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.

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.

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.

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.

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.

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]