Understanding the neural mechanisms of antidepressant withdrawal and links with depressive symptoms, reward processing and relapse

2021年，英国六分之一的成年人患有抑郁症，NHS在精神健康服务上花费了143亿英镑。研究工作必须集中在努力提高目前对抑郁症治疗的疗效和副作用的理解上。医学研究理事会将精神健康诊断和治疗方面的进展作为研究优先事项列入了《2022 - 2025年战略实施计划》。抗抑郁药（AD）是治疗抑郁症的主要药物，人们服用抗抑郁药的时间越来越长。选择性血清素再摄取抑制剂（SSRI）是最广泛使用的AD，因为与其他类型的AD相比，它们的副作用更少。AD停药发生在患者停止服用AD时，并且更有可能在长时间使用AD后（超过4至6周）。戒断症状包括恶心、疲劳、感觉和情绪障碍，可能在阿尔茨海默病停止后几天出现，并可能持续长达一年：通常导致抑郁症复发。虽然对阿尔茨海默病对身体和心理功能的副作用有更多的了解，但对阿尔茨海默病停药对情绪和认知的影响了解较少。如果临床医生能够预测哪些患者会出现戒断症状和抑郁症复发，那么他们就可以为那些最脆弱的患者提供额外的支持，这将大大受益。奖励处理的损伤与核心抑郁症状有关，如快感缺乏、食欲不振和社交退缩。SSRIs被认为是通过改变单胺传递来起作用的，这反过来又恢复了奖励不敏感，使抑郁症患者更容易接受奖励体验。研究表明，在服用AD的前两周，奖励反应能力有所改善。然而，目前对AD停药后奖励处理缺陷可能重新出现的性质缺乏了解。例如，目前尚不清楚是否存在与阿尔茨海默病戒断相关的奖励敏感性领域特异性缺陷，或者奖励不敏感是否与特定戒断效应有关。奖赏敏感性改变的神经标记可以预测成人和青少年日后的抑郁症状。如果在阿尔茨海默病停药后确实发生了奖励敏感性的改变，并且与特定的阿尔茨海默病戒断症状有关，那么这些神经反应可以为抑郁症复发提供有价值的预测性生物标志物。在我的博士学位中，我将研究阿尔茨海默病停药对奖励神经机制的纵向影响，并分析这与初级保健队列中日常情绪、戒断症状和抑郁症复发的关系。我将使用一系列的研究方法，包括事件相关电位（ERPs），生态瞬间评估（EMA）和神经认知任务。在第一年，我将进行一项社区研究，以建立这些措施的有效性，作为我对临床患者的主要纵向研究。使用健康志愿者，我将确认与奖励相关的erp重新测试的可靠性，并试行为期一周的每日EMA方案。在我的主要研究中，我将使用这些措施来监测初级保健患者在AD停药后1周、2周、3个月和6个月的停药情况。我还将获得基线前的测量值，用于个体内部比较和后续评估。在每个时间点，我将使用erp和神经认知评估来测量对奖励的敏感性；我还将在基线时进行临床访谈和6个月的随访评估。患者还将完成每日EMA调查，以评估情绪、抑郁症状和对社会奖励的敏感性。在数据收集之后，我计划使用先进的计算方法对ERP， EMA，神经认知和临床数据进行三角测量，以确定是否有任何评估可以预测后来的抑郁症复发。

In 2021, 1 in 6 adults in the UK suffered from depression and the NHS spent £14.3 billion on mental health services. Research efforts must be focused on trying to improve current understanding of the efficacy, as well as side-effects, of treatments for depression. The Medical Research Council have included advances in mental health diagnosis and treatment as a research priority in the Strategic Delivery Plan for 2022 - 2025. Antidepressants (AD) are a leading treatment for depression and individuals are taking ADs for increasingly longer periods of time. Selective serotonin reuptake inhibitors (SSRI) are the most widely prescribed AD due to the fewer side effects they are associated with compared to other types of ADs. AD withdrawal occurs when a patient stops taking their ADs and is more likely after a protracted period of AD use (more than four to six weeks). Withdrawal symptoms can include nausea, fatigue, sensory and emotional disturbances and may emerge a few days following AD cessation and can last up to a year: often leading to depression relapse. Whilst there is greater knowledge on the side-effects of ADs for physical and psychological function, there is less understanding on the impact of AD discontinuation on mood and cognition. Clinicians would benefit substantially if they could predict which patients will experience withdrawal symptoms and depression relapse so they could provide additional support to those most vulnerable. Impairments in reward processing have been linked with core depressive symptoms, such as anhedonia, loss of appetite and social withdrawal. SSRIs are thought to work by altering monoamine transmission that in turns reinstates reward insensitivity and allows depressed individuals to be more receptive to rewarding experiences. Research has shown reward responsiveness to improve in the first two weeks of taking ADs. However, current knowledge is lacking on the nature by which deficits in reward processing may re-emerge following AD discontinuation. For example, it is not clear whether there are domain-specific deficits in reward sensitivity related to AD withdrawal, or if reward insensitivity is linked to specific withdrawal effects. Neural markers of altered reward sensitivity have predicted later depression symptoms in adults and adolescents. If alterations in reward sensitivity do occur following AD discontinuation, and are associated with specific AD withdrawal symptoms, these neural responses could provide a valuable predictive biomarker for depression relapse. In my PhD, I will investigate the longitudinal effects of AD discontinuation on neural mechanisms of reward and analyse how this relates to daily mood, withdrawal symptoms and depression relapse in a primary care cohort. I will use a range of research methods, including event-related potentials (ERPs), ecological momentary assessment (EMA) and neurocognitive tasks. In my first year, I will conduct a community study to establish the validity of these measures for my main longitudinal study with clinical patients. Using healthy volunteers, I will confirm the re-test reliability of reward-related ERPs and pilot a daily EMA protocol across a one-week period. In my main study, I will use these measures to monitor withdrawal in primary care patients 1-week, 2-week, 3-months and 6 months from AD discontinuation. I will also obtain pre-baseline measures for intra-individual comparisons with follow-up assessments. At each time point I will measure sensitivity to reward using ERPs and neurocognitive assessments; I will also conduct clinical interviews at the baseline and 6-month follow-up assessments. Patients will also complete daily EMA surveys to assess mood, depressive symptoms, and sensitivity to social rewards. Following data collection, I plan to triangulate ERP, EMA, neurocognitive and clinical data using advanced computational methods to determine whether any of the assessments included predict later depression relapse.