Improving Depression Treatment Outcomes with an Insulin-Sensitizing Agent

描述（由申请人提供）：抑郁症影响四分之一的2型糖尿病患者，这是胰岛素抵抗（IR）的主要表现，并与高血糖、糖尿病并发症和死亡率相关。血糖控制在抑郁治疗中得到显著改善，并且在随后的无抑郁期持续改善。然而，目前的抑郁症治疗策略不能使一半的患者康复，并允许三分之一的患者在一年内复发。一些证据表明，IR（抑郁相关或抑郁独立）干扰对抑郁症治疗的反应和维持无抑郁状态。因此，我们建议采用两期治疗(急性期，16周；维持期，24周)，随机，双盲，安慰剂对照试验治疗IR患者的重度抑郁症（MDD），检验以下假设：与单独接受常规药物治疗的患者相比，接受胰岛素增敏剂增加常规抗抑郁药物治疗的患者抑郁症状减轻更大（急性期），抑郁复发延迟（维持期）。200名重度抑郁症和IR患者[BMI为28.7 kg/m2，胰岛素抵抗稳态模型（HOMA-IR）为>3.6]接受舍曲林（SRT）和随机分配的罗格列酮（ROS）或安慰剂（PBO）治疗。出于实际和伦理原因，只有患有IR且没有明显糖尿病的患者将被纳入研究。那些符合抑郁症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介进行研究外抑郁管理。抑郁、IR（来自OGTT最小模型）、血糖、人体测量、治疗依从性、身体活动和生活质量的测量将在基线（治疗前）和抑郁恢复/不恢复时进行。在恢复的亚组中，在重度抑郁症复发时或在恢复后6个月仍无抑郁症的患者中，将采取额外的措施。主要终点是急性期抑郁症状严重程度的减轻和维持期MDD的复发时间（TTR）。将使用多元回归（急性期）和Cox比例风险模型（维持期）来确定治疗效果以及抑郁改善和TTR的独立预测因子。主要的假设是，与接受SRT+PBO的患者相比，接受SRT+ROS治疗的患者抑郁程度降低更大，TTR明显更长，IR的降低独立地预测了这些有利的结果。如果假设得到支持，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新的治疗目标，以增强对抗抑郁治疗的反应性，并延长IR患者（伴或不伴糖尿病）随后的无抑郁间隔。这一发现代表了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.