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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| 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 Drug absorption Bioavailability Treatment-resistant depression trd Concentration-response relationship |
| Citations | 2 |
| Key findings | 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.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.
Citations in the library
Cites 25
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
and 20 more in the library