Impact of actionable genotypes on antidepressant treatment discontinuation in inpatients with depressive disorders: a prospective observational study

Introduction

Antidepressants commonly used for depressive disorders are extensively metabolised by cytochrome P450 enzymes, particularly CYP2D6 and CYP2C19. Genetic polymorphisms in these enzymes are frequent in psychiatric populations, affecting 87% of patients treated in hospitals [1,2], and lead to inter-individual variations in serum levels at the same dose, which may impair tolerability and treatment response. International pharmacogenetic guidelines (CPIC, DPWG) therefore recommend deviating from ‘standard treatment’ in non‑normal metabolizer phenotypes when gene-drug pairs are classified as actionable. In routine care, however, pharmacogenetic information is often unavailable at treatment initiation, resulting in multiple rapid antidepressant switches that can exacerbate psychological distress and delay remission. Meta‑analyses suggest that pharmacogenetic‑guided selection of antidepressants improves response and remission rates compared with treatment as usual (41% and 71% respectively) [3,4].

This study examined whether receiving an antidepressant that is incongruent with the patient’s genotype (i.e. an actionable antidepressant not adapted to the CYP2D6/CYP2C19‑based phenotype) is associated with a higher likelihood of discontinuation during inpatient treatment and follow‑up.

Methods

This prospective observational study was conducted at the Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, as part of the PharmGen‑TRD project (DRKS00036105).

Adult inpatients with depressive disorder (ICD-10 F32.x, F33.x) admitted April 2025–April 2026 were genotyped for CYP2D6, CYP2C19 and CYP2B6 and assigned a metaboliser phenotype according to current guideline definitions. Phenoconversion was considered in the phenotype assignement following Cicali et al. [5]. For each patient, one index antidepressant was defined at admission and at discharge. Based on the individual phenotype and CPIC/DPWG recommendations, the index antidepressant at each timepoint was classified as actionable (genotype‑congruent dosing or drug change recommended) or non‑actionable. Two analyses assessed: (I) admission actionable status vs. inpatient discontinuation (Group I, n=88); (II) discharge actionable status vs. 4-week post-discharge discontinuation (Group II, n=98). Of these, 32 patients per group received an actionable index antidepressant. Odds ratios (OR) with 95% confidence intervals (CI) and p-value were calculated in R (version 4.5.1).

Results

The index antidepressant was discontinued in 23/88 (26%) cases in Group I and 13/98 (13%) in Group II, independent of actionable status. In both analyses, patients receiving an actionable antidepressant showed higher odds of discontinuing the index drug than patients on non‑actionable antidepressants (OR(I) = 1.2, 95% CI 0.38 - 3.45 , p=0,803; OR(II) = 2,7, 95% CI 0.68 - 10.45 , p=0,12). However, these associations did not reach statistical significance, consistent with limited power due to small sample size.

Conclusions

This study suggests that the actionable genotype status of the antidepressant prescribed at admission and at discharge may influence subsequent treatment discontinuation during inpatient care and early follow‑up, although the observed effects were not statistically robust. Early pharmacogenetic testing could help to avoid initiating antidepressants that are incongruent with the patient’s CYP2D6/CYP2C19 phenotype, potentially reducing the need for switches, improving tolerability, and supporting more stable treatment trajectories in severe depression. Larger, adequately powered studies are warranted to confirm these findings and to better define which patient subgroups benefit most from pre‑emptive pharmacogenetic testing in routine psychiatric care.

References

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