An integrated view of pathophysiological models of schizophrenia

Pathophysiological processes that underlie the profound neuropsychiatric di sturbances in schizophrenia are poorly understood. However, the clinical co urse of the disease, and a number of clinical and basic science observation s, provide direction for formulating pathophysiological models that could b e empirically tested. For example, repeated psychostimulant administration to healthy subjects can induce psychotic symptoms, and acute stimulant chal lenge in schizophrenia patients can precipitate psychosis. Also, NMDA antag onists induce positive, negative, and cognitive schizophrenic-like symptoms in healthy volunteers and precipitate thought disorder and delusions in sc hizophrenia patients. These human studies provide support for the dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Well-documented effects of NMDA antagonists on dopamine systems provide a basis to integra te the dopamine and NMDA receptor hypofunction hypotheses. Furthermore, it has become apparent that prominent actions of antipsychotic drugs, especial ly those with 'atypical' properties, involve antagonism of behavioral, elec trophysiological and brain metabolic effects produced by administration of NMDA receptor antagonists. A confluence of clinical and basic science data suggests that an early developmental insult, potentially involving reduced NMDA receptor function, could facilitate sensitization of dopamine systems, leading to the formal onset of schizophrenia in late adolescence and early adulthood. Although clearly speculative, this conceptual model is consiste nt with existing evidence and suggests lines of future experimental investi gation. (C) 1999 Published by Elsevier Science B.V. All rights reserved.