A feasibility trial of esketamine plus cognitive behavioral therapy for patients with major depressive disorder who are hospitalized for suicidal ideation

摘要 自杀是一种公共卫生危机，在过去20年中，自杀死亡率不断上升。司氯胺酮 作为第一种FDA批准的速效抗抑郁药，最近的积极 在因自杀风险而住院的患者中进行的3期试验的结果也令人鼓舞。但有 考虑到这些3期试验的方案已经停止， 在住院后几周内接受艾司氯胺酮治疗，这是一个极高风险期。我们提出 认知行为疗法（CBT）维持艾司氯胺酮抗抑郁药的两中心安全性和可行性试验 对因自杀意念或企图住院的重度抑郁症患者的影响。这 该提案是对RFA-MH-20-345的回应， 心理社会/行为.方法.单独或组合。 有显著证据表明艾司氯胺酮在治疗抑郁症中具有短期疗效 情绪障碍和自杀意念患者的症状。此外，还有有力的证据表明， CBT 1）在预防抑郁症复发方面有效; 2）即使在 停止治疗;和3）在长期随访中已显示可降低自杀企图率 在高危患者中。使用艾司氯胺酮和CBT联合给药的进一步依据是 从艾司氯胺酮诱导神经可塑性的能力和CBT利用这种状态产生 神经回路的持续积极变化可能与抑郁症状的恢复有关， 包括自杀意念我们收集的试点数据强烈表明，CBT可以维持 对难治性抑郁症患者的抗抑郁作用。这一试点数据还表明，根据 我们的假设，认知功能的变化可能与氯胺酮后的缓解有关。 这项拟议的研究将招募60名患有重度抑郁症的患者，他们因 自杀意念或企图。这些患者将接受艾司氯胺酮治疗（开放标签）4周（符合 在该患者群体中进行的3期试验的先前方案）。在第2周，患者将被随机分配至 接受常规治疗（TAU）或TAU加CBT。CBT将是一种计算机辅助的CBT模式， 在NIH资助的试验中，已经证明它不劣于传统的CBT，并且更容易实施 传统的CBT。该项目的主要目的与RFA的明确目的一致， 评估本试验的安全性和可行性，以便计划后续更大、更有效的 临床试验其他目的将通过以下方式研究治疗组合的功效和认知机制： 艾司氯胺酮+ CBT治疗可能起作用。该提案的优点包括使用两个地点进行测试 多中心方法的可行性，招募因自杀风险住院的患者，以及我们的 在TRD实施类似协议的经验和试点数据。

ABSTRACT Suicide is a public health crisis, with rising rates of suicide death over the last 20 years. Esketamine has generated considerable excitement as the first FDA-approved rapid-acting antidepressant. Recent positive results from Phase 3 trials in patients hospitalized for risk of suicide are also encouraging. However, there are legitimate concerns about longer-term outcomes given that the protocols for these Phase 3 trials stopped esketamine treatment within a few weeks following hospitalization, a period of extremely high risk. We propose a two-site safety and feasibility trial of cognitive behavior therapy (CBT) to sustain esketamine’s antidepressant effects in individuals with major depressive disorder who are hospitalized for suicidal ideation or attempt. This proposal is in response to RFA-MH-20-345 seeking to test “interventions that include pharmacological, psychosocial/behavioral … approaches … alone or in combination.” There is significant evidence that esketamine has short-term efficacy in the treatment of depressive symptoms in individuals with mood disorders and suicidal ideation. Moreover, there is also strong evidence that CBT 1) is effective in depression relapse prevention; 2) has an enduring effect even following discontinuation of therapy; and 3) has been shown to reduce rates of suicide attempts over long-term follow-up periods in patients at high-risk. Further rationale for using the combination of esketamine and CBT derives from esketamine’s ability to induce neuroplasticity and the potential of CBT to harness such a state to produce lasting positive changes in neuro-circuitry that may be associated with recovery from depressive symptoms, including suicidal ideation. We have collected pilot data that strongly suggests that CBT can sustain the antidepressant effects in patients with treatment-resistant depression. This pilot data also suggests, in line with our hypotheses, that changes in cognitive functioning may be related to remission following ketamine. The proposed study will enroll 60 patients with major depressive disorder who are hospitalized for suicidal ideation or attempt. These patients will be treated (open-label) with esketamine for 4 weeks (in line with prior protocols of phase 3 trials in this patient population). At week 2, patients will be randomly assigned to receive treatment as usual (TAU) or TAU plus CBT. The CBT will be a computer-assisted modality of CBT that has been shown to be non-inferior to traditional CBT in NIH-funded trials and can be more readily implemented than traditional CBT. The primary aim of this project, in keeping with the explicit purpose of the RFA, is to evaluate the safety and feasibility of this trial to allow for the planning of a subsequent larger, well-powered clinical trial. Other aims will investigate efficacy of the treatment combination and the cognitive mechanisms by which the esketamine + CBT treatment may work. Strengths of the proposal include the use of two sites to test the feasibility of a multisite approach, the recruitment of patients hospitalized for suicide risk, and our experience and pilot data from implementing similar protocols in TRD.