The dopamine hypothesis of schizophrenia is the most fully developed theory of causation for this disorder, and until recently, it has been the foundation for the rationale underlying drug therapy for this disease. The hypothesis is based on multiple lines of evidence suggesting that excessive dopaminergic activity underlies schizophrenia: (1) drugs that increase dopaminergic activity, such as levodopa and amphetamines, either aggravate existing schizophrenia or induce a psychosis indistinguishable from the acute paranoid form of the disorder; (2) traditional antipsychotic drugs strongly block D2-dopaminergic receptors in the central nervous system (CNS), and clinical efficacy is highly correlated with the potency of individual agents to bind to this receptor; (3) some postmortem studies have reported increases in dopamine receptor density in brains of schizophrenics who were not treated with antipsychotic drugs; and (4) clinical response to antipsychotic drug treatment is correlated with a decrease in homovanillic acid, a primary dopamine metabolite, in cerebrospinal fluid (CSF), plasma, and urine.
However, the dopamine hypothesis does not account for some important observations. If an abnormality of dopamine physiology were solely responsible for the pathogenesis of schizophrenia, antipsychotic drugs would do a much better job in treating patients. As it is, they are only partially effective for most and ineffective for some patients. Moreover, there is evidence that diminished glutamatergic activity also plays a role in the disease. The primary defect could emanate from nondopaminergic systems that exert a regulatory effect on dopamine neurons, leading to disinhibition of some dopaminergic pathways.
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