Progressive changes in schizophrenia: Do they exist and what do they mean?

Schizophrenia is a disorder characterized by multiple symptoms, with a vari ed course and outcome. The etiology is yet unknown, but multiple pathologic al processes or, equally likely, a unique pathophysiological process, may b e involved. Here, we review evidence for progressive changes in schizophren ia in order to understand further the pathophysiology of this disorder. We first present evidence for clinical and psychosocial changes over time, fol lowed by evidence from structural brain studies that suggests that schizoph renia is a brain disorder. We then review findings from the small number of longitudinal studies that have evaluated structural brain changes in schiz ophrenia, followed by a review of the evidence for neurophysiological chang es, both cross-sectional and longitudinal. This is followed by a discussion of possible cellular mechanisms, including NMDA receptor abnormalities, th at might account for structural and functional brain changes (temporal and frontal), and we discuss how these abnormalities might be related to not on ly the specific signs and symptoms of schizophrenia but also to the onset a nd course of the illness. Finally, we discuss neurodevelopmental (static an d perhaps non-static alterations) and neurodegenerative theories of schizop hrenia. We propose that the two are not mutually exclusive, but instead lik ely reflect a "two-hit" model for some subtypes of schizophrenia.