3/3 Buprenorphine for Late-Life Treatment Resistant Depression

描述（由申请人提供）：多达一半的老年抑郁症患者发展为晚期治疗难治性抑郁症（LLTRD）。LL-TRD的后果包括自杀、医疗状况恶化、照顾者负担加重和全因死亡率升高。新机制药物疗法的开发和测试是NIMH接受的公共卫生优先事项。在神经肽能递质中，阿片类物质被认为可以调节情绪，而这一系统在重度抑郁症患者中经常发生改变。在LL-TRD中靶向阿片系统可能正向调节阿片循环与mu和kappa阿片受体密度和结合亲和力之间存在年龄相关失衡的系统。丁丙诺啡（BPN）是阿片受体的拮抗剂和阿片受体的部分激动剂。这些药效学作用中的任何一种或两者都可能是其假定的抗抑郁作用的基础。我们的研究小组有来自15名老年人的开放试点数据，这些老年人暴露于低剂量BPN，前瞻性地表现出对文拉法辛的治疗耐药，表明具有临床意义的抗抑郁作用。此外，由于BPN: 1)可用于舌下制剂，2)具有良好的安全性和药代动力学特征，因此它是一个有吸引力的候选分子，可以重新用作LL-TRD的分子。因此，这一修订后的精神障碍创新治疗合作R34先导研究（PA-12-071）的总体目标是研究低剂量BPN作为一种治疗LL-TRD的新方法的可行性、安全性、耐受性和临床效果，并获得有关作用机制（MOA）的初步数据。三个合作站点包括匹兹堡（协调站点）、多伦多（CAMH）和华盛顿大学（圣路易斯）。在这3个地点，我们将利用一项临床试验，在双盲、随机、安慰剂对照的低剂量BPN暴露10周之前，前瞻性地建立治疗耐药性。共同的可行性目标是：a)在三个地点随机抽取30名受试者；b)收集

DESCRIPTION (provided by applicant): Up to one half of older patients with major depression develop Late-Life Treatment Resistant Depression (LLTRD). Consequences of LL-TRD include suicide, worsened medical conditions, increased caregiver burden, and higher all-cause mortality. The development and testing of novel-mechanism pharmacotherapies is a public health priority embraced by NIMH. Among the neuropeptidergic transmitters, opioids are known to modulate mood, and this system is often altered in patients with major depression. Targeting the opiate system in LL-TRD may positively modulate a system in which there is age-associated imbalance between circulating opiates and the density and binding affinity of mu and kappa opiate receptors. Buprenorphine (BPN) is an antagonist at the kappa opiate receptor and a partial agonist at the mu opiate receptor. Either, or both, of these pharmacodynamic actions may underlie its putative antidepressant effects. Our research group has open pilot data from 15 older adults with prospectively demonstrated treatment resistance to venlafaxine who were exposed to low-dose BPN, suggesting a clinically meaningful antidepressant effect. In addition, since BPN: 1) is available in sublingual formulation and 2) has a favorable safety and pharmacokinetic profile, it is an attractive candidate to re-purpose as a molecule for LL-TRD. Thus, the overarching aims of this amended application for a Collaborative R34 Pilot Study of Innovative Treatments in Mental Disorders (PA-12-071) are to examine the feasibility, safety, tolerability and clinical effect of low-dose BPN as a novel treatment for LL-TRD and to develop preliminary data about mechanism of action (MOA). The three collaborative sites include Pittsburgh (coordinating site), Toronto (CAMH), and Washington University (St. Louis). Across the 3 sites, we will utilize a clinical trial that establishes treatment resistance prospectively pior to 10 weeks of double-blind, randomized, placebo-controlled exposure to low-dose BPN. Shared feasibility aims are to: a) randomize 30 subjects at each of the three sites; and b) collect BPN and metabolite plasma levels on all 90 subjects to explore a dose-effect relationship on treatment response. MOA study methods unique to each site are: 1) Neuroreceptor PET study of opiate receptors before and after exposure to BPN/placebo in 30 subjects to demonstrate pharmacodynamic MOA at our dosing range (St. Louis); 2) fMRI study in 30 subjects comparing activation in the limbic system and reward circuits before and after BPN/placebo exposure to examine neurocircuitry-level MOA (Pittsburgh); and 3) transcranial magnetic stimulation study of cortical inhibition deficits (a neurophysiological proxy for dysfunctional GABA-ergic neurotransmission) in 30 subjects before and after BPN/placebo exposure to examine neurophysiological MOA (Toronto). These findings will be scientifically integrated by the team, and are an efficient response to the novel-mechanism treatment development priorities of NIMH as described in the 2008 Strategic Plan and the 2010 Council Report "From Discovery to Cure."