RAPIDLY-ACTING TREATMENTS FOR TREATMENT-RESISTANT DEPRESSION (RAPID)

抑郁症是心理健康从业人员治疗的最常见和最严重的疾病之一。虽然有许多药物，心理治疗，和组合 由于临床医生可选择的治疗方案有限，许多抑郁症患者对提供的初始治疗没有最佳反应。当初始治疗仅限于抗抑郁药物时，约20-35%的患者没有反应。即使经过多次序贯干预，也只有约50%的患者达到完全缓解。 由于大量的死亡率和发病率与治疗不足有关，难治性抑郁症是一个主要的公共卫生问题。这一问题的范围很广，无论是受影响的人数还是由此造成的社会和经济负担。尽管这一问题具有巨大的公共卫生意义， 治疗难治性抑郁症只取得了有限的成功。特别是，及时和准确地识别耐药患者一直是个问题。人们普遍认为，存在生物学决定的延迟抗抑郁药治疗反应开始的潜伏期。这种滞后被认为反映了达到治疗药物水平或达到足够强度的心理治疗所需的时间，以及发生必要的生化和电生理适应所需的时间。 在过去的十年里，一系列的研究已经证明了新方法的能力，包括氯胺酮和睡眠剥夺疗法，以提供显着的改善 几小时内出现症状然而，症状通常在急性干预停止后几天内复发。这些方式的确切作用机制尚不清楚。氯胺酮的药理学作用似乎涉及阻断谷氨酸能NMDA受体和促进AMPA受体。一个研究问题是，剂量水平的变化是否会产生更持久的影响，而不会显著增加不良事件（迄今为止，不良事件很少）。最后，虽然最近的一项研究表明， 在几天内重复给予氯胺酮的耐受性良好，但几乎所有患者的症状在停药后几天内又出现。虽然最近的研究增加了对昼夜节律和睡眠-觉醒周期机制的理解，但睡眠剥夺和症状缓解之间的联系的基本原理仍然不清楚。 这些概念验证试验的可喜结果表明，一个更雄心勃勃的研究计划可能会加速快速起效的抗抑郁治疗的发展。该倡议旨在测试新化合物（例如NMDA拮抗剂（盐酸氯胺酮除外）、AMPA受体的变构调节剂、5-HT 4受体化合物、促甲状腺激素释放激素（TRH））或睡眠剥夺以外的非药物干预（例如，TMS、ECT、MST）。由于NIMH目前的投资组合包括对氯胺酮和睡眠剥夺的研究， 没有征求研究这些干预措施的建议。拟议的倡议设想包括NIMH的校内研究计划（IRP）的独特资源和专业知识。这一举措的成果有望提高对难治性抑郁症的潜在机制的理解，并开发出创新的、快速起效的治疗方法。 该计划所需的一般方法是首先建立一个小型临床试验中心团队，然后在充分把握度的人类概念验证试验中测试已确定的干预措施（药理学和/或非药理学）。试验将在团队成员（包括NIMH校内研究计划）确定有希望的干预措施后启动，并由RAPID指导委员会和NIMH合同官员的技术代表（COTR）（有时也称为政府项目官员）批准。 如果根据本合同或在该领域确定的任何化合物/干预措施被证明是有前途的，政府可以选择使用该化合物/干预措施进行更大规模的疗效试验，以代替其他较小的概念验证试验（见任务4和5）。下文概述的每个任务领域内的所有工作将由合同中更详细概述的任务订单程序控制。这些程序要求NIMH发出任务订单请求，承包商对请求的响应/建议（包括技术方法和预算），以及NIMH对开始任务订单的最终批准。在任务订单获得批准之前，不得产生或报销费用。核定费用总额是一个上限，未经进一步授权不得超过。 本合同的重点和目标是确定和测试最有希望的治疗难治性抑郁症的干预措施（药物或非药物）。

Depression is one of the most common and serious disorders treated by mental health practitioners. While there are many pharmacologic, psychotherapeutic, and combination treatment options available to clinicians, many patients with depression do not respond optimally to the initial treatment offered. When initial treatment is limited to antidepressant medications, approximately 20-35% of patients do not respond. Even after multiple, sequential interventions only about 50% of patients achieve complete remission. Because of the substantial mortality and morbidity associated with inadequate treatment, treatment-resistant depression is a major public health problem. The scope of this problem is vast both in terms of the numbers of affected individuals and the resultant societal and economic burdens. Despite the enormous public health significance of this problem, systematic research on treatment-resistant depression has yielded only limited success. In particular, the timely and accurate identification of treatment-resistant patients has been problematic. It is generally accepted that there is a biologically-determined latency period that delays the onset of response to antidepressant treatment. This lag is believed to reflect the time required to reach therapeutic drug levels or to achieve adequate intensity of psychotherapy coupled with the time needed for the requisite biochemical and electrophysiological adaptations to occur. Over the last decade, a series of studies has demonstrated the ability of novel approaches ¿ including ketamine and sleep deprivation therapy ¿ to provide significant amelioration of symptoms within a few hours. However, symptoms typically return within a period of days after discontinuation of the acute intervention. The exact mechanism(s) of action of these modalities is not clear. The pharmacologic effect of ketamine appears to involve blockade of glutamatergic NMDA receptors and facilitation of AMPA receptors. One research question concerns whether variations in dose levels might produce longer-lasting effects without a significant increase in adverse events (which, to date, have been minimal). Finally, while a recent study has shown that repeated administration of ketamine over several days is well tolerated, symptoms nevertheless returned within days of drug discontinuation for almost all patients. While recent research has increased understanding of the mechanism of circadian rhythms and the sleep-wake cycle, the rationale for an association between sleep deprivation and symptom relief also remains unclear. The promising results of these Proof of Concept trials suggest that a more ambitious program of research might accelerate development of rapid-onset antidepressant treatment. This initiative aims to test new compounds (e.g. NMDA antagonists (other than Ketamine Hydrochloride), allosteric modulators of AMPA receptors, 5HT4 receptor compounds, Thyrotropin-Releasing Hormone (TRH)) or non-pharmacologic interventions other than sleep deprivation (e.g., TMS, ECT, MST). As NIMH¿s current portfolio includes research on both ketamine and sleep deprivation, proposals to study these interventions are not solicited. The proposed initiative is envisioned to include the unique resources and expertise of NIMH¿s Intramural Research Program (IRP). The outcome of this initiative could be expected to lead to an enhanced understanding of underlying mechanisms and development of innovative, rapidly-acting treatment approaches for treatment-resistant depression. The general approach required for this initiative will be to first establish a small team of clinical trial sites and subsequently to test identified interventions (pharmacologic and/or non-pharmacologic) in adequately powered Proof of Concept trials in humans. Trials will be initiated after promising interventions are identified by members of the team (including the NIMH Intramural Research Program), and approved by the RAPID steering committee and the NIMH Contracting Officer¿s Technical Representative (COTR) (sometimes also referred to as the Government Program Officer (GPO)). If any compound/intervention identified under this contract or in the field proves to be promising, the Government may choose to conduct a larger efficacy trial with that compound/intervention in lieu of other smaller Proof of Concept trials (see Tasks 4 and 5). All efforts within each task area outlined below will be controlled by task order procedures outlined in more detail in the contract. These procedures require the issuance of a task order request by NIMH, the Contractor¿s response/proposal to a request (including a technical approach and budget), and final NIMH approval to begin the task order. Costs shall not be incurred or reimbursed until a task order has been approved. The approved total cost is a ceiling that cannot be exceeded without further authorization. The emphasis and objective in this contract is to identify and test the most promising interventions for treatment resistant depression (either pharmacologic or nonpharmacologic).