The Potential Influence of Associated Antidepressants on the Pharmacokinetic Profile of Esketamine in Patients Affected by Treatment-resistant Depression.
Current neuropharmacology – April 07, 2025
Source: PubMed
Summary
Certain antidepressant drugs can significantly boost blood levels of esketamine, a breakthrough treatment for stubborn depression. This finding shows how combining medications affects the body's processing of esketamine through cytochrome P450 enzymes. Patients taking specific antidepressants like paroxetine showed higher esketamine levels, though this didn't impact treatment success. These insights help doctors optimize dosing for safer, more effective depression care.
Abstract
Esketamine is administered intranasally in combination with at least another antidepressant in patients with treatment-resistant depression. Some of these antidepressants might affect ketamine's pharmacokinetic profile by inhibiting cytochrome-P450 (CYP450) isoforms. Our aim was to establish how different types of combined antidepressants affect serum and salivary levels of esketamine at the time of maximum plasma concentrations and afterward in TRD patients receiving esketamine in a real-world context. Serum and salivary samples were collected from 53 patients receiving intranasal esketamine (56 mg) at baseline, after 20 min (roughly corresponding to Tmax), 7 hours (corresponding to the t½ value), 24, and 72 hours. Patients were stratified according to the combined antidepressant medication. Salivary esketamine levels were several-fold higher than the corresponding serum levels at all time points, and showed high inter-individual variability. Serum 20-min post-esketamine levels and AUC0-72 levels were significantly higher in patients on antidepressants known to inhibit different isoforms of CYP450 (paroxetine, fluoxetine, duloxetine, venlafaxine), with respect to levels detected in patients on sertraline, citalopram, escitalopram, vortioxetine. These changes in the pharmacokinetic profile of esketamine did not affect the clinical outcome of esketamine. However, changes in systolic blood pressure in response to esketamine positively correlated with serum esketamine levels, suggesting a reduction of esketamine dose in patients with cardiovascular comorbidity under treatment with paroxetine, fluoxetine, duloxetine, venlafaxine. The CYP450-related status of co-administered antidepressants may affect esketamine levels. However, the small sample sizes of the co-administered drug subgroups and multiple prescriptions do not allow for drawing strong conclusions.