Association of CYP2D6*4 Polymorphism with the Steady-State Concentration of Haloperidol in Patients with Alcohol-Induced Psychotic Disorders

A A Parkhomenko; M S Zastrozhin; S A Pozdnyakov; V V Noskov; I A Zaytsev; V A Ivanchenko; N P Denisenko; K A Akmalova; VYu Skryabin; E A Bryun; D A Sychev

Association of ***CYP2D6*4*** Polymorphism with the Steady-State Concentration of Haloperidol in Patients with Alcohol-Induced Psychotic Disorders

Psychopharmacol Bull. 2022 Oct 27;52(4):52-60.

Authors

A A Parkhomenko¹, M S Zastrozhin², S A Pozdnyakov³, V V Noskov⁴, I A Zaytsev⁵, V A Ivanchenko⁶, N P Denisenko⁷, K A Akmalova⁸, VYu Skryabin⁹, E A Bryun¹⁰, D A Sychev¹¹

Affiliations

¹ Parkhomenko, postgraduate student of addiction psychiatry department.
² Zastrozhin, MD, PhD, associate professor of addiction psychiatry department, head of laboratory of genetics and fundamental studies, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation; Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia; University of California, San Francisco, San Francisco, CA, USA.
³ Pozdnyakov, researcher of the laboratory of genetics and fundamental studies.
⁴ Noskov, laboratory assistants, Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia.
⁵ Zaytsev, laboratory assistants, Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia.
⁶ Ivanchenko, laboratory assistants, Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia.
⁷ Denisenko, PhD in Medicine, Head of the Department of Personalized Medicine.
⁸ Akmalova, Researcher in the Department of Molecular Medicine.
⁹ Skryabin, MD, PhD, associate professor of addiction psychiatry department, head of clinical department.
¹⁰ Bryun, MD, PhD, professor, head of addiction psychiatry department, president, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation; Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russia.
¹¹ Sychev, corresponding member of the Academy of Sciences of Russia, MD, PhD, professor, rector, head of clinical pharmacology and therapy department, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation.

PMID: 36339274
PMCID: PMC9611797

Abstract

Background: CYP2D6 subfamily isoenzymes play an important role in the biotransformation of haloperidol, and their activity may influence the efficacy and safety of haloperidol. The use of haloperidol is often associated with the occurrence of adverse drug reactions (ADRs), such as dyskinesia, acute dystonia, and orthostatic hypotension. Previous studies have demonstrated the relationship between the CYP2D6*4 genetic polymorphism and CYP2D6 activity, as well as haloperidol efficacy and safety rates.

Purpose: To evaluate the association of CYP2D6*4 genetic polymorphism with the steady-state concentration of haloperidol in patients with acute alcohol-induced psychotic disorders (AIPDs).

Material and methods: The study involved 100 male patients with AIPD (average age 41.4 ± 14.4 years) who received haloperidol by injections in a dose of 5-10 mg/day. The efficacy profile was assessed using a validated psychometric PANSS scale (Positive and Negative Syndrome Scale). Therapy safety was assessed using the internationally validated UKU (Side-Effect Rating Scale) and SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scales. Genotyping was performed with the real-time polymerase chain reaction.

Results: We revealed the statistically significant results in terms of therapy safety evaluation (dynamics of the UKU scores: (GG) 8.00 [7.00; 10.00], (GA) 15.0 [9.25; 18.0], p < 0.001; dynamics of the SAS scores: (GG) 11.0 [9.0; 14.0], (GA) 14.50 [12.0; 18.0], p < 0.001. Pharmacokinetic study showed a statistically significant difference across the groups with different genotypes: (GG) 3.13 [2.32; 3.95], (GA) 3.89 [2.92; 5.26], p = 0.010.

Conclusion: It can be concluded that patients with the GA genotype have a higher risk of ADRs compared to patients who carry the GG genotype. It was shown that CYP2D6*4 genetic polymorphism has a statistically significant effect on the steady-state concentration of haloperidol.

Keywords: CYP2D6; alcohol-induced psychotic disorders; haloperidol; personalized medicine; pharmacogenetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antipsychotic Agents* / therapeutic use
Cytochrome P-450 CYP2D6 / genetics
Cytochrome P-450 CYP2D6 / metabolism
Genotype
Haloperidol / adverse effects
Haloperidol / pharmacokinetics
Humans
Male
Middle Aged
Polymorphism, Genetic
Psychoses, Alcoholic* / drug therapy
Psychotic Disorders* / drug therapy
Psychotic Disorders* / genetics

Substances

Haloperidol
Cytochrome P-450 CYP2D6
Antipsychotic Agents