Neurocognitive signatures predicting risk of recurrent depression

抑郁症是导致残疾的主要原因，因为许多从症状中恢复过来的人(“症状期”)会反复发作。大多数研究都集中在抑郁症的症状阶段，通常认为当人们没有症状时，他们就会被治愈。然而，即使患者没有症状，疾病也可能持续下去。在这种“无症状”状态下，人们将来出现症状的风险很高。许多患者多年来服用抗抑郁药物以降低复发风险，因为我们目前基于先前发作次数预测风险的方法非常不准确。人们通常认为，那些有效地减少抑郁症状的治疗在未来的预防中也会是有益的，但这在很大程度上是未经证实的。由于缺乏对作为风险因素的心理和大脑变化的了解，预防复发的新疗法的开发一直受到阻碍。在一项由MRC资助的研究中，我们在康复期抑郁症患者中确定了这样的风险因素，这些因素可以预测哪个患者明年会再次发作。通过添加功能MRI扫描，以及在标准测量中倾向于自责的新测试，我们实现了83%的准确率，超过了有用的所谓预后标记物的推荐目标。相比之下，仅有标准的衡量标准并不比猜测谁会发展成另一种疾病更好。患者在经历自责的同时接受了扫描，自责被认为是抑郁的重要原因，因为它降低了自我价值和希望。我们已经证明，继续发展为抑郁症的无症状患者表现出与自责相关的大脑网络中的连接改变，这与那些保持良好的患者不同。尽管在50名患者中得到了这些令人鼓舞的结果，但尚不清楚：1)我们是否可以在一个更大的独立群体中证实功能MRI和自责心理测试预测抑郁症随后复发的结果2)是否需要MRI来预测谁将在个人层面上发展为抑郁症，或者是否可以通过增加进一步的心理和激素措施来替代3)当在抑郁症中责怪自己时发现的大脑网络中断是否与异常的应激激素有关，这是唯一确定的导致复发的化学风险因素4)自责时大脑网络的中断是否会使人们在每周通过移动应用程序测量的压力生活事件后更容易患上抑郁症回答这些问题，我们建议招募150名抑郁症康复患者，他们已经根据指南停止了抗抑郁药物治疗(与我们之前的研究一样)。最初的MRI扫描、认知测试和应激激素将用于预测一年后的复发。这将为可重复的心理和基于大脑的风险因素提供亟需的证据，以1)为新的心理和大脑训练以及脑刺激治疗方法提供信息，以及2)开发所谓的“预后标记”，以预测受影响个人的复发风险。这一标记物可以用于未来的临床试验，以选择复发风险较高的患者。这将大大减少试验所需的病人数量，从而降低试验成本。此外，如果我们能用更便宜的方法取代昂贵的核磁共振扫描，这个预后标志物可以在未来的试验中进行研究，以确定它是否有助于抑郁症患者做出是否继续服用抗抑郁药物的决定。在完成这个项目后，我们未来的目标是促进新疗法的发展，更有可能通过防止复发而不是只治疗症状来长期治疗抑郁症。我们的合作者Janssen正在积极开发抑郁症复发的标志物，并高度致力于此。

Depression is a leading cause of disability, because many people who have recovered from its symptoms ("symptomatic phase") will experience recurring episodes. Most research has focused on the symptomatic phase of depression and often assumed that when people have no symptoms, they are cured. A disorder can, however, be ongoing even when patients do not experience symptoms. In this "asymptomatic" state people can be at high risk of developing symptoms in the future. Many patients take antidepressant medication over years to reduce the risk of recurrence, because our current way of predicting their risk based on number of previous episodes is very inaccurate. It is usually assumed that those treatments working to reduce symptoms of depression will also be beneficial in their future prevention, but this is largely unproven. The development of new treatments that prevent recurrence has been hampered by a lack of knowledge about psychological and brain changes that are risk factors. In an MRC-funded study, we have identified such risk factors in recovered depression patients that predict, on an individual basis, which patient will have another episode in the next year. By adding functional MRI scans, and a novel test of being inclined to self-blame to standard measures, we achieved 83% accuracy, exceeding the recommended target for useful so-called "prognostic markers". In contrast, standard measures alone were no better than chance guessing who would develop another episode. Patients were scanned whilst they experienced self-blame, which is thought to play an important role in depression by decreasing self-worth and hope. We have demonstrated that asymptomatic patients who go on to develop depression show altered connections in the self-blame-related brain network which differed from those who remained well. Despite these encouraging results in 50 patients, it is unknown: 1) whether we can confirm the result that functional MRI and psychological tests of self-blame predict subsequent recurrence of depression in a larger independent group2) whether MRI is needed for predicting who will develop depression at an individual level or could be replaced by adding further psychological and hormonal measures 3) whether the brain networks found to be disrupted when blaming oneself in depression are linked to abnormal stress hormones, the only established chemical risk factor for recurrence 4) whether the disruption in brain networks when blaming oneself makes people more vulnerable to develop depression after a stressful life event measured weekly via a mobile appTo answer these questions, we propose to enrol 150 patients recovered from depression who have stopped their antidepressant medication in accordance with guidelines (as in our previous study). An initial MRI scan, cognitive tests, and stress hormones will be used to predict recurrence after one year. This will deliver much needed evidence for reproducible psychological and brain-based risk factors to 1) inform novel psychological and brain training, as well as brain stimulation treatment approaches and 2) develop a so-called "prognostic marker" to predict recurrence risk for affected individuals. This marker could be used in future clinical trials to select patients that are at high risk of recurrence. This would greatly reduce the number of patients needed for a trial and thereby reduce its cost. Further, if we can replace expensive MRI scans with cheaper measures, the prognostic marker could be studied in future trials to determine whether it helps people with depression to make decisions about continuing their antidepressant medication. After completing this project, our future goal is to facilitate the development of novel treatments more likely to remedy depression in the long-term by preventing recurrence rather than to only treat its symptoms. Our collaborator, Janssen, are actively developing markers for depression recurrence and are highly committed.