CYP2D6 Phenotype as a Predictor of Adverse Drug Reactions in Patients Treated With Trazodone: An Explorative Pharmacogenetic Study.

Purpose
Trazodone is metabolized by CYP3A4 to the active metabolite meta-chlorophenylpiperazine (mCPP), which is associated with various adverse drug reactions (ADRs). mCPP is further inactivated by CYP2D6. Despite the knowledge of trazodone metabolism, the evidence regarding the impact of pharmacogenetics remains limited. This study aimed to examine the association between pharmacogenetic variants in genes involved in the metabolism of trazodone and the occurrence of ADRs during trazodone treatment.Methods
We performed an explorative observational study using available data and serum samples from 2 ongoing pharmacogenetic studies. For patients treated with trazodone, we analyzed information on trazodone tolerability, genetic variants in CYP2D6, CYP3A5, and ABCB1, as well as co-medications to assess potential drug-drug-gene interactions (phenoconversion). Serum levels of mCPP and trazodone were measured in a subset of patients.Results
Data from 98 patients were analyzed. Reduced CYP2D6 activity was associated with an increased risk of ADRs during trazodone therapy. After accounting for phenoconversion and adjusting for sex, trazodone dose, and CYP3A5 phenotype, CYP2D6 poor metabolizers were found to be more likely to develop ADRs compared with normal metabolizers (OR: 8.96; 95% CI=1.67-48.08). No association with ADRs was found for genetic variants in CYP3A5 and ABCB1. Subgroup analysis revealed that reduced CYP2D6 activity was associated with a higher mCPP-to-trazodone ratio and a greater tendency for ADRs.Conclusions
Our findings suggest that mCPP could contribute to trazodone-related ADRs, especially in individuals with reduced CYP2D6 metabolism. Larger clinical studies are needed to confirm that CYP2D6 genotyping could contribute to preventing ADRs in clinical practice.