Woodward Neil D, Jayathilake Karu, Meltzer Herbert Y
Department of Psychology, Vanderbilt University, Nashville, TN 37203, USA.
Schizophr Res. 2007 Feb;90(1-3):86-96. doi: 10.1016/j.schres.2006.10.002. Epub 2006 Nov 22.
Preliminary evidence suggests that a single nucleotide polymorphism (SNP), the val108/158met SNP, within the gene that codes for catechol-O-methyltransferase (COMT), a key enzyme involved in regulating dopamine (DA) transmission within the prefrontal cortex (PFC), is related to cognitive function in schizophrenia and cognitive improvement with atypical antipsychotic drugs (APDs). Specifically, several studies have identified an association between working memory and executive functions, and COMT val108/158met genotype in schizophrenia; although there have been several negative findings that are likely related to small sample sizes and, possibly, medication status of patients at the time of testing. The association between COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine was investigated in a relatively large prospective sample of patients with schizophrenia, most of whom were unmedicated at baseline. Patients were genotyped for the COMT val108/158met SNP after completing a cognitive battery consisting of tests of attention, working memory, verbal learning and memory, executive function, and verbal fluency at baseline and after 6 weeks and 6 months of treatment with clozapine. Consistent with several previous studies, an association between COMT genotype and tests of executive function and working memory was identified at baseline. In addition, a novel interaction between genotype and improvement on tests of attention and verbal fluency was identified. Specifically, met homozygous and val/met heterozygous patients demonstrated significantly greater improvement than val homozygous patients following 6 months of treatment with clozapine. The results are discussed in relation to previous cross-sectional studies and prospective investigations of the associations between COMT genotype, cognition, and cognitive improvement with atypical APDs in schizophrenia.
初步证据表明，儿茶酚-O-甲基转移酶（COMT）基因内的一个单核苷酸多态性（SNP），即val108/158met SNP，与精神分裂症的认知功能以及非典型抗精神病药物（APD）治疗后的认知改善有关。COMT是一种关键酶，参与调节前额叶皮质（PFC）内的多巴胺（DA）传递。具体而言，多项研究已确定精神分裂症患者的工作记忆和执行功能与COMT val108/158met基因型之间存在关联；尽管也有一些阴性结果，这可能与样本量小以及测试时患者的用药状态有关。本研究在一个相对较大的精神分裂症患者前瞻性样本中，调查了COMT val108/158met基因型、认知功能以及氯氮平治疗后的认知改善之间的关系，这些患者大多数在基线时未用药。患者在基线时以及氯氮平治疗6周和6个月后，完成了一组包括注意力、工作记忆、言语学习和记忆、执行功能以及言语流畅性测试的认知评估后，对COMT val108/158met SNP进行基因分型。与之前的多项研究一致，在基线时确定了COMT基因型与执行功能和工作记忆测试之间的关联。此外，还发现了基因型与注意力和言语流畅性测试改善之间的一种新的相互作用。具体而言，在接受氯氮平治疗6个月后，纯合子met和杂合子val/met患者的改善明显大于纯合子val患者。本文结合之前关于COMT基因型、认知以及精神分裂症患者使用非典型APD后的认知改善之间关联的横断面研究和前瞻性调查，对研究结果进行了讨论。
