Genetic testing is superior over endogenous pharmacometabolomic markers to predict safety of haloperidol in patients with alcohol-induced psychotic disorder

Valentin Skryabin; Mikhail Zastrozhin; Alexandra Parkhomenko; Volker M Lauschke; Valery Smirnov; Aleksey Petukhov; Elena Pankratenko; Sergei Pozdnyakov; Sergei Koporov; Natalia Denisenko; Kristina Akmalova; Evgeny Bryun; Dmitry Sychev

doi:10.2174/1389200224666221228112643

Genetic testing is superior over endogenous pharmacometabolomic markers to predict safety of haloperidol in patients with alcohol-induced psychotic disorder

Curr Drug Metab. 2022 Dec 28. doi: 10.2174/1389200224666221228112643. Online ahead of print.

Authors

Valentin Skryabin^{1

2}, Mikhail Zastrozhin^{1

2

3}, Alexandra Parkhomenko², Volker M Lauschke^{4

5

6}, Valery Smirnov^{7

8}, Aleksey Petukhov^{1

7}, Elena Pankratenko¹, Sergei Pozdnyakov¹, Sergei Koporov¹, Natalia Denisenko², Kristina Akmalova², Evgeny Bryun^{1

2}, Dmitry Sychev²

Affiliations

¹ Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, 37/1 Lyublinskaya street, Moscow, Russia, 109390.
² Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, 2/1 Barrikadnaya street, Moscow, Russian Federation, 123995.
³ University of California, San Francisco, 1701 Divisadero St, San Francisco, CA 94115, USA.
⁴ Karolinska Institutet, Department of Physiology and Pharmacology, Solnavägen 1, 171 77 Solna, Sweden.
⁵ Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstraße 112, 70376 Stuttgart, Germany.
⁶ University of Tuebingen, Geschwister-Scholl-Platz, 72074 Tuebingen, Germany.
⁷ I.M. Sechenov First Moscow State Medical University (Sechenov University), 8с2 Trubetskaya street, Moscow, Russian Federation, 119991.
⁸ NRC Institute of Immunology FMBA of Russia, 24 Kashirskoe shosse, Moscow, Russian Federation, 115478.

PMID: 36579390
DOI: 10.2174/1389200224666221228112643

Abstract

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.

Method: 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-НО-ТНВС/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.

Keywords: Alcohol-induced psychotic disorder; Alcoholic hallucinosis; CYP2D6; Haloperidol.; Personalized medicine; Pharmacogenetic.