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
This meta-analysis (2016; 14 RCTs) found that single infusions of ketamine (to a lesser extent, non-ketamine NMDAR antagonists) has rapid anti-depressant effects that can last for up to one week.
Abstract
Background
Ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists (NMDAR antagonists) recently demonstrated antidepressant efficacy for the treatment of refractory depression, but effect sizes, trajectories and possible class effects are unclear.
Method
We searched PubMed/PsycINFO/Web of Science/clinicaltrials.gov until 25 August 2015. Parallel-group or cross-over randomized controlled trials (RCTs) comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses. Hedges’ g and risk ratios and their 95% confidence intervals (CIs) were calculated using a random-effects model. The primary outcome was depressive symptom change. Secondary outcomes included response, remission, all-cause discontinuation and adverse effects.
Results
A total of 14 RCTs (nine ketamine studies: n = 234; five non-ketamine NMDAR antagonist studies: n = 354; MDD = 554, BD = 34), lasting 10.0 ± 8.8 days, were meta-analysed. Ketamine reduced depression significantly more than placebo/pseudo-placebo beginning at 40 min, peaking at day 1 (Hedges' g = −1.00, 95% CI −1.28 to −0.73, p < 0.001), and loosing superiority by days 10-12. Non-ketamine NMDAR antagonists were superior to placebo only on days 5-8 (Hedges' g = −0.37, 95% CI −0.66 to −0.09, p = 0.01). Compared with placebo/pseudo-placebo, ketamine led to significantly greater response (40 min to day 7) and remission (80 min to days 3-5). Non-ketamine NMDAR antagonists achieved greater response at day 2 and days 3-5. All-cause discontinuation was similar between ketamine (p = 0.34) or non-ketamine NMDAR antagonists (p = 0.94) and placebo. Although some adverse effects were more common with ketamine/NMDAR antagonists than placebo, these were transient and clinically insignificant.
Conclusions
A single infusion of ketamine, but less so of non-ketamine NMDAR antagonists, has ultra-rapid efficacy for MDD and BD, lasting for up to 1 week. Development of easy-to-administer, repeatedly given NMDAR antagonists without risk of brain toxicity is of critical importance.
Research Summary of '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'
Introduction
Kishimoto and colleagues frame the study against a backdrop of substantial unmet need in treating mood disorders: standard monoaminergic antidepressants have delayed onset and only partial efficacy, and fewer proven options exist for bipolar depression. Recent research implicates glutamate-related neuroplasticity in depression and has shown that subanaesthetic doses of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, can produce rapid antidepressant effects and reduce suicidal ideation within hours in both major depressive disorder (MDD) and bipolar depression (BD). Given ketamine's mechanism of NMDAR blockade and consequent glutamate release, the authors note an open question about whether other, non-ketamine NMDAR modulators might produce similar clinical benefits. This meta-analysis aimed to quantify the efficacy, safety and time course of effect after a single intravenous infusion of ketamine or non-ketamine NMDAR antagonists versus placebo or pseudo-placebo in randomized trials of adults with MDD and/or BD. The investigators sought to synthesise randomized evidence across agents, to characterise trajectories of symptom change at specific post-infusion time points, and to compare response, remission and adverse-event profiles between ketamine and non-ketamine NMDAR antagonists.
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Study Details
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Kishimoto, T., Chawla, J. M., Hagi, K., Zarate, C. A., Kane, J. M., Bauer, M., & Correll, C. U. (2016). 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. Psychological Medicine, 46(7), 1459-1472. https://doi.org/10.1017/S0033291716000064
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