Trajectories of treatment response as window into the heterogeneity of psychosis: a longitudinal multimodal imaging study in medication-naieve first episode psychosis patients

摘要 精神分裂症是一种异质性疾病，可能涉及多种潜在的病理因素。 机制，这一直困扰着寻找合理的治疗靶点的努力。所有可用的抗精神病药物 药物(Apd)是多巴胺受体拮抗剂，但临床反应各不相同，三分之一的患者 部分应答者和第三个无应答者。可以说，那些对警方反应良好的人主要有 多巴胺能异常，但也必须确定这些患者的特定潜在病理特征 以期解开精神病的异质性，有效开发新的治疗方法。 我们建议对apd的治疗反应进行8个月的纵向追踪--天真优先 使用互补脑成像技术的发作性精神病(FEP)受试者。 我们已经为几种不同的病理生理机制确定了临时标记 潜在的精神病，包括谷氨酸、大脑连接和神经发育的异常，我们 可以通过大脑成像进行追踪。此外，我们建议研究早期在大脑中发生的变化 与延迟治疗相比，应答者和随时间发生的变化是对治疗的反应。通过 描述治疗轨迹及其与基线病理生理改变的关系，我们将 进一步补充了我们对精神病异质性的机械论理解。 我们建议对60名特征良好的FEP受试者进行研究，这些受试者用药很天真，并用 使用频率最高的警局达32周。我们将遵循严格的纵向设计来捕获治疗 反应：那些在16周治疗后没有足够反应的患者将被切换到另一种治疗方案 在警察局待了16周。所有患者将接受四次扫描：在基线以及治疗6、16和32周后 治疗。我们将使用(1)质子磁共振波谱(MRS)，(2)任务和静息状态功能磁共振和(3) MRI和弥散加权成像(DWI)测量脑生化、功能和结构。vbl.使用 几种成像方式有可能询问治疗的不同神经生物学方面。 响应，并将提供更多机会来聚集底层的模式和组合 那些反应不佳的人的病理反应。 解构精神病的异质性对于识别特定的 药物开发的目标，并为在患者身上进行治疗试验奠定必要的基础 以其特定的潜在精神病态为特征。

ABSTRACT Schizophrenia is a heterogeneous disorder that likely involves multiple underlying pathological mechanisms, which has plagued attempts to identify rational therapeutic targets. All available antipsychotic drugs (APD) are dopamine receptor antagonists, but clinical response is variable, with a third of patients being partial responders, and a third non-responders. Arguably, those who respond well to APD have primarily dopaminergic abnormalities but it is imperative to also characterize the specific underlying pathologies in those with poor response in order to unravel the heterogeneity of psychosis and effectively develop new treatments. We propose to longitudinally follow treatment response to APD for eight months in medication-naïve first episode psychosis (FEP) subjects using complementary brain imaging techniques. We already have identified provisional markers for several different pathophysiological mechanisms underlying psychosis, including abnormalities in glutamate, brain connectivity, and neurodevelopment that we can track with brain imaging. In addition, we propose to study the changes that occur in the brain in early compared to delayed treatment responders and changes that occur over time in response to treatment. By characterizing treatment trajectories and their relationship to baseline pathophysiologic alterations, we will further complement our mechanistic understanding of the heterogeneity of psychosis. We propose to study 60 well-characterized FEP subjects who are medication naïve and treat them with the most frequently used APD for 32 weeks. We will follow a rigorous longitudinal design to capture treatment response whereby those without an adequate response after 16 weeks of treatment will be switched to another APD for 16 weeks. All patients will be scanned four times: at baseline and after 6, 16, and 32 weeks of treatment. We will use (1) proton MR Spectroscopy (MRS), (2) task and resting state functional MRI and (3) MRI and diffusion weighted imaging (DWI) to measure brain biochemistry, function and structure. Using several imaging modalities has the potential to interrogate different neurobiological aspects of treatment response and will offer greater opportunities for clustering the patterns and combinations of the underlying pathologies in those with poor response. Deconstructing the heterogeneity of psychosis has broad implications for the identification of specific targets for drug development, and to lay the groundwork needed to conduct therapeutic trials on patients characterized by their specific underlying psychopathology.