Genotype influences antidepressant discontinuation in a pre-emptive pharmacogenetic testing population

The Pharmacogenomics Journal ARTICLE www.nature.com/tpj OPEN Genotype influences antidepressant discontinuation in a preemptive pharmacogenetic testing population ✉ Jordan F. Baye 1,2,3 , Natasha J. Petry 2,3 Amanda Massmann and April Schultz 2,4 , Lindsay Hines 2,5 , Max Weaver2, Michael Reinke5, Halle Brady 2 , 2,3 1234567890();,: © The Author(s) 2026 We performed a retrospective cohort study to evaluate risk of antidepressant discontinuation as a function of CYP2C19 and CYP2D6 phenotype. Patients who participated in an elective genomic screening and had a diagnosis of depression or anxiety with a corresponding antidepressant were analyzed. This resulted in 5 808 patients comprising 8 571 antidepressant orders. Of the total antidepressant orders, 51% of the antidepressants ordered before pharmacogenetic testing were discontinued. A multivariate analysis – accounting for age, medication tenure, allergies, PHQ-9, malaise/fatigue, and medication indication – revealed a significant association between metabolizer status and discontinuation for CYP2C19 increased metabolizers (ultrarapid plus rapid metabolizers) compared to normal metabolizers (n = 4 635) (HR = 1.17 [1.08, 1.27], p < 0.001) for CPIC guideline-recommended medications (i.e., citalopram, escitalopram, sertraline). Stratifying risk by individual drug maintained significant associations for escitalopram (HR = 1.27 [1.1, 1.46], p < 0.05) and sertraline (HR = 1.15 [1.01, 1.31], p < 0.05). While the CYP2D6 decreased metabolizer group (intermediate plus poor metabolizers) did not reach statistical significance for guideline recommended medications (i.e., paroxetine, venlafaxine, vortioxetine), the individual effect for venlafaxine showed an increased risk of discontinuation (HR = 1.23 [1.01, 1.5], p < 0.05). These results suggest phenotypic variations may have variable impact on risk of discontinuation amongst different antidepressant medications, but for escitalopram, sertraline, and venlafaxine, the risk of discontinuation in particular phenotypes should be considered at the time of therapy initiation. The Pharmacogenomics Journal (2026)26:22 ; https://doi.org/10.1038/s41397-026-00416-2 INTRODUCTION An estimated 21 million adults in the United States -- about 8.3% of the adult population -- live with depression with the majority receiving pharmacotherapy treatment [1]. Selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) have been first-line pharmacotherapy options for more than twenty years; however, these medications typically require a minimum of 4-6 weeks for an adequate trial of the treatment. Even with ideal use, over 50% of patients will experience at least one treatment failure and only about 30% will achieve remission on their first agent [2]. Additionally, since multiple medication trials are attempted before achieving an acceptable outcome, many individuals may experience extended periods of unmanaged psychiatric illness. Premature discontinuation and non-adherence of antidepressant medications can result in unfavourable outcomes in patients being treated for depressive disorders at all stages of treatment. Poor adherence has been associated with decreased treatment response and remission rates, worsening severity, and increased healthcare cost and utilization [3, 4]. Furthermore, around half of all patients will discontinue an antidepressant prematurely with a common reason being side effect burden [5]. Abrupt discontinuation can cause acutely distressing symptoms of antidepressant discontinuation syndrome further perpetuating beliefs that antidepressants cause adverse effects [6]. Following remission of depressive symptoms, some recent guidelines recommend continuation of medication therapy for at least 6 months, and even longer in individuals at higher risk of future episodes [7, 8]. During continued therapy, premature discontinuation has been associated with increased risk for recurrence of future depressive episodes [9]. Current guidelines by the Clinical Pharmacogenetics Implementation Consortium (CPIC) offer pharmacogenetic (PGx) dosing recommendations for several SSRIs/SNRIs [10]. Recommendations focus predominantly on three Cytochrome P450 metabolism genes - CYP2B6, CYP2C19, and CYP2D6. The enzymes produced by these genes metabolize seven different medications: CYP2C19 – citalopram and escitalopram; CYP2D6 – fluvoxamine, paroxetine, venlafaxine, and vortioxetine; and CYP2B6/CYP2C19 – sertraline. These medications experience differential metabolism on the basis of genotype, and per the guidelines, there is a direct genotype-phenotype-outcome association that is both consistent and predictable. Increased enzyme function is associated with lower serum drug concentrations and a corresponding decrease in efficacy. Inversely, decreased CYP450 function is associated with higher serum drug concentrations and a proportional risk of adverse effects. Notably, fluoxetine is also metabolized by 1 Department of Pharmacy Practice, South Dakota State University, College of Pharmacy & Allied Health Professions, Brookings, SD, USA. 2Sanford Imagenetics, Sioux Falls, SD, USA. 3Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Vermillion, SD, USA. 4Department of Pharmacy Practice, North Dakota State University, Fargo, ND, USA. 5Department of Psychiatry and Behavorial Science, University of North Dakota, Grand Forks, ND, USA. ✉email: Received: 3 January 2025 Revised: 3 March 2026 Accepted: 12 May 2026 J.F. Baye et al. 2 CYP2D6, though clinical studies have not discovered differences in clinical outcomes based on phenotype. With many patients experiencing suboptimal response and remission with a first or second agent, PGx has demonstrated clinical impact amongst individuals with depressive symptoms and major depressive disorder (MDD). Previous studies have shown that with guidance from PGx testing, patients were more likely to switch to a congruent therapy based on their results that led to significant improvement in time to remission or response compared to those that received standard of care [11, 12]. While improvement in symptoms, response, remission, and adverse toxicities has been evaluated in other studies; the impact of PGx testing on antidepressant discontinuation has not been fully explored. Herein, we evaluated real-world data on the effect of genetic variations on therapy discontinuation in patients with depression and anxiety. METHODS Site description and implementation This study was conducted in a rural, not-for-profit health system located in the upper Great Plains of the U.S. inclusive of South Dakota, North Dakota, Iowa, and Minnesota. The patient biogeographical group is predominantly European, with over 90% identifying as European American. PGx testing was implemented system-wide within our health system in 2014, and CYP2C19 and CYP2D6 have been a standard component of PGx testing since that time (...truncated)