Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials

Abstract

Background: Due to unmet clinical needs for efficient drugs with a rapid onset of antidepressant effects, we aimed to evaluate the efficacy of single-dose ketamine in different subgroups of patients with major depression and establish whether repeated ketamine administration could be a viable strategy to maintain treatment gains.

Methods: Electronic databases (Medline via PubMed, Embase, Cochrane Library, Trip Database) were systematically searched until February 22, 2019, for published peer-reviewed randomized controlled trials (RCTs) concerning a single and repeated administration of ketamine in patients with major depression. All relevant RCTs were selected and critically appraised, and a meta-analysis of eligible studies was performed.

Results: A total of 20 studies were included in the meta-analysis. The largest effect of ketamine vs. controls in reducing depressive symptoms was observed at 24 h (SMD = - 0.89; 95% CI - 1.24; - 0.53; p < 0.00001); however, a significant difference was shown for up to 7 days after a single dose. Significant differences compared with controls were observed for up to 7 days in treatment-resistant patients and when ketamine was added to ongoing antidepressant treatment, while there were no significant differences at 7 days when ketamine was used as monotherapy. In patients with major depression, initial antidepressant effects of ketamine were maintained during repeated dosing. At 2-3 weeks of repeated ketamine treatment, significant reduction of depression severity scores was observed: SMD = - 0.70; 95% CI - 1.15; - 0.25 or SMD = - 0.81; 95% CI - 1.41; - 0.20 (depending on the dosing regimen used); p ≤ 0.009 vs placebo.

Conclusions: Our meta-analysis revealed rapid and robust antidepressant effects of single-dose ketamine in patients with treatment-resistant depression (TRD). By pooling data from RCTs, we showed for the first time that repeated ketamine administration is effective in sustaining initial antidepressant effects observed after single dosing.

Keywords: Antidepressants; Bipolar disorder; Ketamine; Major depressive disorder; Meta-analysis; RCT.

Fig. 1

PRISMA flow diagram for selection of studies identified in the systematic review

Fig. 2

Risk of bias summary: review authors’ judgements about each risk of bias item for each included study

Fig. 3

Effects of single-dose ketamine on depression rating scale at 24 h, 3–4 days, and 7 days

Fig. 4

Effects of single-dose ketamine on response rates at 24 h (sensitivity analysis after exclusion of the study by Grunebaum et al. [29]), 3–4 days, and 7 days

Fig. 5

Effects of single-dose ketamine on remission rates at 24 h, 3–4 days, and 7 days

Fig. 6

Meta-analysis results: time course of overall standardized mean differences (SMD) between ketamine and control in major depression—a subgroup analysis (abbreviations, see Table 2)

Fig. 7

Effects of serial ketamine on depression rating scale at 2–3 weeks; data regarding twice-weekly (a) or thrice-weekly (b) dosing from the study by Singh et al. [32]. Sensitivity analysis excluded data from the study by Ionescu et al. [30]

Fig. 8

Effects of serial ketamine on response at 2–3 weeks, data regarding twice-weekly (a) or thrice-weekly (b) dosing from the study of Singh et al. [32]. Sensitivity analysis excluded data from the study by Ionescu et al. [30]

Fig. 9

Effects of serial ketamine on remission at 2–3 weeks, data regarding twice-weekly (a) or thrice-weekly (b) dosing from the study of Singh et al. [32]. Sensitivity analysis excluded data from the study by Ionescu et al. [30]