Regardless of which dopamine receptors are involved in antipsychotic drug action, all antipsychotic drugs, including clozapine, achieve maximum clinical efficacy over a period of weeks. Therefore, it is necessary to distinguish the acute receptor antagonist effects of antipsychotic drugs from their chronic effects. What therapeutically relevant, delayed-onset neurobiological effects antipsychotic drugs possess remain unknown. It is believed that the therapeutic actions of antipsychotic drugs are exerted via the mesolimbic and mesocortical dopamine projections in the brain. Blockade of D 2 receptors in the striatum is responsible for the extrapyramidal effects of the typical antipsychotic drugs.
Hypothalamic effects result in weight gain and, occasionally, abnormalities of thermoregulation.
Blockade of pituitary D 2 dopamine receptors interferes with the normal dopaminergic inhibition of prolactin secretion, resulting in elevated prolactin levels. Sedation appears to result from antagonism of several neurotransmitter receptors, including alpha 1 -adrenergic, muscarinic, and histamine H 1 receptors. Because the low-potency antipsychotics, including chlorpromazine and thioridazine, have a substantial affinity for these receptor types, these agents are extremely sedating. An additional property of many antipsychotic drugs is blockade of certain calcium channels on neurons, cardiac muscle, and smooth muscle. Thioridazine and pimozide are potent calcium channel blockers, which may explain their cardiac toxicity, including prolongation of the QT interval and, for thioridazine, increased risk of torsade de pointes ventricular tachycardia.