精神分裂症诊疗新进展

increasingly seeking help in the prodromal period. The positive symptoms generally respond well to antipsychotic medication, but negative and cognitive symptoms show less response
Corvin A. Schizophr Bull. 2013;39(3):490-495.
Ripke et al 2013 (Nature Genetics)
Psychiatric Genomics Consortium
遗传：同卵双生子50% 基因：108个位点
(80,000 subjects world-wide—over 120 associated risk variants)
delays associated with autism and intellectual disabilities. During late adolescence or early adulthood, a prodromal phase characterized by attenuated psychotic, negative, and cognitive
neurobiological changes thought to be relevant to the development of symptoms. Note that altered synaptogenesis and synaptic pruning have not been clearly demonstrated in vivo, and
From: Schizophrenia— Cortical Circuits, Neural Oscillations, and Brain Networks in Schizophrenia JAMA Psychiatry. Published online October 30, 2019.1-10 doi:10.1001/jamapsychiatry.2019.3360
symptoms and functional impairment often precedes the first psychotic episode. The first psychotic episode occurs when symptoms meet the threshold for a clinical diagnosis, as opposed
病因相关因素与目前假说
遗传
多个基因的SNP异常（如：ZNF804A);拷贝数变异（22q11缺 失）；罕见变异（SETD1A)
早期环境
孕期营养不良、感染；（农村出生）？；童年心理创伤；冬 天出生
社会因素
移民；少数族群（国外，中国不同：多个少数民族）；使用 兴奋剂（大麻）
假说（进展）神经发育障碍；基因-环境交互作用
the precise timing regarding all the changes listed remains unclear.
Date of download: 10/31/2019
Copyright 2019 American Medical Association. All Rights Reserved.
Dotoaf tpehyeroacfmodgiodnawitlinvcleeolalsndod:cnc1eu0gr/sa3t(1i3v/)e2.0sT1yhm9espetoamltseroaftitohnesilalnreeCspsor.oppyorsigehdtt2o0le1Aa9ldl ARtomigaehbrteiscrraRannetMsgeearmdveimcdaa.l aAcstisvoityciaantidond.ysfunction of functional networks and thereby contribute
Stress, Dopamine, and PsychosisPsychosocial stressors sensitize the subcortical dopamine system to increase the response to subsequent triggers, while cortical deficits mean that regulatory control is also impaired. Later triggers, such as stress, then lead to inappropriate striatal dopamine release. This leads to the aberrant assignment of salience to stimuli and the development of psychotic symptoms. Psychosis itself is stressful, and this in turn may provide feedback that further dysregulates the system.
and may even be exacerbated by antipsychotic medication in some cases. Most patients will relapse after stopping antipsychotic treatment, and the risk of relapse is reduced by continued
精神分裂症谷氨酸假说的证据
• NMDA受体拮抗剂（PCP）加重精神病性症状 • NMDA受体激动剂（D-丝氨酸）减轻精神病性症
状 • 分裂症患者大脑内谷氨酸受体和标记物有变化 • 波谱发现分裂症患者大脑内谷氨酸与代谢物浓度
有变化 • 分裂症风险基因中有影响谷氨酸通路的基因 • 一些分裂症患者发现存在抗NMDA受体的抗体
Schizophrenia—Clinical Course JAMA Psychiatry. Published online October 30, 2019.1-10 doi:10.1001/jamapsychiatry.2019.3360
The Clinical Course of Schizophrenia People who go on to develop schizophrenia may show subtle motor and cognitive deviation in childhood but do not show the marked developmental
神经发育障碍假说的支持证据
• 在孕期与围产期有较多环境风险因素 • 发病前或发病早期就有大脑结构的改变 • 发病以后大脑结构的进行性改变不明显 • 发展成精神分裂症的青少年有运动、认知和社交损害 • 有神经系统软体征 • 动物模型研究发现分裂症风险基因影响大脑发育 • 不规则畸形的皮肤纹理 • 侧脑室扩大的几率升高 • 海马和前额叶皮质的神经元变小 • 丘脑的细胞数减少
Date of download: 10/31/2019
Copyright 2019 American Medical Association. All Rights Reserved.
精神分裂症的神经遗传学因素
风险基因
Risk Genes
拷贝数变异
Copy number variations
突变
每10万人中每年发病（Incidence)
患病率不变，遗传度最 高，为什么病因和发病 机理至今不明？
Owen MJ, et al. Schizophrenia. Lancet. 2016;388(10039):86 -97.
艺术家Sue Morgan患精 神分裂症20年，在症状 缓解以后，他试图通过 这幅画传达精神分裂症 所引起大脑的可怕混乱 感。 Morgan表示，连接到大 脑的这些线条表达的感 觉:“我感受到的无形信 号和连接（多而杂乱无 章）。”
Cortical Circuits, Neural Oscillations, and Brain Networks in SchizophreniaA, In healthy individuals, the excitatory output of cortical pyramidal cells is tempered secondary to gamma aminobutyric acid (GABA)–ergic inhibition from interneurons. The interplay between excitatory and inhibitory neurons generates gamma oscillations, which in turn are crucial to the generation of slow fluctuations in neural activity that underlie functional brain networks. B, In individuals with schizophrenia, several mechanisms appear to be altered within these cortical circuits. Loss of pyramidal cell dendritic spines leads to a net reduction in excitatory activity (1); reduced excitatory input to GABAergic interneurons leads to reduced inhibition of pyramidal cells (2); and reduced interneuron inhibition
to the subthreshold symptoms seen in the prodrome (although these may still be debilitating). The first psychotic episode is frequently the first contact with services, although patients are
多巴胺；谷氨酸；神经环路失连接；免疫/炎性异常
From: Schizophrenia—Stress, Dopamine, and Psychosis JAMA Psychiatry. Published online October 30, 2019.1-10 doi:10.1001/jamapsychiatry.2019.3360
Mutations
表观遗传学
Epigenetics
精神分裂症综合症
The schizophrenia syndrome
基因研究的困难：1.分裂症表型中有一些内或中间表型（阴性症状，认知损害）； 2.不是单基因或主效基因，是多个微效作用基因；3.遗传异质性；4.基因-基因交互 作用；5.缺乏好的疾病候选基因
antipsychotic treatment even when psychotic symptoms have fully resolved. This Figure also highlights some key risk factors for the development of schizophrenia together with
精神分裂症诊疗新进展
精神分裂症Biblioteka Baidu流行病学
普遍认为，精神分裂症无论何时、何地、何种性别，终生患病率（lifetime
prevalence)均为1%左右。（在移民人群中稍高）
2008年McGrath等的分析显示 （Prevalence）
时点患病率 约为0.46%
终生患病率 约为0.7%
15名 男性
10名 女性