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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) α 2C antagonist and, therefore, also an indirect 5-HT 1A agonist. In contrast, aripiprazole is a partial 5-HT 1A agonist (weak antagonist) and an HT 3 antagonist. Activation of 5-HT 1A receptors enhances vagal activity while HT 3 blockade reduces it. Vagus nerve activation is therapeutic for hiccups. A definitive answer continues to be elusive., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Published by IMR Press.)

Sir Louis Francis Knuthsen (1869-1957), the physician who painstakingly listed almost all treatments known for obstinate hiccough, ascribes the holding of breath method to Philip Henry Pye-Smith, FRS (1840-1914), consultant at Guy's Hospital in London. In fact, the strategy is much older and was mentioned by greats such as Francis Bacon (1561-1626), Aristoteles (384-322 BC), and Eryximachus (late-fifth century bce). Hypoventilation to reduce central nervous system excitability was used in antiquity as evidenced by Cyriacus' treatment of Artemia, the daughter of Emperor Diocletian (≈ 244-311). She was suffering from (among others) seizures that Cyriacus was apparently controlling by tightening a scarf around her neck, as depicted by Mathias Grünewald (1460-1528) on a wing of the so-called Heller Altar now on display at the Historical Museum, Frankfurt, Germany. In modern times, around 1920, inducing hypercapnia by CO 2 inhalation as therapy for hiccups was suggested and tried by a number of anesthetists, such as Americans Russel Firth Sheldon (1885-1960) and Brian Collins Sword (1889-1956) in Boston; Briton Christopher Langton Hewer (1896-1986) at St. Bartholomew's Hospital in London; Austrian Karl Doppler (1887-1947) in Vienna; and the German/Polish Arthur Dzialoszynski (1893-1977) in Berlin. Although various authors assign the scientific primate to any of them, the first mention of carbon dioxide inhalation as treatment of singultus in the scientific literature is of French origin and was made by Paris pharmacist Henri Bocquillon-Limousin (1856-1917) in his 1892 Formulaire des médicaments nouveaux et des médications nouvelles .

German gynecologist Alphons Mermann (1852-1908) is best known for establishing the Luisenheim Woechnerinnenasyl (lying-in asylum) at the end of the 19th century in Mannheim. The Luisenheim, owing its name to HRH the Grand Duchess Luise of Baden (1838-1923), was a significant step forward in the provision of a safe delivery environment for mothers of modest means. During his life, Mermann used his position as the Luisenheim's director to promote both the training of midwives and a strict maintenance of asepsis in the hospital. Historically, he has been viewed as the first physician to describe fetal hiccups in a peer-reviewed scientific publication, although the phenomena were described nearly two centuries before his account. This short work explores the life, family and contributions of Dr Mermann.

During intrauterine life, hiccups are universally present, their incidence peaking in the third trimester. Alfons Mermann (1852-1908), a gynecologist from Mannheim, Germany, best known for having established the Luisenheim Woechnerinnenasyl [lying-in asylum] there in 1887, is viewed as the first physician to name and describe singultus foetalis [fetal hiccups] in a modern peer-reviewed scientific publication. This short report attempts to shed some light on the work of Dr. Mermann and to explore whether or not he was indeed the first to recognize this phenomenon.

A multitude of nonpharmacological interventions to terminate hiccup belong to the public-domain hiccup "mythology" or have been described in the medical literature as case reports. While usually effective in terminating bouts of acute hiccup, they are mostly ineffective in cases of hiccupping that have been present for an extended period. The common denominator of most of these therapeutic maneuvers (some also used to terminate paroxysmal supraventricular tachycardia) is their ability to directly or indirectly increase efferent vagal activity. Among the best known "vagal maneuvers" are the oculo-cardiac reflex (Dagnini-Aschner), the carotid sinus massage, the Valsalva maneuver, stimulation of the ear/auditory canal, ice ingestion, and induction of emesis. This short report provides an overview on hiccups and attempts to identify the lesser known personalities who pioneered its treatment by vagal maneuvers. The recent introduction of electrical vagus nerve stimulation for therapy-resistant hiccup is the ultimate compliment to these pioneers.

Sir William Osler (1849-1919) is associated with a long list of contributions and eponymous entities including filaria, maneuvers, nodules, syndromes, and triads. Among the less known ones is the Oslerian pulling of the tongue for termination of obstinate hiccup (singultus). Janet Travell (1901-1977) , physician to two United States presidents, attributed the tongue-pulling maneuver to Osler. Dr. Travell cites Osler's Principles and Practice of Medicine from 1912, where mention of the remedy can be found. The therapy, however, is much older and (perhaps not surprisingly) of French origin. It can be viewed as a spin-off of attempts by Jean Laborde (1830-1903) to resuscitate the "presque morts" (almost dead) via rhythmic traction of the tongue. Lesser known physicians involved in the treatment of singultus by traction of the tongue are Jean Viaud (1862-1946) and Raphaël Lépine (1840-1919).

Chronic idiopathic singultus (hiccup) is a debilitating condition affecting mostly elderly males. While in the past, pharmacologic singultus treatment was mostly "trial and error," more recently, treatment has become both more evidence based and pathophysiology guided. A combination of an acidity-reducing drug (H(2)-receptor blocker or proton pump inhibitor) with baclofen (gamma-amino-butyric-acid receptor type B agonist) has become the most widely used regimen. Some clinicians replace or supplement baclofen with gabapentin. We present three cases of chronic idiopathic hiccup managed with gabapentin or another alpha-2-delta ligand, pregabalin. This is the first reported use of pregabalin for this indication.

This short report attempts to shed light on the interesting but controversial personality of George T Dexter (ca1812 -?), the physician who first described manipulation of the female genitalia in a hysterical impressionable girl as being associated with the termination of singultus. Although his interaction with the young female patient would not meet today's ethical standards, his medical observation was valid and contributes to our understanding of the pathophysiology of singultus. He was well ahead of his colleagues who presented hiccup therapy case reports with similar or related pathophysiology mechanisms some 150 years later. [ABSTRACT FROM AUTHOR]