A rare adverse effect of aripiprazole: hiccups and dose-dependent tolerance

Abstract

Hiccups result from sudden, irregular contraction of the diaphragm and intercostal muscles, leading to immediate closure of the larynx. Aripiprazole, a third-generation antipsychotic, functions as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors while antagonizing serotonin 5-HT2A receptors. Hiccup is a rarely reported side effect of aripiprazole. Research indicates that neurotransmitters, especially dopamine, serotonin, and GABAergic transmission are likely central to hiccup development, though specific mechanisms remain unclear. Here we present a 52-year-old male patient with a long-standing psychosis, who developed hiccups after initiation of aripiprazole. A 52-year-old male patient with a long-standing psychotic disorder, characterized by delusions of misidentification, social withdrawal, and impaired self-care. Shortly after initiation of aripiprazole, the patient developed persistent hiccups that continued overnight, prompting hospitalization. Symptomatic treatment with chlorpromazine and metoclopramide resulted in the resolution of hiccups. Aripiprazole was discontinued, and brexpiprazole was initiated. Despite its pharmacological similarity to aripiprazole, brexpiprazole was well tolerated and did not induce hiccups. Interestingly, hiccups did not recur after we re-challenged with aripiprazole starting from ultra-low doses and titrated slowly. With this case report, we concluded that aripiprazole may induce hiccups, particularly during treatment initiation. This effect may be related to its dopaminergic agonism at D2 receptors at low doses, while brexpiprazole’s lower agonistic activity at D2 receptors may explain the absence of hiccups. Our case suggests that when aripiprazole is initiated at ultra-low doses and titrated slowly, hiccups may not recur, and discontinuation or switching to an alternative antipsychotic may not be necessary.