Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysisā
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 ketamineās 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, ketamineās 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 ketamineās 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
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2022, Journal of Affective DisordersCitation Excerpt :This is in keeping with studies showing that individuals with lower baseline scores are more likely to meet the criteria set for response and remission. The effect sizes reported here for sublingual ketamine are comparable to the higher end of those reported for KIT in lab settings (see Lee et al., 2015 for a meta-analysis) and just above those in real-world KIT settings (McInnes et al., 2022). The critical factor here appears to be ongoing administration of treatment.
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Conflict of interest: Authors E.E.L., M.P.D., A.L. and S.H. declare no conflicts of interest.