A systematic review and meta-analysis of 12 randomized controlled trials found that intravenous ketamine reduces depression symptoms in treatment-resistant depression at doses as low as 0.2 mg/kg, with increasing response at 0.5 mg/kg but no additional benefit at 1 mg/kg. Intranasal esketamine doses of 56–84 mg were more effective than 28 mg. Higher intravenous doses above 0.5 mg/kg did not lead to greater treatment response. The overall quality of evidence was low, limited by few studies, and publication bias was high.
Ketamine can rapidly reduce depression and suicidal thoughts in treatment-resistant depression, but its effectiveness for bipolar depression is less certain. An updated systematic review and meta-analysis of 11 studies, including 7 in the meta-analysis, found that a single ketamine infusion significantly improved depression symptoms measured by the MADRS scale at 1 and 2 days. Non-randomized studies showed a 53% response rate at study endpoint. Response and remission rates were similar for single versus serial infusions. The rate of switching to mania was about 2.4%. Evidence for esketamine in bipolar depression remains limited and based on small, non-randomized studies.
Repetitive transcranial magnetic stimulation (rTMS) produced significantly larger reductions in depression scores than electroconvulsive therapy (ECT) in adolescents with treatment-resistant depression, and potentially larger reductions than ketamine. A meta-analysis of 10 observational studies examined standardized mean differences in depression scores for youth aged 10-24 treated with ECT, rTMS, or ketamine. ECT had a significantly lower standardized mean difference of 1.99. No significant difference was found between ECT and ketamine. The comparison of ketamine versus rTMS suggested a potential difference favoring rTMS. rTMS shows promise as a first-line treatment for pediatric treatment-resistant depression due to its favorable side effect profile compared to ECT.