Department of Psychiatry, McGill University, Montreal, QC, Canada.
Behavioral Neuroscience Laboratory, University of South Santa Catarina (UNISUL), Tubarão, Brazil., Tubarão, Brazil.
Transl Psychiatry. 2024 Sep 4;14(1):359. doi: 10.1038/s41398-024-03055-y.
Rapid-acting antidepressants (RAADs), including dissociative anesthetics, psychedelics, and empathogens, elicit rapid and sustained therapeutic improvements in psychiatric disorders by purportedly modulating neuroplasticity, neurotransmission, and immunity. These outcomes may be mediated by, or result in, an acute and/or sustained entrainment of epigenetic processes, which remodel chromatin structure and alter DNA accessibility to regulate gene expression.
In this perspective, we present an overview of the known mechanisms, knowledge gaps, and future directions surrounding the epigenetic effects of RAADs, with a focus on the regulation of stress-responsive DNA and brain regions, and on the comparison with conventional antidepressants.
Preliminary correlative evidence indicates that administration of RAADs is accompanied by epigenetic effects which are similar to those elicited by conventional antidepressants. These include changes in DNA methylation, post-translational modifications of histones, and differential regulation of non-coding RNAs in stress-responsive chromatin areas involved in neurotrophism, neurotransmission, and immunomodulation, in stress-responsive brain regions. Whether these epigenetic changes causally contribute to the therapeutic effects of RAADs, are a consequence thereof, or are unrelated, remains unknown. Moreover, the potential cell type-specificity and mechanisms involved are yet to be fully elucidated. Candidate mechanisms include neuronal activity- and serotonin and Tropomyosine Receptor Kinase B (TRKB) signaling-mediated epigenetic changes, and direct interaction with DNA, histones, or chromatin remodeling complexes.
Correlative evidence suggests that epigenetic changes induced by RAADs accompany therapeutic and side effects, although causation, mechanisms, and cell type-specificity remain largely unknown. Addressing these research gaps may lead to the development of novel neuroepigenetics-based precision therapeutics.
快速作用抗抑郁药（RAADs），包括分离麻醉剂、迷幻剂和共情增强剂，据称通过调节神经可塑性、神经递质传递和免疫来快速和持续地改善精神障碍。这些结果可能是由急性和/或慢性的表观遗传过程的调节介导的，这些过程重塑染色质结构并改变 DNA 的可及性，以调节基因表达。
在本文中，我们概述了 RAADs 的表观遗传效应的已知机制、知识空白和未来方向，重点是应激反应 DNA 和大脑区域的调节，以及与传统抗抑郁药的比较。
初步的相关性证据表明，RAADs 的给药伴随着类似于传统抗抑郁药引起的表观遗传效应。这些变化包括 DNA 甲基化、组蛋白的翻译后修饰以及涉及神经发生、神经递质传递和免疫调节的应激反应染色质区域中非编码 RNA 的差异调节，以及应激反应大脑区域中的变化。这些表观遗传变化是否因果地导致 RAADs 的治疗效果，是其结果，还是与之无关，目前尚不清楚。此外，潜在的细胞类型特异性和涉及的机制尚未完全阐明。候选机制包括神经元活动和血清素和 Tropomyosine Receptor Kinase B（TRKB）信号介导的表观遗传变化，以及与 DNA、组蛋白或染色质重塑复合物的直接相互作用。
相关性证据表明，RAADs 诱导的表观遗传变化伴随着治疗效果和副作用，尽管因果关系、机制和细胞类型特异性在很大程度上仍不清楚。解决这些研究空白可能会导致新的基于神经表观遗传学的精准治疗方法的发展。
