Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder

Mikhail Sergeevich Zastrozhin; Vadim Markovich Brodyansky; Valentin Yurievich Skryabin; Elena Anatolievna Grishina; Dmitry Vladimirovich Ivashchenko; Kristina Anatolievna Ryzhikova; Ludmila Mikhaylovna Savchenko; Alexander Olegovich Kibitov; Evgeny Alekseevich Bryun; Dmitry Alekseevich Sychev

doi:10.2147/PGPM.S140700

Pharmacodynamic genetic polymorphisms affect adverse drug reactions of haloperidol in patients with alcohol-use disorder

Pharmgenomics Pers Med. 2017 Jul 7:10:209-215. doi: 10.2147/PGPM.S140700. eCollection 2017.

Affiliations

¹ Department of Addictology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russia.
² Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Center for the Prevention of Dependent Behavior, Moscow, Russia.
³ Federal Medical Research Centre of Psychiatry and Addictology, Laboratory of Molecular Genetics, Moscow, Russia.
⁴ Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Department of Addictology, Moscow, Russia.
⁵ Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Research Centre, Moscow, Russia.
⁶ Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Department of Clinical Pharmacology and Therapy, Moscow, Russia.

Abstract

Background: Antipsychotic action of haloperidol is due to blockade of D₂ receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D₂ receptor blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-methyltransferase [COMT], glycine transporter and gene encoding the density of D₂ receptors on the neuronal membrane) are described.

Objective: The objectives of this study were to evaluate the correlation between DRD2, SLC6A3 (DAT) and COMT genetic polymorphisms and to investigate their effect on the development of adverse drug reactions in patients with alcohol-use disorder who received haloperidol.

Patients and methods: The study included 64 male patients (average age 41.38 ± 10.14 years, median age 40 years, lower quintile [LQ] 35 years, upper quintile [UQ] 49 years). Bio-Rad CFX Manager™ software and "SNP-Screen" sets of "Syntol" (Russia) were used to determine polymorphisms rs4680, rs1800497, rs1124493, rs2242592, rs2298826 and rs2863170. In every "SNP-Screen" set, two allele-specific hybridizations were used, which allowed to determine two alleles of studied polymorphism separately on two fluorescence channels.

Results: Results of this study detected a statistically significant difference in the adverse drug reaction intensity in patients receiving haloperidol with genotypes 9/10 and 10/10 of polymorphic marker SLC6A3 rs28363170. In patients receiving haloperidol in tablets, the increases in the UKU Side-Effect Rating Scale (UKU) score of 9.96 ± 2.24 (10/10) versus 13 ± 2.37 (9/10; p < 0.001) and in the Simpson-Angus Scale (SAS) score of 5.04 ± 1.59 (10/10) versus 6.41 ± 1.33 (9/10; p = 0.006) were revealed.

Conclusion: Polymorphism of the SCL6A3 gene can affect the safety of haloperidol, and this should be taken into account during the choice of drug and its dosage regimen.

Keywords: COMT; DAT; DRD2; alcohol addiction; alcohol-use disorder; haloperidol; pharmacogenetics.