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.