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The Association Study of Polymorphisms in DAT, DRD2, and COMT Genes and Acute Extrapyramidal Adverse Effects in Male Schizophrenic Patients Treated With Haloperidol

Zivković, Maja MD*; Mihaljević-Peles, Alma MD, PhD; Bozina, Nada MD, PhD; Sagud, Marina MD, PhD; Nikolac-Perkovic, Matea BSc§; Vuksan-Cusa, Bjanka MD, PhD; Muck-Seler, Dorotea PhD§

Journal of Clinical Psychopharmacology: October 2013 - Volume 33 - Issue 5 - p 593–599
doi: 10.1097/JCP.0b013e31829abec9
Original Contributions

Extrapyramidal symptoms (EPSs) are common adverse effects of antipsychotics. The development of acute EPSs could depend on the activity of dopaminergic system and its gene variants. The aim of this study was to determine the association between dopaminergic type 2 receptor (DRD2) dopamine transporter (SLC6A3) and catechol-O-methyltransferase (COMT) gene polymorphisms and acute EPSs in 240 male schizophrenic patients treated with haloperidol (15-mg/d) over a period of 2 weeks. Acute EPSs were assessed with Simpson-Angus Scale. Three dopaminergic gene polymorphisms, the DRD2 Taq1A, the SLC6A3 VNTR, and the COMT Val158Met, were determined.

Extrapyramidal symptoms occurred in 116 (48.3%) of patients. Statistically significant associations were found for SLC6A3 VNTR and COMT Val158Met polymorphisms and EPS susceptibility. Patients with SLC6A3 9/10 genotype had almost twice the odds to develop EPSs compared with those with all other SLC6A3 genotypes (odds ratio, 1.9; 95% confidence interval, 1.13–3.30), and patients with COMT Val/Met genotype had 1.7 times greater odds to develop EPSs than those with all other COMT genotypes (odds ratio, 1.7; 95% confidence interval, 1.01–2.88). There was no statistically significant association between genotype and allele frequencies of DRD2, SLC6A3, or COMT polymorphisms and the development of particular EPSs.

In conclusion, the results of the present study showed for the first time the association between acute haloperidol-induced EPSs and SLC6A3 VNTR and COMT Val158Met polymorphisms. Although the precise biological mechanisms underlying these findings are not yet understood, the results suggest that the dopaminergic gene variations could predict the vulnerability to the development of the acute EPSs in haloperidol-treated schizophrenic patients.

From the *University Psychiatric Hospital Vrapce; †University of Zagreb, School of Medicine and Department of Psychiatry, ‡Department of Laboratory Diagnostics, University Hospital Centre Zagreb; and §Division of Molecular Medicine, Institute Ruder Boskovic, Zagreb, Croatia. †University of Zagreb, School of Medicine and Department of Psychiatry, and ‡Department of Laboratory Diagnostics, University Hospital Centre Zagreb; and§Division of Molecular Medicine, Institute Ruder Boskovic, Zagreb, Croatia.

Received September 7, 2012; accepted after revision January 15, 2013.

Reprints: Maja Zivković, MD, University Psychiatric Hospital Vrapce, Bolnicka cesta 32, 10 090 Zagreb, Croatia (e-mail:

Statistical analysis was carried out by Biometrika Healthcare Research, Croatia.

This study was supported by the Croatian Ministry of Science, Education and Sport (grants 108-1083509-3513, 098-0982522-2455, and 098-0982522-2457).

© 2013 by Lippincott Williams & Wilkins.