European journal of pharmacology
July 5, 2025
Jolien K E Veraart, Sanne Y Smith-Apeldoorn, Jeanine Kamphuis et al.
2 citations
Oral 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.
Pharmaceuticals (Basel, Switzerland)
April 25, 2025
Jolien K E Veraart, Cornelis F Vos, Nieko C Punt et al.
2 citations
In patients with treatment-resistant depression receiving oral esketamine for six weeks, plasma concentrations of esketamine and noresketamine on day 39 were 59% and 35% lower than predicted by a pharmacokinetic model. This suggests that auto-induction of drug-metabolizing enzymes CYP3A4 and CYP2B6 occurs, which may explain the diminished therapeutic effects and side effects observed with long-term use. Identifying auto-induction as a mechanism of tolerance could have important clinical implications for maintaining efficacy.
The pharmacogenomics journal
April 24, 2026
Daniël T Coerts, Sanne Y Smith-Apeldoorn, Jérôme C Oude Nijhuis et al.
A genetic variation in the CYP2B6 enzyme, known as 516 G > T, is linked to higher blood levels of oral esketamine four hours after dosing in people with treatment-resistant depression. In a small sample of 18 participants from a placebo-controlled trial, carriers of the variant had median esketamine levels of 5.1 µg/L, compared to 2.1 µg/L in non-carriers. No significant associations were found for two other genetic variants, CYP3A4*22 and CYP3A5*3, but the numbers of carriers were very small. Larger studies are needed to clarify their effects.