Elsevier

General Hospital Psychiatry

Volume 37, Issue 2, Marchā€“April 2015, Pages 178-184
General Hospital Psychiatry

Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysisā˜†

https://doi.org/10.1016/j.genhosppsych.2015.01.003Get rights and content

Abstract

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 0.69ā€“1.34) (P<Ā .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.

Introduction

With its high prevalence, disability, morbidity and mortality, depression poses a significant public health issue [1], [2], [3], [4]. Patients with depression have elevated risk of suicide and increased medical and psychiatric comorbidities [5]. Yet only half of individuals with major depressive episodes respond to the first-line treatment, and symptom response time can be as high as 3 to 4 weeks [6], [7], [8]. With the challenges of existing pharmacotherapies, novel more rapidly acting treatments for major depression are clearly needed.

Ketamine, an N-methyl-d-aspartate (NMDA)-receptor antagonist and FDA-approved anesthetic, has been used in rodent models of depression with consistently positive results [9], [10], [11], [12], [13], [14]. Existing literature suggests that glutamate levels and NMDA receptor mRNA expression are abnormal in patients with major depressive disorder (MDD) and bipolar affective disorder (BPAD), and long-term antidepressant treatment reduces NMDA receptor mRNA transcription [15], [16], [17], [18], [19]. Additionally, prior studies evaluating postmortem hippocampal samples of people who have committed suicide report decreased NMDA receptor expression, suggesting an alteration in the glutamatergic system [20], [21]. These findings led to the experimental use of ketamine for treatment of depression. Results of early studies of ketamineā€™s use as an antidepressant in humans were promising. Specifically, several open-label trials suggested that ketamine had a rapid antidepressant effect [22], [23]. Follow-up randomized controlled trials confirmed that ketamine performed significantly better than placebo with relatively few safety concerns [24], [25], [26], [27], [28], [29].

Given the public health burden of major depression, challenges of existing depression treatments, and promising basic and clinical evidence, ketamine may be an important rapid-acting treatment for major depression. However, controversy exists regarding the use of ketamine. Ketamine has notoriety as a club drug with a brief hallucinogenic and euphoric effect that can last 1 to 2 h and thus must be administered in controlled settings [30]. Reports of off-label ketamine use in emergency rooms, pain clinics and private psychiatric clinics are alarming given the lack of close monitoring outside a research environment, unclear clinical context and short duration of effects [31]. Additionally, ketamineā€™s rapid but short-lived effects provide practical challenges for appropriate clinical use. One recent systematic review concluded that single dosages of intravenous, oral and intramuscular ketamine were useful for treating unipolar and bipolar depression [32]. Another recent meta-analysis reported that ketamine intervention had higher rates of response and remission of depression compared to placebo in seven randomized controlled trials [33]. Two other meta-analyses have similarly shown ketamineā€™s efficacy as an antidepressant [34], [35]. Limitations of these approaches include reliance on published data rather than using original data collected from the investigators, presentation of outcomes using odds ratios that may overestimate the intended effect, inclusion of studies with high risk of bias, and inclusion of both intravenous and intranasal ketamine interventions when the intravenous route may deliver a more consistent dose of medication.

This meta-analysis was conducted to assess the efficacy of intravenous ketamine in comparison with placebo for the reduction of depressive symptoms in adult individuals who meet criteria for a major depressive episode. Additionally, this analysis sought to better understand the rapid (i.e., 1 day) versus intermediate-term (i.e., 7 days) effect of ketamine.

Section snippets

Eligibility criteria

English-language articles from January 1990 to September 2013 were searched in two electronic databases (Pubmed, PsycInfo). The criteria for inclusion required studies to be randomized placebo-controlled trials of ketamine in the treatment of patients with treatment-refractory MDD or BPAD depression by the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. The studies were restricted to adult outpatient samples; those that included children or adolescents

Study characteristics

A total of six randomized, double-blind, placebo-controlled studies were included in this meta-analysis (TableĀ 1). All six of these studies included both male and female patients older than 17 years. There are some notable differences between the studies. Three of the studies (Zarate 2006, Murrough, Sos) included participants with a diagnosis of MDD while excluding those with BPAD. The other three studies (Zarate 2012, Berman, Diazgranados) included patients with BPAD I and II depression. All

Discussion

The results of this meta-analysis signify that ketamine has a significant impact on depressive symptoms in subjects with MDD and BPAD at 1 day and 7 days postinfusion. Although these findings are consistent with previous results in suggesting that ketamine treatment is associated with a large and significant antidepressant effect at 24 h postinfusion, the results of this meta-analysis may be: (a) more reliable, as our results used data provided directly from study authors of manuscripts

References (61)

  • M. Ghasemi et al.

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

    Psychiatry Res

    (2014)
  • G.W. Valentine et al.

    The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS

    Psychiatry Res

    (2011)
  • K.A. Lapidus et al.

    A randomized controlled trial of intranasal ketamine in major depressive disorder

    Biol Psychiatry

    (2014)
  • M. aan het Rot et al.

    Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression

    Biol Psychiatry

    (2010)
  • R. Shahani et al.

    Ketamine-associated ulcerative cystitis: a new clinical entity

    Urology

    (2007)
  • R.B. Price et al.

    Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression

    Biol Psychiatry

    (2009)
  • C.A. Zarate et al.

    Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression

    Biol Psychiatry

    (2012)
  • G. Salvadore et al.

    Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine

    Biol Psychiatry

    (2009)
  • L.E. Phelps et al.

    Family history of alcohol dependence and initial antidepressant response to an N-methyl-d-aspartate antagonist

    Biol Psychiatry

    (2009)
  • R.C. Kessler et al.

    Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the national comorbidity survey replication

    Arch Gen Psychiatry

    (2005)
  • World Health Organization

    The global burden of disease: 2004 update

    (2008)
  • P.Y. Collins et al.

    Grand challenges in global mental health

    Nature

    (2011)
  • D.E. Bloom et al.

    The global economic burden of non-communicable diseases

    (2011)
  • D. Chisholm et al.

    Depression status, medical comorbidity and resource costs. evidence from an international study of major depression in primary care (LIDO)

    Br J Psychiatry

    (2003)
  • M.H. Trivedi et al.

    Medication augmentation after the failure of SSRIs for depression

    N Engl J Med

    (2006)
  • M. Fava et al.

    Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report

    Am J Psychiatry

    (2008)
  • A.J. Rush et al.

    Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report

    Am J Psychiatry

    (2006)
  • E. Moryl et al.

    Potential antidepressive properties of amantadine, memantine and bifemelane

    Pharmacol Toxicol

    (1993)
  • G. Sanacora et al.

    Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression

    Arch Gen Psychiatry

    (2004)
  • G. Sanacora et al.

    Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders

    Nat Rev Drug Discov

    (2008)
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    ā˜†

    Conflict of interest: Authors E.E.L., M.P.D., A.L. and S.H. declare no conflicts of interest.

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