Pharmacogenetic factors of haloperidol’s safety in adolescents experiencing acute psychotic episodes


D.V. Ivashchenko, A.Yu. Kravchenko, S.Z. Khoang, N.I. Buromskaya, P.V. Shimanov, R.V. Deitch, M.I. Nastovich, K.A. Akmalova, A.A Kachanova, L.M. Savchenko, Yu.S. Shevchenko, D.A. Sychev

1) Russian Medical Academy of Continuous Professional Education, Moscow, Russia; 2) Penza State University, Medical Institute, Penza, Russia; 3) Mental Health Research Center, Moscow, Russia; 4) Scientific-Practical Childrens and Adolescents Mental Health Center n.a. G.E. Sukhareva, Moscow, Russia
Background. Pharmacogenetic testing is an effective method of predicting the safety of pharmacotherapy. Some antipsychotics can now be prescribed based on genotyping results - for example, haloperidol. The pharmacogenetics of haloperidol safety in adolescents with an acute psychotic episode are poorly understood at this time.
Objective. To identify pharmacogenetic predictors of adverse reactions to haloperidol in adolescents with an acute psychotic
Methods. A prospective observational study included 56 adolescents diagnosed with acute polymorphic psychotic disorder. Patients were followed up for 14 days. All patients received haloperidol as their primary pharmacotherapy. Safety of psychopharmacotherapy was assessed using UKU Side Effects Rating Scale (UKU SERS), Sympson-Angus Scale (SAS), Barnes Akathisia rating scale (BARS). CYP3A4*22 (rs2740574), CYP3A5*3 (6986A>G, rs7776746), CYP2D6*4,*9 gene polymorphisms,*10 (rs3892097, rs1065852), ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642), COMT rs4680 (G>A - Val158Met), DRD3 rs6280 (C>T), DRD3 rs324026 (C>T), HTR2A rs6313 (T102C), ZNF804A rs1344706 (G>T), ANKS1B rs7968606 (C>T) were determined by real-time polymerase chain reaction (PCR). Results. Carriage of the COMT rs4680 polymorphism (Met allele) was associated with a lower severity of adverse psychiatric reactions. The presence of the HTR2A rs6313 and ZNF804A rs1344706 polymorphisms was significantly associated with a higher UKU SERS scale score. Carriers of the HTR2A rs6313 polymorphism variant (TC+CC genotypes) complained more frequently about the development of tremor (37.2 vs. 0%, p=0.009). Carriage of ABCB1 1236C>T and 2677G>T/A was more frequently associated with the presence of orthostatic vertigo (35 vs. 6.3%, p=0.028, due to nonequilibrium linkage, the data were the same for both polymorphic variants). The incidence of orthostatic vertigo was significantly higher in carriers of the ZNF804A rs1344706 polymorphism (37.5 vs. 12.5%; p=0.037). Carriers of the DRD3 rs6280 and rs324026 polymorphisms were less likely to develop «increased dream intensity.»
Conclusion. An increased risk of adverse reactions was observed in carriers of HTR2A rs6313 polymorphisms (TC+CC genotypes), ABCB1 1236C>T and 2677G>T/A, ZNF804A rs1344706. Carriage of COMT rs4680 (Met allele), DRD3 rs6280 and rs324026 was found to be associated with a lower severity of adverse reactions compared to «wild-type» genotypes.

About the Autors

Corresponding author: Dmitry V. Ivashchenko, Dr. Sci. (Med.), Acting head Department of Child Psychiatry and Psychotherapy, Leading Researcher, Research Institute of Molecular and Personalized Therapy, Russian Medical Academy of Continuing Professional Education, Moscow, Russia;

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