Bertolino Alessandro, Caforio Grazia, Blasi Giuseppe, De Candia Mariapia, Latorre Valeria, Petruzzella Vittoria, Altamura Mario, Nappi Gaetano, Papa Sergio, Callicott Joseph H, Mattay Venkata S, Bellomo Antonello, Scarabino Tommaso, Weinberger Daniel R, Nardini Marcello
Dipartimento di Scienze Neurologiche e Psichiatriche, Universita' degli Studi di Bari, Piazza Giulio Cesare-9, 70124, Bari, Italy.
Am J Psychiatry. 2004 Oct;161(10):1798-805. doi: 10.1176/ajp.161.10.1798.
Deficits in working memory and in prefrontal cortical physiology are important outcome measures in schizophrenia, and both have been associated with dopamine dysregulation and with a functional polymorphism (Val(108/158)Met) in the catechol O-methyltransferase (COMT) gene that affects dopamine inactivation in the prefrontal cortex. The purpose of the present study was to evaluate in patients with schizophrenia the effect of COMT genotype on symptom variation, working memory performance, and prefrontal cortical physiology in response to treatment with an atypical antipsychotic drug.
Thirty patients with acute untreated schizophrenia were clinically evaluated with the Positive and Negative Syndrome Scale, underwent COMT Val/Met genotyping, and entered an 8-week prospective study of olanzapine treatment. Twenty patients completed two 3-T functional magnetic resonance imaging scans at 4 and 8 weeks during performance of N-back working memory tasks.
There was a significant interaction of COMT genotype and the effects of olanzapine on prefrontal cortical function. Met allele load predicted improvement in working memory performance and prefrontal physiology after 8 weeks of treatment. A similar effect was found also for negative symptoms assessed with the Positive and Negative Syndrome Scale.
These results suggest that a genetically determined variation in prefrontal dopamine catabolism impacts the therapeutic profile of olanzapine.
工作记忆缺陷和前额叶皮质生理学异常是精神分裂症重要的结局指标，二者均与多巴胺调节异常以及儿茶酚-O-甲基转移酶（COMT）基因的一个功能性多态性（Val(108/158)Met）有关，该基因影响前额叶皮质中多巴胺的失活。本研究旨在评估精神分裂症患者中COMT基因型对非典型抗精神病药物治疗反应的症状变化、工作记忆表现及前额叶皮质生理学的影响。
30例未经治疗的急性精神分裂症患者接受阳性和阴性症状量表临床评估，进行COMT Val/Met基因分型，并进入一项为期8周的奥氮平治疗前瞻性研究。20例患者在执行N-回溯工作记忆任务期间，于第4周和第8周完成两次3-T功能磁共振成像扫描。
COMT基因型与奥氮平对前额叶皮质功能的影响之间存在显著交互作用。Met等位基因负荷预测了治疗8周后工作记忆表现和前额叶生理学的改善。用阳性和阴性症状量表评估的阴性症状也发现了类似效果。
这些结果表明，前额叶多巴胺分解代谢的基因决定变异影响奥氮平的治疗特征。
