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、照顾者负担增加和全因死亡率升高。新机制药物疗法的开发和测试是NIMH的公共卫生优先事项。在神经肽能递质中，已知阿片类物质调节情绪，并且该系统在重度抑郁症患者中经常改变。靶向LL-TRD中的阿片系统可以积极调节系统，其中循环阿片与μ和κ阿片受体的密度和结合亲和力之间存在年龄相关的失衡。丁丙诺啡（BPN）是κ阿片受体的拮抗剂和μ阿片受体的部分激动剂。这些药效学作用中的一种或两种可能是其推定的抗抑郁作用的基础。我们的研究小组有来自15名老年人的开放性试验数据，这些老年人对暴露于低剂量BPN的文拉法辛具有前瞻性治疗抗性，表明具有临床意义的抗抑郁作用。此外，自BPN以来：1）舌下制剂可用，2）具有良好的安全性和药代动力学特征，是重新用作LL-TRD分子的有吸引力的候选物。因此，精神疾病创新治疗的合作R34初步研究（PA-12-071）的修订申请的总体目的是检查低剂量BPN作为LL-TRD新型治疗的可行性、安全性、耐受性和临床效果，并开发有关作用机制（MOA）的初步数据。这三个合作地点包括匹兹堡（协调地点）、多伦多（CAMH）和华盛顿大学（圣路易斯）。在这3个研究中心，我们将利用一项临床试验，在10周的双盲、随机、安慰剂对照低剂量BPN暴露前前瞻性确定治疗耐药性。共同的可行性目标是：a）在三个研究中心各随机分配30例受试者;和B）收集 所有90例受试者的BPN和代谢产物血浆水平，以探索治疗应答的剂量效应关系。每个研究中心独有的MOA研究方法是：1）在30例受试者中进行的暴露于BPN/安慰剂前后阿片受体的神经受体PET研究，以证明我们剂量范围内的药效学MOA（圣路易斯）; 2）在30名受试者中进行的fMRI研究，比较BPN/安慰剂暴露前后边缘系统和奖励回路的激活，以检查神经回路水平的MOA（匹兹堡）;和3）在BPN/安慰剂暴露前后对30名受试者进行皮层抑制缺陷（GABA能神经传递功能障碍的神经生理学代表）的经颅磁刺激研究，以检查神经生理学MOA（多伦多）。这些研究结果将由该团队进行科学整合，并且是对2008年战略计划和2010年理事会报告“从发现到治愈”中描述的NIMH新机制治疗开发优先事项的有效回应。"

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."