A Neurobiological Study on Heterogeneity of Schizophrenia: Genetic Variations and Neurobiological Differentiations

Schizophrenia (SCH) is a devastating brain disorder with grave personal, family and social cost. SCH is a complex and heterogeneous (both genetic and clinical) disorder with oligogenetic endowed vulnerability risk of disease, which manifested as a clinical syndrome comprised of positive, negative and cognitive symptoms in late adolescent or young adulthood under the interaction with environmental stress. The fact that most positive psychotic symptoms can be well controlled by dopamine-blocking antipsychotics substantiates that dopamine hyperactivity is the pathophysiological model of SCH positive symptoms. This is the dopamine model of SCH. The presence of negative and cognitive symptoms has not being fully explained by the dopamine model. The hypo-glutaminergic function was hypothesized to replace or to supplement the dopamine pathological model. The hypo-glutaminergic state was due to a neurodevelopmental disturbance in early-stage of life, and was coined as a pathophysiological mechanism of SCH. The neurodevelopmental disturbance supports the hypo-glutamine model based on the cytoarchitecture abnormality in glutamate-pyramidal cells and reduced gray matter volume. We have found potential vulnerability genes of DISC1 and NRG1 in our Taiwanese SCH family samples. These two genes have functions on neurodevelopmental process. Besides, we, the investigators, also found two vulnerability genes of DRD2 receptor gene and COMT genes in our Taiwanese SCH families. The dopamine neurotransmission disturbance could be another pathophysiological mechanism of SCH. With the awareness of confounding variables of antipsychotic treatment response revealed in pharmacogenetic studies, such as drug metabolism related genes and plasma HVA level, we intend to test the etiological genetic hypotheses in antipsychotic treatment response: (1) The group of neurodevelopmental etiology with risk variations in DISC1 and NRG1 genes is of poor treatment response group; (2) The group of pure hy