Impact of sex on antidepressant discontinuation in groups of similar cytochrome P450 phenotypes

Dylan L Kosaski; Kristin C Cole; Jessica A Wright; Razan M El Melik; Simon Kung; Wayne T Nicholson; Jonathan G Leung

doi:10.9740/mhc.2023.12.303

Impact of sex on antidepressant discontinuation in groups of similar cytochrome P450 phenotypes

Ment Health Clin. 2023 Dec 1;13(6):303-310. doi: 10.9740/mhc.2023.12.303. eCollection 2023 Dec.

Authors

Dylan L Kosaski¹, Kristin C Cole², Jessica A Wright¹, Razan M El Melik¹, Simon Kung³, Wayne T Nicholson⁴, Jonathan G Leung^{1

2

1

1

3

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Affiliations

¹ Pharmacist, Department of Pharmacy, Mayo Clinic, Rochester, Minnesota.
² Statistician, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
³ Psychiatrist, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota.
⁴ Physician, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota.

Abstract

Introduction: Although there are studies assessing reasons for antidepressant discontinuation, little is known about the impact of sex differences or cytochrome P450 phenotypes. Our objective is to assess discontinuation rates between males and females and whether CYP450 phenotype influences discontinuation.

Methods: This is a retrospective review of patients previously enrolled in the Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment database with major depressive disorder. Patients were evaluated for antidepressants trialed between January 1, 2009, and September 30, 2019. Survival analyses with competing risks were used to analyze discontinuation reasons. A Kaplan-Meier estimation method was used to assess the time to discontinuation and discontinuation rates. Analyses were also completed to assess discontinuation between men and women by phenotypic groups. All tests were two-sided, and p-values ≤ .05 were considered statistically significant.

Results: There were 620 antidepressant discontinuation events discovered from 1015 antidepressant trials included. Overall, the median time to discontinuation for males was 2.6 years and 1.9 years for females (hazard ratio [HR] 0.97 [95% confidence interval (CI): 0.80, 1.19], p = .77). The risk of discontinuation was not different between males and females in any of the phenotype groups, which was consistent in the multivariable analyses. Concomitant use of medications that inhibited or induced antidepressant metabolism increased the overall risk of discontinuation (HR 1.45, 95% CI [1.06, 1.99], p = .020) in a time-dependent analysis.

Discussion: We did not detect a significant difference in risk of antidepressant discontinuation rates between males and females even when accounting for cytochrome P450 phenotype. Future studies should account for whether medications that inhibit or induce antidepressant metabolism may be a crucial factor in antidepressant discontinuation.

Keywords: antidepressants; cytochrome P450; depression; drug interactions; gender; pharmacogenomics; pharmacokinetics; sex.