Defining, understanding, and treating lack of motivation in schizophrenia

精神分裂症是一种鲜为人知的大脑疾病。在过去的50年里，精神病学将精神分裂症定义为一种精神障碍，意味着患有妄想症和幻觉。药物(抗精神病药物)的开发取得了一些成功。矛盾的是，即使精神病得到了成功的治疗，大多数精神分裂症患者仍然无法工作或拥有家庭生活。原因是人们对阴性症状(以及认知症状)知之甚少。消极症状指的是之前的功能，即动力和情感生活的减弱或缺失。目前还没有治疗该病的许可药物。在这项提案中，我将着重于定义、理解和治疗精神分裂症患者的不良动机。我的印象是，目前用来衡量精神分裂症患者动机的量表不符合目的。至于“阴性症状”，这不是一个患者友好的术语，临床医生经常避免使用它，而其他领域，如神经病学，使用了不同的术语，如冷漠(防止在研究中联合使用相同的现象，因为我们有不同的词)。此外，描述和处理不良动机的方法没有考虑到显著的局限性。动机不佳是“终点”行为，但可能是主要特征，也可能是其他因素的次要因素。这些包括药物诱导的镇静，精神病本身(回避)，或需要完全不同的药理学非药理学干预的共病抑郁状态。与该领域的世界领导者合作，并与公关合作。Peter Jones，我在这个提案中有三个主要目标。首先，探索哪些新的低动机措施可以用于临床实践。我们在一项国际研究中收集数据，然后根据经验与专家合作，定义在未来的临床实践中描述这些症状的最佳策略。第二，使用计算机任务描述动机的不同步骤(例如，提出想法、评估所需的努力或自尊水平)。然后，评估哪些次要因素会影响激励的每一步。例如，我们预计，患有抑郁症的人会考虑太多的努力来发起任何活动。相比之下，患有精神病的人不会产生想法，也不会努力制定计划来实施这些想法。解构不同的步骤及其次要原因将告知临床医生实施个性化干预。最后，我们将使用新的统计技术来探索药物如何影响动机。例如，我们已经发现一种药物(氯氮平)通过改善次要因素来改善动力：降低精神病严重程度和镇静(当氯氮平减少时)。我们现在可以通过仔细分析我们的患者队列来分析20多种不同药物对动机的影响。最终目标是获得详细的信息，以设计未来的临床试验，并帮助临床医生决定哪种药物对每个方面更有效。这项雄心勃勃的提案建立在20年来治疗精神分裂症患者的经验和三个伦理批准的研究项目的基础上，这些项目将分别于2022年、2023年和2024年完成。需要资金来限制分析结果的时间，并应用于根据结果制定的临床试验。研究组为慢性精神分裂症患者(起病5年)。与第一次精神病发作的人相比，他们受到动机和情绪障碍的影响不成比例。他们是在剑桥精神病中心看到的核心群体，该中心是我领导的NHS部门。

Schizophrenia is a barely understood brain disorder. Over the last fifty years, psychiatry has defined schizophrenia as a psychotic disorder, meaning suffering from delusions and hallucinations. Medication (antipsychotics) has been developed with some success. Paradoxically, most people with schizophrenia remain unable to work or have a family life even after psychosis is successfully treated. The reason is the poorly understood negative symptoms (along with cognitive symptoms). Negative symptoms refer to a lessening or absence of a previous function, namely motivation and emotional life. There is no licenced medication for its treatment. In this proposal I will focus on defining, understanding and treating poor motivation in schizophrenia. My impression is that the current scales for measuring motivation in schizophrenia are not fit for purpose. As 'negative symptoms', it is not a patient-friendly term, it is often avoided by clinicians, and other fields like neurology use different terms such as apathy (preventing joining forces in studies the same phenomenon as we have different words). Additionally, the approach to describe and treat poor motivation have not considered significant limitations. Poor motivation is the 'end point' behaviour but could be either a primary feature or secondary to other factors. These include medication-induced sedation, psychosis itself (avoidance), or a comorbid depressive state requiring completely different pharmacological non-pharmacological intervention.Working with world leaders in the field and under the partnership with Pr. Peter Jones, I have three primary aims in this proposal. First, to explore which of the novel measures of poor motivation can be used in clinical practice. We gather data in an international study to then work with experts by experience to define the best strategy to describe these symptoms in clinical practice in the future. Second, to describe the different steps of motivation (e.g. coming up with ideas, evaluation of effort needed or self-esteem level) using computer tasks. Then, to evaluate which secondary factor impacts each step of motivation. For instance, we anticipate that someone suffering from depression will consider too much effort to initiate any activity. In contrast, someone distracted with psychosis will not develop ideas or struggle to put a plan to establish them in place. Deconstructing the different steps and their secondary causes will inform clinicians to implement personalised interventions. Finally, we will explore how medication impacts motivation using novel statistical techniques. For instance, we have already found that a drug (clozapine) improves motivation by improving secondary factors: reducing psychosis severity and sedation (when clozapine is reduced). We can now analyse the impact of over 20 different medications on motivation using our cohort of patients carefully characterised. The end goal is to have detailed information to design a future clinical trial and help clinicians decide which medication is more effective for each aspect. This ambitious proposal builds upon two decades of experience treating people with schizophrenia and on three ethically approved research projects to be completed by 2022, 2023 and 2024, respectively. Funds are requested to ringfence time to analyse results and apply to a clinical trial formulated on the results. The study group is patients with chronic schizophrenia (>5 years since illness onset). They are disproportionally affected by motivation and emotional dysfunction compared to those with the first episode of psychosis. They are the core group seen at the Cambridge Psychosis Centre, an NHS unit that I lead.