Augmentation of clozapine with dextromethorphan in treatment-resistant schizophrenia: A randomized, group sequential...

Dextromethorphan is a low-affinity, non-competitive NMDA receptor antagonist with multimodal properties, including sigma-1 receptor agonism and potential neuroprotective effects, characterized by rapid unblocking kinetics that may be therapeutically relevant in treatment-resistant schizophrenia (TRS). This study was designed to test the hypothesis that adjunctive dextromethorphan would improve clinical outcomes in TRS by evaluating the efficacy and safety of dextromethorphan augmentation of clozapine.

A randomized, double-blind, placebo-controlled, group-sequential clinical trial was conducted, and recruited participants were randomly assigned to receive either dextromethorphan (30 mg/day) or a placebo in addition to clozapine for 12 weeks. The primary outcome was the change in Positive and Negative Syndrome Scale (PANSS) scores, whereas the secondary outcomes were responder rate, patients developing clozapine resistance, patients requiring clozapine dose modification, clinical status based on clinical global impression (CGI) and cognitive status based on Mini-Mental State Examination (MMSE), and incidence of treatment-emergent adverse events (TEAE).

The dextromethorphan group significantly outperformed the placebo group in terms of change in total PANSS scores at the predefined second interim analysis (n = 40), which crossed the O'Brien-Fleming efficacy boundary, leading to protocol-specified early termination of recruitment for demonstrated efficacy (Mean difference: -10.68; 95%CI: -18.65, -3.69; p = 0.004) [Bias-adjusted estimate: -7.18 (95% GSD-adjusted CI: -11.8, -2.52, p = 0.006)]. PANSS subscales, response rate (NNT=2.19), and CGI scores also showed significant group differences. No significant differences were found in serum clozapine, clozapine resistance, or MMSE scores. Regression analyses identified treatment group and serum clozapine as predictors of clinical outcome. There was no significant difference between the groups in the occurrence of TEAE.

Augmentation of clozapine with dextromethorphan was associated with improvement in symptom severity and response rate and was well tolerated in this proof-of-concept trial; however, larger, multicentric studies with longer follow-up are required to confirm efficacy and safety.

ClinicalTrials.gov identifier: NCT05944510.