East Region, Institute of Mental Health, Singapore 539747, Singapore.
Research Division, Institute of Mental Health, Singapore 539747, Singapore.
Genes (Basel). 2023 Mar 10;14(3):689. doi: 10.3390/genes14030689.
Treatment-resistant schizophrenia (TRS) is often associated with severe burden of disease, poor quality of life and functional impairment. Clozapine is the gold standard for the treatment of TRS, although it is also known to cause significant side effects in some patients. In view of the burgeoning interest in the role of genetic factors in precision psychiatry, we conducted a scoping review to narratively summarize the current genetic factors associated with TRS, clozapine resistance and side effects to clozapine treatment. We searched PubMed from inception to December 2022 and included 104 relevant studies in this review. Extant evidence comprised associations between TRS and clozapine resistance with genetic factors related to mainly dopaminergic and serotoninergic neurotransmitter systems, specifically, TRS and rs4680, rs4818 within COMT, and rs1799978 within DRD2; clozapine resistance and DRD3 polymorphisms, CYP1A2 polymorphisms; weight gain with LEP and SNAP-25 genes; and agranulocytosis risk with HLA-related polymorphisms. Future studies, including replication in larger multi-site samples, are still needed to elucidate putative risk genes and the interactions between different genes and their correlations with relevant clinical factors such as psychopathology, psychosocial functioning, cognition and progressive changes with treatment over time in TRS and clozapine resistance.
治疗抵抗性精神分裂症（TRS）常与严重的疾病负担、生活质量差和功能障碍有关。氯氮平是治疗 TRS 的金标准，但它也已知会在一些患者中引起明显的副作用。鉴于人们对遗传因素在精准精神病学中的作用越来越感兴趣，我们进行了范围综述，以叙述性总结与 TRS、氯氮平耐药和氯氮平治疗副作用相关的当前遗传因素。我们从创建到 2022 年 12 月在 PubMed 上进行了搜索，并将 104 项相关研究纳入了本综述。现有证据包括 TRS 和氯氮平耐药与主要与多巴胺能和血清素能神经递质系统相关的遗传因素之间的关联，具体而言，TRS 和 COMT 内的 rs4680、rs4818，以及 DRD2 内的 rs1799978；氯氮平耐药与 DRD3 多态性、CYP1A2 多态性；体重增加与 LEP 和 SNAP-25 基因有关；以及与 HLA 相关多态性有关的粒细胞缺乏症风险。仍需要进一步的研究，包括在更大的多地点样本中进行复制，以阐明潜在的风险基因以及不同基因之间的相互作用及其与相关临床因素（如精神病理学、心理社会功能、认知和随时间推移的治疗进展变化）的相关性，以明确 TRS 和氯氮平耐药的相关性。
