Al-Janabi Ismail, Arranz Maria J, Blakemore Alexandra I F, Saiz Pilar A, Susce Margaret T, Glaser Paul E A, Clark Daniel, de Leon Jose
Section of Genomic Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
Psychiatr Genet. 2009 Dec;19(6):305-11. doi: 10.1097/YPG.0b013e3283328dcd.
The products of the serotonin receptor genes are important targets for conventional and atypical antipsychotics, and may be relevant for antipsychotic activity and associated adverse reactions. It has been shown that the high potency at 5-HT2 receptors may also be associated with the production of moderate extrapyramidal side effects (EPS). In addition, serotonin neurotransmitter systems in the central nervous system play an important role in eating behaviours, and are involved in the symptomatology related to the metabolic syndrome, including obesity, diabetes and hyperlipidemia.
This study was designed to investigate the hypothesis that serotonin pathway genes play a part in mediating antipsychotic-induced adverse reactions, including EPS, tardive dyskinesia, obesity and diabetes. Polymorphisms in the 5-HT2A (102 (T/C), His452Tyr), 5-HT2C (Cys23Ser, -759 (C/T), -995 (G/A), TPH2 (-366 (C/T), -8933 (A/G) and 5-HTT (LPR, -15370 (A/G)) genes were investigated in a cohort of 427 US Caucasian patients undergoing antipsychotic treatment, using automated genotyping techniques.
5-HTT (LPR) and 5-HT2A (102 (T/C) polymorphisms were found to be associated with BMI (P=0.05 and 0.005, respectively). The genotype distribution of the TPH2-366 (T/C) polymorphism was found to be significantly associated with the presence of diabetes (P=0.01). A trend towards an association (P=0.07) between the 5-HT2C Cys23Ser polymorphism and tardive dyskinesia was found when age, duration of treatment, dose and sex were considered. Genotype distributions of the 5-HT2C -995 (G/A), 5-HT2C -759 (C/T) and 5-HT2A His452Tyr polymorphisms differed among patients presenting EPS and those without (P=0.08, 0.06 and 0.08, respectively). No other statistically significant associations were observed.
Serotonergic polymorphism may play a moderate role in the development of side effects associated with antipsychotic treatment.
血清素受体基因的产物是传统和非典型抗精神病药物的重要靶点，可能与抗精神病活性及相关不良反应有关。研究表明，对5-HT2受体的高效能作用也可能与中度锥体外系副作用（EPS）的产生有关。此外，中枢神经系统中的血清素神经递质系统在进食行为中起重要作用，并参与与代谢综合征相关的症状，包括肥胖、糖尿病和高脂血症。
本研究旨在探讨血清素途径基因在介导抗精神病药物引起的不良反应（包括EPS、迟发性运动障碍、肥胖和糖尿病）中发挥作用的假说。使用自动基因分型技术，对427名接受抗精神病治疗的美国白种人患者队列中的5-HT2A（102（T/C），His452Tyr）、5-HT2C（Cys23Ser，-759（C/T），-995（G/A））、TPH2（-366（C/T），-8933（A/G））和5-HTT（LPR，-15370（A/G））基因的多态性进行了研究。
发现5-HTT（LPR）和5-HT2A（102（T/C）多态性分别与体重指数相关（P值分别为0.05和0.005）。发现TPH2 -366（T/C）多态性的基因型分布与糖尿病的存在显著相关（P = 0.01）。在考虑年龄、治疗持续时间、剂量和性别时，发现5-HT2C Cys23Ser多态性与迟发性运动障碍之间存在关联趋势（P = 0.07）。出现EPS的患者和未出现EPS的患者之间，5-HT2C -995（G/A）、5-HT2C -759（C/T）和5-HT2A His452Tyr多态性的基因型分布存在差异（P值分别为0.08、0.06和0.08）。未观察到其他具有统计学意义的关联。
血清素能多态性可能在抗精神病治疗相关副作用的发生中起一定作用。
