Auto-Induction in Oral Esketamine Treatment for Treatment-Resistant Depression: An Exploratory Study.

In patients with treatment-resistant depression receiving oral esketamine for six weeks, plasma concentrations of esketamine and noresketamine on day 39 were 59% and 35% lower than predicted by a pharmacokinetic model. This suggests that auto-induction of drug-metabolizing enzymes CYP3A4 and CYP2B6 occurs, which may explain the diminished therapeutic effects and side effects observed with long-term use. Identifying auto-induction as a mechanism of tolerance could have important clinical implications for maintaining efficacy.

Study at a glance

Abstract

Background: Esketamine is a rapidly acting antidepressant with robust efficacy in treatment-resistant depression (TRD). Diminishing therapeutic effects and attenuated side effects have been reported after long-term use. This study aimed to investigate its long-term pharmacokinetics and factors that may contribute to reduced efficacy over time in patients with TRD by evaluating the potential role of auto-induction. Methods: Pharmacokinetic data were collected from 18 patients receiving oral esketamine for six weeks. A pharmacokinetic model was developed to predict esketamine and noresketamine plasma concentrations. Observed esketamine and noresketamine plasma concentrations were compared to model-predicted concentrations to assess deviations suggestive of auto-induction. Results: On day 39, plasma concentrations of esketamine and noresketamine were 59% and 35% lower than predicted, respectively, indicative of auto-induction of CYP3A4 and CYP2B6. Conclusions: Auto-induction appears to occur in oral esketamine treatment, which may contribute to reduced therapeutic efficacy and side effects in long-term treatment. Identifying auto-induction as a mechanism of tolerance potentially has important clinical implications. Further studies are warranted to confirm these findings and evaluate strategies to maintain therapeutic efficacy.