Data_Sheet_5_Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD.CSV

BackgroundPrevious research has demonstrated that epigenetic changes in specific hypothalamic-pituitary-adrenal (HPA) genes may predict successful psychotherapy in post-traumatic stress disorder (PTSD). A recent Phase 3 clinical trial reported high efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for treating patients with severe PTSD compared to a therapy with placebo group (NCT03537014). This raises important questions regarding potential mechanisms of MDMA-assisted therapy. In the present study, we examined epigenetic changes in three key HPA axis genes before and after MDMA and placebo with therapy. As a pilot sub-study to the parent clinical trial, we assessed potential HPA epigenetic predictors for treatment response with genomic DNA derived from saliva (MDMA, n = 16; placebo, n = 7). Methylation levels at all 259 CpG sites annotated to three HPA genes (CRHR1, FKBP5, and NR3C1) were assessed in relation to treatment response as measured by the Clinician-Administered PTSD Scale (CAPS-5; Total Severity Score). Second, group (MDMA vs. placebo) differences in methylation change were assessed for sites that predicted treatment response.
ResultsMethylation change across groups significantly predicted symptom reduction on 37 of 259 CpG sites tested, with two sites surviving false discovery rate (FDR) correction. Further, the MDMA-treatment group showed more methylation change compared to placebo on one site of the NR3C1 gene.
ConclusionThe findings of this study suggest that therapy-related PTSD symptom improvements may be related to DNA methylation changes in HPA genes and such changes may be greater in those receiving MDMA-assisted therapy. These findings can be used to generate hypothesis driven analyses for future studies with larger cohorts.

背景 既往研究表明，特定下丘脑-垂体-肾上腺（hypothalamic-pituitary-adrenal, HPA）基因的表观遗传改变，可预测创伤后应激障碍（post-traumatic stress disorder, PTSD）患者的心理治疗疗效。近期一项3期临床试验报道，与安慰剂辅助治疗组相比，3,4-亚甲二氧基甲基苯丙胺（3,4-methylenedioxymethamphetamine, MDMA）辅助疗法治疗重度PTSD患者的疗效显著（临床试验编号：NCT03537014）。这一结果引出了关于MDMA辅助疗法潜在作用机制的重要问题。本研究针对MDMA辅助治疗与安慰剂辅助治疗前后的3种关键HPA轴基因的表观遗传改变进行了分析。作为主体临床试验的先导子研究，我们基于唾液来源的基因组DNA，评估了HPA表观遗传标记对治疗应答的预测潜力（MDMA组：n=16；安慰剂组：n=7）。我们针对注释于CRHR1、FKBP5及NR3C1这3种HPA基因的全部259个CpG位点的甲基化水平，结合临床医师评定的创伤后应激障碍量表（Clinician-Administered PTSD Scale, CAPS-5）总严重程度评分所衡量的治疗应答进行了分析。其次，我们针对与治疗应答相关的位点，评估了组间（MDMA组vs.安慰剂组）的甲基化变化差异。
结果 在所检测的259个CpG位点中，跨组的甲基化变化可显著预测其中37个位点对应的症状减轻，其中2个位点通过了错误发现率（false discovery rate, FDR）校正。进一步分析显示，在NR3C1基因的1个位点上，MDMA治疗组的甲基化变化幅度显著高于安慰剂组。
结论 本研究结果表明，与治疗相关的PTSD症状改善可能与HPA基因的DNA甲基化改变有关，且接受MDMA辅助疗法的患者此类甲基化变化更为显著。上述发现可为未来纳入更大队列的研究提供假说驱动的分析方向。