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

2021年，英国每6名成年人中就有1人患有抑郁症，NHS在心理健康服务上花费了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。医学研究理事会已将精神健康诊断和治疗的进展作为2022 - 2025年战略交付计划的研究重点。抗抑郁药（AD）是抑郁症的主要治疗方法，人们服用AD的时间越来越长。选择性5-羟色胺再摄取抑制剂（SSRI）是最广泛的处方AD，因为与其他类型的AD相比，它们的副作用较少。当患者停止服用他们的AD时，AD停药发生，并且更有可能在长期使用AD（超过四至六周）后发生。戒断症状可能包括恶心，疲劳，感觉和情绪障碍，可能在AD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AD对身体和心理功能的副作用有更多的了解，但对AD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，那么他们将受益匪浅，这样他们就可以为那些最脆弱的人提供额外的支持。奖励处理的障碍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的传输，从而恢复奖励不敏感性，并允许抑郁的人更容易接受奖励的经验。研究表明，在服用AD的前两周，奖励反应会有所改善。然而，目前的知识是缺乏的性质，在奖励处理赤字可能会重新出现后AD停药。例如，目前尚不清楚是否有特定领域的赤字奖励敏感性相关的AD撤退，或奖励不敏感性是否与特定的撤退效果。奖赏敏感性改变的神经标记物可以预测成年人和青少年后期的抑郁症状。如果奖励敏感性的改变确实发生在AD停药后，并且与特定的AD戒断症状相关，则这些神经反应可以为抑郁症复发提供有价值的预测生物标志物。在我的博士学位，我将调查的纵向影响AD中止奖励的神经机制，并分析这是如何与日常情绪，戒断症状和抑郁症复发的初级保健队列。我将使用一系列的研究方法，包括事件相关电位（ERP），生态瞬时评估（EMA）和神经认知任务。在我的第一年，我将进行一项社区研究，以确定这些措施的有效性，我的主要纵向研究与临床病人。使用健康志愿者，我将确认奖励相关ERP的重新测试可靠性，并在一周内试行每日EMA方案。在我的主要研究中，我将使用这些指标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。我还将获得基线前指标，用于与随访评估进行个体内比较。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;我还将在基线和6个月随访评估时进行临床访谈。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包括预测以后的抑郁症复发。

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.