2026 ECNP Congress

EP02-2036

Pharmacogenomic testing in major depressive disorder: Cytochrome P450 polymorphisms as predictors of antidepressant response and adverse effects

Mihaela Belous — J. Dorin · Nicolae Testemițanu State University of Medicine and Pharmacy USMF, Department of Mental Health- Medical Psychology and Psychotherapy “Alexandru Nacu”, Chisinau, Moldova

2026 ECNP Congress

Introduction

Major depressive disorder is one of the leading causes of disability worldwide, yet only about 50% of patients respond to first-line antidepressant treatment. The traditional trial-and-error prescribing model prolongs symptomatic suffering and contributes to treatment dropout. Cytochrome P450 (CYP) enzymes, particularly CYP2D6 and CYP2C19, metabolise the majority of widely prescribed antidepressants, including selective serotonin reuptake inhibitors and tricyclic antidepressants [1,2]. Polymorphisms in these genes give rise to distinct metaboliser phenotypes (poor, intermediate, normal, rapid and ultrarapid), with documented effects on drug plasma exposure, treatment response and adverse drug reactions, particularly for escitalopram, sertraline, paroxetine, vortioxetine and tricyclic agents [1-3]. The Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenomics Working Group have issued actionable prescribing recommendations based on these phenotypes, yet pharmacogenomic testing remains underused in routine psychiatric practice [1,2]. Reported clinical benefits vary across trials, reflecting heterogeneity in panel composition, outcome definitions and adherence to genotype-guided recommendations.

Aims

To synthesise current evidence on the clinical utility of pharmacogenomic testing based on CYP2D6 and CYP2C19 polymorphisms for guiding antidepressant prescribing in adults with major depressive disorder.

Methods

Six databases were searched: MEDLINE, Embase, PsycINFO, Web of Science, Cochrane and Scopus. Eligible studies were peer-reviewed randomised controlled trials, systematic reviews and meta-analyses including adult patients with major depressive disorder treated with antidepressants metabolised by CYP2D6 or CYP2C19. Primary outcomes were response, remission and adverse drug reactions, using validated psychometric or clinical measures. Pooled odds ratios, response rates and adverse drug reaction frequencies were extracted, with priority given to studies published between 2020 and 2025.

Results

A 2023 meta-analysis of 12 randomised controlled trials reported that pharmacogenomic-guided treatment significantly improved response (OR 1.46, 95% CI 1.16-1.85), remission (OR 1.85, 95% CI 1.23-2.76) and overall improvement (OR 1.63, 95% CI 1.19-2.24) compared with treatment as usual [2]. These findings underscore the clinical relevance of genotype-guided prescribing in improving patient outcomes. The 2023 PREPARE trial (7 European countries, 12-gene pharmacogenetic panel including CYP2D6 and CYP2C19) reported a 30% reduction in clinically relevant adverse drug reactions in the genotype-guided arm [3]. A 2024 randomised trial in 665 adults with depression demonstrated higher remission rates in the pharmacogenomic-guided group at week 8 (24.0% vs 15.1%, p=0.007) and week 12 (31.0% vs 20.0%, p=0.003), and higher response rates at week 8 (39.3% vs 25.7%, p<0.001) [4]. A 2024 meta-analysis confirmed dose-normalised plasma exposure differences for escitalopram and sertraline across CYP2C19 metaboliser phenotypes [5].

Conclusions

Pharmacogenomic testing based on CYP2D6 and CYP2C19 polymorphisms is associated with measurable improvements in remission and response rates and a meaningful reduction in clinically relevant adverse drug reactions in adults with major depressive disorder. These findings support the integration of pharmacogenomic testing into personalised medicine approaches in psychiatry. Implementation in routine psychiatric practice remains limited, and future research should focus on cost-effectiveness, long-term outcomes and equitable access across diverse populations.

References

  1. Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and antidepressant dosing: 2023 update. Clin Pharmacol Ther. 2023;113(5):1101–1120.
  2. Arnone D, Omar OM, Arora T, et al. Effectiveness of pharmacogenomic tests including CYP2D6 and CYP2C19 genomic variants for guiding the treatment of depressive disorders: systematic review and meta-analysis of randomized controlled trials. Neurosci Biobehav Rev. 2023;144:104965.
  3. Swen JJ, van der Wouden CH, Manson LE, et al. A 12-gene pharmacogenetic panel to prevent adverse drug reactions (PREPARE): an open-label, multicentre, controlled trial. Lancet. 2023;401(10374):347–356.
  4. Greden JF, Parikh SV, Rothschild AJ, et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2024;81(2):150–160.
  5. Jukic MM, Haslemo T, Molden E, Ingelman-Sundberg M. Impact of CYP2C19 genotype on escitalopram and sertraline exposure: systematic review and meta-analysis. Clin Pharmacol Ther. 2024;115(2):398–408.