DataSheet_1_Predicting Treatment Outcome in Major Depressive Disorder Using Serotonin 4 Receptor PET Brain Imaging, Functional MRI, Cognitive-, EEG-Based, and Peripheral Biomarkers: A NeuroPharm Open Label Clinical Trial Protocol.pdf

BackgroundBetween 30 and 50% of patients with major depressive disorder (MDD) do not respond sufficiently to antidepressant regimens. The conventional pharmacological treatments predominantly target serotonergic brain signaling but better tools to predict treatment response and identify relevant subgroups of MDD are needed to support individualized and mechanistically targeted treatment strategies. The aim of this study is to investigate antidepressant-free patients with MDD using neuroimaging, electrophysiological, molecular, cognitive, and clinical examinations and evaluate their ability to predict clinical response to SSRI treatment as individual or combined predictors.
MethodsWe will include 100 untreated patients with moderate to severe depression (>17 on the Hamilton Depression Rating Scale 17) in a non-randomized open clinical trial. We will collect data from serotonin 4 receptor positron emission tomography (PET) brain scans, functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), cognitive tests, psychometry, and peripheral biomarkers, before (at baseline), during, and after 12 weeks of standard antidepressant treatment. Patients will be treated with escitalopram, and in case of non-response at week 4 or intolerable side effects, offered to switch to a second line treatment with duloxetine. Our primary outcome (treatment response) is assessed using the Hamilton depression rating subscale 6-item scores at week 8, compared to baseline. In a subset of the patients (n = ~40), we will re-assess the neurobiological response (using PET, fMRI, and EEG) 8 weeks after initiated pharmacological antidepressant treatment, to map neurobiological signatures of treatment responses. Data from matched controls will either be collected or is already available from other cohorts.
DiscussionThe extensive investigational program with follow-up in this large cohort of participants provides a unique possibility to (a) uncover potential biomarkers for antidepressant treatment response, (b) apply the findings for future stratification of MDD, (c) advance the understanding of pathophysiological underpinnings of MDD, and (d) uncover how putative biomarkers change in response to 8 weeks of pharmacological antidepressant treatment. Our data can pave the way for a precision medicine approach for optimized treatment of MDD and also provides a resource for future research and data sharing.
Clinical Trial RegistrationThe study was registered at clinicaltrials.gov prior to initiation (NCT02869035; 08.16.2016, URL: https://clinicaltrials.gov/ct2/results?cond=&term=NCT02869035&cntry=&state=&city=&dist=)

背景：约30%至50%的重性抑郁障碍（major depressive disorder, MDD）患者对抗抑郁治疗方案应答不足。常规药物治疗主要靶向5-羟色胺能脑信号传导，但目前仍需更优工具以预测治疗应答、识别MDD相关亚组，从而支撑个体化且基于机制的靶向治疗策略。本研究旨在通过神经影像学、电生理学、分子生物学、认知及临床检查，对未接受抗抑郁治疗的MDD患者进行研究，并评估其作为单一或联合预测因子，预测选择性5-羟色胺再摄取抑制剂（Selective Serotonin Reuptake Inhibitor, SSRI）类药物治疗临床应答的能力。

方法：本研究为一项非随机开放临床试验，将纳入100例未经治疗的中重度抑郁症患者（汉密尔顿抑郁量表17项版得分>17）。我们将在标准抗抑郁治疗前（基线时）、治疗期间及治疗12周后，收集5-羟色胺4受体正电子发射断层扫描（PET）脑成像、功能磁共振成像（fMRI）、脑电图（EEG）、认知测验、心理测量学指标及外周生物标志物数据。患者将接受艾司西酞普兰治疗，若第4周无应答或出现难以耐受的不良反应，则可换用度洛西汀作为二线治疗方案。本研究的主要结局（治疗应答）以第8周的汉密尔顿抑郁量表6项子量表得分与基线相比的变化进行评估。在约40例患者组成的亚组中，我们将在启动抗抑郁药物治疗8周后，重新评估其神经生物学应答（采用PET、fMRI及EEG），以绘制治疗应答的神经生物学特征图谱。匹配对照的数据将通过其他队列收集，或已从其他队列中获取。

讨论：本大型队列研究配套随访的全面研究计划，为以下方面提供了独特契机：（a）发掘抗抑郁治疗应答的潜在生物标志物；（b）将研究发现应用于未来MDD的分层管理；（c）加深对MDD病理生理基础的理解；（d）揭示假定生物标志物在8周抗抑郁药物治疗过程中的变化规律。本研究数据可为优化MDD治疗的精准医学方案铺平道路，同时也将为未来研究及数据共享提供宝贵资源。

临床试验注册：本研究于启动前在clinicaltrials.gov完成注册（NCT02869035；2016年8月16日，URL：https://clinicaltrials.gov/ct2/results?cond=&term=NCT02869035&cntry=&state=&city=&dist=）