Neuropathological Substrate

Schizophrenia is clearly a brain disease, and numerous abnormalities in structure, function, and neurochemistry have been reported (Chapter 9). Nevertheless, although certain areas of abnormality and dysfunction have emerged as especially suspect, no clear pathologic basis for the disease or any of its component symptoms has been identified. It appears likely that the abnormalities in schizophrenia arise from an early lesion (genetic, acquired, or both), interacting with altered postnatal developmental processes to produce the symptoms of the illness.

From the perspective of neurochemistry, the dopamine hypothesis has dominated biochemical and pharmacological research on schizophrenia for four decades. In its simplest form, the hypothesis states that schizophrenia is related to a relative excess of dopamine-dependent neuronal activity (Haase and Janssen, 1958). The major support for this hypothesis derives from the efficacy of the dopamine-blocking antipsychotics in treating psychotic symptomatology and the ability of dopamine-enhancing agents such as amphetamine to exacerbate the symptoms of schizophrenia. No drugs without dopamine-blocking activity have any proven efficacy in the treatment of schizophrenia. In fact, the clinical potency of various antipsychotic drugs is directly related to their in vitro ability to bind to dopamine D2 receptors (Creese et al., 1976; Seeman et al., 1976).

Despite this body of pharmacological data supporting the dopamine hypothesis, there is little direct evidence of altered dopamine functioning in schizophrenic patients. Furthermore, while pharmacological data implicate increased dopamine activity in the pathogenesis of positive symptoms of schizophrenia, there is minimal association with negative or cognitive/neuropsychological symptoms. These observations have encouraged a reappraisal of the role of the dopamine system in schizophrenia. A "modified dopamine model" postulates a decrease in cortical dopamine activity, and a reciprocal increase in subcortical dopamine activity, these changes being linked to negative and positive symptoms, respectively. The other approach emphasizes interactions between dopamine and other neurotransmitters, with models of dopamine interactions with serotonin, glutamate, acetylcholine, and gamma-amino butyric acid (GABA) proposed.

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