Neurocognitive signatures predicting risk of recurrent depression

抑郁症是残疾的主要原因，因为许多从症状（“症状阶段”）中恢复的人会经历反复发作。大多数研究都集中在抑郁症的症状阶段，并经常假设当人们没有症状时，他们被治愈了。然而，即使患者没有出现症状，疾病也可能持续存在。在这种“无症状”状态下，人们未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，因为我们目前基于既往发作次数预测其风险的方法非常不准确。人们通常认为，那些治疗工作，以减少抑郁症的症状也将有利于他们未来的预防，但这在很大程度上是未经证实的。预防复发的新疗法的开发受到了缺乏对心理和大脑变化的知识的阻碍，这些变化是风险因素。在一项由MRC资助的研究中，我们已经在康复的抑郁症患者中确定了这些风险因素，这些风险因素可以预测，在个体的基础上，哪个患者将在明年再次发作。通过增加功能性MRI扫描，以及一种倾向于自责标准测量的新测试，我们达到了83%的准确率，超过了有用的所谓“预后标志物”的推荐目标。相比之下，单靠标准测量并不比偶然猜测谁会再次发作更好。患者在经历自责的同时进行扫描，这被认为是通过降低自我价值和希望在抑郁症中发挥重要作用。我们已经证明，无症状的抑郁症患者在与自责相关的大脑网络中显示出改变的连接，这与那些保持健康的人不同。尽管50例患者的结果令人鼓舞，但尚不清楚：1）我们是否可以证实功能性磁共振成像和自责心理测试预测较大独立组中随后复发的抑郁症的结果2）是否需要磁共振成像来预测谁会在个人水平上发展抑郁症，或者可以通过增加进一步的心理和激素测量来取代3）在抑郁症中责备自己时大脑网络被破坏是否与异常的压力荷尔蒙有关，唯一确定的复发化学风险因素4）是否在责备自己时大脑网络的中断会使人们在每周通过移动的应用程序测量的压力生活事件后更容易患上抑郁症问题，我们建议入组150例抑郁症康复患者，这些患者已根据指南（如我们先前的研究）停止抗抑郁药物治疗。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。这将为可重现的心理和基于大脑的风险因素提供急需的证据，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，2）开发所谓的“预后标记物”来预测受影响个体的复发风险。该标记物可用于未来的临床试验，以选择复发风险高的患者。这将大大减少试验所需的患者数量，从而降低其成本。此外，如果我们可以用更便宜的措施取代昂贵的MRI扫描，那么可以在未来的试验中研究预后标志物，以确定它是否有助于抑郁症患者做出继续服用抗抑郁药的决定。在完成这个项目后，我们未来的目标是促进开发新的治疗方法，更有可能通过预防复发而不仅仅是治疗其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，并高度承诺。

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.