Improving Depression Treatment Outcomes with an Insulin-Sensitizing Agent

描述（由申请人提供）：抑郁症影响1/4的2型糖尿病患者，2型糖尿病是胰岛素抵抗（IR）的主要表现，与高血糖症、糖尿病并发症和死亡率相关。抑郁症治疗显著改善了血糖控制，并且在随后的无抑郁症间隔期间持续增加。然而，目前的抑郁症治疗策略未能在这些患者中的一半中诱导康复，并允许在一年内复发三分之一。几条证据表明，IR（抑郁相关或抑郁无关）干扰抑郁治疗的反应和无抑郁状态的维持。因此，我们建议分两个阶段（急性期，16周;维持期，24周）、随机化、双盲、安慰剂对照试验，在IR患者中治疗重度抑郁症（MDD），检验以下假设：抑郁症状的减少更大（急性期）和抑郁症复发延迟（维持期）接受胰岛素增敏剂增强常规抗抑郁药物治疗的患者与仅接受常规药物治疗的患者相比。200名患有MDD和IR的受试者[BMI >28.7 kg/m2且胰岛素抵抗的稳态模型（HOMA-IR）>3.6]接受舍曲林（SRT）和另外随机分配的罗格列酮（ROS）或安慰剂（PBO）治疗。出于实践和伦理原因，仅纳入IR且无明显糖尿病的患者。符合MOD恢复标准的受试者将继续治疗6个月，而未恢复的受试者将被转诊接受研究外抑郁管理。将在基线（治疗前）和抑郁恢复/未恢复时测量抑郁、IR（来自OGTT最小模型）、BMI、人体测量、治疗依从性、体力活动和生活质量。在已恢复的亚组中，将在MDD复发时或在恢复后6个月（其余无抑郁症）时采取额外措施。主要终点是急性期抑郁症状严重程度的降低和维持期MDD的复发时间（TTR）。将使用多元回归（急性期）和考克斯比例风险模型（维持期）确定治疗效果以及抑郁改善和TTR的独立预测因素。主要假设是，与接受SRT+PBO的患者相比，接受SRT+ROS治疗的患者抑郁症的减少更大，TTR显著更长，IR的减少独立预测这些有利的结局。如果这些假设得到支持，该研究将具有深远的科学和公共卫生意义：它将确定一种新的治疗方法和一种新的治疗靶点，用于增强抗抑郁治疗的反应性，并延长IR患者（伴或不伴糖尿病）随后的无抑郁间期。这一发现将代表抑郁症治疗的重大进展。

DESCRIPTION (provided by applicant): Depression affects 1 in 4 individuals with type 2 diabetes, the principal manifestation of insulin resistance (IR), and is associated with hyperglycemia, diabetes complications, and mortality. Glycemic control improves significantly with depression treatment, and the gains are sustained throughout the subsequent depression- free interval. However, current depression treatment strategies fail to induce recovery in one-half of these patients and permit recurrence in one-third within a year. Several lines of evidence indicate that IR (depression-related or depression-independent) interferes with response to depression treatment and maintenance of the depression-free state. Therefore, we propose a two-phase (acute, 16 weeks; maintenance, 24 weeks), randomized, double-blind, placebo-controlled trial of treatment for major depressive disorder (MDD) in persons with IR, testing the following hypothesis: reduction in depression symptoms is greater (acute phase) and recurrence of depression is delayed (maintenance phase) in patients receiving insulin sensitizer augmentation of conventional antidepressant pharmacotherapy compared to patients treated with conventional pharmacotherapy alone. 200 subjects with MDD and IR [BMI >28.7 kg/m2 and homeostasis model of insulin resistance (HOMA-IR) >3.6] receive sertraline (SRT) and additional randomly assigned treatment with rosiglitazone (ROS) or placebo (PBO). For practical and ethical reasons, only patients with IR and without overt diabetes will be included. Those meeting criteria for MOD recovery will continue treatment for an additional 6 months while nonrecovered subjects will be referred for out-of- study depression management. Measures of depression, IR (from OGTT minimal model), glycemia, anthropometries, treatment adherence, physical activity and quality of life will be taken at baseline (pre- treatment) and the point of depression recovery/nonrecovery. In the recovered subset, additional measures will be taken at the time of MDD recurrence or 6 months after recovery in those remaining depression free. The primary endpoints are the reduction in depression symptom severity during the acute phase and elapsed time-to-recurrence (TTR) of MDD during the maintenance phase. Multiple regression (acute phase) and Cox proportional hazards models (maintenance phase) will be used to determine treatment effects as well as independent predictors of depression improvement and TTR. The principal hypotheses are that reduction in depression is greater and TTR is significantly longer in patients treated with SRT+ROS compared to those receiving SRT+PBO, and that reduction in IR independently predicts these favorable outcomes. If the hypotheses are supported, the study would have far-reaching scientific and public health implications: It will identify a novel treatment and a new treatment target for enhancing responsiveness to antidepressant therapy and lengthening the subsequent depression-free interval in patients with IR (With or without diabetes). The findings would represent a significant advance in depression treatment.