MRC Clinical Sciences Centre, Imperial College, London, UK; Institute of Psychiatry, King's College London, London, UK.
Institute of Psychiatry, King's College London, London, UK.
Lancet. 2014 May 10;383(9929):1677-1687. doi: 10.1016/S0140-6736(13)62036-X. Epub 2013 Dec 6.
Schizophrenia remains a major burden on patients and society. The dopamine hypothesis attempts to explain the pathogenic mechanisms of the disorder, and the neurodevelopmental hypothesis the origins. In the past 10 years an alternative, the cognitive model, has gained popularity. However, the first two theories have not been satisfactorily integrated, and the most influential iteration of the cognitive model makes no mention of dopamine, neurodevelopment, or indeed the brain. In this Review we show that developmental alterations secondary to variant genes, early hazards to the brain, and childhood adversity sensitise the dopamine system, and result in excessive presynaptic dopamine synthesis and release. Social adversity biases the cognitive schema that the individual uses to interpret experiences towards paranoid interpretations. Subsequent stress results in dysregulated dopamine release, causing the misattribution of salience to stimuli, which are then misinterpreted by the biased cognitive processes. The resulting paranoia and hallucinations in turn cause further stress, and eventually repeated dopamine dysregulation hardwires the psychotic beliefs. Finally, we consider the implications of this model for understanding and treatment of schizophrenia.
精神分裂症仍然是患者和社会的主要负担。多巴胺假说试图解释该疾病的发病机制，而神经发育假说则试图解释其起源。在过去的 10 年中，另一种替代理论，即认知模型，已经流行起来。然而，前两种理论并没有得到令人满意的整合，而最有影响力的认知模型迭代版本并没有提到多巴胺、神经发育，甚至没有提到大脑。在这篇综述中，我们表明，变异基因、早期大脑危害和儿童期逆境引起的发育变化会使多巴胺系统敏感化，导致过多的突触前多巴胺合成和释放。社会逆境使个体用来解释经验的认知模式偏向于偏执解释。随后的压力导致多巴胺释放失调，导致对刺激的显著性错误归因，然后这些刺激被有偏见的认知过程错误地解释。由此产生的偏执和幻觉反过来又会导致进一步的压力，最终导致多巴胺的反复失调，从而使精神病性信念根深蒂固。最后，我们考虑了该模型对理解和治疗精神分裂症的意义。
