Basile V S, Ozdemir V, Masellis M, Walker M L, Meltzer H Y, Lieberman J A, Potkin S G, Alva G, Kalow W, Macciardi F M, Kennedy J L
Neurogenetics Section, Clarke Division, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, ON, Canada.
Mol Psychiatry. 2000 Jul;5(4):410-7. doi: 10.1038/sj.mp.4000736.
Tardive dyskinesia (TD) is a common and potentially irreversible side effect associated with long-term treatment with typical antipsychotics. Approximately, 80% or more of patients with schizophrenia are smokers. Smoking is a potent inducer of the CYP1A2 enzyme, and is known to cause a significant decrease in plasma concentrations of some antipsychotics. Therefore, person-to-person differences in the extent of CYP1A2 induction by smoking may contribute to risk for the development of TD. Recently, a (C-->A) genetic polymorphism in the first intron of the CYP1A2 gene was found to be associated with variation in CYP1A2 inducibility in healthy volunteer smokers. The aim of this study was to test the clinical importance of the (C-->A) polymorphism in CYP1A2 in relation to TD severity. A total of 85 patients with schizophrenia were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS), and were subsequently genotyped for the (C-->A) polymorphism in CYP1A2. The mean AIMS score in patients with the (C/C) genotype (associated with reduced CYP1A2 inducibility) was 2.7- and 3.4-fold greater than in those with the (A/C) or (A/A) genotype, respectively (F[2,82] = 7.4, P = 0.0007). Further, a subanalysis in the 44 known smokers in our sample, revealed a more pronounced effect. The means AIMS score in smokers was 5.4- and 4. 7-fold greater in (C/C) homozygotes when compared to heterozygotes and (A/A) homozygotes, respectively (F[2,41] = 3.7, P = 0.008). These data suggest that the (C-->A) genetic polymorphism in the CYP1A2 gene may serve as a genetic risk factor for the development of TD in patients with schizophrenia. Further studies in independent samples are warranted to evaluate the applicability of our findings to the general patient population receiving antipsychotic medications.
迟发性运动障碍（TD）是一种常见且可能不可逆的副作用，与使用典型抗精神病药物进行长期治疗有关。大约80%或更多的精神分裂症患者是吸烟者。吸烟是CYP1A2酶的强效诱导剂，已知会导致某些抗精神病药物的血浆浓度显著降低。因此，吸烟对CYP1A2诱导程度的个体差异可能会导致TD发生的风险。最近，发现CYP1A2基因第一个内含子中的（C→A）基因多态性与健康志愿者吸烟者中CYP1A2诱导性的变化有关。本研究的目的是测试CYP1A2中（C→A）多态性与TD严重程度相关的临床重要性。使用异常不自主运动量表（AIMS）对总共85名精神分裂症患者的TD严重程度进行评估，随后对CYP1A2中的（C→A）多态性进行基因分型。（C/C）基因型（与CYP1A2诱导性降低相关）患者的平均AIMS评分分别比（A/C）或（A/A）基因型患者高2.7倍和3.4倍（F[2,82]=7.4，P=0.0007）。此外，对我们样本中的44名已知吸烟者进行的亚分析显示出更明显的效果。吸烟者中（C/C）纯合子的平均AIMS评分分别比杂合子和（A/A）纯合子高5.4倍和4.7倍（F[2,41]=3.7，P=0.008）。这些数据表明，CYP1A2基因中的（C→A）基因多态性可能是精神分裂症患者发生TD的遗传风险因素。有必要在独立样本中进行进一步研究，以评估我们的发现对接受抗精神病药物治疗的一般患者群体的适用性。
