamotrigine, carbamazepine, and
valproic acid (mood stabilizers); haloperidol, ziprasidone, risperidone,
amisulpride, and clozapine (neuroleptic drugs); metoclopramide and SCH 23390
(dopamine antagonists without antipsychotic properties); and ketamine (a
psychotomimmetic). The effects of paradoxical sleep deprivation (that worsens
psychotic symptoms) and the performance in a latent inhibition protocol (an
animal model of schizophrenia) were also verified. No differences in the
sensitivity to the shock were observed. The repeated exposure to the CFC task did
not modify the deficit in CFC presented by SHR. Considering pharmacological
treatments, only the neuroleptic drugs reversed this deficit. This deficit was
potentiated by proschizophrenia manipulations. Finally, a deficit in latent
inhibition was also presented by SHR. These findings suggest that the deficit in
CFC presented by SHR could be a useful animal model to study abnormalities in
emotional context processing related to schizophrenia.

PMCID: PMC2696367
PMID: 18281713 [PubMed - indexed for MEDLINE]

112. Neuropsychopharmacology. 2008 Aug;33(9):2080-92. doi: 10.1038/sj.npp.1301652.
Epub 2008 Jan 2.

Novel drugs and therapeutic targets for severe mood disorders.

Mathew SJ(1), Manji HK, Charney DS.

Author information:
(1)Mood and Anxiety Disorders Program, Department of Psychiatry, Mount Sinai
School of Medicine, New York, NY 10029, USA. sanjay.mathew@mssm.edu

Erratum in
Neuropsychopharmacology. 2008 Aug;33(9):2300.

Monoaminergic-based drugs remain the primary focus of pharmaceutical industry
drug discovery efforts for mood disorders, despite serious limitations regarding
their ability to achieve remission. The quest for novel therapies for unipolar
depression and bipolar disorder has generally centered on two complementary
approaches: (1) understanding the presumed therapeutically relevant biochemical
targets of currently available medications, and using that knowledge to design
new drugs directed at both direct biochemical targets and downstream targets that
are regulated by chronic drug administration; and (2) developing
pathophysiological models of the illness to design therapeutics to attenuate or
prevent those pathological processes. This review describes several promising
drugs and drug targets for mood disorders using one or both of these approaches.
Agents interacting with non-catecholamine neurotransmitter systems with
particular promise for unipolar and bipolar depression include excitatory amino
acid neurotransmitter modulators (eg, riluzole, N-methyl-D-aspartate antagonists,
and AMPA receptor potentiators) and neuropeptide antagonists (targeting
corticotropin releasing factor-1 and neurokinin receptors). Potential
antidepressant and mood-stabilizing agents targeting common intracellular
pathways of known monoaminergic agents and lithium/mood stabilizers are also
reviewed, such as neurotrophic factors, extracellular receptor-coupled kinase
(ERK) mitogen-activated protein (MAP) kinase and the bcl-2 family of proteins,
and inhibitors of phosphodiesterase, glycogen synthase kinase-3, and protein
kinase C. A major thrust of drug discovery in mood disorders will continue
efforts to identify agents with rapid and sustained onsets of action (such as
intravenous administration of ketamine), as well as identify drugs used routinely
in non-psychiatric diseases for their antidepressant and mood-stabilizing
properties.

PMID: 18172433 [PubMed - indexed for MEDLINE]

113. Neuropsychopharmacology. 2008 Aug;33(9):2175-86. Epub 2007 Nov 21.

Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein
transcripts in the prefrontal cortex in schizophrenia and bipolar disorder.

Beneyto M(1), Meador-Woodruff JH.

Author information:
(1)Department of Psychiatry and Behavioral Neurobiology, University of Alabama at
Birmingham, Birmingham, AL, USA. beneytom@upmc.edu

The hypothesis of N-methyl-D-aspartate (NMDA) receptor hypofunction in
schizophrenia was initially based on observations that blockade of the NMDA
subtype of glutamate receptor by noncompetitive antagonists, such as
phencyclidine and ketamine, can lead to clinical symptoms similar to those
present in schizophrenia. Recently, glutamate has also been implicated in the
pathophysiology of the mood disorders. As impaired NMDA receptor activity may be
the result of a primary defect in the NMDA receptors themselves, or secondary to
dysfunction in the protein complexes that mediate their signaling, we measured
expression of both NMDA subunits and associated postsynaptic density (PSD)
proteins (PSD95, neurofilament-light (NF-L), and SAP102) transcripts in the
dorsolateral prefrontal cortex in subjects with schizophrenia, bipolar disorder,
major depression, and a comparison group using tissue from the Stanley Foundation
Neuropathology Consortium. We found decreased NR1 expression in all three
illnesses, decreased NR2A in schizophrenia and major depression, and decreased
NR2C in schizophrenia. We found no changes of NR2B or NR2D. Receptor
autoradiography revealed no alterations in receptor binding in any of the
illnesses, indicating no change in total receptor number, but taken with the
subunit data suggests abnormal receptor stoichiometry. In the same subjects,
PSD95 was unchanged in all three illnesses, while reduced NF-L expression was
found in schizophrenia, especially in large cells of layer V. SAP102 expression
was reduced in bipolar disorder restricted to small cells of layer II and large
cells of layer III in bipolar disorder. These alterations likely reflect altered
signaling cascades associated with glutamate-mediated neurotransmission within
specific cortical circuits in these psychiatric illnesses.

PMID: 18033238 [PubMed - indexed for MEDLINE]

114. Schizophr Res. 2008 Aug;103(1-3):138-42. doi: 10.1016/j.schres.2008.02.020. Epub
2008 Apr 2.

The psychotomimetic states inventory (PSI): measuring psychotic-type experiences
from ketamine and cannabis.

Mason OJ(1), Morgan CJ, Stefanovic A, Curran HV.

Author information:
(1)Sub-Department of Clinical Health Psychology, University College London, Gower
Street, London WC1E 6BT, United Kingdom. o.mason@ucl.ac.uk

BACKGROUND: This study reports a new measure of psychotomimetic states in the
context of cannabis and ketamine use. The Psychotomimetic States Inventory (PSI)
has sub-scales of Delusory Thinking, Perceptual Distortions, Cognitive
Disorganization, Anhedonia, Mania and Paranoia.
METHODS: The PSI was administered in two independent group, repeated measures
designs: an experimental study of ketamine and a naturalistic study of cannabis.
RESULTS: Both cannabis and ketamine produced reliable increases in ratings of
psychotomimetic state effects across several sub-scales.
CONCLUSIONS: The PSI is a potentially useful measure of the nature and extent of
the phenomenological effects of psychotropic drugs in schizophrenia-related
research.

PMID: 18387788 [PubMed - indexed for MEDLINE]

115. Dialogues Clin Neurosci. 2008;10(2):193-201.

Promising avenues of therapeutics for bipolar illness.

Post RM(1).

Author information:
(1)George Washington University School of Medicine, USA.
robert.post@speakeasy.net

Basic scientific advances in understanding the neuropsychobiology of bipolar
disorder have given us a multitude of opportunities to explore and exploit new
avenues of therapeutics. Pharmacotherapeutic approaches include: neuropeptides
(agonists such as thyrotropin-releasing hormone and antagonists such as
corticotropin-releasing hormone), neurotrophic factors (especially brain-derived
neurotrophic factor), and glutamatergic mechanisms (such as riluzole, ketamine,
and antagonists of the NR-2B subunit of the glutamate receptor). Physiological
interventions that would offer alternatives to electroconvulsive therapy include:
repeated transcranial magnetic stimulation, especially at more intense
stimulation parameters; magnetic stimulation therapy (seizures induced more
focally by magnetic rather than electrical stimulation with resulting reduced
meaning loss); vagal nerve stimulation, and deep brain stimulation. However,
these, as well as the panoply of existing treatments, require further intensive
investigation to place each of them in the proper therapeutic sequence and
combination for the individual patient, based on development of better clinical
and biological predictors of response. Large clinical trial networks and
development of systematic research in clinical practice settings, such as that
featured by the National Cancer Institute for cancer chemotherapy, would greatly
accelerate the progress in incorporating new, as well as existing, agents into
the best treatment strategies. The bipolar disorders, which are increasingly
recognized as complex, highly comorbid conditions with a high morbidity and
mortality, of which the majority start in childhood and adolescence, are not
likely to respond completely to any single new treatment agent, and new public
health initiatives and research strategies are needed as much as any new single
treatment advance.

PMCID: PMC3181870
PMID: 18689289 [PubMed - indexed for MEDLINE]

116. Brain Res. 2007 Oct 12;1174:7-17. Epub 2007 Aug 2.

The expression of Troponin T1 gene is induced by ketamine in adult mouse brain.

Lowe XR(1), Lu X, Marchetti F, Wyrobek AJ.

Author information:
(1)Life Science, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
XRLowe@lbl.gov

The glutamatergic system has been implicated in neuropsychiatric disorders, such
as schizophrenia, bipolar disorder and Alzheimer's disease, which also have a
high prevalence of metabolic syndrome. Treatment with ketamine, a non-competitive
glutamate N-methyl-d-aspartic acid (NMDA) receptor antagonist, is known to have
paradoxical effects of neuroprotection and neurotoxicity. We investigated gene
expression in brain tissue of adult mice treated with ketamine to characterize
the expression profiles and to identify the affected metabolic pathways. Adult
male mice were treated by a single intraperitoneal (i.p.) injection of either
s(+)ketamine (80 mg/kg) or distilled water (as the control). Fifty genes were
differentially expressed in ketamine-treated mouse brains compared with control
mice using oligonucleotide microarray analysis, and the expression of Troponin T1
(Tnnt1) gene was consistently elevated (2- to 4-fold) (p<0.001). Ketamine-induced
Tnnt1 expression was confirmed and characterized using RNA in situ hybridization
techniques in paraffin embedded brain tissue sections. Tnnt1 expression was
induced in the granule layer of the hippocampus, amygdala, hypothalamus, Purkinje
cells of cerebellum (p<0.0001), and cerebral cortex. Tnnt1 gene is known to
interact directly with FoxO1, which is involved in multiple peripheral metabolic
pathways and central energy homeostasis. Our findings suggest that the induction
of Tnnt1 gene expression in adult mouse brains by ketamine may illustrate the
genes involved in the metabolic syndromes observed in neuropsychiatric disorders.

PMID: 17850769 [PubMed - indexed for MEDLINE]

117. Brain Res. 2007 Aug 8;1162:121-9. Epub 2007 Jun 21.

High-frequency stimulation of the subthalamic nucleus increases glutamate in the
subthalamic nucleus of rats as demonstrated by in vivo enzyme-linked glutamate
sensor.

Lee KH(1), Kristic K, van Hoff R, Hitti FL, Blaha C, Harris B, Roberts DW, Leiter
JC.

Author information:
(1)Department of Neurosurgery, Mayo Clinic, 200 First Street, S.W., Rochester, MN
55902, USA.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective
therapy for Parkinson's disease; however, the mechanism whereby DBS ameliorates
the symptoms of Parkinson's disease remains an area of intense research. In the
present study, we investigated the hypothesis that the neurotransmitter glutamate
is released within the STN during high-frequency stimulation (HFS) of the STN.
Direct measurements of extracellular glutamate concentration in the STN were made
using a dual enzyme-based electrochemical sensor. The studies were carried out in
ketamine/xylazine anesthetized rats placed in a Kopf stereotaxic head frame.
Various electrical stimulations (100-micros cathodic pulses; 100-3000 microA; 10-
to 1000-Hz frequency; 5-s to 60-min stimulus durations) using bipolar stimulating
electrodes were delivered to the STN. Stimulation of the STN elevated the
concentration of glutamate in the STN. The concentration of glutamate rose
quickly during HFS, remained elevated for the duration of stimulation, and
descended slowly towards baseline upon cessation of stimulation. Elevation of the
extracellular concentration of glutamate in the STN may be an important mechanism
whereby DBS in the STN improves the symptoms of Parkinson's disease. Furthermore,
our data argue against the hypothesis that DBS works primarily by electrotonic
inhibition of the stimulated structure.

PMID: 17618941 [PubMed - indexed for MEDLINE]

118. Epilepsy Behav. 2007 Jun;10(4):515-20. Epub 2007 Apr 6.

Psychosis: atypical limbic epilepsy versus limbic hyperexcitability with onset at
puberty?

Sharp FR(1), Hendren RL.

Author information:
(1)Department of Neurology, MIND Institute, University of California at Davis,
Wet Labs Room 2416, 2805 50th Street, Sacramento, CA 95817, USA.
frsharp@ucdavis.edu

Phencyclidine (PCP), ketamine (Special K), and MK-801 are noncompetitive
N-methyl-d-aspartate (NMDA) antagonists that produce acute psychosis in humans.
The psychosis produced by these psychomimetic drugs is indistinguishable from
schizophrenia and includes both positive and negative symptoms. This drug-induced
psychosis occurs after puberty in humans. On the basis of the MK-801-induced
spike-and-wave activity in rats and increased blood flow and metabolism in brain
of patients with psychosis caused by these psychomimetics, this brief review
argues that this psychosis is an atypical form of limbic epilepsy. Moreover,
there is a specific limbic thalamcortical psychosis circuit that mediates cell
injury in limbic cortex of rodents and may mediate this PCP-induced psychosis in
humans. It is proposed that this thalamocortical psychosis circuit develops at
puberty and can mediate PCP and ketamine-mediated psychosis and possibly the
psychosis of schizophrenia, bipolar disease and other disorders that have their
onset at puberty. Finally, based on this developmentally regulated
psychosis/epilepsy-related thalamocortical circuitry, it is proposed that
antiepileptic drugs that promote GABAergic mechanisms may decrease the
probability of episodic psychosis from any cause.

PMCID: PMC2680611
PMID: 17416210 [PubMed - indexed for MEDLINE]

119. Braz J Med Biol Res. 2006 Apr;39(4):421-9. Epub 2006 Apr 3.

Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug.

Zuardi AW(1), Crippa JA, Hallak JE, Moreira FA, Guimarães FS.

Author information:
(1)Departamento de Neurologia, Psiquiatria e Psicologia Médica, Faculdade de
Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP,
Brazil. awzuardi@fmrp.usp.br

A high dose of delta9-tetrahydrocannabinol, the main Cannabis sativa (cannabis)
component, induces anxiety and psychotic-like symptoms in healthy volunteers.
These effects of delta9-tetrahydrocannabinol are significantly reduced by
cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects
of the plant. This observation led us to suspect that CBD could have anxiolytic
and/or antipsychotic actions. Studies in animal models and in healthy volunteers
clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like
properties of CBD have been investigated in animal models using behavioral and
neurochemical techniques which suggested that CBD has a pharmacological profile
similar to that of atypical antipsychotic drugs. The results of two studies on
healthy volunteers using perception of binocular depth inversion and
ketamine-induced psychotic symptoms supported the proposal of the
antipsychotic-like properties of CBD. In addition, open case reports of
schizophrenic patients treated with CBD and a preliminary report of a controlled
clinical trial comparing CBD with an atypical antipsychotic drug have confirmed
that this cannabinoid can be a safe and well-tolerated alternative treatment for
schizophrenia. Future studies of CBD in other psychotic conditions such as
bipolar disorder and comparative studies of its antipsychotic effects with those
produced by clozapine in schizophrenic patients are clearly indicated.

PMID: 16612464 [PubMed - indexed for MEDLINE]

120. J Pharmacol Exp Ther. 2005 Dec;315(3):1163-71. Epub 2005 Aug 25.

An investigation of the efficacy of mood stabilizers in rodent models of prepulse
inhibition.

Ong JC(1), Brody SA, Large CH, Geyer MA.

Author information:
(1)Department of Psychiatry, University of California, San Diego, 9500 Gilman
Dr., La Jolla, CA 92093-0804, USA.

Acutely manic bipolar patients, like patients with schizophrenia, Tourette's
syndrome, panic disorder, and obsessive compulsive disorder, exhibit deficits in
sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle
response. Here, we assessed the ability of four drugs used in the treatment of
bipolar mania-phenytoin, carbamazepine, valproate, and lithium-to reduce the
PPI-disruptive effects of ketamine or amphetamine in the 129SvPasIco inbred
strain of mice. For comparison, we also assessed the interaction of lithium and
amphetamine in C57BL/6J mice. This set of studies yielded four major results. 1)
Lithium chloride (85 mg/kg) prevented amphetamine-induced but not
ketamine-induced disruption of PPI in both strains of mice. 2) Carbamazepine (50
mg/kg) prevented ketamine-induced but not amphetamine-induced disruption of PPI.
3) Sodium valproate (100 mg/kg) did not prevent amphetamine- or ketamine-induced
disruption of PPI. 4) Phenytoin (30 mg/kg) did not prevent amphetamine- or
ketamine-induced disruption of PPI but increased PPI on its own. These studies
did not reveal a consistent relationship between the ability of a drug to protect
PPI from disruption by ketamine or amphetamine and efficacy in the treatment of
bipolar mania. Instead, the diverse effect profiles of these four treatments in
reversing the PPI deficits produced by amphetamine or ketamine in mice presumably
reflect the differences in their respective pharmacological mechanisms. Hence,
further studies using these dopaminergic and glutamatergic models of deficient
PPI may provide valuable insights into the mechanisms underlying the differential
therapeutic effects of antimanic and mood-stabilizing treatments.

PMID: 16123308 [PubMed - indexed for MEDLINE]

121. Vision Res. 2004 Dec;44(28):3253-68.

In vivo studies of signaling in rod pathways of the mouse using the
electroretinogram.

Robson JG(1), Maeda H, Saszik SM, Frishman LJ.

Author information:
(1)College of Optometry, University of Houston, Houston, TX 77204-2020, USA.

PURPOSE: (a) To examine the possibility that there is a threshold in the synaptic
mechanism linking rods to rod bipolar cells that can reduce the transmission of
continuous noise from the rods without blocking the transmission of any
significant proportion of single-photon responses. (b) To estimate the level of
this threshold and the amplitude of the continuous noise which it can serve to
reduce. (c) To identify the location of the threshold mechanism in the rod to rod
bipolar cell pathway.
METHODS: Corneal electroretinogram recordings were made from dark-adapted mice
anesthetized with ketamine/xylazine after inner-retinal components had been
suppressed to isolate PII, the response of depolarizing bipolar cells.
Suppression was achieved by intravitreal injections of GABA, TTX, or in Cx36 KO
animals by crushing the optic nerve and waiting for ganglion cells to degenerate.
RESULTS: All energy-scaled records of isolated PII obtained with ganzfeld stimuli
that gave rise to much less than one photoisomerization (R*) per rod (0.01-0.2
R*/rod), had an essentially identical waveform. Stronger stimuli caused a
reduction in the peak amplitude of energy-scaled records (saturation) and stimuli
strong enough to produce multiple isomerizations in individual rods resulted in a
shortening of the response latency and an increase of the energy-scaled amplitude
at early times (supralinearity). The shape of the rising edge of isolated PII
changed with flash energy in a way that was consistent with the existence of a
synaptic threshold whose level was less than one tenth of the amplitude of
single-photon signals and a continuous noise whose rms amplitude was even less
than this. However, when measured at the time of the peak, the amplitude of PII
increased linearly in proportion to stimulus energy from the very lowest levels
up to the point where there was, on average, 0.2 R*/rod.
CONCLUSIONS: There is a threshold nonlinearity operating at the output of the rod
to rod bipolar cell synapse that can usefully reduce the transmission of
continuous rod noise without significantly affecting the transmission of
single-photon signals. This nonlinearity does not affect the overall linear
function of the rod pathway at levels at which it is effectively operating in a
photon-counting mode.

PMID: 15535993 [PubMed - indexed for MEDLINE]

122. Toxicol Sci. 2003 Dec;76(2):437-42. Epub 2003 Nov 4.

QT and RR intervals in conscious and anesthetized guinea pigs with highly varying
RR intervals and given QTc-lengthening test articles.

Hamlin RL(1), Kijtawornrat A, Keene BW, Hamlin DM.

Author information:
(1)Department of Veterinary Biosciences, The Ohio State University, Columbus,
Ohio 43210, USA. rhamlin@qtestlabs.com

A facile system for obtaining electrocardiograms from conscious animals was used
to conduct studies on 12 animals studied both conscious and anesthetized, on 4
conscious animals given vehicle (0.5% methylcellulose) and QT-lengthening test
articles, and on 6 animals given test articles thought to not lengthen QTc. In 12
animals whose ECGs were monitored via a bipolar transthoracic ECG, heart rates
were slowed with 1.0 mg/kg zatebradine, while they were conscious in their
slings, and after being anesthetized with ketamine/xylazine. The following
regression equations were obtained relating QT to RR: QT = 44.7 ln RR - 132.9, r2
= 0.7, for conscious animals; QT = 79.4 ln RR - 287.4, r2 = 0.8 for anesthetized
animals, with RR intervals varying between 150 and 550 ms. The anesthetic
increases QT at all RR intervals (p < 0.001), but does not change the slope of
the relationship between QT and RR when compared with the conscious guinea pig.
The Fridericia method was best for correcting QT for RR interval in conscious
guinea pigs, but the Bazett method was best for correcting in anesthetized
animals. QTc lengthened significantly in all conscious guinea pigs given, orally,
cisapride, ketoconazole, and sotalol (positive test articles) and did not change
with methylcellulose (the vehicle) or with propranolol, verapamil, or enalapril
(negative controls). These techniques and relationships demonstrate that this
methodology may be useful in exploring torsadogenic effects of novel
pharmacological entities.

PMID: 14600288 [PubMed - indexed for MEDLINE]

123. Psychopharmacology (Berl). 2003 Sep;169(3-4):240-6. Epub 2003 Apr 16.

Lamotrigine prevents ketamine but not amphetamine-induced deficits in prepulse
inhibition in mice.

Brody SA(1), Geyer MA, Large CH.

Author information:
(1)Department of Psychiatry and Neurosciences, University of California, 9500
Gilman Drive, La Jolla, San Diego, CA 92093-0804, USA.

RATIONALE: Lamotrigine, a broad-spectrum anticonvulsant known to block brain
sodium channels, is effective in the treatment of persons with bipolar disorder,
perhaps by virtue of its ability to reduce glutamate release. Furthermore,
lamotrigine decreases the perceptual abnormalities produced by the N-methyl-
d-aspartate (NMDA) antagonist ketamine in humans, similar to the effects of the
atypical antipsychotic clozapine. Acutely manic bipolar patients, like persons
with schizophrenia, Tourette's, and obsessive compulsive disorder, exhibit
decreases in sensorimotor gating, as measured by prepulse inhibition of the
startle response (PPI).
OBJECTIVE: We assessed the ability of lamotrigine to reduce the PPI-disruptive
effects of ketamine and the dopaminergic agent amphetamine in two inbred mouse
strains, C57BL/6J and 129SvPasIco.
METHODS: Mice were tested in a standard PPI paradigm after administration of
lamotrigine (0, 6.7, 13, or 27 mg/kg) or a combination of lamotrigine (27 mg/kg)
and either d-amphetamine (10 mg/kg) or ketamine (100 mg/kg).
RESULTS: In the 129SvPasIco mice, lamotrigine reversed the ketamine-induced PPI
deficit, without altering PPI in control mice. In C57BL/6J mice, however, 27
mg/kg lamotrigine generally increased PPI in both control and ketamine-treated
mice. Lamotrigine did not ameliorate the amphetamine-induced PPI deficit in
either strain.
CONCLUSIONS: In conclusion, lamotrigine can increase PPI on its own and prevent
ketamine-induced, but not amphetamine-induced, disruptions of PPI. These results
suggest that lamotrigine may exert its effects on PPI through the glutamatergic
system.

PMID: 12698229 [PubMed - indexed for MEDLINE]

124. Hear Res. 2003 Aug;182(1-2):48-55.

Electrophysiological findings in the Sprague-Dawley rat induced by moderate-dose
carboplatin.

Hatzopoulos S(1), Petruccelli J, Laurell G, Previati M, Martini A.

Author information:
(1)Department of Audiology, University of Ferrara, 203 Corso Giovecca, 44100
Ferrara, Italy. sdh@dns.unife.it

Carboplatin is a second generation platinum-containing anti-tumor drug which
selectively alters the micromechanical function of the inner hair cells (IHCs) of
the organ of Corti in the chinchilla. Data from a recent study [Wake et al., Acta
Otolaryngol. 116 (1996) 374-381], using the chinchilla model, have suggested that
a moderate dose of carboplatin alters the efferent feedback loop gain of the
OHCs. The present study was designed to evaluate the possible 'efferent feedback
alteration mechanism' in the Sprague-Dawley rat using distortion product
otoacoustic emissions (DPOAEs). A moderate dose of carboplatin (50 mg/kg body
weight) was administered by a 30 min i.p. infusion. Pre- and 72-h post-treatment
DPOAE and auditory brainstem response (ABR) recordings were acquired from a group
of 12 rats. The animals were anesthetized with a ketamine-atropin anesthesia
administered in two consecutive phases. The DPOAE responses (cubic distortion
products) were recorded with four asymmetrical protocols: P1=60-50, P2=50-40,
P3=40-30 and P4=30-20 dB SPL (sound pressure level), in the frequency range from
4.0 to 16 kHz. ABR responses were obtained for bipolar clicks and tone pips at
the frequencies 8.0, 10.0, 20.0 and 30 kHz using stimuli in the range from 100 to
30 dB SPL. Significant ABR threshold shifts of 15 dB were observed at 30 kHz, and
shifts of 10 dB at 20, 16 and 10 kHz. The comparison of pre- and post-treatment
DPOAE responses did not reveal any significant changes for protocols P1, P2 and
P4. Data from the P3 protocol indicated a decrease of the DPOAE amplitude. The
findings from the rat model suggest that (a) moderate doses of carboplatin do not
affect the efferent feedback loop OHC function and (b) the cochlear
susceptibility to carboplatin across species is different, even at moderate-dose
regimes.

PMID: 12948601 [PubMed - indexed for MEDLINE]

125. Vis Neurosci. 2003 May-Jun;20(3):297-306.

Pharmacological analysis of the rat cone electroretinogram.

Xu L(1), Ball SL, Alexander KR, Peachey NS.

Author information:
(1)Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

The electroretinogram (ERG) of the cone system provides a useful noninvasive
measure of the activity of the cone pathway. Despite a wide application of the
cone ERG in the study of rodent models of human hereditary retinal disease, the
cellular origins of the rat cone ERG have not been well defined. Here, we address
this issue using a pharmacological approach that has been used previously to
derive ERG response components. Agents that impair synaptic transmission at
well-defined retinal loci were dissolved in saline and injected into the vitreous
of adult Sprague-Dawley rats anesthetized with ketamine/xylazine, and cone ERGs
were recorded approximately 2 h later. Analysis of the resulting waveforms
indicated that the rat cone ERG includes a relatively small-amplitude component
of negative polarity that is derived from the activity of cone photoreceptors,
and perhaps retinal glial (Müller) cells. The cone depolarizing bipolar cell
pathway contributes a positive potential of large amplitude to the rat cone ERG.
In comparison, the contribution of hyperpolarizing bipolar cells is of negative
polarity and of much smaller amplitude. The inner retina contributes a negative
wave upon which higher frequency oscillations are superimposed. These results
provide a foundation for interpreting changes in the waveform of the rat cone ERG
that may be observed following genetic alteration or other experimental
treatment.

PMID: 14570251 [PubMed - indexed for MEDLINE]

126. Anesth Analg. 2003 Jan;96(1):238-44, table of contents.

S(+)-ketamine attenuates myogenic motor-evoked potentials at or distal to the
spinal alpha-motoneuron.

Scheufler KM(1), Thees C, Nadstawek J, Zentner J.

Author information:
(1)Department of NeurosurgeryUniversity of Freiburg, Germany.
scheufle@nz11.ukl.uni-freiburg.de

We investigated the effect of S(+)-ketamine on spinal cord evoked potentials
(ESCPs) and myogenic motor-evoked potentials after electrical stimulation of the
motor cortex in a rabbit model. This study was designed to characterize the
relationship between ESCP characteristics and corresponding changes in compound
muscle action potentials (CMAPs) derived from fore and hind limbs. Direct (D) and
indirect (I) corticospinal volleys (ESCP) from the upper and lower thoracic
spinal cord, recorded by two bipolar epidural electrodes, were assessed during IV
administration of 0.02, 0.05, 0.1, and 0.2 mg. kg(-1) x min(-1) of S(+)-ketamine,
each before and after neuromuscular blockade (0.4 mg/kg of cisatracurium), in 16
New Zealand White rabbits after single-pulse bipolar electrical stimulation of
the motor cortex at 50 (threshold), 60, and 70 V. CMAP amplitudes at fore and
hind limbs were significantly suppressed (P < 0.01) during infusion at 0.1 and
0.2 mL x kg(-1) x min(-1), whereas neither corresponding D- nor I-waves were
altered. Similar findings were obtained during variation of stimulus amplitude
(50-70 V). Multivariate regression analysis of CMAP amplitudes and various ESCP
characteristics demonstrated no apparent interparametric association. These
findings indicate that S(+)-ketamine modulates CMAP independent from
corticospinal D- and I-wave-mediated facilitation at or distal to the spinal
alpha-motoneuron.IMPLICATIONS: S(+)-Ketamine combines several anesthetic
properties suitable for total IV neuroanesthesia, including minimal effects on
neurophysiological monitoring. Recording of neural and myogenic responses after
electrical stimulation of the motor cortex indicates that S(+)-ketamine modulates
myogenic motor-evoked potentials by a peripheral mechanism at or distal to the
spinal alpha-motoneuron.

PMID: 12505959 [PubMed - indexed for MEDLINE]

127. J Neuropsychiatry Clin Neurosci. 2003 Winter;15(1):27-34.

Comparison of seizure duration, ictal EEG, and cognitive effects of ketamine and
methohexital anesthesia with ECT.

Krystal AD(1), Weiner RD, Dean MD, Lindahl VH, Tramontozzi LA 3rd, Falcone G,
Coffey CE.

Author information:
(1)Department of Psychiatry and Behavioral Sciences, Duke University Medical
Center, Durham, North Carolina, USA. krystal@phy.duke.edu

The authors retrospectively compared the seizure duration, ictal EEG, and
cognitive side effects of ketamine and methohexital anesthesia with ECT. This
comparison was carried out with data from consecutive index ECT treatments that
occurred immediately before and after a switch from methohexital to ketamine in
36 patients. Ketamine was well tolerated and prolonged seizure duration overall,
but particularly in those who had a seizure duration shorter than 25 seconds with
methohexital at the maximum available stimulus intensity. Ketamine also increased
midictal EEG slow-wave amplitude. Thus, a switch to ketamine may be useful when
it is difficult to elicit a robust seizure. Faster post-treatment reorientation
with ketamine may suggest a lower level of associated cognitive side effects.

PMID: 12556568 [PubMed - indexed for MEDLINE]

128. J Physiol. 2002 Sep 15;543(Pt 3):899-916.

The scotopic threshold response of the dark-adapted electroretinogram of the
mouse.

Saszik SM(1), Robson JG, Frishman LJ.

Author information:
(1)College of Optometry, University of Houston, Houston, TX 77204-2020, USA.

The most sensitive response in the dark-adapted electroretinogram (ERG), the
scotopic threshold response (STR) which originates from the proximal retina, has
been identified in several mammals including humans, but previously not in the
mouse. The current study established the presence and assessed the nature of the
mouse STR. ERGs were recorded from adult wild-type C57/BL6 mice anaesthetized
with ketamine (70 mg kg(-1)) and xylazine (7 mg kg(-1)). Recordings were between
DTL fibres placed under contact lenses on the two eyes. Monocular test stimuli
were brief flashes (lambda(max) 462 nm; -6.1 to +1.8 log scotopic Troland
seconds(sc td s)) under fully dark-adapted conditions and in the presence of
steady adapting backgrounds (-3.2 to -1.7 log sc td). For the weakest test
stimuli, ERGs consisted of a slow negative potential maximal approximately 200 ms
after the flash, with a small positive potential preceding it. The negative wave
resembled the STR of other species. As intensity was increased, the negative
potential saturated but the positive potential (maximal approximately 110 ms)
continued to grow as the b-wave. For stimuli that saturated the b-wave, the
a-wave emerged. For stimulus strengths up to those at which the a-wave emerged,
ERG amplitudes measured at fixed times after the flash (110 and 200 ms) were
fitted with a model assuming an initially linear rise of response amplitude with
intensity, followed by saturation of five components of declining sensitivity: a
negative STR (nSTR), a positive STR (pSTR), a positive scotopic response (pSR),
PII (the bipolar cell component) and PIII (the photoreceptor component). The nSTR
and pSTR were approximately 3 times more sensitive than the pSR, which was
approximately 7 times more sensitive than PII. The sensitive positive components
dominated the b-wave up to > 5 % of its saturated amplitude. Pharmacological
agents that suppress proximal retinal activity (e.g. GABA) minimized the pSTR,
nSTR and pSR, essentially isolating PII which rose linearly with intensity before
showing hyperbolic saturation. The nSTR, pSTR and pSR were desensitized by weaker
backgrounds than those desensitizing PII. In conclusion, ERG components of
proximal retinal origin that are more sensitive to test flashes and adapting
backgrounds than PII provide the 'threshold' negative and positive (b-wave)
responses of the mouse dark-adapted ERG. These results support the use of the
mouse ERG in studies of proximal retinal function.

PMCID: PMC2290546
PMID: 12231647 [PubMed - indexed for MEDLINE]

129. Epilepsy Res. 2002 Aug;50(3):313-25.

An anticonvulsant profile of the ketogenic diet in the rat.

Bough KJ(1), Gudi K, Han FT, Rathod AH, Eagles DA.

Author information:
(1)Department of Biology, Georgetown University, Washington, DC 20057-1229, USA.

The present study was designed to evaluate the anticonvulsant effects of a
high-fat ketogenic diet (KD) in rats. Animals were maintained on one of four
experimental diets: (1) calorie-restricted ketogenic (KCR); (2)
calorie-restricted normal (NCR); (3) ad libitum ketogenic (KAL); or (4) ad
libitum normal (NAL). The calorie-restricted diets were fed in quantities such
that they were calorically equivalent. All animals began diet treatment at age
P37 and each was subjected to one of five chemically-induced seizure tests:
bicuculline (BIC; s.c.), picrotoxin (PIC; s.c.), kainate (KA, i.p. or s.c.) and
gamma-butyrolactone (GBL, i.p.), strychnine (s.c.). Bipolar epidural electrodes
were implanted under ketamine/xylazine anesthesia to permit recording the spike
and wave discharges (SWD) characteristic of electroencephalograms during absence
seizures. Ketonemia was assayed by measuring blood levels of beta-hydroxybutyrate
(BHB) spectrophotometrically prior to induction of seizures in each experiment.
Animals fed ketogenic diets (i.e. either calorie restricted or ad libitum)
exhibited greater blood levels of BHB compared to control groups. Seizure results
show that treatment with a KD: (1) reduced the incidence of bicuculline-induced
convulsions; (2) diminished the number of picrotoxin-induced seizures (KCR group
only); (3) increased latency to GBL-induced SWD and reduced both the number and
duration of SWD; but (4) conferred no protection from strychnine-induced
seizures; and (5) made KA-induced seizures more severe. Together these results
indicate a spectrum of anticonvulsant action for the KD in rats that includes
threshold seizures induced via GABA receptors (BIC, PIC, GBL) but not those
induced at glycine (strychnine) or the KA-subclass of glutamate receptors.
Uniquely, the KD is the only treatment described that protects against both
convulsive and non-convulsive (absence) seizures in rats.

PMID: 12200222 [PubMed - indexed for MEDLINE]

130. Hear Res. 2002 Aug;170(1-2):116-26.

Effects of electrical stimulation of the inferior colliculus on 2f1-f2 distortion
product otoacoustic emissions in anesthetized guinea pigs.

Popelar J(1), Mazelová J, Syka J.

Author information:
(1)Institute of Experimental Medicine, Academy of Sciences, Vi;denská 1083, 142
20 4, Prague, Czech Republic. jpopelar@biomed.cas.cz

The effects of electrical stimulation of the inferior colliculus (IC) on the
activation of olivocochlear nerve fibers were investigated in guinea pigs in
which the 2f1-f2 distortion product otoacoustic emissions (DPOAE) were recorded.
Animals were anesthetized with ketamine (33 mg/kg) and xylazine (6.6 mg/kg).
Bipolar electrical stimulation of the IC by a train of pulses with currents less
than the threshold for evoking muscle twitches resulted in a small depression of
the DPOAE amplitude by 0.1-2 dB. The maximal effect was observed when the
stimulating electrodes were located in the rostro-medial or ventral parts of the
IC. The suppression of electrically evoked DPOAE was similar to the DPOAE
suppression produced by acoustical stimulation of the contralateral ear by a
broad-band noise. Suppression of DPOAE amplitude in response to both acoustical
and electrical stimulation was abolished 1-2 h after a single intramuscular
injection of gentamicin (210-250 mg/kg). The results indicate that electrical
stimulation of the IC can activate the efferent system and produce DPOAE changes
by similar mechanisms as does acoustical stimulation of the contralateral ear.

PMID: 12208546 [PubMed - indexed for MEDLINE]

131. Clin Neurophysiol. 2002 Jul;113(7):1152-64.

Thalamocortical dysrhythmia and the thalamic reticular nucleus in behaving rats.

Marini G(1), Ceccarelli P, Mancia M.

Author information:
(1)INB, C.N.R., 20090 Segrate, Milano, Italy. gabriella.marini@unimi.it

OBJECTIVES: The aim of this study was to investigate the effects of bilateral
chemical lesion of the rostral pole of the thalamic reticular nucleus on EEG
activities in freely moving rats applying quantitative analysis and brain mapping
of power spectra distribution.
METHODS: Ketamine-sedated Sprague-Dawley rats were implanted to monitor
behavioral states with frontoparietal electrodes in a first series of experiments
and with multiple electrodes along the antero-posterior axis (F1, F2, F7, F8, T3,
T4, P3, P4) in a second series. Monopolar and bipolar recordings were obtained in
animals stereotaxically injected with ibotenic acid into both rostral poles of
the thalamic reticular nucleus. Long-term video-EEG recordings and brain mapping
based on quantitative spectral analysis were made.
RESULTS: Two forms of dysrhythmia gradually emerged in the neocortical EEG at
12-24h post-injection: potentiation of theta waves and spontaneous high-voltage
spindles (HVS) at 4.5-8Hz frequency. Brain mapping during these dysrhythmia shows
highest power posteriorly (parietotemporal) for theta and mesiofrontally for HVS.
CONCLUSIONS: Given the lack of inhibitory intrinsic interneurons in the rat
thalamus, bilateral destruction of a small part of the solely GABAergic
population may promote cortical dysrhythmia (probably by dis-inhibition). The
topographic differences in power might indicate different involved structures.

PMID: 12088712 [PubMed - indexed for MEDLINE]

132. Ann Biomed Eng. 2002 Feb;30(2):169-79.

Measuring the electrical stapedius reflex with stapedius muscle electromyogram
recordings.

Clement RS(1), Carter PM, Kipke DR.

Author information:
(1)Department of Bioengineering, Arizona State University, Tempe, USA.

Previous studies have demonstrated a correlation between cochlear implant
recipients' comfort levels (C level, upper limit of dynamic range of stimulation)
and the contralateral electrical stapedius reflex (ESR) threshold, detected by
acoustic impedance change. However, the utility of the approach is limited
because many recipients have no detectable impedance change. The goals of this
study were to investigate the utility of the stapedial electromyogram (EMG) for
estimating onset and strength of the ESR. Ketamine-anesthetized guinea pigs were
implanted with Nucleus electrode arrays and stimulated with biphasic current
pulse trains (250 pps) via a Cochlear Corporation CI24M stimulator. Typical EMG
recordings (obtained with bipolar microwire electrodes) contained easily
detectable unit potentials up to 300 microV in amplitude. Growth response curves
(obtained from threshold-crossing counts or rms of the EMG signal) were typically
monotonic with dynamic ranges spanning 700 microA or 8 dB. Based on adaptation
and temporal properties, the stimulus protocol (500 ms duration with 4-5 s
interstimulus intervals) was adequate for producing independent responses. The
data presented are consistent with ESR characteristics (acoustic impedance
technique) of cochlear implant recipients and with EMG properties of acoustically
stimulated guinea pigs. Use of the EMG for characterizing the ESR may eventually
be applied to human cochlear implant recipients as a guide in setting the upper
limit of the dynamic range.

PMID: 11962769 [PubMed - indexed for MEDLINE]

133. J Neurophysiol. 2002 Jan;87(1):478-92.

Auditory cortical images of cochlear-implant stimuli: dependence on electrode
configuration.

Bierer JA(1), Middlebrooks JC.

Author information:
(1)Kresge Hearing Research Institute (Department of Otorhinolaryngology) and
Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109-0506,
USA.

This study examines patterns of auditory cortical activity elicited by
single-pulse cochlear implant stimuli that vary in electrode configuration,
cochlear place of stimulation, and stimulus level. Recordings were made from the
primary auditory cortex (area A1) of ketamine-anesthetized guinea pigs. The
spatiotemporal pattern of neural spike activity was measured simultaneously
across 16 cortical locations spanning approximately 2-3 octaves of the tonotopic
axis. Such a pattern, averaged over 40 presentations of any particular stimulus,
was defined as the "cortical image" of that stimulus. Acutely deafened guinea
pigs were implanted with a 6-electrode animal version of the 22-electrode Nucleus
banded electrode array (Cochlear). Cochlear electrode configurations consisted of
monopolar (MP), bipolar (BP + N) with N inactive electrodes between the active
and return electrodes (0 < or = N < or = 4), tripolar (TP) with one active
electrode and two flanking return electrodes, and common ground (CG) with one
active electrode and as many as five return electrodes. Cortical images typically
showed a focus of maximum spike probability and minimum latency. Spike
probabilities tended to decrease, and latencies tended to increase, with
increasing cortical distance from that focus. Cortical images of TP stimuli were
the most spatially compact, followed by BP + N images, and then MP images, which
were the broadest. Images of CG stimuli were rather variable across animals and
stimulus channels. The locations of cortical images shifted systematically from
caudal to rostral as the cochlear place of stimulation changed from basal to
apical. At the most sensitive cortical site for each condition, the dynamic
ranges over which spike rates increased with increased current level were
restricted to about 1-2 dB, regardless of configuration. Dynamic ranges tended to
increase with increasing cortical distance from the most sensitive site.
Electrode configurations that produced compact cortical images (e.g., TP and BP +
0) showed the greatest range of thresholds within each cortical image and the
largest dynamic range at cortical sites removed from the most sensitive site.

PMID: 11784764 [PubMed - indexed for MEDLINE]

134. Neurol Res. 2001 Dec;23(8):881-6.

High-dose ketamine hydrochloride maintains somatosensory and magnetic motor
evoked potentials in primates.

Ghaly RF(1), Ham JH, Lee JJ.

Author information:
(1)Department of Anesthesiology and Pain Management, Cook County Hospital,
Chicago, IL 60612, USA. RFGHALY@AOL.com

Monitoring the descending neural motor volleys (MEPs), in comparison to muscle
action potentials, allows sensitive motor assessment under anesthesia
irrespective of the use of muscular blockade and status of skeletal musculature.
Ketamine hydrochloride (KH) had preserved muscle MEPs on a pre-established
primate model. The present work examines the effect of incremental hypnotic KH
dosages thoracic neural on somatosensory (SEP) and MEPs recorded epidurally in
response to transcranial magnetic stimulation (TMS). Through a small thoracic
T11-T12 laminotomy, an insulated double bipolar electrode was inserted epidurally
and cephalad in seven cynomolgus monkeys. Thoracic spinal TMS-MEPs, and SEPs,
were tested against graded increase of KH doses (0.01, 0.018, 0.032, 0.056, 0.1,
and 0.18 mg kg(-1) min(-1) i.v. infusion). The direct (D-) and indirect (I-)
epidural MEP peaks were well-defined under sole KH infusion. The waveforms were
consistent at various dosages. At the highest cumulative dose (0.18 mg kg(-1)
min(-1), total 6.5 mg kg(-1) over 150 min), I5 was host and I3 and I4 latencies
were delayed. The scalp and spinal SEP showed no significant change. Recording of
both neural D- and I- MEPs and SEPs is feasible under high sole i.v. KH. It is
the first agent to maintain up to four later I1 peaks. The reproducibility of
both modalities is unquestionable under KH-based deep anesthesia. This reflects
the maintenance of state of neural excitability under KH.

PMID: 11760882 [PubMed - indexed for MEDLINE]

135. No To Shinkei. 2001 Aug;53(8):729-35.

[The number and form of cerebellar fastigial neurons projecting to the thalamic
suprageniculate nucleus in cats studied using WGA-HRP tracing method].

[Article in Japanese]

Katoh YY(1).

Author information:
(1)Department of Anatomy, Fujita Health University, School of Health Sciences,
Toyoake, Aichi 470-1192, Japan.

This study was designed to investigate the number and form of cerebellar
fastigial neurons projecting to the suprageniculate nucleus(Sg) by using
retrograde axonal transport of wheat germ agglutinin-horseradish
peroxidase(WGA-HRP). Six adult cats(weighing 2.5-3.5 kg) were anesthetized with
ketamine hydrochloride(30 mg/kg, i.m.) and sodium pentobarbital(15 mg/kg, i.p.).
In experiments using injected WGA-HRP in the Sg, retrogradely labeled neurons by
WGA-HRP were found only in the caudal part of the bilateral fastigial nucleus
(Ft) with ipsilateral predominance, and the ratio of labeled neurons in the
contralateral Ft to that in the ipsilateral Ft in all cats was 496:670(1:1.35).
Five types of Ft-Sg neurons were distinguished morphologicaly. Of the 246 labeled
neurons that could be characterized, 6.1% were large stellate neurons, 43.5%
medium stellate neurons, 24.0% bipolar neurons, 20.3% triangular neurons, and
6.1% granular neurons. Thus, we concluded that a mixed population of Ft neurons
projects to the Sg. In summary, as shown in the Figure 4 the Ft-Sg connection is
an important pathway joining two closed circuits, and can be part of the
extrageniculate visual system. We also speculate that the Ft-Sg connections may
have a role in sending visual modulating information.

PMID: 11577414 [PubMed - indexed for MEDLINE]

136. Vision Res. 2001 Apr;41(8):1091-101.

On-bipolar cells and depolarising third-order neurons as the origin of the
ERG-b-wave in the RCS rat.

Wurziger K(1), Lichtenberger T, Hanitzsch R.

Author information:
(1)Carl-Ludwig-Institute of Physiology, University of Leipzig, Liebigstr. 27,
D-04103, Leipzig, Germany.

In the retinas of Royal College of Surgeons (RCS) rats light induces an increase
in distal extracellular potassium irrespective of the age, between days 19-24 and
days 29-35 postpartum, but by days 29-35 the ERG b-wave has become reduced. The
synaptic blocker 2-amino-4-phosphonobutyric acid (APB) causes the abolition of
both the b-wave and the potassium increase at any age. MgCl2 greatly reduces the
b-wave at all ages and abolishes the potassium increase in older rats, but in
younger rats the potassium increase is enlarged. Since this increase occurs in
the absence of the b-wave it is unlikely that the on-bipolar cells are the only
sources of the b-wave. Because the NMDA receptor blocker ketamine reduces the
b-wave, third order neurons, which possess NMDA receptors, could contribute to
the b-wave.

PMID: 11301082 [PubMed - indexed for MEDLINE]

137. Diabetes. 1998 Oct;47(10):1637-42.

Peripheral neuropathy in transgenic diabetic mice: restoration of C-fiber
function with human recombinant nerve growth factor.

Elias KA(1), Cronin MJ, Stewart TA, Carlsen RC.

Author information:
(1)Genentech, San Francisco, California 94080, USA. kelias@gene.com

Mice (Ins.Dd1) with hypoinsulinemic diabetes were created by increased expression
of syngeneic major histocompatibility complex (MHC) class I protein in pancreatic
beta-cells. The diabetic state was characterized in these mice by high glucose
concentrations and islet pathology. To determine whether a neuropathy would
develop, motor and sensory conduction velocities (CV) were determined in the
sciatic nerves of 2-, 4-, and 7-month-old control and diabetic littermate male
mice. Recording bipolar electrodes were placed in the plantar muscles of the hind
foot of anesthetized (ketamine/xylazine) mice. Bipolar stimulating electrodes
were positioned near the sciatic nerve at the sciatic notch or near the tibial
nerve at the ankle. Motor CV from alpha-motor fibers and sensory CV from
proprioceptive Aalpha nerves were measured and expressed as meters per second
(m/s). Group data are reported as mean +/- SE and compared by analysis of
variance. The CVs from nondiabetic mice (controls) were not different across the
three ages and averaged 41.3 +/- 1.7 m/s for motor and 38.7 +/- 1.7 m/s for
sensory. The motor CVs from diabetic mice at 2 and 4 months were similar to
controls. Sensory CVs were unchanged at 2 months but were lower at 4 months (18.9
+/- 2.4 m/s). Both sensory (23.9 +/- 2.1 m/s) and motor (18.9 +/- 1.8 m/s) CVs
were significantly reduced at 7 months, which is indicative of a polyneuropathy.
NGF has well-known trophic effects on sympathetic and small sensory neurons. To
determine whether NGF could influence this neuropathy, 6-month-old control and
diabetic mice were divided into the following groups: 1) control + vehicle, 2)
diabetic + vehicle, and 3) diabetic + NGF (1 mg/kg, 3x week, s.c.). After 1 month
of treatment, motor and sensory CVs were determined. In some mice, the branches
of the sciatic nerve were exposed and in situ recordings from the sural nerve
were performed to determine compound C-fiber CV, integral, and amplitude. Sensory
CV, determined via Hoffmann's reflex (H-reflex) (A-fiber), was decreased in
diabetic compared with control animals as expected (P < 0.05), and NGF did not
alter this parameter. Continuing diabetes reduced the amplitude (0.9 +/- 0.2 vs.
3.2 +/- 0.7 mV x 10(-2); P < 0.05) and integral (6.9 +/- 1.9 mV/ms vs. 18.8 +/-
4.4 mV/ms; P < 0.05) of the C-fiber response versus control, suggesting fiber
loss. NGF treatment normalized C-fiber amplitude (2.9 +/- 0.8 mV x 10(-2)) and
integral (21.2 +/- 6.5 mV/ms) in animals with established diabetes, with no
effect on blood glucose. The C-fiber CV was similar in all groups, indicating
that the animals had some normally conducting small fiber sensory nerves. These
studies characterized a motor and sensory polyneuropathy in transgenic diabetic
mice and are the first to demonstrate directly that NGF treatment can protect or
restore abnormal sensory C-fiber function.

PMID: 9753304 [PubMed - indexed for MEDLINE]

138. Anesth Analg. 1997 Jul;85(1):106-10.

Spinal conduction block by intrathecal ketamine in dogs.

Iida H(1), Dohi S, Tanahashi T, Watanabe Y, Takenaka M.

Author information:
(1)Department of Anesthesiology and Critical Care Medicine, Gifu University
School of Medicine, Gifu City, Japan. iida@cc.gifu-u.ac.jp

In addition to its use for intravenous (I.V.) anesthesia, ketamine can provide
pain relief in humans when administered spinally. To elucidate the mechanisms of
intrathecal (I.T.) ketamine analgesia, we observed differences in the effects of
I.V. and I.T. ketamine on intraspinal evoked potentials (ISEPs) in 28 dogs
anesthetized with pentobarbital. Bipolar extradural electrodes were inserted at
the cervical and lumbar regions of the spinal cord for recording descending ISEPs
represented by the two negative deflections, Waves I and II. I.V. ketamine 2 and
10 mg/ kg did not affect the amplitude and latency of Wave I, whereas the large
dose (10 mg/kg) significantly decreased the amplitude but not the latency of Wave
II. I.T. ketamine 1 and 5 mg/kg caused significant dose-dependent decreases in
both Wave I and II amplitudes and prolongations of both Wave I and II latencies.
These I.T. effects on ISEPs are consistent with previous in vitro observations
that ketamine blocks axonal conduction. We conclude that axonal conduction block
may contribute to the analgesic mechanism of I.T. ketamine.

PMID: 9212131 [PubMed - indexed for MEDLINE]

139. Anesthesiology. 1997 Feb;86(2):410-9.

Stereospecific effect of bupivacaine isomers on atrioventricular conduction in
the isolated perfused guinea pig heart.

Graf BM(1), Martin E, Bosnjak ZJ, Stowe DF.

Author information:
(1)Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226,
USA.

BACKGROUND: The local anesthetic bupivacaine is an equal mixture of two optically
active isomers known to exert different cardiotoxic profiles in vivo.
Enantiomer-specific forms of bupivacaine may have differential effects on
cardiovascular function, specifically on cardiac electrophysiology. The authors'
aim was to determine if there were any direct functional differences in the
cardiac effects of bupivacaine isomers. The isolated heart was used to avoid
possible indirect cardiac effects of bupivacaine, such as autonomic nervous and
hormonal influences, as well as preload and afterload factors.
METHODS: The hearts of 12 ketamine-anesthetized guinea pigs were perfused with
Krebs-Ringer's solution (97% oxygen, 3% carbon dioxide) at constant perfusion
pressure using the Langendorff technique. Atrial and ventricular bipolar
electrodes were placed to measure heart rate (HR) and atrioventricular (AV)
conduction time. Left ventricular pressure (LVP), coronary flow, and inflow and
outflow oxygen tensions were also measured. Oxygen delivery, oxygen consumption
(MVO2), and percentage of oxygen extraction were calculated. Each heart was
perfused with increasing randomized concentrations (0.5, 1, 5, 10 microM) of both
isomers and the racemate of bupivacaine.
RESULTS: Racemic and isomeric bupivacaine equally and dose dependently decreased
cardiac function. At 10 microM bupivacaine these changes were HR, -17 +/- 2%;
LVP, -50 +/- 3%; coronary flow, -20 +/- 4%; and MVO2, -46 +/- 4%. The (+) isomer
significantly prolonged AV conduction compared with the racemate and the (-)
isomer at all concentrations. At 10 microM, AV time was 54 +/- 6% longer with the
(+) isomer and 30 +/- 4% longer with the (+/-) racemate than with the (-) isomer.
The greater delay in AV time with the (+) than the racemate or (-) isomer led to
a second-degree AV dissociation in 10 of 12 of hearts treated with (+)
bupivacaine.
CONCLUSIONS: This study shows that bupivacaine has an enatiomer-specific effect
to delay AV conduction and to produce second-degree AV dissociation in the
isolated perfused heart. This suggests that bupivacaine isomers probably have
differential effects on one or more ion-specific channels regulating AV
conduction. Other measured direct cardiac effects of bupivacaine appear to be
independent of the isomeric form.

PMID: 9054259 [PubMed - indexed for MEDLINE]

140. Pharmacol Biochem Behav. 1995 Nov;52(3):489-92.

Suppression of cortical epileptic afterdischarges by ketamine is not stable
during ontogenesis in rats.

Kubová H(1), Mares P.

Author information:
(1)Institute of Physiology, Czechoslovak Academy of Sciences, Prague, Czech
Republic.

Anticonvulsant action of ketamine, a noncompetitive NMDA antagonist, was studied
in three groups of immature rats (12-, 18-, and 25-day-old) using cortically
elicited epileptic afterdischarges (ADs) as a model. Rats with implanted
electrodes were used, so that EEG and motor phenomena could be recorded.
Stimulation (bipolar pulses of 1-ms duration and 8-Hz frequency) lasting 15 s was
repeated four times with intervals of 10 min. Ketamine was administered IP 5 min
after the first AD in doses of 5, 10, 20, or 40 mg/kg. Control groups did not
receive any drug. Ketamine shortened ADs and suppressed motor correlates of
stimulation as well as of ADs in a dose-dependent manner in 12- and 25-day-old
rats. No significant changes were observed in 18-day-old animals, demonstrating
thus a rather complicated development of anticonvulsant action of ketamine. Not
only NMDA antagonism, but also other possible effects of ketamine must be taken
into account.

PMID: 8545464 [PubMed - indexed for MEDLINE]

141. J Appl Physiol (1985). 1995 Apr;78(4):1485-8.

Stability of evoked parasternal intercostal muscle electromyogram at increased
end-expiratory lung volume.

Road JD(1), Osborne S, Cairns A.

Author information:
(1)Department of Medicine, University of British Columbia, Vancouver, Canada.

The diaphragmatic electromyogram has been measured as an index of the level of
diaphragmatic activation. The diaphragmatic electromyogram, however, even when
measured by intramuscular electrodes, can be artifactually altered by a change in
lung volume (A. Brancatisano, S. M. Kelly, A. Tully, S. H. Loring, and L. A.
Engel. J. Appl. Physiol. 66: 1699-1705, 1989) or by a change in body position.
The parasternal intercostal muscle may be less subject to the mechanisms that are
believed to produce this artifactual change. We asked whether the parasternal
intercostal electromyographic activity could be reliable when lung volume
changes. Six supine rabbits were anesthetized with ketamine and xylazine. Fine
bipolar copper wires, with their tips exposed, were inserted into the left
parasternal intercostal muscle in the third interspace. A stimulus that was three
times maximal was applied to the corresponding intercostal nerve, and the
resulting action potential (AP) was photographed. Parasternal intercostal muscle
length was measured by sonomicrometry over the vital capacity range. There were
small nonsignificant changes in the AP from functional residual capacity (FRC) to
total lung capacity. From FRC to residual volume there was variation in the AP.
The AP was also quite stable when regional conductivity was altered but showed
variation when the parasternal intercostal muscle length change was accentuated
by traction on the rib cage. We conclude that the parasternal intercostal
electromyographic activity can be reliably used to measure inspiratory motoneuron
output to it over the range of lung volumes from FRC to total lung capacity.

PMID: 7615459 [PubMed - indexed for MEDLINE]

142. Acta Neurochir (Wien). 1994;127(3-4):191-8.

Intraoperative transcranial electrical motor evoked potential monitoring during
spinal surgery under intravenous ketamine or etomidate anaesthesia.

Yang LH(1), Lin SM, Lee WY, Liu CC.

Author information:
(1)Department of Surgery, College of Medicine, National Taiwan University,
Republic of China.

Motor evoked potentials (MEPs), monitoring the motor function directly, are
superior to somatosensory evoked potentials (SSEPs) in monitoring the motor
system during spinal surgery. Reliable MEPs are difficult to elicit under normal
anaesthesia. Using intravenous anaesthesia with either ketamine or etomidate
infusion, we performed intraoperative MEP monitoring in 12 spinal operations for
11 cases from February 1992 to May 1992. For anaesthesia, ketamine was used in 5,
etomidate in 7, fentanyl was supplemented in all, muscle relaxation at 30% to 50%
of pre-anaesthetic muscle power was maintained with atracurium or vencuronium
infusion. Transcranial bipolar electrical stimulation was used to induce MEPs.
Concomitant SSEP monitoring was performed in 3. No significant anaesthesia
related side effects were noted except one episode of unpleasant dream occurred
in the ketamine anaesthesia group. Successful monitoring was achieved in 10
sessions. In 5 of which warning to the surgeons was made due to sudden MEP
deterioration, which recovered followed by definite management in four and
persisted in one. In the other 5 sessions, no warning was made due to stationary
or gradual change in MEPs. Bilateral two-channel recordings were used in 3
sessions. In 2 of which unilateral transient change was noted. Loss of SSEPs was
noted in one despite unchanged MEPs, in whom only new sensory deficits occurred
postoperatively. Compared to the baseline MEPs in terms of latency and amplitude,
the final MEPs improved in 5 sessions, did not change significantly in 4
sessions, deteriorated in one session, and were correlated well with the
immediate postoperative motor status.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 7942202 [PubMed - indexed for MEDLINE]

143. Ann Emerg Med. 1993 Feb;22(2):164-70.

Development of a piglet model of status epilepticus: preliminary results.

Terndrup TE(1), Paskanik AM, Fordyce WE, Kanter RK.

Author information:
(1)Department of Emergency Medicine, State University of New York Health Science
Center, Syracuse.

STUDY OBJECTIVE: Ventilation frequently is impaired during prolonged clinical
seizures and their treatment. In a pilot study, respiratory, metabolic, and
hemodynamic variables were studied during induced seizures in a lightly
anesthetized, spontaneously breathing piglet model.
PARTICIPANTS: Weanling, mixed-breed domestic piglets.
INTERVENTIONS: Piglets were instrumented with a tracheostomy, arterial catheter,
and epidural electrodes. Conditions included hyperoxia, normothermia, and
ketamine maintenance infusion throughout recordings. After baseline recordings, 2
mg/kg IV bicuculline was administered. For further model validation, piglets were
randomized to infusions of diazepam (three), lorazepam (two), or saline (control;
five) groups after ten minutes of untreated seizures.
MEASUREMENTS AND MAIN RESULTS: Integrated tidal volume, respiratory rate, PaCO2,
pH, arterial pressure, rectal temperature, heart rate, and bipolar EEG waveforms
were recorded and compared at intervals for 60 minutes. Vigorous tonic-clonic
seizures occurred in all piglets, confirmed by sudden synchronization and
large-amplitude EEG waveforms. Increases in heart rate, arterial pressure, tidal
volume, respiratory rate, PaCO2, minute ventilation, and base deficit occurred in
all piglets during seizures as compared with baseline. Five minutes after
bicuculline was administered, increases in minute ventilation (4.5 +/- 0.4 L/min
at baseline to 13 +/- 2.1 L/min) were accounted for by increases in both tidal
volume and respiratory rate. More abrupt decreases in respiratory rate were
observed in anticonvulsant-treated piglets as compared with controls. The
duration of continuous seizure activity (12 +/- 1.0 minutes versus 21 +/- 3.3
minutes; P < .05) was reduced in anticonvulsant-treated piglets.
CONCLUSION: Significant increases in ventilation occur during generalized
seizures in tracheostomized piglets given bicuculline. Diazepam and lorazepam
infusions ameliorate seizure activity and suppress increases in respiratory rate
but not minute ventilation as compared with controls. Problems with this model
included baseline variability, temperature instability, and that direct
respiratory stimulation from the convulsant agent may have occurred.

PMID: 8427425 [PubMed - indexed for MEDLINE]

144. Am J Vet Res. 1992 Sep;53(9):1553-7.

Effects of general anesthesia on myoelectric activity of the intestine in horses.

Lester GD(1), Bolton JR, Cullen LK, Thurgate SM.

Author information:
(1)Department of Applied Veterinary Medicine, School of Veterinary Studies,
Murdoch University, Western Australia.

Myoelectric activity was monitored from the terminal ileum, cecum, and colonic
pelvic flexure by use of AgpAgCl bipolar electrodes in 4 adult horses before,
during, and after general anesthesia. Horses were anesthetized by way of 3
commonly used regimens, including xylazine (1.1 mg/kg of body weight) and
ketamine hydrochloride (2.2 mg/kg); thiopental sodium (7.7 mg/kg), followed by
halothane vaporized in oxygen; and thiopental sodium (2.5 g) in guaifenesin (100
mg/ml) solution given to effect, followed by halothane in oxygen. All 3
anesthetic regimens decreased intestinal spike-burst activity in the areas
monitored. The slowest return to preanesthetic myoelectric activity was observed
after xylazine and ketamine administration. After both of the
barbiturate/halothane anesthetic regimens, there was a rebound increase in
spike-burst frequency, without alteration in the proportion of propagative
myoelectric events. All 3 anesthetic regimens appeared to reset the timing of the
small and large intestinal migrating myoelectric complexes. By 9 hours after
recovery from anesthesia, the effects of anesthesia, irrespective of regimen, had
disappeared. Although anesthesia significantly (P less than 0.05) altered
intestinal myoelectric activity, no particular anesthetic regimen had a prolonged
effect. Results of our study indicate that the particular chosen regimen of
general anesthesia is unimportant in development of motility disturbances in
horses after anesthesia.

PMID: 1416353 [PubMed - indexed for MEDLINE]

145. Childs Nerv Syst. 1992 Sep;8(6):307-9.

Occlusion of the sagittal sinus in craniectomized rabbits.

Olivero WC(1), Asner N.

Author information:
(1)Department of Neuroscience, University of Illinois College of Medicine, Peoria
61656.

Most attempts at production of hydrocephalus in experimental animals by
obstructing the venous sinuses have failed. In adult humans, venous sinus
occlusion usually results in the clinical syndrome of pseudotumor cerebri with
small or normal sized ventricles. However, in children less than 18 month old
with venous sinus hypertension, ventriculomegaly has been reported. We examined
the change in ventricular size in craniectomized animals (simulating children
with open sutures) with occlusion of the superior sagittal sinus. New Zealand
rabbits weighing 1500-1800 g were anesthetized with an intramuscular injection of
2 ml 7:3 ketamine (100 mg/ml): Rompun (xylazine) (20 mg/ml) solution. The scalp
was shaved, prepped with Betadine, and infiltrated with 1% lidocaine, and a
midline scalp incision made. The periosteum was reflected laterally and a
craniectomy performed with microscopic magnification. The dura was exposed
overlying both cerebral hemispheres and the superior sagittal sinus from its
origin to the torcular. In five control animals, the scalp was then closed. In
ten experimental animals, small incisions were made in the dura just lateral to
the superior sagittal sinus with a no. 11 scalpel and then with microscopic
magnification the sinus was coagulated with bipolar cautery and transected; the
scalp was then closed. All animals were allowed 5-7 days to recover, then
ultrasound was used to assess ventricular size. We observed a small but
statistically significant increase in ventricular size in the experimental group
compared to the control group. This model provides evidence that venous sinus
occlusion in animals with expandable crania can produce ventriculomegaly.

PMID: 1394276 [PubMed - indexed for MEDLINE]

146. Eye (Lond). 1991;5 ( Pt 4):476-80.

Non-competitive NMDA-receptor antagonists and anoxic degeneration of the ERG
B-wave in vitro.

Huang JC(1), Salt TE, Voaden MJ, Marshall J.

Author information:
(1)Institute of Ophthalmology, London.

Studies have been undertaken to see if the non-competitive NMDA antagonists,
ketamine, MK-801 and dextromethorphan would preserve the b-wave of the
electroretinogram (ERG) in vitro. The drugs had no effect on the ERG b-wave, nor
prolonged its survival postmortem. The present results support previous evidence
suggesting that NMDA-receptors are not involved directly in synaptic transmission
between photoreceptors and ON-bipolar cells. Further, loss of the b-wave in
post-mortem anoxia does not appear to be mediated via NMDA-receptors.

PMID: 1660413 [PubMed - indexed for MEDLINE]

147. Jpn J Ophthalmol. 1989;33(4):490-500.

Properties of the pupillary dilation produced by the humoral factor in the
pupillary reflex dilation: an experimental study in the cat.

Shoumura K(1), Kimura S, Kaneko M.

Author information:
(1)Department of Anatomy, Hirosaki University School of Medicine, Japan.

Physiopharmacological properties of the pupillary dilation produced by the
humoral factor in the reflex pupillary dilation were studied in cats anesthetized
with ketamine-HC1. Pupillary dilation produced by the humoral factor was
separated from that produced by the neural mechanism, ie, sympathetic activation
and parasympathetic inhibition, by atropinization of acutely sympathectomized
pupil. To evoke the pupillary reflex dilation, the sciatic nerve was stimulated
by using a bipolar electrode. The stimulus consisted of trains of 0.5
milliseconds duration rectangular pulses and was given for 5 seconds. The
stimulus frequency was usually 50 Hz; high frequency stimuli were more effective
to evoke pupillary dilation produced by the humoral factor. The pupillary
dilation was recorded with an infrared pupillo-analyzing system. A long latency
(about 6 seconds) and long peak latency (about 10 seconds) pupillary dilation was
produced by the humoral factor. The threshold of pupillary dilation produced by
the humoral factor was always higher than that produced by parasympathetic
inhibition. The pupillary dilation produced by the humoral factor was not
affected by local application and intravitreal injection of 10(-2) M
propranolol-HC1 and 10(-2) M yohimbine-HC1. However, the dilation was markedly
inhibited by intravitreal injection of 10(-2) M phenoxybenzamine-HC1 or local
application of 10(-2) M bunazosin-HC1.

PMID: 2625782 [PubMed - indexed for MEDLINE]

148. J Surg Res. 1988 Jul;45(1):60-5.

The effect of increased intracranial pressure (ICP) on gastric motility.

Matthews DE(1), Heimansohn DA, Papaila JG, Lopez R, Vane DW, Grosfeld JL.

Author information:
(1)Department of Surgery, Indiana University Medical Center, Indianapolis 46223.

This study evaluates the effect of increased intracranial pressure (ICP) on
gastric motility. Nine male cats (weight, 4.84 +/- 1.16 kg) were anesthetized
with ketamine and underwent laparotomy for placement of bipolar (silver-silver
chloride) electrodes on the serosal surface of the gastroesophageal junction
(GEJ), antrum, and prepyloric areas of the stomach. At 1 week frontoparietal burr
holes were performed with placement of an epidural Fogarty catheter. Migrating
myoelectric complexes (MMCs) were evaluated at the GEJ, antrum, and prepyloric
areas at varying levels of ICP (baseline and 20, 40, and 60 mm Hg) using balloon
inflation. MMCs at the GEJ were triphasic with a period of 4 sec (+/- 1 sec) at
baseline levels. At ICP levels above baseline, periodicity and waveforms at the
GEJ became irregular. Waveforms became multiphasic with 1- to 2-sec periods and
variable amplitudes. In the antral and prepyloric areas, duration and amplitude
of the triphasic MMCs was unchanged from baseline. At 60 mm Hg ICP periodicity
was significantly altered at both 1 and 2 weeks. MMCs returned to baseline levels
with balloon deflation. The data indicate that elevated ICP (to 60 mm Hg) results
in consistent and reproducible alterations of MMC periodicity, suggesting that
such alterations may influence gastric motility.

PMID: 3392994 [PubMed - indexed for MEDLINE]

149. J Pharmacol Exp Ther. 1983 Mar;224(3):489-93.

Effects of anesthetics and electrical stimulation on nigrostriatal dopaminergic
neurons.

McCown TJ, Mueller RA, Breese GR.

Induction of anesthesia with pentobarbital (40 mg/kg), urethane (1.8 g/kg),
chloral hydrate (400 mg/kg) or ketamine (150 mg/kg) followed by a 20-min sham
implantation of a bipolar electrode in substantia nigra fibers caused a marked,
ipsilateral increase in caudate dihydroxyphenylacetic acid (DO-PAC). Conversely,
no sham stimulation was found after gamma-butyrolactone (500 mg/kg) anesthesia or
in a paralyzed, artificially respired preparation. By using gamma-butyrolactone
anesthesia, the nigrostriatal fibers were electrically stimulated (25 Hz, 1.5
msec duration) at differing current intensities (40, 80, 100, 120 and 180
microA). The maximum increase in caudate DOPAC occurred at 120 microA. Electrical
stimulation (100 microA, 25 Hz, 1.5 msec duration) in the paralyzed preparation
yielded similar increases in caudate DOPAC. By using a 50% effective current (100
microA), variation of the frequency (5, 10, 25 and 125 Hz) produced a maximum in
caudate DOPAC at 10 Hz. These data reveal an interaction between many anesthetics
and physical disruption of dopaminergic neurons, as well as provide an in vivo
model of stimulus-dependent dopamine release.

PMID: 6827473 [PubMed - indexed for MEDLINE]

150. Br J Anaesth. 1981 Mar;53(3):229-33.

Effect of some i.v. anaesthetic agents on canine gastrointestinal motility.

Healy TE, Foster GE, Evans DF, Syed A.

Thiopentone 20 mg kg-1, ketamine 8 mg kg-1 and minaxolone 2 mg kg-1 were
administered to fasting greyhound dogs. Mechanical and electrical activities from
stomach, duodenum, jejunum and ileum were recorded using strain gauge force
transducers and implanted bipolar electrodes. Thiopentone and minaxolone caused
intense activity in the duodenum and jejunum (phase I and phase II of the
interdigestive cycle), but not the stomach or ileum. The activity following
injection of thiopentone or minaxolone was prevented by premedication with either
atropine 0.05 mg kg-1 or pentolinium 0.2 mg kg-1. Ketamine had no influence on
gastrointestinal activity or the response to thiopentone or minaxolone. None of
these drugs altered the basal electrical rhythm of the intestine.

PMID: 7470357 [PubMed - indexed for MEDLINE]

151. Anesth Analg. 1975 Mar-Apr;54(2):189-95.

Further studies of the neural mechanisms of ketamine-induced anesthesia in the
rhesus monkey.

Sparks DL, Corssen G, Aizenman B, Black J.

Bipolar stimulation of tooth pulp was used to elicit evoked potentials in the
cortex, thalamus, and midbrain reticular formation (MBRF) of 4 monkeys. Averaged
evoked potentials in MBRF and medial thalamic nuclei were either completely
obliterated or markedly reduced in amplitude by anesthetic dosages of ketamine.
In contrast, little effect was observed upon the primary response elicited in the
ventrobasal complex of the thalamus. These results suggest that anesthetic doses
of ketamine block afferent signals concerned with the affective-emotional
components of pain perception, but conduction of signals related to the
localization of somatic stimuli in time and space may be relatively unimpaired.

PMID: 1168426 [PubMed - indexed for MEDLINE]

152. Br Med J. 1972 Jan 22;1(5794):246.

Psychosis and ketamine.

Laird SM, Sage M.

PMCID: PMC1789190
PMID: 5058743 [PubMed - indexed for MEDLINE]

"One form of pain resulting from sensitization is called complex regional pain syndrome (CRPS), in which a seemingly minor trauma becomes more painful with time rather than less and is accompanied by changes in the skin and autonomic response in the affected limb. The pain can be severe and is often both chronic and resistant to conventional therapy. In 2002, a team in Germany led by Ralph-Thomas Kiefer, MD, kept six patients with CRPS unconscious with a continuous ketamine infusion for a week and found that four were cured and two were relieved of their pain for one and three months respectively. Mindful that a week of intensive monitoring in the ICU is seldom a practical treatment for anything, G.E. Correll’s group at Penn State Hershey Medical Center reviewed the medical records of 33 patients given lowdose (subhallucinogenic) ketamine for CRPS instead and found that three quarters had experienced complete pain relief and 31 percent were still pain-free six months later. This was enough to prompt a prospective trial in which 40 patients with CRPS were given sub-hallucinogenic doses of ketamine. They reported significant pain relief that lasted for weeks in most of the patients and caused a permanent remission in three."*

Ketamine is not FDA Approved for treatment of Pain

* From Ketamine: Peril and Promise by R. Andrew Sewell, MD

http://www.maps.org/news-letters/v17n1/ketamine-peril_and_promise.pdf

Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE. Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med 2004;5:263-275.

Goldberg ME, Domsky R, Scaringe D, et al. Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician 2005;8:175-179. 11. Jovaisa T, Laurinenas G, Vosylius S, Sipylai

Ketamine is not FDA approved for the treatment of Autistic Spectrum Disorders

It is too early to know if Ketamine treatment can help Autism and spectrum disorders, but

in those with depression, there is early evidence that it could be helpful for one or both problems

161. J Clin Psychiatry. 2014 Aug;75(8):835-6. doi: 10.4088/JCP.13cr08917.

Intranasal ketamine treatment in an adult with autism spectrum disorder.

Wink LK(1), O'Melia AM, Shaffer RC, Pedapati E, Friedmann K, Schaefer T, Erickson
CA.

Author information:
(1)Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave MLC 4002,
Cincinnati, OH 45229 logan.wink@cchmc.org.

PMID: 25191906 [PubMed - indexed for MEDLINE]

Depression among addicted, alcoholic and people in recovery is extremely common.

Some in the treatment community are excited about the potential of Ketamine treatment.

Because the patient does not have access to the medication, abuse and dependence is a remote possibility.

Ketamine is not FDA Approved for treatment of Addiction & Alcoholism

"Evgeny Krupitsky, MD, PhD, chief of the research laboratory at St. Petersburg Regional Center of Addictions and Psychopharmacology, has been researching the treatment of alcoholism and addiction with ketamine since the 1980s and hopes to extend his research to encompass post-traumatic stress disorder in the near future. In 1985, he developed ketamine psychedelic therapy - which was initially merely a method for increasing suggestibility and enhancing aversive treatment for alcoholism - publishing his first report on the method in 1992.

He found that ketamine induced total abstinence in 66 percent of his alcoholic patients (versus 24 percent of the nonpsychedelic control group) for as long as a year. He observed improvement in personality profile, positive transformation of self-concept and emotional attitudes to various aspects of self, positive changes in life values, and improved spiritual development in the ketamine group. What is the contribution of the psychedelic experience to this improvement? Krupitsky posited nine factors:

1. Stable, positive psychological changes.

2. Personality growth and self-cognition.

3. Important insights into existential problems and the meaning of life.

4. Transformation of one’s “life value system.”

5. A change of view of one’s self and the world around.

6. Insight into life and death.

7. A rise of creative energies.

8. Broadening of spiritual horizons.

9. Harmonization of a person’s relationships with the world and with other people.

In 1991, another Soviet psychiatrist, Igor Kungurtsev MD, who had initially worked with Krupitsky and later immigrated to the United States, published a summary of his own experiences treating alcoholism with ketamine.

Although, like Krupitsky, he initially felt that ketamine simply made alcohol aversive in a purely behavioral way, he radically changed his approach following a series of ketamine self-administrations and instead It is gratifying to see that NIMH is following MAPS’ lead in supporting the treatment of psychiatric disorders with psychedelic drugs adopted a transpersonal model for therapy in order to better utilize the profound mystical experiences induced by ketamine. He found that successful treatment of alcoholism with ketamine was correlated with a changed spiritual outlook in the same way that 12-step programs also achieve success by changing addicts’ spiritual outlook, albeit in a nonpsychedelic manner.*

"There are also suggestions that ketamine might be useful in the treatment of heroin withdrawal. In one recent study, 58 opiate-dependent patients were given “ultra-rapid detox” under general anaesthesia with either ketamine or placebo saline infusion.11 The ketamine group had noticeably better control of withdrawal symptoms, although there was no difference in abstinence between the two groups four months later. "*

Krupitsky EM, Grinenko AY. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. J Psychoactive Drugs 1997;29:165-183.

Krupitsky EM, Grinenko AY. Psychedelic drugs in psychiatry: Past, present and future. V. M. Bekhterev Review of Psychiatry and Medical Psychology 1992;1:31-47.

Kungurtsev I. “Death-Rebirth” Psychotherapy with Ketamine. The Albert Hofmann Foundation Bulletin 1991;2:1-6.

Krupitsky EM, Burakov AM, Dunaevsky IV, Romanova TN, Slavina TY, Grinenko AY. Single Versus Repeated Sessions of Ketamine-Assisted Psychotherapy for People with Heroin Dependence. Journal of Psychoactive Drugs March 31, 2007

Ketamine is not FDA Approved for treatment of Addiction or Alcoholism

*From Ketamine: Peril and Promise by R. Andrew Sewell, MD

http://www.maps.org/news-letters/v17n1/ketamine-peril_and_promise.pdf

456. J Psychoactive Drugs. 2007 Mar;39(1):13-9.

Single versus repeated sessions of ketamine-assisted psychotherapy for people
with heroin dependence.

Krupitsky EM(1), Burakov AM, Dunaevsky IV, Romanova TN, Slavina TY, Grinenko AY.

Author information:
(1)Research Laboratory, St. Petersburg Regional Center of Addictions and
Psychopharmacology, St. Petersburg State Pavlov Medical University, St.
Petersburg, Russia. kru@ek3506.spb.edu

A prior study found that one ketamine-assisted psychotherapy session was
significantly more effective than active placebo in promoting abstinence
(Krupitsky et al. 2002). In this study of the efficacy of single versus repeated
sessions of ketamine-assisted psychotherapy in promoting abstinence in people
with heroin dependence, 59 detoxified inpatients with heroin dependence received
a ketamine-assisted psychotherapy (KPT) session prior to their discharge from an
addiction treatment hospital, and were then randomized into two treatment groups.
Participants in the first group received two addiction counseling sessions
followed by two KPT sessions, with sessions scheduled on a monthly interval
(multiple KPT group). Participants in the second group received two addiction
counseling sessions on a monthly interval, but no additional ketamine therapy
sessions (single KPT group). At one-year follow-up, survival analysis
demonstrated a significantly higher rate of abstinence in the multiple KPT group.
Thirteen out of 26 subjects (50%) in the multiple KPT group remained abstinent,
compared to 6 out of 27 subjects (22.2%) in the single KPT group (p < 0.05). No
differences between groups were found in depression, anxiety, craving for heroin,
or their understanding of the meaning of their lives. It was concluded that three
sessions of ketamine-assisted psychotherapy are more effective than a single
session for the treatment of heroin addiction.

PMID: 17523581 [PubMed - indexed for MEDLINE]

Ketamine is not FDA Approved for treatment of OCD (Obsessive Compulsive Disorder)

OCD (Obsessive Compulsive Disorder) usually is accompanied by depressive symptoms often severe Depression.

This can make treatment more difficult due to impaired concentration and reduced motivation.

The possibility of using Ketamine treatment for OCD Is an active area of investigation.

303. Biol Psychiatry. 2012 Dec 1;72(11):964-70. doi: 10.1016/j.biopsych.2012.05.028.

Epub 2012 Jul 10.

Effects of ketamine in treatment-refractory obsessive-compulsive disorder.

Bloch MH(1), Wasylink S, Landeros-Weisenberger A, Panza KE, Billingslea E,
Leckman JF, Krystal JH, Bhagwagar Z, Sanacora G, Pittenger C.

Author information:
(1)Yale Child Study Center, Yale University School of Medicine, New Haven,
Connecticut, USA. michael.bloch@yale.edu

BACKGROUND: Treatments for obsessive-compulsive disorder (OCD) usually lead to
incomplete symptom relief and take a long-time to reach full effect. Convergent
evidence suggests that glutamate abnormalities contribute to the pathogenesis of
OCD. Ketamine is a potent noncompetitive antagonist of the N-methyl-D-aspartate
glutamate receptor. Trials have reported rapid antidepressant effects after
low-dose ketamine infusion.
METHODS: We conducted an open-label trial of ketamine (.5 mg/kg IV over 40 min)
in 10 subjects with treatment-refractory OCD. Response was defined as >35%
improvement in OCD symptoms and >50% improvement in depression symptoms from
baseline at any time between 1 and 3 days after infusion.
RESULTS: None of 10 subjects experienced a response in OCD symptoms in the first
3 days after ketamine. Four of seven patients with comorbid depression
experienced an antidepressant response to ketamine in the first 3 days after
infusion. Both OCD and depression symptoms demonstrated a statistically
significant improvement in the first 3 days after infusion compared with
baseline, but the OCD response was <12%. The percentage reduction in depressive
symptoms in the first 3 days after ketamine infusion was significantly greater
than the reduction in OCD symptoms.
CONCLUSIONS: Ketamine effects on OCD symptoms, in contrast to depressive
symptoms, did not seem to persist or progress after the acute effects of ketamine
had dissipated.

PMCID: PMC3667652
PMID: 22784486 [PubMed - indexed for MEDLINE]

262. J Psychopharmacol. 2013 Jul;27(7):651-4. doi: 10.1177/0269881113486718. Epub 2013
May 15.

Two cases of delayed-onset suicidal ideation, dysphoria and anxiety after
ketamine infusion in patients with obsessive-compulsive disorder and a history of
major depressive disorder.

Niciu MJ(1), Grunschel BD, Corlett PR, Pittenger C, Bloch MH.

Author information:
(1)Yale University, Department of Psychiatry/Connecticut Mental Health Center
(CMHC), Clinical Neuroscience Research Unit (CNRU), New Haven, Connecticut, USA.
mark.niciu@nih.gov

Ketamine is a non-competitive N-methyl-D-aspartate receptor antagonist that is
Food and Drug Administration-approved in the United States for anesthesia due to
its sedative effects with low risk of severe respiratory depression.
Subanesthetic dose intravenous ketamine has rapidly acting antidepressant effects
in treatment-resistant unipolar and bipolar depression. We recently reported an
open-label trial of ketamine in 10 subjects with treatment-refractory
obsessive-compulsive disorder, seven of whom had active comorbid depression.
Although ketamine had no sustained anti-obsessive effect, four of the seven
subjects with comorbid depression experienced an acute antidepressant effect.
However, we unexpectedly observed delayed-onset dysphoria, worsening anxiety and
suicidal thinking in two of the three subjects with obsessive-compulsive disorder
and extensive psychiatric comorbidity but minimal depressive symptoms at the
start of infusion. The implications of these adverse neuropsychiatric effects in
two patients with similar psychiatric comorbidity are discussed. We conclude that
there remains insufficient data on therapeutic ketamine in the presence of
comorbid psychiatric disorders to promote its off-label use in a non-research
milieu.

PMID: 23676198 [PubMed - indexed for MEDLINE]

There is conflicting evidence for the use of Ketamine treatment for PTSD

Ketamine is not FDA Approved for the treatment of PTSD

24. Pediatrics. 2015 Sep;136(3):e694-6. doi: 10.1542/peds.2014-4152. Epub 2015 Aug
10.

Remission From Behavioral Dysregulation in a Child With PTSD After Receiving
Procedural Ketamine.

Donoghue AC(1), Roback MG(2), Cullen KR(3).

Author information:
(1)Department of Psychiatry, linds368@umn.edu. (2)Department of Pediatrics, and
Department of Emergency Medicine University of Minnesota, Minneapolis, Minnesota.
(3)Department of Psychiatry.

Ketamine, an N-methyl-D-aspartate-type glutamate receptor antagonist, has long
been used for anesthesia and has recently been investigated for its rapid
antidepressant effects in adults with treatment-resistant depression and
posttraumatic stress disorder (PTSD). We report a case of a child with PTSD and
episodes of severe aggression and emotional dysregulation that were refractory to
multiple medical and behavioral interventions. This child demonstrated sustained
(8-13 days) remission from these symptoms when exposed to ketamine in the context
of 2 procedures. We review the sparse literature on the uses of ketamine for
behavioral purposes in children. This case suggests that ketamine should be
further explored as a potential treatment option for children with severe
refractory behavioral aggression.

PMID: 26260717 [PubMed - in process]

179. JAMA Psychiatry. 2014 Jun;71(6):681-8. doi: 10.1001/jamapsychiatry.2014.62.

Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress
disorder: a randomized clinical trial.

Feder A(1), Parides MK(2), Murrough JW(3), Perez AM(4), Morgan JE(1), Saxena
S(5), Kirkwood K(2), Aan Het Rot M(6), Lapidus KA(3), Wan LB(1), Iosifescu D(3),
Charney DS(7).

Author information:
(1)Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York,
New York. (2)Department of Health Evidence and Policy, Icahn School of Medicine
at Mount Sinai, New York, New York. (3)Department of Psychiatry, Icahn School of
Medicine at Mount Sinai, New York, New York3Department of Neuroscience, Icahn
School of Medicine at Mount Sinai, New York, New York. (4)Department of
Anesthesiology, Icahn School of Medicine at Mount Sinai, New York, New York.
(5)School of Public Health, Charité-Universitätsmedizin Berlin, Berlin, Germany.
(6)Department of Psychology, University of Groningen, Groningen, the Netherlands.
(7)Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York,
New York3Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New
York, New York7Department of Pharmacology and Systems Therapeutics, Icahn School
of Medicine at.

Comment in
JAMA Psychiatry. 2015 Jan;72(1):95-6.
JAMA Psychiatry. 2015 Jan;72(1):94-5.

IMPORTANCE: Few pharmacotherapies have demonstrated sufficient efficacy in the
treatment of posttraumatic stress disorder (PTSD), a chronic and disabling
condition.
OBJECTIVE: To test the efficacy and safety of a single intravenous subanesthetic
dose of ketamine for the treatment of PTSD and associated depressive symptoms in
patients with chronic PTSD.
DESIGN, SETTING, AND PARTICIPANTS: Proof-of-concept, randomized, double-blind,
crossover trial comparing ketamine with an active placebo control, midazolam,
conducted at a single site (Icahn School of Medicine at Mount Sinai, New York,
New York). Forty-one patients with chronic PTSD related to a range of trauma
exposures were recruited via advertisements.
INTERVENTIONS: Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and
midazolam (0.045 mg/kg).
MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in PTSD
symptom severity, measured using the Impact of Event Scale-Revised. Secondary
outcome measures included the Montgomery-Asberg Depression Rating Scale, the
Clinical Global Impression-Severity and -Improvement scales, and adverse effect
measures, including the Clinician-Administered Dissociative States Scale, the
Brief Psychiatric Rating Scale, and the Young Mania Rating Scale.
RESULTS: Ketamine infusion was associated with significant and rapid reduction in
PTSD symptom severity, compared with midazolam, when assessed 24 hours after
infusion (mean difference in Impact of Event Scale-Revised score, 12.7 [95% CI,
2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with
ketamine was evident in both crossover and first-period analyses, and remained
significant after adjusting for baseline and 24-hour depressive symptom severity.
Ketamine was also associated with reduction in comorbid depressive symptoms and
with improvement in overall clinical presentation. Ketamine was generally well
tolerated without clinically significant persistent dissociative symptoms.
CONCLUSIONS AND RELEVANCE: This study provides the first evidence for rapid
reduction in symptom severity following ketamine infusion in patients with
chronic PTSD. If replicated, these findings may lead to novel approaches to the
pharmacologic treatment of patients with this disabling condition.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00749203.

PMID: 24740528 [PubMed - indexed for MEDLINE]

180. Ann Clin Psychiatry. 2014 May;26(2):145.

Treatment-refractory depression: a case of successful treatment with intranasal
ketamine 10%.

Clark P(1).

Author information:
(1)Private Practice, Chapel Hill, NC, USA. E-mail: Trisheclark@aol.com.

PMID: 24501735 [PubMed - indexed for MEDLINE]

281. AANA J. 2013 Apr;81(2):118-9.

Effects of ketamine on major depressive disorder in a patient with posttraumatic
stress disorder.

Womble AL(1).

Author information:
(1)Southeastern Pain Management, Gadsden, Alabama, USA. Arthur.Womble@us.army.mil

Ketamine has been used in anesthesia for many years and in various environments
with an acceptable safety margin. The side effects of hallucinations and paranoid
thoughts need to be overcome for acceptance of ketamine infusion in mainstream
psychiatry. In this case report, the anesthesia department was consulted because
of familiarity with the medication and the ability to modulate unacceptable side
effects with its use as is done in monitored anesthesia care. It is proposed that
ketamine has potential for treatment of major depression associated with
posttraumatic stress disorder (PTSD) in combat veterans. This patient, who had
debilitating and treatment-resistant major depression and PTSD, was treated by
intravenous infusion of ketamine and experienced substantial short-term
resolution of symptoms.

PMID: 23971230 [PubMed - indexed for MEDLINE]

Against:

198. Eur Neuropsychopharmacol. 2014 Mar;24(3):469-79. doi:
10.1016/j.euroneuro.2013.08.007. Epub 2013 Sep 12.

Immediate ketamine treatment does not prevent posttraumatic stress responses in
an animal model for PTSD.

Juven-Wetzler A(1), Cohen H(2), Kaplan Z(2), Kohen A(1), Porat O(1), Zohar J(3).

Author information:
(1)The Chaim Sheba Medical Center, Division of Psychiatry, Sackler Medical
School, Tel Aviv University, Tel Hashomer, Israel. (2)Ministry of Health, Anxiety
and Stress Research Unit, Ben-Gurion University of the Negev Faculty of Health
Sciences, Beer Sheva, Israel. (3)The Chaim Sheba Medical Center, Division of
Psychiatry, Sackler Medical School, Tel Aviv University, Tel Hashomer, Israel;
Sackler Medical School, Tel Aviv University, Israel. Electronic address:
joseph.zohar@sheba.health.gov.il.

Clinical studies suggest that administration of ketamine hydrochloride-an
antagonist at the N-methyl-d-aspartate ionophore-provides short-term amelioration
for depressive symptoms. The effects of a brief course of ketamine given
immediately following exposure to psychogenic stress on the behavioral stress
responses were assessed in an animal model of posttraumatic stress disorder.
Animals exposed to stress were treated 1h later with ketamine (0.5, 5, and 15
mg/kg) or vehicle for three days (N = 107). Outcome measures included behavior in
the elevated plus maze (EPM) and acoustic startle response (ASR) tests 30 days
after initial exposure and freezing behavior upon exposure to a trauma-cue on day
31. Pre-set cut-off behavioral criteria classified exposed animals according to
their EPM and ASR response-patterns into "extreme," "minimal," or "partial"
behavioral response for analysis of prevalence rates of "PTSD-like behavior."
Circulating corticosterone levels were assessed 20 min after injection of
ketamine in exposed and unexposed animals (N = 62). The dexamethasone suppression
test was used to assess negative feedback inhibition of the HPA axis. Prevalence
rates of extremely-, partially-, or minimally-disrupted behavior demonstrated
that ketamine administered immediately following stress exposure was ineffective
in alleviating "PTSD-like behavior" at day 30 after exposure. Administration of
ketamine was associated with increase in freezing behavior after exposure to a
trauma-cue on day 31. Corticosterone levels were significantly suppressed by
ketamine only in the exposed animals. Administration of ketamine immediately
following trauma-exposure may not only be ineffective but actually detrimental in
the long term. A disruption of the post-stress HPA-response has been raised as a
contributing factor.

PMID: 24239430 [PubMed - indexed for MEDLINE]

Ketamine for Eating Disorders

" a British team found that by combining ketamine (to block long-term potentiation and stimulation of compulsive behavior) with an opioid blocker (to prevent loss of consciousness), patients with refractory …ketamine might be useful in the treatment of heroin withdrawal.

“The speed with which a person changed from the high arousal, compulsive state to the more normal state was occasionally fast enough to resemble a change in personality,” they noted. “This was particularly so with patient 8, whose husband described her as changing back to the personality he knew when he first married her. The patient found the speed of change difficult to adapt to in the first week.” More than half of the patients showed a return to normal eating behavior that persisted long after discharge from the hospital."*

Ketamine is not FDA approved for the treatment of Eating Disorders

it is too soon to know, if it will prove useful

From Ketamine: Peril and Promise by R. Andrew Sewell, MD

http://www.maps.org/news-letters/v17n1/ketamine-peril_and_promise.pdf

Ketamine is not FDA Approved for the treatment of Heart Disease associated depression

Depression often complicates Heart Disease, especially coronary artery disease and Congestive Heart Failure. Untreated, it can cause accelerated disability, reduced quality of life and early mortality. Ketamine treatment may provide a safe, effective and rapid way to break the depressive cycle in Cardiac Patients

Ketamine is not FDA Approved for the treatment of mood disorders associated with

Cancer, Hospice Care or Palliative treatment

Cancer, Hospice and Palliative Care patients sometimes have a limited time and antidepressant often take too long to work. Clinical researchers in La Jolla, CA have presented evidence that Ketamine Treatement may be helpful for depression in Cancer and end of life situations.

49. Psychosomatics. 2015 Jul-Aug;56(4):329-37. doi: 10.1016/j.psym.2014.05.005. Epub
2014 Jun 5.

Ketamine for the treatment of depression in patients receiving hospice care: a
retrospective medical record review of thirty-one cases.

Iglewicz A(1), Morrison K(2), Nelesen RA(3), Zhan T(4), Iglewicz B(5), Fairman
N(6), Hirst JM(3), Irwin SA(7).

Author information:
(1)Department of Psychiatry and Moores Cancer Center, University of California,
La Jolla, CA (AI, RAN, JMH, SAI); San Diego Veterans Affairs Healthcare System,
La Jolla, CA (AI). (2)Department of Internal Medicine and Inpatient Palliative
Medicine Service, University of Colorado, Aurora, CO (KM). (3)Department of
Psychiatry and Moores Cancer Center, University of California, La Jolla, CA (AI,
RAN, JMH, SAI). (4)Division of Biostatistics, Department of Pharmacology and
Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA (TZ).
(5)Department of Statistics, Temple University, Philadelphia, PA (BI).
(6)Department of Psychiatry and Behavioral Sciences, University of California
Davis School of Medicine, Sacramento, CA (NF). (7)Department of Psychiatry and
Moores Cancer Center, University of California, La Jolla, CA (AI, RAN, JMH, SAI).
Electronic address: sirwin@ucsd.edu.

BACKGROUND: Depression is prevalent in patients receiving hospice care. Standard
antidepressant medications do not work rapidly enough in this setting. Evidence
suggests that ketamine rapidly treats treatment refractory depression in the
general population. Ketamine׳s role for treating depression in the hospice
population warrants further study.
METHODS: A retrospective medical record review of 31 inpatients receiving hospice
care who received ketamine for depression on a clinical basis was conducted. The
primary outcome measure was the Clinical Global Impression Scale, which was used
retrospectively to rate subjects׳ therapeutic improvement, global improvement,
and side effects from ketamine over 21 days. Additionally, time to onset of
therapeutic effect was analyzed.
RESULTS: Using the Clinical Global Impression Scale, ketamine was found to be
significantly therapeutically effective through the first week after ketamine
dosing (p < 0.05), with 93% of patients showing positive results for days 0-3 and
80% for days 4-7 following ketamine dosing. Patients experienced global
improvement during all 4 studied time periods following ketamine dosing (p <
0.05). Significantly more patients had either no side effects or side effects
that did not significantly impair functioning at each of the 4 assessed time
periods following ketamine dosing (p < 0.05). Additionally, significantly more
patients experienced their first therapeutic response during days 0-1 following
ketamine dosing (p < 0.001) than during any other time period.
CONCLUSIONS: These data suggest that ketamine may be a safe, effective, and rapid
treatment for clinical depression in patients receiving hospice care. Blinded,
randomized, and controlled trials are required to substantiate these findings and
support further clinical use of this medication in hospice settings.

PMCID: PMC4308579 [Available on 2016-07-01]
PMID: 25616995 [PubMed - in process]

256. J Palliat Med. 2013 Aug;16(8):958-65. doi: 10.1089/jpm.2012.0617. Epub 2013 Jun
27.

Daily oral ketamine for the treatment of depression and anxiety in patients
receiving hospice care: a 28-day open-label proof-of-concept trial.

Irwin SA(1), Iglewicz A, Nelesen RA, Lo JY, Carr CH, Romero SD, Lloyd LS.

Author information:
(1)The Institute for Palliative Medicine at San Diego Hospice, San Diego,
California 92103, USA. sirwin@ucsd.edu

BACKGROUND: Depression and anxiety are prevalent and undertreated in patients
receiving hospice care. Standard antidepressants do not work rapidly or often
enough to benefit most of these patients. Ketamine has many properties that make
it an interesting candidate for rapidly treating depression and anxiety in
patients receiving hospice care. To test this hypothesis, a 28-day, open-label,
proof-of-concept trial of daily oral ketamine administration was conducted in
order to evaluate the tolerability, potential efficacy, and time to potential
efficacy in treating depression and anxiety in patients receiving hospice care.
METHODS: In this open-label study, 14 subjects with symptoms of depression or
depression mixed with anxiety warranting psychopharmacological intervention
received daily oral doses of ketamine hydrochloride (0.5 mg/kg) over a 28-day
period. The primary outcome measure was the Hospital Anxiety and Depression Scale
(HADS), which was used to rate overall depression and anxiety symptoms at
baseline, and on days 3, 7, 14, 21, and 28.
RESULTS: Over the 28-day trial there was significant improvement in both
depressive symptoms (F5,35=8.03, p=0.002, η(2)=0.534) and symptoms of anxiety
(F5,35=14.275, p<0.001, η(2)=0.67) for the eight subjects that completed the
trial. One hundred percent of subjects completing the trial responded to ketamine
for both anxiety and depression. A significant response in depressive symptoms
occurred by day 14 for depression (mean Δ=3.5, d=1.14, 95% CI=1.09-5.9, p=0.01)
and day 3 for anxiety (mean Δ=2.4, d=0.67, 95% CI=1.0-3.7, p=0.004). These
improvements remained significant through day 28 for both depression (mean Δ=4.0,
d=1.34, 95% CI=2.3-5.9, p=0.001) and anxiety (mean Δ=6.09, d=1.34, 95%
CI=3.6-8.6, p<0.001). Side effects were rare, the most common being diarrhea,
trouble sleeping, and trouble sitting still.
CONCLUSIONS: Patients who received daily oral ketamine experienced a robust
antidepressant and anxiolytic response with few adverse events. The response rate
for depression is similar to those found with IV ketamine; however, the time to
response is more protracted. The findings of the potential efficacy of oral
ketamine for depression and the response of anxiety symptoms are novel. Further
investigation with randomized, controlled clinical trials is necessary to firmly
establish the efficacy and safety of oral ketamine for the treatment of
depression and anxiety in patients receiving hospice care or other subject
populations.

PMCID: PMC3717203
PMID: 23805864 [PubMed - indexed for MEDLINE]

327. J Palliat Med. 2012 Apr;15(4):400-3. doi: 10.1089/jpm.2011.0314. Epub 2012 Apr 2.

Mood and pain responses to repeat dose intramuscular ketamine in a depressed
patient with advanced cancer.

Zanicotti CG(1), Perez D, Glue P.

Author information:
(1)Department of Psychological Medicine, Dunedin School of Medicine, University
of Otago, Dunedin, New Zealand. claudiagrott@hotmail.com

Depression is highly prevalent in patients with advanced cancer, commonly
affecting quality of life. Considering the response delay with conventional
antidepressants and the short life expectancy for these patients, treatments for
Major Depressive Disorder (MDD) with faster onset of action are desirable. In
this case report, a female patient with metastatic ovarian cancer presented rapid
and sustained response to intramuscular (IM) injections of ketamine (1mg/kg).
Over a course of six treatments, her mood response was identical on each occasion
and provided remission of her depressive symptoms. Pain was also improved,
although for a shorter duration. These findings support the use of IM ketamine as
a possible antidepressant option for this population.

PMID: 22468772 [PubMed - indexed for MEDLINE]

385. J Palliat Med. 2010 Jul;13(7):903-8. doi: 10.1089/jpm.2010.9808.

Oral ketamine for the rapid treatment of depression and anxiety in patients
receiving hospice care.

Irwin SA(1), Iglewicz A.

Author information:
(1)Institute for Palliative Medicine at San Diego Hospice, Palliative Care
Psychiatry, San Diego, California 92103, USA. sirwin@sdhospice.org

Depression is prevalent and undertreated in patients receiving hospice care.
Standard antidepressants do not work rapidly or often enough to benefit most of
these patients. Here, two cases are reported in which a single oral dose of
ketamine provided rapid and moderately sustained symptom relief for both
depression and anxiety. In addition, no adverse effects were noted. Further
investigation with randomized, controlled clinical trials is necessary to firmly
establish the effectiveness of oral ketamine for the treatment of depression and
anxiety in patients receiving hospice care. Ketamine may be a promising safe,
effective, and cost-effective rapid treatment for depression and anxiety in this
population.

PMCID: PMC3120058
PMID: 20636166 [PubMed - indexed for MEDLINE]

427. J Palliat Med. 2008 Nov;11(9):1268-71. doi: 10.1089/jpm.2008.9828.

Intravenous ketamine "burst" for refractory depression in a patient with advanced
cancer.

Stefanczyk-Sapieha L(1), Oneschuk D, Demas M.

Author information:
(1)Palliative Medicine, University Health Network, Toronto General Hospital
Toronto, Ontario, Canada. msapieha@hotmail.com

Major Depressive Disorder (MDD) is prevalent in patients with advanced cancer,
and can have a negative impact on patients' quality of life. Available
antidepressants, often have delayed benefits of several weeks, and therefore are
of limited utility in the palliative care setting. Psychostimulants provide more
rapid onset of action, but frequently require dose escalation because of problems
with tolerance. There is a growing body of evidence that N-methyl-D-aspartate
(NMDA) receptor antagonists, such as ketamine, signficantly and rapidly improve
depressive symptoms in treatment resistant depression. However, studies conducted
to date have not included advanced cancer patients. We report on a case where
intravenous ketamine 'bursts' (0.5 mg/kg infused over 60 minutes) were used to
treat an intractable MDD in a patient with metastatic prostate cancer. Initial
positive response was not sustained, and response to a repeat treatment was even
more transient. Adverse effects were mild and self-limiting. We conclude that a
well-designed, randomized study of IV ketamine "bursts" in cancer patients
suffering from depression is needed to further establish the role and appropriate
dosing of ketamine in this patient population. Given that ketamine can be used as
an adjuvant for difficult pain syndromes in cancer patients, it would be of
interest to assess its impact on the mood in patients receiving this treatment
for pain.

PMID: 19021495 [PubMed - indexed for MEDLINE]

Ketamine is not FDA Approved for the treatment of Headache

Migraine, Cluster and Stress Headache with or without Depression, can be treated (off label) with Ketamine

292. Neurology. 2013 Feb 12;80(7):642-7. doi: 10.1212/WNL.0b013e3182824e66. Epub 2013
Jan 30.

A randomized controlled trial of intranasal ketamine in migraine with prolonged
aura.

Afridi SK(1), Giffin NJ, Kaube H, Goadsby PJ.

Author information:
(1)Headache Group, Department of Neurology, University of California, San
Francisco, USA.

OBJECTIVE: The aim of our study was to test the hypothesis that ketamine would
affect aura in a randomized controlled double-blind trial, and thus to provide
direct evidence for the role of glutamatergic transmission in human aura.
METHODS: We performed a double-blinded, randomized parallel-group controlled
study investigating the effect of 25 mg intranasal ketamine on migraine with
prolonged aura in 30 migraineurs using 2 mg intranasal midazolam as an active
control. Each subject recorded data from 3 episodes of migraine.
RESULTS: Eighteen subjects completed the study. Ketamine reduced the severity (p
= 0.032) but not duration of aura in this group, whereas midazolam had no effect.
CONCLUSIONS: These data provide translational evidence for the potential
importance of glutamatergic mechanisms in migraine aura and offer a pharmacologic
parallel between animal experimental work on cortical spreading depression and
the clinical problem.
CLASSIFICATION OF EVIDENCE: This study provides class III evidence that
intranasal ketamine is effective in reducing aura severity in patients with
migraine with prolonged aura.

PMID: 23365053 [PubMed - indexed for MEDLINE]

Ketamine Pharmacology

1) Pharmacokinetics

a) Absorption works within 2 hours, effect lasts 1-2 weeks

Intravenous (IV),

Intramuscular(IM)

Oral (PO) Bioavailability = 20% due to 1st pass liver metabolism

Sublingual (SL)

Topical (TD) - creams and gels for local pain relief

b) Distribution

c) Metabolism - CYP3A4 - with Grapefruit juice 12 X Level, after 24 hours 2.4 X level, 3 days 1.5X, 7 days = same

d) Elimination

2) Pharmacodynamics

Ketamine binds to and inhibits the NMDA Receptor (NMDA-R).

The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively.[69]

also Opiate Agonist

Ketamine has been tested in

1) Major Depressive Disorder

2) Treatment-Resistant Bipolar Depression, and

3) Emergency room Suicidal Patients

potential Adverse Effects

Cardiovascular: abnormal heart rhythms, slow heart rate or fast heart rate, high blood pressure or low blood pressure

Dermatologic: Transient erythema, transient morbilliform rash

Gastrointestinal: Anorexia, nausea, increased salivation, vomiting

Local: Pain or exanthema of the injection site

Central nervous system: Ketamine is traditionally avoided in people with or at risk of intracranial hypertension (ICP) due to concerns about ketamine causing increased intracranial pressure. It does not increase ICP more than opioids.

Neuromuscular and skeletal: Increased skeletal muscle tone (tonic-clonic movements)

Ocular: Double vision, increased intraocular pressure, nystagmus

Respiratory: Airway obstruction, apnea, increased bronchial secretions, respiratory depression, laryngospasm

Other: Anaphylaxis, dependence, emergence reaction

Urinary & Bladder - One patient had bladder problems from the medical use and when it was discontinued, the symptoms resolved.

Psychiatric: Hallucinations, confusion, disorientation up to 24 hours after dose

Dose of ketamine for Anesthesia is about 2mg per kilogram (2.2 pounds) of body weight.

This dose usually causes loss of consciousness, and has minimal therapeutic effect

Dose of ketamine for Psychiatric Ketamine Treatment is much less, about .25 -.5 mg/kg

This dose not cause loss of consciousness, and has more therapeutic effect

the Therapeutic effect of ketamine is variable, for some people there is almost no effect, but for many people there is a complete remission of symptoms. Even when an excellent effect is obtained, it is not permanent, for some people it lasts weeks, but for others it only lasts 3-8 hours