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

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.

Keywords: Bipolar depression; N-methyl-d-aspartate receptor antagonists; depression; ketamine; meta-analyses; trajectories.

Fig. 1

Hedges’s g in change in depression rating scale score between ketamine-treated and placebo (PBO) control subjects in the articles analysed. Squares are effect sizes of single studies, diamonds of pooled results. CI, Confidence interval.

Fig. 2

Hedges’s g in change in depression rating scale score between non-ketamine N-methyl-D-aspartate receptor (NMDAR) antagonist-treated and placebo (PBO) control subjects in the articles analysed. Squares are effect sizes of single studies, diamonds of pooled results. CI, Confidence interval.

Fig. 3

Risk ratio in treatment response (a) (≥50% reduction in Hamilton Depression Rating Scale/Montgomery–Åsberg Depression Rating Scale score) and remission (b) between ketamine-treated and placebo (PBO) control subjects in the articles analysed. Squares are effect sizes of single studies, diamonds of pooled results. CI, Confidence interval.

Fig. 4

Risk ratio in treatment response (a) (≥50% reduction in Hamilton Depression Rating Scale/Montgomery–Åsberg Depression Rating Scale score) and remission (b) between non-ketamine N-methyl-D-aspartate receptor (NMDAR) antagonist-treated and placebo (PBO) control subjects in the articles analysed. Squares are effect sizes of single studies, diamonds of pooled results. CI, Confidence interval.