Kahn R S, Sommer I E
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.
Mol Psychiatry. 2015 Feb;20(1):84-97. doi: 10.1038/mp.2014.66. Epub 2014 Jul 22.
It is evident that once psychosis is present in patients with schizophrenia, the underlying biological process of the illness has already been ongoing for many years. At the time of diagnosis, patients with schizophrenia show decreased mean intracranial volume (ICV) as compared with healthy subjects. Since ICV is driven by brain growth, which reaches its maximum size at approximately 13 years of age, this finding suggests that brain development in patients with schizophrenia is stunted before that age. The smaller brain volume is expressed as decrements in both grey and white matter. After diagnosis, it is mainly the grey matter loss that progresses over time whereas white matter deficits are stable or may even improve over the course of the illness. To understand the possible causes of the brain changes in the first phase of schizophrenia, evidence from treatment studies, postmortem and neuroimaging investigations together with animal experiments needs to be incorporated. These data suggest that the pathophysiology of schizophrenia is multifactorial. Increased striatal dopamine synthesis is already evident before the time of diagnosis, starting during the at-risk mental state, and increases during the onset of frank psychosis. Cognitive impairment and negative symptoms may, in turn, result from other abnormalities, such as NMDA receptor hypofunction and low-grade inflammation of the brain. The latter two dysfunctions probably antedate increased dopamine synthesis by many years, reflecting the much earlier presence of cognitive and social dysfunction. Although correction of the hyperdopaminergic state with antipsychotic agents is generally effective in patients with a first-episode psychosis, the effects of treatments to correct NMDA receptor hypofunction or low-grade inflammation are (so far) rather modest at best. Improved efficacy of these interventions can be expected when they are applied at the onset of cognitive and social dysfunction, rather than at the onset of psychosis.
显然，精神分裂症患者一旦出现精神病症状，该疾病潜在的生物学过程已持续多年。在诊断时，与健康受试者相比，精神分裂症患者的平均颅内体积（ICV）减小。由于ICV由脑生长驱动，而脑生长在大约13岁时达到最大尺寸，这一发现表明精神分裂症患者的脑发育在该年龄之前就受到了阻碍。较小的脑体积表现为灰质和白质的减少。诊断后，主要是灰质损失随时间进展，而白质缺陷保持稳定，甚至在疾病过程中可能有所改善。为了理解精神分裂症第一阶段脑变化的可能原因，需要整合治疗研究、尸检和神经影像学研究以及动物实验的证据。这些数据表明，精神分裂症的病理生理学是多因素的。纹状体多巴胺合成增加在诊断前就已明显，始于处于精神病风险状态期间，并在明显精神病发作时增加。认知障碍和阴性症状可能反过来由其他异常引起，如NMDA受体功能低下和脑部低度炎症。后两种功能障碍可能比多巴胺合成增加早很多年出现，反映出认知和社会功能障碍出现得更早。尽管用抗精神病药物纠正多巴胺能亢进状态对首发精神病患者通常有效，但纠正NMDA受体功能低下或脑部低度炎症的治疗效果（迄今为止）充其量只能说是相当有限。当这些干预措施在认知和社会功能障碍发作时应用，而不是在精神病发作时应用时，可以预期其疗效会有所提高。
