Longitudinal changes in DNA methylation associated with clozapine use in treatment-resistant schizophrenia from two international cohorts.

IF 5.8 1区医学 Q1 PSYCHIATRY Translational Psychiatry Pub Date : 2024-09-27 DOI:10.1038/s41398-024-03102-8

Amy L Gillespie, Emma M Walker, Eilis Hannon, Grant A McQueen, Kyra-Verena Sendt, Alessia Avila, John Lally, Cynthia Okhuijsen-Pfeifer, Marte van der Horst, Alkomiet Hasan, Emma L Dempster, Joe Burrage, Jan Bogers, Dan Cohen, Marco P Boks, David A Collier, Alice Egerton, Jurjen J Luykx, Jonathan Mill, James H MacCabe

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Abstract

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^-5) 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.

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来自两个国际队列的耐药精神分裂症患者使用氯氮平相关的 DNA 甲基化纵向变化。

第二代抗精神病药物氯氮平是一种治疗耐药性精神分裂症的药物。在临床前啮齿类动物模型和耐药性精神分裂症的横断面研究中，氯氮平曾与表观遗传学变化有关。然而，横断面研究容易受到混杂因素的影响，而且无法区分诊断和药物治疗的影响。因此，我们对两个独立队列的耐药精神分裂症谱系障碍患者（38 人）的连续血液样本（126 份）中的 DNA 甲基化进行了分析，这些患者在加入研究后开始服用氯氮平，并接受了长达 6 个月的随访。我们发现，从 DNA 甲基化数据中得出的细胞类型比例估计值（特别是 B 细胞）与服用氯氮平的时间有明显的非线性变化。我们使用混合效应回归模型来确定与服用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 个差异甲基化位点（DMPs）（p -5），在非线性二次模型中确定了 90 个差异甲基化位点。我们将这些结果与之前的表观基因组全关联研究（EWAS）中有关精神病的荟萃分析数据进行了比较，发现有证据表明，之前发现的许多与精神分裂症和耐药精神分裂症相关的 DMPs 可能反映了氯氮平的暴露。总之，我们的研究结果表明，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，药物的影响可能会混淆许多在血液中进行的神经精神疾病病例对照研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Psychiatry PSYCHIATRY-

CiteScore

11.50

自引率

2.90%

发文量

484

审稿时长

23 weeks

期刊介绍： Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.