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

艾氯胺酮联合认知行为疗法治疗因自杀意念住院的重度抑郁症患者的可行性试验

• 批准号: 10688291
• 负责人: SAMUEL WILKINSON
• 金额: $ 96.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688291
• 关键词: Admission activity; Adult; Alabama; Antidepressive Agents; Back; Behavioral; Binding; Caring; Clinical Trials; Cognitive; Cognitive Therapy; Combined Modality Therapy; Computer Assisted; Data; Disease remission; Emotional; Enrollment; Feeling suicidal; Funding; Future; General Population; Grant; Hospitalization; Individual; Intervention; Ketamine; Longterm Follow-up; Major Depressive Disorder; Measures; Mental Depression; Meta-Analysis; Modality; Modeling; Mood Disorders; N-Methylaspartate; Neuronal Plasticity; Outcome; Patient Recruitments; Patients; Persons; Pharmaceutical Preparations; Phase III Clinical Trials; Protocols documentation; Public Health; Randomized; Recovery; Recurrence; Relapse; Research Design; Reversal Learning; Sample Size; Series; Serious Adverse Event; Site; Suicide; Suicide attempt; Suicide prevention; Testing; Time; Treatment Efficacy; United States; United States Food and Drug Administration; United States National Institutes of Health; Universities; Work; Youth; antagonist; antidepressant effect; cognitive control; cognitive function; cognitive testing; community setting; depressive symptoms; design; effectiveness evaluation; efficacy evaluation; enantiomer; evidence base; experience; feasibility testing; feasibility trial; follow-up; high risk; high risk population; hospital readmission; improved; mortality; multi-site trial; neural circuit; novel therapeutics; open label; participant retention; patient population; pharmacologic; phase III trial; preservation; primary endpoint; programs; psychosocial; randomized trial; recruit; reducing suicide; relapse prevention; response; safety and feasibility; single episode major depressive disorder; suicidal; suicidal morbidity; suicidal risk; suicide rate; therapy design; treatment as usual; treatment planning; treatment-resistant depression; trial design

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.

摘要 自杀是一种公共健康危机，在过去20年里，自杀死亡率不断上升。埃斯氯胺酮 作为FDA批准的第一种快速作用抗抑郁药，已经引起了相当大的兴奋。最近呈阳性反应 在因自杀风险住院的患者中进行的第三阶段试验的结果也令人鼓舞。然而，有一些 考虑到这些第三阶段试验的方案停止了，对长期结果的担忧是合理的 埃斯氯胺酮在住院后几周内接受治疗，这段时期的风险极高。我们建议 认知行为疗法(CBT)维持埃斯氯胺酮抗抑郁药的安全性和可行性的双部位试验 对因有自杀念头或企图自杀而住院的严重抑郁障碍患者的影响。这 该提案是对RFA-MH-20-345寻求测试“包括药理学、 心理社会/行为…接近…无论是单独还是结合在一起。 有重要证据表明埃斯氯胺酮在治疗抑郁症方面有短期疗效。 有情绪障碍和自杀意念的个体的症状。此外，也有强有力的证据表明， CBT 1)在预防抑郁症复发方面有效；2)即使在以下情况下仍有持久的效果 停止治疗；以及3)已被证明在长期随访中可以降低自杀未遂的比率 高危患者经期。使用埃斯氯胺酮和CBT联合使用的进一步理由是 从埃斯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， 包括自杀念头。我们收集的试点数据有力地表明，CBT可以维持 难治性抑郁症患者的抗抑郁作用。这一试点数据还表明，与 我们的假设是，认知功能的变化可能与氯胺酮的缓解有关。 这项拟议的研究将招募60名患有严重抑郁障碍的患者，他们因 自杀念头自杀的想法或企图这些患者将接受埃斯氯胺酮(开放标签)治疗4周(按顺序) 与该患者群体中的3期试验的先前方案相同)。在第二周，患者将被随机分配到 接受照常治疗(TAU)或TAU加CBT。CBT将是计算机辅助CBT模式， 在NIH资助的试验中已被证明不逊于传统的CBT，并且可以更容易地实施 而不是传统的CBT。该项目的主要目的是，与《框架协议》的明确目的保持一致，以 评估这项试验的安全性和可行性，以便规划后续更大、更强大的试验 临床试验。其他目标将通过以下方式调查联合治疗的有效性和认知机制 埃斯氯胺酮+CBT治疗可能起作用。该提议的优点包括使用两个地点进行测试 多地点方法的可行性，招募有自杀风险住院的患者，以及我们的 在TRD中实施类似协议的经验和试点数据。