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. Issue 7 (12th February 2016)

• Record Type: Journal Article
• Authors: Kishimoto, T.; Chawla, J. M.; Hagi, K.; Zarate, C. A.; Kane, J. M.; Bauer, M.; Correll, C. U.
• Is Part Of: Psychological medicine. Volume 46:Issue 7(2016)
• Page Start: 1459
• Page End: 1472
• Publication Date: 2016-02-12
• Subjects: Bipolar depression, -- depression, -- ketamine, -- meta-analyses, -- N-methyl-d-aspartate receptor antagonists, -- trajectories; Psychiatry -- Periodicals; Medicine and psychology -- Periodicals; Clinical psychology -- Periodicals; 616.89
• DOI: 10.1017/S0033291716000064
• Languages: English
• ISSNs: 0033-2917

Abstract

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.