Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression
D. Jeffrey Newport, Linda L. Carpenter, William M. Mcdonald, James B. Potash, Mauricio Tohen, Charles B. Nemeroff
American Journal of Psychiatry October 1, 2015 DOI: 10.1176/appi.ajp.2015.15040465 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and meta-analysis Randomized Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Population | Participants with major depression in placebo-controlled, double-blind, randomized clinical trials |
| Interventions | Ketamine D-cycloserine Rapastinel |
| Topics | Depression Esketamine Ketamine |
| Citations | 594 |
| Key findings | Ketamine produces a rapid but transient antidepressant effect, with high odds of response and remission at 24 hours, but its use warrants caution due to brief psychotomimetic and dissociative effects and potential for abuse and neurotoxicity. |
Abstract
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.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Ketamine produced a rapid but transient antidepressant effect, with high odds of response and remission at 24 hours, alongside brief psychotomimetic and dissociative effects.
Synthesized
Comparable studies
Other systematic reviews and meta-analyses on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Side-effects associated with ketamine use in depression: a systematic review. Patients with depression | 2018 | Systematic review | |
| Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Adults with unipolar or bipolar major depression | 2020 | Systematic review and meta-analysis | n = 1,877 |
| Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories Patients with major depressive disorder or bipolar depression | 2016 | Systematic review and meta-analysis | n = 588 |
| The use of ketamine as an antidepressant: a systematic review and meta‐analysis People with major depressive disorder or bipolar disorder receiving ketamine infusion | 2015 | Meta-analysis | n = 437 |
| Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review | 2021 | Systematic review |