Early augmentation therapy with dextromethorphan in mild to moderate major depressive disorder: A group sequential, response adaptive randomized controlled trial.

Adding 30 mg of dextromethorphan daily to standard SSRI treatment for eight weeks led to significantly greater reductions in depression severity, higher response and remission rates, and better clinical global improvement in patients with mild to moderate major depressive disorder, compared to adding a placebo. The combination was well-tolerated, with adverse events comparable between groups. No significant difference in serum BDNF levels was observed. These results suggest that early augmentation of SSRIs with dextromethorphan may improve clinical outcomes.

Study at a glance

Abstract

Therapeutic latency, lack of response, and adverse drug reactions are major challenges in current treatment approaches for major depressive disorder (MDD). Following the success of ketamine, more clinical research on NMDA antagonists is needed for a safe and long-term therapy in MDD. Hence, this study was conducted to evaluate the efficacy and safety of adjunct dextromethorphan to SSRIs in MDD. In this randomized, double-blind, add-on, placebo-controlled, group sequential design clinical trial, 60 patients with MDD were randomized to receive either adjunct dextromethorphan (30 mg) or adjunct placebo to SSRI for eight weeks. The primary outcome was the change in the MADRS score over eight weeks, and the secondary outcome parameters were response rate, remission rate, change in CGI-S, CGI-I, change in serum BDNF and serum dextromethorphan. The results showed a significantly greater reduction in MADRS score from baseline (MD: -3.94; 95 %CI: -5.81 to -2.06; p < 0.001; Cohen's d: 1.05), reduction in CGI-S score (p = 0.002), higher response (p = 0.008) and remission (p = 0.007) rate in the test group compared to the control group. The test group also showed significantly better CGI-I score (p = 0.001) compared to the control group. However, no significant difference was found in the change in serum BDNF (p = 0.751) between the groups. In the test group, serum dextromethorphan levels in all patients were within the therapeutic range. The occurrence of adverse events was comparable in both study groups. Early augmentation of SSRIs with dextromethorphan (30 mg/day) for the treatment of mild to moderate MDD may improve clinical outcomes significantly in terms of improvement in symptoms, response rate and remission rate. Trial registration ClinicalTrials.gov identifier: NCT05181527.