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

## TL;DR

This study explores how long-term use of oral esketamine for depression may lead to reduced effectiveness due to auto-induction of enzymes that break it down.

## Contribution

The study identifies auto-induction as a potential mechanism for diminished efficacy of oral esketamine over time.

## Key findings

- Esketamine and noresketamine plasma concentrations were significantly lower than predicted on day 39.
- Auto-induction of CYP3A4 and CYP2B6 enzymes is suggested as a cause for reduced drug levels.
- This mechanism may explain reduced therapeutic effects and side effects during long-term treatment.

## 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.