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The role of cytochrome P450 polymorphisms in the pharmacokinetics of oral esketamine.

Daniël T Coerts, Sanne Y Smith-Apeldoorn, Jérôme C Oude Nijhuis, Ron H N Van Schaik, Wim J. Tamminga, Daan J Touw, Jolien K E Veraart, Robert A Schoevers, Jens H van Dalfsen

The pharmacogenomics journal April 24, 2026 DOI: 10.1038/s41397-026-00405-5 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Placebo-controlled trial Peer reviewed
Sample size 18
Population Patients with treatment-resistant depression
Intervention oral esketamine
Dose low dose (not further specified)
Topics Esketamine
Key findings CYP2B6 516 G > T carriers had higher esketamine plasma levels than non-carriers.

Abstract

Oral esketamine displays therapeutic potential for treatment-resistant depression. However, treatment is complicated by a low and variable bioavailability. Genetic polymorphisms in the cytochrome P450 (CYP) enzymes responsible for esketamine's metabolism may influence bioavailability. In a subsample of patients included in a placebo-controlled trial investigating repeated, low dose oral esketamine (N = 18), blood samples were collected four hours after dosing. CYP2B6 516 G > T, CYP3A4*22, and CYP3A5*3 genotyping was performed, and the plasma levels of esketamine and its metabolites were measured. CYP2B6 516 G > T carriers (Mdn = 5.1 µg/L) demonstrated higher esketamine plasma levels compared to non-carriers (Mdn = 2.1 µg/L) (U = 45.00, p = 0.032). No significant associations were observed for CYP3A4*22 carriership (n = 2) or CYP3A5*3 heterozygosity (n = 2), nor for esketamine's metabolites. In summary, CYP2B6 516 G > T is associated with higher esketamine plasma concentrations. Further research with more participants is warranted to draw conclusions about CYP3A4*22 and CYP3A5*3. Clinical trial registration: NTR6161 (Dutch Trial Register).

Comparable studies

Other randomized controlled trials on esketamine, most cited first.

Study Year Design Participants
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 Adults with moderate to severe nonpsychotic depression and a history of nonresponse to... 2019 Phase 3, double-blind, active-controlled, multicenter randomized controlled trial n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable... 2019 Phase 3, multicenter, double-blind, randomized withdrawal study n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate... 2017 Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study n = 67
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study Depressed patients at imminent risk for suicide 2018 Randomized controlled trial n = 68
Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) Adults with moderate-to-severe depression and nonresponse to at least two... 2019 Randomized controlled trial n = 346

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