Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Transl Psychiatry. 2024 Sep 27;14(1):390. doi: 10.1038/s41398-024-03102-8.
The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle the effects of diagnosis and medication. We therefore profiled DNA methylation in sequential blood samples (n = 126) from two independent cohorts of patients (n = 38) with treatment-resistant schizophrenia spectrum disorders who commenced clozapine after study enrolment and were followed up for up to six months. We identified significant non-linear changes in cell-type proportion estimates derived from DNA methylation data - specifically B-cells - associated with time on clozapine. Mixed effects regression models were used to identify changes in DNA methylation at specific sites associated with time on clozapine, identifying 37 differentially methylated positions (DMPs) (p < 5 × 10) in a linear model and 90 DMPs in a non-linear quadratic model. We compared these results to data from our previous epigenome-wide association study (EWAS) meta-analysis of psychosis, finding evidence that many previously identified DMPs associated with schizophrenia and treatment-resistant schizophrenia might reflect exposure to clozapine. In conclusion, our results indicate that clozapine exposure is associated with changes in DNA methylation and cellular composition. Our study shows that medication effects might confound many case-control studies of neuropsychiatric disorders performed in blood.
第二代抗精神病药氯氮平被用作治疗耐药性精神分裂症的药物。它以前与临床前啮齿动物模型和治疗耐药性精神分裂症的横断面研究中的表观遗传变化有关。然而，横断面研究容易受到混杂因素的影响，无法区分诊断和药物治疗的影响。因此，我们对两个独立的治疗耐药性精神分裂症谱系障碍患者队列（n=38）的序贯血液样本（n=126）进行了 DNA 甲基化分析，这些患者在研究入组后开始使用氯氮平，并在最多 6 个月的时间内进行了随访。我们从 DNA 甲基化数据中发现了与氯氮平时间相关的细胞类型比例估计值的显著非线性变化-特别是 B 细胞。混合效应回归模型用于识别与氯氮平时间相关的特定位点的 DNA 甲基化变化，在线性模型中确定了 37 个差异甲基化位置（DMP）（p<5×10），在非线性二次模型中确定了 90 个 DMP。我们将这些结果与我们之前的精神病全基因组关联研究（EWAS）荟萃分析的数据进行了比较，发现有证据表明，许多以前与精神分裂症和治疗耐药性精神分裂症相关的 DMP 可能反映了氯氮平的暴露。总之，我们的结果表明，氯氮平暴露与 DNA 甲基化和细胞组成的变化有关。我们的研究表明，药物治疗的影响可能会混淆许多在血液中进行的神经精神疾病的病例对照研究。
