Drug-Induced CYP2D6 Phenoconversion Among Individuals with a Psychiatric Disorder: Prevalence and Association with Psychological Distress

CYP2D6

Drug-mediated inhibition of CYP2D6 converting the genotype-predicted metabolic phenotype into a slower one, independently of any genetic variation

Phenoconversion is the conversion of the genotype-predicted metabolic phenotype into a different one through non-genetic factors, chiefly inhibitory drugs. The authors estimated the prevalence of CYP2D6 phenoconversion in UK Biobank by applying a standard multiplication factor to genotype-based activity scores according to CYP2D6 inhibitor use. Among the 35,338 participants reporting a psychiatric or psychological disorder, 17% (n = 5,942) were estimated to be phenoconverted, with higher comorbidity and polypharmacy burdens (p < 0.001 for each). A registered meta-analysis (PROSPERO) of 12 studies found a pooled prevalence of 17% (n = 7,498, 95% CI 12-24%, I2 = 98%), falling to 13% (n = 1,633, 95% CI 11-15%, I2 = 24.2%) in a more homogeneous adult-only subgroup. Phenoconversion was associated with higher modified PHQ-4 scores (p < 0.001, r = 0.067), with scores 10% higher (IRR 1.10, 95% CI 1.07-1.13) and 19% greater odds of a high score, defined as a modified PHQ-4 of 6 or more (OR 1.19, 95% CI 1.11-1.28).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The figure to remember is the prevalence: one psychiatric patient in six has their CYP2D6 phenotype shifted by their own prescription, which is enough to make any genotype-only phenotype report misleading. The effect size on psychological distress, by contrast, is very small (r = 0.067) and allows no individual attribution of symptoms to phenoconversion. The main limitation is methodological: phenoconversion here is estimated by a multiplication factor applied to the activity score, never measured through an exposure marker.

Analysis by Dr Thibaut Benquey