Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Faculty of Medicine, Institute of Clinical Sciences, Imperial College London, London, UK.
Nat Rev Neurol. 2024 Jan;20(1):22-35. doi: 10.1038/s41582-023-00904-0. Epub 2023 Dec 18.
Schizophrenia is a leading cause of global disability. Current pharmacotherapy for the disease predominantly uses one mechanism - dopamine D2 receptor blockade - but often shows limited efficacy and poor tolerability. These limitations highlight the need to better understand the aetiology of the disease to aid the development of alternative therapeutic approaches. Here, we review the latest meta-analyses and other findings on the neurobiology of prodromal, first-episode and chronic schizophrenia, and the link to psychotic symptoms, focusing on imaging evidence from people with the disorder. This evidence demonstrates regionally specific neurotransmitter alterations, including higher glutamate and dopamine measures in the basal ganglia, and lower glutamate, dopamine and γ-aminobutyric acid (GABA) levels in cortical regions, particularly the frontal cortex, relative to healthy individuals. We consider how dysfunction in cortico-thalamo-striatal-midbrain circuits might alter brain information processing to underlie psychotic symptoms. Finally, we discuss the implications of these findings for developing new, mechanistically based treatments and precision medicine for psychotic symptoms, as well as negative and cognitive symptoms.
精神分裂症是全球致残的主要原因之一。目前针对该疾病的药物治疗主要采用一种机制，即多巴胺 D2 受体阻断，但往往疗效有限，耐受性差。这些局限性突出表明需要更好地了解疾病的病因，以帮助开发替代治疗方法。在这里，我们回顾了关于前驱期、首发期和慢性精神分裂症的神经生物学的最新荟萃分析和其他研究结果，以及与精神病症状的联系，重点是该疾病患者的影像学证据。这些证据表明存在区域性特定的神经递质改变，包括基底神经节中谷氨酸和多巴胺水平升高，以及皮质区域（尤其是额叶皮质）中谷氨酸、多巴胺和γ-氨基丁酸（GABA）水平降低。我们考虑皮质-丘脑-纹状体-中脑回路的功能障碍如何改变大脑信息处理以引起精神病症状。最后，我们讨论了这些发现对开发新的、基于机制的治疗方法和针对精神病症状以及阴性和认知症状的精准医学的意义。
