Authors: Mason, E.R.¹, Ali, M.Y.¹, Burns, R.M.²·³, Shukla, P.¹, Courtenay, A.⁴, Gibson, D.S.¹, Murray, E.K.¹, Kelly, C.¹

Affiliations: 1. Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Builiding, Altnagelvin Hospital Campus, Glenshane Road, Derry⁓Londonderry, BT47 6SB, UK . 2. Department of Health and Nutritional Science, Atlantic Technological University, Faculty of Science, Sligo, Ireland. 3. Health and Biomedical Research Centre (HEAL), Atlantic Technological University, Faculty of Science, Sligo, Ireland. 4. School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, UK

Background/ Introduction: Phenoconversion extends pharmacogenomics to include drug-drug-gene interactions that dynamically alter metaboliser status, influence treatment response, adverse effect risk, and overall patient outcomes in clinical care. CYP2D6 phenoconversion is problematic in people with psychiatric conditions due to the high proportion of psychiatric medications that are inhibitors of CYP2D6 metabolism, or directly metabolised by CYP2D6. We aimed to determine the prevalence and impact of CYP2D6 phenoconversion among individuals with a psychiatric condition.

Material & Methods: Using UK Biobank data, CYP2D6 phenoconversion in those with psychiatric disorders was determined by reviewing medications to identify CYP2D6 inhibitor use and applying a standard multiplication factor to genotype-based activity scores accordingly. Findings were validated through a systematic review and meta-analysis (PROSPERO, CRD420251177663). Regression analyses were used to assess the relationship between CYP2D6 phenoconversion status and psychological distress, measured by Patient Health Questionnaire-4 (PHQ-4) scores from UK Biobank. 

Results: Seventeen percent (n=5,942) of UK Biobank participants with a psychiatric disorder (n=35,338) were subject to CYP2D6 phenoconversion because of concurrent use of a CYP2D6 inhibitor. CYP2D6 phenoconverted individuals were more likely to be female (69.7% vs 63.2%), have higher levels of co-morbidity (3.70 [SD 2.39] vs 3.55 [SD 2.32] conditions) and polypharmacy (5.76 [SD 3.39] vs 4.83 [SD 3.24] medications), all p <0.001. From 818 records, 12 studies were included in our meta-analysis, producing a pooled prevalence of 17% (n=7,498, 95% CIs:12%-24%, PIs:4%-50%, I2=98%), and 13% (n=1,633, 95% CIs:11%-15%, PIs:10%-17%, I2=24.2%), in a more homogenous adult-only subgroup. CYP2D6 phenoconversion was significantly associated with higher PHQ-4 scores (p<0.001, r=0.067) in the UK Biobank, with individuals subject to phenoconversion scoring 10% higher (IRR 1.10, 95% CIs:1.07-1.13), and having 19% greater odds of moderate-to-severe psychological distress (OR 1.19, 95% CIs:1.11-1.28).

Conclusion: CYP2D6 phenoconversion is highly prevalent in people with a psychiatric condition and is associated with worse mental health outcomes.