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Cytochrome P450 II D6 gene polymorphisms and the neuroleptic-induced extrapyramidal symptoms in Japanese schizophrenic patients

Inada, Toshiyaa d; Senoo, Hisashib; Iijima, Yoshimia; Yamauchi, Tadamitsub; Yagi, Goheic

Original Articles

Objective: The purpose of this study was to examine whether the neuroleptic-induced extrapyramidal symptoms are associated with the CYP2D6 activity.

Methods: The CYP2D6 gene polymorphisms (CYP2D6*2, CYP2D6*3, CYP2D6*4, CYP2D6*10, and CYP2D6*12) were genotyped in 196 normal controls and 320 schizophrenic patients receiving neuroleptics. The relationships with susceptibility to extrapyramidal symptoms (EPS) and tardive dyskinesia, and with steady-state serum haloperidol levels in maintenance therapy, were investigated.

Results: The allele frequency of CYP2D6*2 was significantly higher, while that of CYP2D6*10 tended to be higher in the schizophrenic patients susceptible to acute EPS. The steady-state serum haloperidol levels per daily dosage were observed to be significantly higher in schizophrenic patients with the mutant-type homozygote of CYP2D6*2, while this difference was trend level in those of CYP2D6*10. However, no significant difference was observed in the distribution of both CYP2D6*2 (C2938T) and CYP2D6*10 (C188T) polymorphisms between schizophrenic patients with or without tardive dyskinesia.

Conclusion: The present results suggest that the homozygotes of CYP2D6*2 and CYP2D6*10 appear to be a susceptibility factor for developing acute EPS in schizophrenic patients and for impaired neuroleptic metabolism in Japanese schizophrenic patients.

aNational Institute of Mental Health, National Center of Neurology and Psychiatry, Chiba, Japan

bSakuragaoka Memorial Hospital, Tokyo, Japan

cDepartment of Neuropsychiatry, Keio University, School of Medicine, Tokyo, Japan

dPresent affiliation: Department of Psychiatry and Psychobiology, Nagoya University, Graduate School of Medicine, Nagoya, Japan

Sponsorship: This study was partly supported by a grant-in-aid from the scientific fund of the Ministry of Education of Japan (No. 06770789, No. 07770817 and No. 08770805), a research grant for nervous and mental disorders from the Ministry of Health and Welfare of Japan (8A-1), a research grant from the Science and Technology Agency of Japan, and a grant from the Pharmacopsychiatry Research Foundation, Osaka, Japan.

Correspondence to Toshiya Inada, Associate Professor, Department of Psychiatry and Psychobiology, Nagoya University, Graduate School of Medicine, 65 Tsurumai, Showa-Ku, Nagoya 466-8550, Japan

Tel: +81 52 744 2284; fax: +81 52 744 2293;

e-mail: inada@med.nagoya-u.ac.jp

Received 15 July 2002 Accepted 11 November 2002

© 2003 Lippincott Williams & Wilkins, Inc.