Pathophysiologic mechanisms in the pathogenesis and clinical course of schizophrenia.

It is widely accepted that schizophrenia originates from abnormalities occurring during the early stages of neural development. Although large studies have revealed behavioral precursors of schizophrenia in childhood, the disorder is usually not evident until patients are in their 20s or 30s. Some patients will be resistant to typical antipsychotic treatment at this first-onset of schizophrenia; however, treatment resistance develops in the majority of patients during the course of successive episodes. This ongoing deterioration suggests that a degenerative process operates during the active psychotic phase of the illness. This review presents evidence of neurodevelopmental and neurodegenerative mechanisms for the development of schizophrenia. These data indicate the importance of effective treatment at the first onset of schizophrenia to improve patient outcome. In addition, animal studies suggest that treatment with clozapine may prevent the neurodegenerative component responsible for the development of treatment resistance.