Defining, understanding, and treating lack of motivation in schizophrenia

精神分裂症是一种几乎不为人所知的脑部疾病。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，意味着患有妄想和幻觉。药物（抗精神病药）已经开发并取得了一些成功。奇怪的是，大多数精神分裂症患者即使在精神病得到成功治疗后仍然无法工作或拥有家庭生活。原因是对阴性症状（沿着认知症状）知之甚少。阴性症状是指减少或缺乏以前的功能，即动机和情感生活。没有许可的药物用于治疗。在这个建议中，我将集中在定义，理解和治疗精神分裂症的动机不良。我的印象是，目前用于衡量精神分裂症患者动机的量表并不适用。作为“消极情绪”，它不是一个对患者友好的术语，临床医生经常避免使用它，其他领域如神经病学使用不同的术语，如冷漠（防止研究中的合力相同的现象，因为我们有不同的词）。此外，描述和治疗不良动机的方法并没有考虑到重大的局限性。动机不佳是“终点”行为，但可能是主要特征，也可能是次要因素。这些包括药物诱导的镇静，精神病本身（回避），或共病抑郁状态，需要完全不同的药理学非药理学干预。与该领域的世界领导者合作，并与教授彼得琼斯合作，我在这个建议中有三个主要目标。首先，探索哪些新的措施，不良动机，可用于临床实践。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，确定未来在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开始任何活动。相比之下，精神错乱的人不会发展想法或努力制定计划来建立它们。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，我们将探讨药物如何影响动机使用新的统计技术。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机：降低精神病的严重程度和镇静作用（当氯氮平减少时）。我们现在可以分析超过20种不同药物对动机的影响，使用我们仔细描述的患者队列。最终目标是获得详细的信息来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。这一雄心勃勃的提议建立在二十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。要求提供资金，以便有时间对结果进行分析，并根据结果进行临床试验。研究组为慢性精神分裂症患者（发病5年以上）。与那些首次精神病发作的人相比，他们受到动机和情感功能障碍的影响。他们是剑桥精神病中心的核心小组，这是我领导的一个国民保健服务单位。

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.