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The Psychopharmacology of Ziprasidone: Receptor-Binding Properties and Real-World Psychiatric Practice

Stephen M. Stahl, MD, PhD, and Darius K. Shayegan, BS

Published: December 1, 2003

Article Abstract

Schizophrenia is a highly complex disorder characterized by a diversity of symptoms, psychoticand nonpsychotic, that most likely arise from heterogeneous neuroanatomical and neurochemicalmalfunctions. As with all antipsychotic agents, ziprasidone targets the key hypothetical neurochemicaldisturbance in psychosis—excessive dopamine neurotransmission at dopamine D2 receptors in themesolimbic pathway of the brain—presumably responsible for the positive symptoms of schizophrenia.Like other atypical antipsychotic agents, ziprasidone is a serotonin-2A (5-HT2A)/dopamine D2antagonist; however, its in vitro 5-HT2A/D2 receptor affinity ratio is higher than that of the other firstline atypical antipsychotic agents (namely, risperidone, olanzapine, quetiapine, and aripiprazole). Ziprasidone also exhibits potent interaction with 5-HT2C, 5-HT1D, and 5-HT1A receptors in human brain tissue, characteristics that predict heightened negative symptom relief, enhanced modulation of mood, cognitive improvement, and reduced motor dysfunction. Ziprasidone has moderate affinity for serotonin and norepinephrine reuptake sites, predicting antidepressant/anxiolytic activity. On the otherhand, ziprasidone’s low affinity for α1-adrenoceptors, as well as histamine H1 and muscarinic M1 receptors, suggests that patients should experience relatively little orthostatic hypotension, sedation,cognitive disturbance, weight gain, or dysregulation of prolactin levels. Efficacy and tolerability datafrom trials to date indicate that ziprasidone’s clinical activity is consistent with its receptor profile.

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