Resistance Exercise to Treat Major Depression via Cerebrovascular Mechanisms: Confirming Efficacy and Informing Precision Medicine

严重抑郁障碍(MDD)的一线治疗，包括心理治疗和药物治疗， 疗效有限，一年后常规护理治疗成功率仅为29%。缓解率 如果能够优化治疗，并将治疗处方给那些最有可能受益的人，抑郁将会加剧。 迫切需要开发和测试治疗MDD的新的、有效的治疗方法，同时努力 优化他们的福利。阻力运动训练(RET)是一种有希望但研究不足的治疗方法 接近。我们最近的荟萃分析发现，在少数几个非常小的试验中，RET有很大的抗抑郁作用 临床抑郁样本(d=0.90)，突出了RET治疗MDD的潜力。这些试验，虽然 没有能力确定临床上有意义的影响，显示出积极的结果，并为 更大的机械信息试验，以确认其有希望的早期效果。重要的是，脑血流量 在患有MDD的成年人中，RET的水平较低，与治疗反应差有关，RET可以改善 成年人。因此，RET可能通过改善脑血流来治疗MDD。然而，机械途径 到目前为止，RET的抗抑郁作用与MDD患者脑血流改善之间的联系尚未得到验证。此外，有了 机器学习的进展，识别临床和机制的可修改和稳定的预测因子 改变和坚持可以为未来治疗MDD的精准医学倡议提供信息。因此，审判是为了 确认RET治疗MDD的疗效，了解其潜在的脑血管机制，揭示 迫切需要对其影响进行可修改的预测。为此，我们提出了1：1的确证效力。 随机对照试验(n=200)：16周进行性RET或小剂量RET(SHAM)治疗成人 DSM-5诊断为MDD。目标1将证实RET与SHAM在16岁时对抑郁症状的疗效 两周，并评估RET在8、26和52周的潜在更快和更持久的效果。目标2将 确定RET与Sham对脑血流速度和搏动的机械指标的影响 它们对抗抑郁疗效的潜在调节作用。目标3将使用有监督的机器学习工具来预测 抑郁改变、脑血管改变和参与者依从性。完成后，这项研究将 朝着我们的长期目标--识别和转换机械驱动的行为治疗--而努力 通过确定一个有希望的、可获得的、 可翻译性RET可通过改善脑血管功能来治疗MDD。同时，这个项目 将为未来的精准医学方法提供信息，这些方法将针对治疗反应的可修改预测因素 以及坚持行为干预，以优化MDD治疗并个别开出处方 那些最有可能受益的人。如果RET有效地治疗MDD，这项试验将为RET作为一种 MDD的单独治疗，并可能作为单独或强化治疗以减少 普遍存在的情绪障碍和严重精神疾病的负担。

Frontline treatments for major depressive disorder (MDD), including psycho- and pharmacotherapy, have limited effectiveness, with usual care treatment success at just 29% after 1 year. Remission rates for depression would be enhanced if treatments could be optimized and prescribed to those most likely to benefit. There is a critical need to develop and test novel, efficacious treatments for MDD and simultaneously work to optimize their benefits. Resistance exercise training (RET) is a promising but understudied treatment approach. Our recent meta-analysis found a large antidepressant effect of RET in the few very small trials with clinically depressed samples (d=0.90), highlighting the potential of RET for treating MDD. These trials, while underpowered to determine clinically meaningful effects, showed positive results and provide the foundation for larger mechanistically-informed trials to confirm their promising early effects. Importantly, cerebral blood flow is lower in adults with MDD, linked with a poor treatment response, and RET can improve cerebral blood flow in adults. As such, RET may treat MDD via improving cerebral blood flow. However, the mechanistic pathway linking RET’s antidepressant effects to improved cerebral blood flow in MDD is as-of-yet untested. Further, with advances in machine learning, the identification of modifiable and stable predictors of clinical and mechanistic change as well as adherence can inform future precision medicine initiatives for treating MDD. Thus, a trial to confirm the efficacy of RET for MDD, understand its potential cerebrovascular mechanisms, and uncover the modifiable predictors of its effects is urgently needed. Toward this end, we propose a confirmatory efficacy 1:1 randomized controlled trial (n=200) of 16 weeks of progressive RET or low dose RET (SHAM) in adults with DSM-5 diagnosed MDD. Aim 1 will confirm the efficacy of RET vs SHAM on depressive symptoms at 16 weeks, and evaluate both potentially quicker and enduring effects of RET at 8, 26 and 52 weeks. Aim 2 will determine the effect of RET vs. SHAM on the mechanistic target of cerebral blood velocity and pulsatility and their potential mediation of antidepressant efficacy. Aim 3 will use supervised machine learning tools to predict depression changes, cerebrovascular changes, and participant adherence. Upon completion, this study will build towards our long-term goal of identifying and translating mechanistically-driven behavioral treatments to reduce the global burden of mental illness by determining the extent to which a promising, accessible, translatable RET approach can treat MDD by improving cerebrovascular function. Simultaneously, this project will inform future precision medicine approaches that will target modifiable predictors of treatment response and adherence to behavioral interventions to optimize MDD treatments and individually prescribe them to those most likely to benefit. If RET effectively treats MDD, this trial would lay the foundation to apply RET as a standalone treatment for MDD, and potentially as a standalone or augmentation treatment to reduce the widespread burden of mood disorders and serious mental illnesses.