Auto-Induction in Oral Esketamine Treatment for Treatment-Resistant Depression: An Exploratory Study.
Jolien K E Veraart, Cornelis F Vos, Nieko C Punt, Dylan Visser, Mireille A Wessels, Sanne Y Smith-Apeldoorn, Jeanine Kamphuis, Robert A Schoevers, Daan J Touw
Pharmaceuticals (Basel, Switzerland) April 25, 2025 DOI: 10.3390/ph18050627 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 18 |
| Population | Patients with treatment-resistant depression receiving oral esketamine |
| Intervention | oral esketamine |
| Duration | Six weeks |
| Topics | Depression Esketamine |
| Keywords | Auto-induction Pharmacokinetics Drug metabolism Antidepressants |
| Citations | 2 |
| Key findings | Auto-induction of CYP3A4 and CYP2B6 appears to occur with oral esketamine treatment, potentially contributing to reduced efficacy and side effects over time. |
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.