Table_1_Toward Predicting Impact of Common Genetic Variants on Schizophrenia Clinical Responses With Antipsychotics: A Quantitative System Pharmacology Study.DOCX

CNS disorders are lagging behind other indications in implementing genotype-dependent treatment algorithms for personalized medicine. This report uses a biophysically realistic computer model of an associative and dorsal motor cortico-striatal-thalamo-cortical loop and a working memory cortical model to investigate the pharmacodynamic effects of COMTVal158Met rs4680, 5-HTTLPR rs 25531 s/L and D2DRTaq1A1 genotypes on the clinical response of 7 antipsychotics. The effect of the genotypes on dopamine and serotonin dynamics and the level of target exposure for the drugs was calibrated from PET displacement studies. The simulations suggest strong gene-gene pharmacodynamic interactions unique to each antipsychotic. For PANSS Total, the D2DRTaq1 allele has the biggest impact, followed by the 5-HTTLPR rs25531. The A2A2 genotype improved efficacy for all drugs, with a more complex outcome for the 5-HTTLPR rs25531 genotype. Maximal range in PANSS Total for all 27 individual combinations is 3 (aripiprazole) to 5 points (clozapine). The 5-HTTLPR L/L with aripiprazole and risperidone and the D2DRTaq1A2A2 allele with haloperidol, clozapine and quetiapine reduce the motor side-effects with opposite effects for the s/s genotype. The COMT genotype has a limited effect on antipsychotic effect and EPS. For cognition, the COMT MM 5-HTTLPR L/L genotype combination has the best performance for all antipsychotics, except clozapine. Maximal difference is 25% of the total dynamic range in a 2-back working memory task. Aripiprazole is the medication that is best suited for the largest number of genotype combinations (10) followed by Clozapine and risperidone (6), haloperidol and olanzapine (3) and quetiapine and paliperidone for one genotype. In principle, the platform could identify the best antipsychotic treatment balancing efficacy and side-effects for a specific individual genotype. Once the predictions of this platform are validated in a clinical setting the platform has potential to support rational personalized treatment guidance in clinical practice.

中枢神经系统（Central Nervous System, CNS）疾病在实施基于基因型的个性化医疗治疗算法方面，较其他适应症仍存在滞后性。本报告采用具有生物物理逼真特性的联络与背侧运动皮层-纹状体-丘脑-皮层环路计算机模型，以及工作记忆皮层模型，探究儿茶酚-O-甲基转移酶（Catechol-O-Methyltransferase, COMT）Val158Met rs4680、5-羟色胺转运体启动子区长度多态性（5-Hydroxytryptamine Transporter Linked Polymorphic Region, 5-HTTLPR）rs25531 s/L与多巴胺D2受体（Dopamine D2 Receptor, D2DR）Taq1A1基因型对7种抗精神病药物临床应答的影响。上述基因型对多巴胺与5-羟色胺动力学的调控效应，以及药物靶点暴露水平，均通过正电子发射断层扫描（Positron Emission Tomography, PET）置换实验完成校准。模拟结果显示，每种抗精神病药物均存在特有的强烈基因-基因药效学相互作用。针对阳性与阴性症状量表（Positive and Negative Syndrome Scale, PANSS）总分而言，D2DR Taq1等位基因的影响最为显著，其次为5-HTTLPR rs25531基因型。A2A2基因型可提升所有受试药物的疗效，而5-HTTLPR rs25531基因型的效应则更为复杂。全部27种基因型组合的PANSS总分极差范围为3分（阿立哌唑组）至5分（氯氮平组）。携带5-HTTLPR L/L基因型联合阿立哌唑或利培酮，以及携带D2DR Taq1 A2A2等位基因联合氟哌啶醇、氯氮平或喹硫平，均可降低运动相关副作用；而s/s基因型则呈现相反效应。COMT基因型对抗精神病药物疗效与锥体外系症状（Extrapyramidal Symptoms, EPS）的影响较为有限。在认知功能层面，除氯氮平外，COMT MM联合5-HTTLPR L/L基因型组合对所有抗精神病药物均表现出最优的认知改善效果。在2-回溯工作记忆任务中，该组合的性能差异可达总动态范围的25%。阿立哌唑是适配最多基因型组合（共10种）的药物，其次为氯氮平与利培酮（各6种）、氟哌啶醇与奥氮平（各3种），以及喹硫平与帕利哌酮（各1种）。原则上，本研究搭建的平台可针对特定个体基因型，筛选出平衡疗效与副作用的最优抗精神病治疗方案。若该平台的预测结果在临床场景中得到验证，则有望为临床实践中的合理化个性化治疗提供决策支持。