Biologic Mechanisms of Psychosis and Antipsychotic Drug Actions: from Dopamine Excess to Dopamine Stabilization*

According to the dopamine hypothesis of schizophrenia, symptoms of psychosis arise, in part, from dysregulation of central dopaminergic pathways. The activity of dopaminergic neurons is in turn modulated by several neurotransmitters, including, most prominently, serotonin and glutamate. The first generation of antipsychotic drugs (ie, typical antipsychotics) are characterized by potent D2 dopamine receptor blockade, whereas most second-generation (ie, atypical) antipsychotics are serotonin-dopamine receptor antagonists. By simultaneously blocking both 5-HT2A serotonin and D2 dopamine receptors, atypical antipsychotic drugs attenuate the positive symptoms of schizophrenia with few of the extrapyramidal side effects associated with typical antipsychotic drugs. Unfortunately, atypical antipsychotic drugs (eg, clozapine, olanzapine, risperidone, quetiapine, and ziprasidone) can be associated with potentially serious side effects (eg, weight gain, cardiovascular and hematologic abnormalities). Conventional atypical antipsychotic drugs interact with a multiplicity of receptors, in addition to 5-HT2A serotonin and D2 dopamine receptors, including various serotonergic, dopaminergic, noradrenergic, muscarinic, and histaminergic receptors. It is likely that the chance interactions of atypical antipsychotic drugs with these and other receptors lead to the associated side effects. The ideal antipsychotic would, therefore, possess a mechanism of action whereby dopaminergic activity is normalized without adverse effects. (Adv Stud Med. 2003;3(8C):S776-S781)