Auto-Induction in Oral Esketamine Treatment for Treatment-Resistant Depression: An Exploratory Study.
Pharmaceuticals (Basel, Switzerland) – April 25, 2025
Source: PubMed
Summary
Breakthrough depression treatment esketamine shows an unexpected twist: the body adapts to reduce its effectiveness over time. After 39 days of oral treatment, patients had 59% less of the drug in their blood than expected. This auto-induction process, where the body speeds up drug metabolism, helps explain why some patients experience diminishing benefits. The findings suggest new approaches may be needed to maintain esketamine's powerful antidepressant effects.
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.