Ziprasidone — not an option for serotonin syndrome

A recent article concerning serotonin syndrome1 contained an inaccuracy that might result in clinicians attempting a misguided, if not fatal, treatment option. While correctly noting the presumed role of 5-HT_1A receptor activation in the pathophysiology of the syndrome, the authors twice surmise that ziprasidone, an atypical antipsychotic, might warrant study as a therapeutic option because of its potent blockade of 5-HT_1A receptors.

The reference that the authors use as the pharmacologic basis for this assertion does acknowledge the potent binding of ziprasidone at the 5-HT_1A receptor;2 however, the high affinity of the drug for this receptor is as an agonist, not as an antagonist.3^,4 Other effects of ziprasidone on the serotonergic system include potent antagonism of 5-HT_1D, 5-HT_2A and 5-HT_2C receptors, as well as moderate inhibition of serotonin reuptake.3^,4

The net result of ziprasidone on serotonergic neurotransmission makes it an inappropriate candidate for treating serotonin syndrome. Aside from the overt problem of directly stimulating 5-HT_1A receptors, there is also the more subtle, yet still concerning, matter of indirectly stimulating these same receptors via antagonism of 5-HT_2A receptors and inhibition of serotonin reuptake. In fact, there have been reported cases of serotonin syndrome precipitated by the use of other atypical antipsychotics, which are also 5-HT_2A receptor antagonists, in combination with serotonergic drugs.5

Thus, the use of ziprasidone for treatment of serotonin syndrome seems ill-advised and could prolong or worsen the patient's symptoms. In cases in which the clinician seeks treatment with serotonin antagonists, purported options include methysergide, cyproheptadine and propranolol.6

Marshall E. Cates Associate Professor of Pharmacy Practice Samford University McWhorter School of Pharmacy Tuscaloosa, Ala.