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.
| Original language | English |
|---|---|
| Article number | 627 |
| Number of pages | 11 |
| Journal | Pharmaceuticals |
| Volume | 18 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 25-Apr-2025 |