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.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.