OBJECTIVES: Ketamine has demonstrated rapid and robust antidepressant effects in patients with treatment resistant depression (TRD) in investigational clinical trials. The objective of this study was to compare the efficacy of ketamine with other pharmacological and somatic treatments in adult TRD patients. METHODS: A systematic literature review was performed in September 2014, using a predefined search strategy including MEDLINE, EMBASE and the Cochrane Library. TRD was defined as ≥ 2 antidepressant treatment failures. Thirty-one randomized controlled trials (RCTs) were included: 19 RCTs investigating 13 pharmacological interventions and 12 RCTs investigating electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (rTMS). Key outcomes were: disease severity change from baseline at 2 weeks measured on the Montgomery–Åsberg Depression Rating Scale (MADRS) and response rate at 2 weeks (i.e. reduction of ≥50% in MADRS total score). Placebo and sham arms were pooled into one reference group.The evidence base was synthesised by means of a Bayesian network meta-analysis. RESULTS: Ketamine seemed more efficacious in reducing depressive symptoms at 2 weeks than aripiprazole augmentation (mean difference in MADRS reduction -11.0; 95% Credible Interval [CrI] -17.8 to -4.1), venlafaxine monotherapy(-12.7; [-23.2 to -2.2]), olanzapine/fluoxetine combination (-12.5; [-24.9 to -0.2]), fluoxetine monotherapy (-12.5; [-24.4 to -0.6]), quetiapine augmentation (-11.6; [-20 to -3.1]), nortriptyline monotherapy (-13; [-25.7 to -0.3]), lamotrigine augmentation (-13.2; [-24.2 to -2.2]), ECT (-9.4; [-18.4 to -0.5]) and rTMS (-9.8; [-16.2 to -3.5]). Also, ketamine showed the highest probability of being the best treatment (57%). The % responders at 2 weeks was 5-fold higher for ketamine than for aripiprazole (odds ratio (OR) 5.2; 95% CrI [1.4-27.5]) and rTMS (4.8; [1.1-27.5]), and 14-fold higher compared to placebo/sham treatment (13.7; [3.8-69.1]). CONCLUSIONS: Based on the evidence synthesis of available RCTs investigating the efficacy of TRD treatments at 2 weeks, ketamine demonstrated superior efficacy compared with other pharmacological and somatic interventions.