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.

Conflict of interest statement

Declaration of Interest T.K. has received consultant fees from Sumitomo Dainippon, Novartis, Otsuka and Taisho and has received speaker’s honoraria from Abbvie, Banyu, Eli Lilly, Dainippon Sumitomo, Janssen, Mochida, Novartis, Otsuka Pfizer and Shionogi. He has received grant support from the Byoutaitaisyakenkyukai Fellowship (Fellowship of Astellas Foundation of Research on Metabolic Disorders), Eli Lilly Fellowship for Clinical Psychopharmacology, Research Group for Schizophrenia Japan, Dainippon-Sumitomo, Mochida and Otsuka. J.M.C. has nothing to disclose. K.H. is an employee of Sumitomo Dainippon Pharma, Japan. C.A.Z. is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. C.A.Z. has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government. J.M.K. has been a consultant to Alkermes, Amgen, Astra-Zeneca, Janssen, Pfizer, Eli Lilly, Bristol-Myers Squibb, Dainippon Sumitomo/Sepracor/Sunovion, Johnson & Johnson, Otsuka, Pierre Fabre, Vanda, Proteus, Takeda, Targacept, IntraCellular Therapies, Merck, Lundbeck, Novartis, Roche, Rules Based Medicine, Sunovion and has received honoraria for lectures from Otsuka, Eli Lilly, Esai, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck and Janssen. He is a shareholder of Vanguard Research Group and MedAvante. He has received grant support from the NIMH. M.B. has received grant/research support from The Stanley Medical Research Institute, NARSAD, Deutsche Forschungsgemeinschaft, European Commission (FP7), American Foundation for Suicide Prevention, Bundesministerium für Bildung und Forschung (BMBF). He is a consultant for Alkermes, AstraZeneca, BristolMyers Squibb, Ferrer Internacional, Janssen, Lilly, Lundbeck, Otsuka, Servier, Takeda, and has received speaker honoraria from AstraZeneca, BristolMyers Squibb, GlaxoSmithKline, Lilly, Lundbeck, Otsuka and Pfizer. C.U.C. has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Actelion, Alexza; Alkermes, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forum, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, NIMH, Janssen/J&J, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva and Vanda. He has received grant support from BMS, Feinstein Institute for Medical Research, Janssen/J&J, NIMH, Novo Nordisk A/S and Otsuka.

Figures

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.