Genetic Testing is Superior Over Endogenous Pharmacometabolomic Markers to Predict Safety of Haloperidol in Patients with Alcohol-induced Psychotic Disorder

Background: Previous studies have shown that haloperidol biotransformation is mainly metabolized by CYP2D6. The CYP2D6 gene is highly polymorphic, contributing to inter-individual differences in enzymatic activity, and may impact haloperidol biotransformation rates, resulting in variable drug efficacy and safety profiles. Objective: The study aimed to investigate the correlation of the CYPD6 activity with haloperidol's efficacy and safety rates in patients with alcohol-induced psychotic disorders. Methods: One hundred male patients received 5-10 mg/day haloperidol by injections for 5 days. The efficacy and safety assessments were performed using PANSS, UKU, and SAS-validated psychometric scales. Results: No relationship between haloperidol efficacy or safety and the experimental endogenous pharmacometabolomic marker for CYP2D6 activity, urinary 6-HO-THBC/pinoline ratio was identified. In contrast, we found a statistically significant association between haloperidol adverse events and the most common CYP2D6 loss-of-function allele CYP2D6*4 (p<0.001). Conclusion: Evaluation of the single polymorphism rs3892097 that defines CYP2D6*4 can predict the safety profile of haloperidol in patients with AIPD, whereas metabolic evaluation using an endogenous marker was not a suitable predictor. Furthermore, our results suggest haloperidol dose reductions could be considered in AIPD patients with at least one inactive CYP2D6 allele.