Plasma esketamine and noresketamine levels and antidepressant response with oral esketamine treatment.
Jolien K E Veraart, Sanne Y Smith-Apeldoorn, Jeanine Kamphuis, Daan J Touw, Robert A Schoevers
European journal of pharmacology July 5, 2025 DOI: 10.1016/j.ejphar.2025.177470 via PubMed
Summary
AI-generated from the abstractOral esketamine shows low and variable bioavailability, complicating its use as an antidepressant. In 17 patients with treatment-resistant depression given oral esketamine twice weekly for six weeks with a titration approach, esketamine and noresketamine serum levels were measured 30 and 60 minutes after administration. No association was found between changes in depressive symptoms and any pharmacokinetic outcomes, including serum levels of esketamine, noresketamine, their sum, or ratios. High inter-individual variability in pharmacokinetics was observed. The small sample and flexible-dose regimen limit conclusions. Clinical response may not correspond to esketamine pharmacokinetics, suggesting individually-based titration according to clinical effects is optimal.
Study at a glance
| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 17 |
| Population | Patients with treatment-resistant depression |
| Intervention | Oral esketamine |
| Duration | 6-week intervention |
| Topics | Depression Esketamine |
| Keywords | Clinical depression Esketamine ketamine Pharmacokinetics drug metabolism |
| Citations | 2 |
| Key finding | No association was found between depressive symptom change and esketamine or noresketamine pharmacokinetic outcomes in patients with treatment-resistant depression. |
Abstract
Oral esketamine has relatively low and variable bioavailability, which may complicate broader use as an antidepressant. This study aimed to investigate associations between different pharmacokinetic outcomes and change in depressive symptoms following oral esketamine administration in patients with treatment-resistant depression. Understanding such associations may inform dosing and administration strategies in clinical practice. Oral esketamine was administered twice weekly for six weeks using a titration approach in 17 patients. Esketamine and noresketamine serum levels were measured 30 min and 60 min after esketamine administration. Change in depression severity was plotted against the serum levels of esketamine and noresketamine, their sum and their ratios. We observed high inter-individual variability in oral esketamine pharmacokinetics, and we found no association between depressive symptom change and the pharmacokinetic outcomes. The small sample size and flexible-dose regimen complicate definitive conclusions. In the treatment of depression, clinical response may not correspond to esketamine pharmacokinetic outcomes. Individually-based titration strategies based on clinical antidepressant effects appear to be the optimal approach moving forward.