IMR Press / JIN / Volume 20 / Issue 1 / DOI: 10.31083/j.jin.2021.01.273
Open Access Commentary
The action of aripiprazole and brexpiprazole at the receptor level in singultus
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1 Department of Pharmacology, College of Medicine and Health Science, Khalifa University of Science and Technology, 127788 Abu Dhabi, United Arab Emirates
2 Center for Biotechnology, Khalifa University of Science and Technology, 127788 Abu Dhabi, United Arab Emirates
3 Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan, 11941 Amman, Jordan
*Correspondence: (Georg A Petroianu)
J. Integr. Neurosci. 2021, 20(1), 247–254;
Submitted: 10 September 2020 | Revised: 6 December 2020 | Accepted: 14 December 2020 | Published: 30 March 2021
Copyright: © 2021 The Authors. Published by IMR Press.
This is an open access article under the CC BY 4.0 license (

The hiccup (Latin singultus) is an involuntary periodic contraction of the diaphragm followed by glottic closure, which can be a rare side effect of aripiprazole. In contrast to the structurally closely related aripiprazole, brexpiprazole was not associated with this particular adverse drug reaction. Having two very similar drugs that differ in their ability to induce hiccups represents a unique opportunity to gain insight into the receptors involved in the pathophysiology of the symptom and differences in clinical effects between aripiprazole and brexpiprazole. The overlap between maneuvers used to terminate paroxysmal supraventricular tachycardia and those employed to terminate bouts of hiccups suggests that activation of efferent vagal fibers can be therapeutic in both instances. Recent work seems to support a pivotal role for serotonin receptors in such vagal activation. It is unlikely that a unique receptor-drug interaction could explain the different effects of the examined drugs on hiccup. The different effect is most likely the consequence of several smaller effects at more than one receptor. Brexpiprazole is a highly affine (potent) α2C antagonist and, therefore, also an indirect 5-HT1A agonist. In contrast, aripiprazole is a partial 5-HT1A agonist (weak antagonist) and an HT3 antagonist. Activation of 5-HT1A receptors enhances vagal activity while HT3 blockade reduces it. Vagus nerve activation is therapeutic for hiccups. A definitive answer continues to be elusive.

Affinity constant
Fig. 1.
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