Schizophrenia: The new etiological synthesis.

Schizophrenia has been an evolutionary paradox: it has high heritability, but it is associated with decreased reproductive success. The causal genetic variants underlying schizophrenia are thought to be under weak negative selection. To unravel this paradox, many evolutionary explanations have been suggested for schizophrenia. We critically discuss the constellation of evolutionary hypotheses for schizophrenia, highlighting the lack of empirical support for most existing evolutionary hypotheses-with the exception of the relatively well supported evolutionary mismatch hypothesis. It posits that evolutionarily novel features of contemporary environments, such as chronic stress, low-grade systemic inflammation, and gut dysbiosis, increase susceptibility to schizophrenia. Environmental factors such as microbial infections (e.g., Toxoplasma gondii) can better predict the onset of schizophrenia than polygenic risk scores. However, researchers have not been able to explain why only a small minority of infected people develop schizophrenia. The new etiological synthesis of schizophrenia indicates that an interaction between host genotype, microbe infection, and chronic stress causes schizophrenia, with neuroinflammation and gut dysbiosis mediating this etiological pathway. Instead of just alleviating symptoms with drugs, the parasite x genotype x stress model emphasizes that schizophrenia treatment should focus on detecting and treating possible underlying microbial infection(s), neuroinflammation, gut dysbiosis, and chronic stress.