Antipsychotic medications are essential when treating schizophrenia spectrum and other psychotic disorders, but the efficacy and tolerability of these medications vary from person to person. This interindividual variation is likely mediated, at least in part, by epigenomic processes that have yet to be fully elucidated. Herein, we systematically identified and evaluated 65 studies that examine the influence of antipsychotic drugs on epigenomic changes, including global methylation (9 studies), genome-wide methylation (22 studies), candidate gene methylation (16 studies), and histone modification (18 studies). Our evaluation revealed that haloperidol was consistently associated with increased global hypermethylation, which corroborates with genome-wide analyses, mostly performed by methylation arrays. In contrast, clozapine seems to promote hypomethylation across the epigenome. Candidate-gene methylation studies reveal varying effects post-antipsychotic therapy. Some genes like Glra1 and Drd2 are frequently found to undergo hypermethylation, whereas other genes such as SLC6A4, DUSP6, and DTNBP1 are more likely to exhibit hypomethylation in promoter regions. In examining histone modifications, the literature suggests that clozapine changes histone methylation patterns in the prefrontal cortex, particularly elevating H3K4me3 at the Gad1 gene and affecting the transcription of genes like mGlu2 by modifying histone acetylation and interacting with HDAC2 enzymes. Risperidone and quetiapine, however, exhibit distinct impacts on histone marks across different brain regions and cell types, with risperidone reducing H3K27ac in the striatum and quetiapine modifying global H3K9me2 levels in the prefrontal cortex, suggesting antipsychotics demonstrate selective influence on histone modifications, which demonstrates a complex and targeted mode of action. While this review summarizes current knowledge, the intricate dynamics between antipsychotics and epigenetics clearly warrant more exhaustive exploration with the potential to redefine our understanding and treatment of psychiatric conditions. By deciphering the epigenetic changes associated with drug treatment and therapeutic outcomes, we can move closer to personalized medicine in psychiatry.

在治疗精神分裂症谱系和其他精神障碍时，抗精神病药物是必不可少的，但这些药物的疗效和耐受性因人而异。这种个体间变异可能至少部分是由尚未完全阐明的表观基因组过程介导的。在此，我们系统地确定并评价了 65 项研究抗精神病药物对表观基因组变化的影响，包括整体甲基化 （9 项研究）、全基因组甲基化 （22 项研究）、候选基因甲基化 （16 项研究） 和组蛋白修饰 （18 项研究）。我们的评估显示，氟哌啶醇始终与整体高甲基化增加相关，这与主要由甲基化阵列进行的全基因组分析相吻合。相比之下，氯氮平似乎促进整个表观基因组的低甲基化。候选基因甲基化研究揭示了抗精神病药物治疗后的不同影响。一些基因（如 Glra1 和 Drd2）经常被发现发生高甲基化，而其他基因（如 SLC6A4、DUSP6 和 DTNBP1）更有可能在启动子区域表现出低甲基化。在检查组蛋白修饰时，文献表明氯氮平改变了前额叶皮层的组蛋白甲基化模式，特别是提高了 Gad1 基因的 H3K4me3，并通过修饰组蛋白乙酰化和与 HDAC2 酶相互作用来影响 mGlu2 等基因的转录。 然而，利培酮和喹硫平对不同大脑区域和细胞类型的组蛋白标志物表现出不同的影响，利培酮减少纹状体中的 H3K27ac，喹硫平改变前额叶皮层的整体 H3K9me2 水平，表明抗精神病药对组蛋白修饰表现出选择性影响，这展示了一种复杂且靶向的作用模式。虽然这篇综述总结了当前的知识，但抗精神病药和表观遗传学之间错综复杂的动态显然需要更详尽的探索，有可能重新定义我们对精神疾病的理解和治疗。通过破译与药物治疗和治疗结果相关的表观遗传变化，我们可以更接近精神病学中的个性化医学。