DataSheet4_Peripheral proteomic changes after electroconvulsive seizures in a rodent model of non-response to chronic fluoxetine.PDF

Major depressive disorder (MDD) is the psychiatric disorder with the highest prevalence in the world. Pharmacological antidepressant treatment (AD), such as selective serotonin reuptake inhibitors [SSRI, i.e., fluoxetine (Flx)] is the first line of treatment for MDD. Despite its efficacy, lack of AD response occurs in numerous patients characterizing Difficult-to-treat Depression. ElectroConvulsive Therapy (ECT) is a highly effective treatment inducing rapid improvement in depressive symptoms and high remission rates of ∼50–63% in patients with pharmaco-resistant depression. Nevertheless, the need to develop reliable treatment response predictors to guide personalized AD strategies and supplement clinical observation is becoming a pressing clinical objective. Here, we propose to establish a proteomic peripheral biomarkers signature of ECT response in an anxio/depressive animal model of non-response to AD. Using an emotionality score based on the analysis complementary behavioral tests of anxiety/depression (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 μg/ml, Cort model) in C57BL/6JRj male mice induced an anxiety/depressive-like behavior. A 28-day chronic fluoxetine treatment (Flx, 18 mg/kg/day) reduced corticosterone-induced increase in emotional behavior. A 50% decrease in emotionality score threshold before and after Flx, was used to separate Flx-responding mice (Flx-R, n = 18), or Flx non-responder mice (Flx-NR, n = 7). Then, Flx-NR mice received seven sessions of electroconvulsive seizure (ECS, equivalent to ECT in humans) and blood was collected before and after ECS treatment. Chronic ECS normalized the elevated emotionality observed in Flx-NR mice. Then, proteins were extracted from peripheral blood mononuclear cells (PBMCs) and isolated for proteomic analysis using a high-resolution MS Orbitrap. Data are available via ProteomeXchange with identifier PXD037392. The proteomic analysis revealed a signature of 33 peripheral proteins associated with response to ECS (7 down and 26 upregulated). These proteins were previously associated with mental disorders and involved in regulating pathways which participate to the depressive disorder etiology.

重度抑郁症（Major depressive disorder, MDD）是全球患病率最高的精神疾病。药物抗抑郁治疗（Pharmacological antidepressant treatment, AD），如选择性5-羟色胺再摄取抑制剂（selective serotonin reuptake inhibitors, SSRI，即氟西汀Fluoxetine, Flx），是MDD的一线治疗方案。尽管此类治疗具有疗效，但仍有大量患者无法产生抗抑郁应答，这类患者被归类为难治性抑郁症。电抽搐治疗（ElectroConvulsive Therapy, ECT）是一种高效治疗手段，可快速改善抑郁症状，在药物抵抗性抑郁症患者中可实现约50%~63%的高缓解率。然而，开发可靠的治疗应答预测标志物以指导个体化抗抑郁策略、补充临床观测手段，正成为一项紧迫的临床目标。本研究旨在在对AD无应答的焦虑/抑郁动物模型中，建立ECT应答的外周蛋白质组学生物标志物特征。我们基于对焦虑/抑郁相关行为学实验：高架十字迷宫（Elevated Plus Maze）、新奇抑制摄食实验（Novelty Suppressed Feeding）、舔舐测试（Splash Test）的互补分析构建情绪评分，发现对C57BL/6JRj雄性小鼠进行为期4周的皮质酮处理（35 μg/ml，皮质酮模型）可诱导其产生焦虑/抑郁样行为。为期28天的慢性氟西汀治疗（Flx，18 mg/kg/天）可降低皮质酮诱导的情绪行为升高。我们以氟西汀治疗前后情绪评分阈值降低50%作为分界，将小鼠分为氟西汀应答组（Flx-R，n=18）与氟西汀无应答组（Flx-NR，n=7）。随后，对Flx-NR小鼠实施7次电惊厥刺激（Electroconvulsive Seizure, ECS，对应人类的ECT治疗），并在ECS治疗前后采集血液样本。慢性ECS可使Flx-NR小鼠升高的情绪行为恢复正常。之后，我们从外周血单个核细胞（peripheral blood mononuclear cells, PBMCs）中提取蛋白质，采用高分辨质谱Orbitrap进行蛋白质组学分析。本研究数据可通过蛋白质组交换数据库（ProteomeXchange）获取，识别号为PXD037392。蛋白质组学分析显示，存在33种外周蛋白质与ECS应答相关（7种表达下调，26种表达上调）。这些蛋白质此前已被证实与精神疾病相关，并参与调控与抑郁症发病机制相关的通路。