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Sertraline in the Treatment of Hiccups

Received August 13, 1999; revised December 3, 1999; accepted December 29, 1999. From the Department of Psychiatry, Johns Hopkins Bayview Medical Center, A4 Center, 4940 Eastern Avenue, Baltimore, Maryland. Address correspondence and reprint requests to Dr. Vaidya, Department of Psychiatry, Johns Hopkins Bayview Medical Center, A4 Center, 4940 Eastern Avenue, Baltimore, MD 21224.

Key Words: Hiccups • Sertraline

Hiccups, or "singultus," is a sudden contraction of the diaphragm terminated by abrupt contraction of the glottis that results in the characteristic "hic" sound. In persistent hiccups, the episodes last for more than 8 hours and may indicate a serious organic disturbance, which may be central or peripheral^1–2 (Table 1). Although most hiccups are self-limiting, chronic or intractable hiccups can be debilitating and require pharmacologic or physical interventions.^3–8 Examples of physical treatments may include initiating the Valsalva maneuver, irritation of the nasopharynx, or counterirritation of the vagus nerve.

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TABLE 1. Etiology of hiccups

Pharmacological treatments have been used, including the following: baclofen, a gamma-aminobutyric acid (GABA) analogue that acts by activating an inhibitory neurotransmitter and has sometimes been helpful in blocking the hiccup stimulus; chlorpromazine, a dimethylamine derivative of phenothiazine, acts centrally by dopamine blockade in the hypothalamus; and metclopramide may help reduce the intensity of the esophageal contractions. Other treatments include the use of valproic acid, which enhances GABA transmission centrally, resulting in the inhibition of the hiccup stimulus. Nifedipine, a calcium channel blocker, is thought to reverse the abnormal depolarization in the hiccup reflex arc. To my best knowledge, there have been no reports on the use of selective serotonin reuptake inhibitors (SSRIs) to treat intractable hiccups.

Sertraline is an SSRI with proven efficacy as treatment for depression and anxiety disorders. This report describes the use of sertraline to successfully treat a patient with intractable hiccups.

Case Report

Mr. A. is a 42-year-old divorced African American man who was admitted to the medicine service for treatment of hyponatremia. Sodium was noted to be at 113 at time of admission. Mr. A. reported that he drank an increased quantity of water to stop "intractable hiccups" that had started 3 years ago after a Mallory Weiss lesion of his esophagus. Mr. A. had a history of alcohol abuse, but he had discontinued his use of alcohol 3 years before the current admission. He had a history of depressive episodes and anxiety symptoms on and off for 15 years, for which he never sought help.

At his mental state examination, Mr. A. was appropriately dressed, hiccuping intermittently, with normal psychomotor activity, relatively normal speech, and no evidence of thought disorder. He had a depressed mood, without suicidal or homicidal ideation, with neurovegetative signs. His Mini Mental State Examination was 26/30, and he appeared to have good insight.

Physical examination and laboratory studies were unremarkable. Mr. A. was diagnosed with adjustment disorder, rule out major depression. Treatment with sertraline (50 mg/day) was initiated. During his follow-up visit, Mr. A. reported that his symptoms of depression had improved and his hiccups had decreased. His sertraline was gradually increased to 150 mg/day to optimize treatment of depression. After 2 weeks of treatment with sertraline (150 mg/day), the patient noted that his hiccups were infrequent with brief episodes lasting 1–2 hours and usually associated with meals. At a follow-up examination 6 months later, Mr. A. maintained improved symptoms of depression and relief from hiccups.

Discussion

The hiccup reflex arc consists of an afferent portion that includes the vagus nerve, the phrenic nerve, and the sympathic chain arising from T6-T12. The phrenic nerve at C3–C5 comprises the efferent limb. A reflex center in the upper cervical region, C3 and C5, along with a higher center have been established.

Sertraline's action as an antidepressant and an antianxiety agent is presumed to be as a result of its inhibitory affect on the reuptake of serotonin in the central nervous system. In vitro studies in animals suggest that it is a potent and selective inhibitor of neuronal 5HT reuptake and has weak effects on norepinephrine and dopamine neuronal uptake.⁹ There are a variety of serotonin receptors and various subtypes that have been related to different disease states.^10,11 For example, the 5HT_1A receptors, located in the hippocampus, have anxiolytic and antidepressant effects when stimulated. The 5HT₂ receptor has been located postsynaptically throughout the hippocampus, cortex, spinal cord, and peripheral blood vessels. When stimulated, the 5HT₂ receptors inhibit the propagation of nerve impulses. 5HT₃ receptors are implicated in vomiting, and the antiemetic effects of certain drugs (e.g., ondansetron) are thought to be mediated via this subtype. The specific receptor effects may not be independent and may interact. SSRIs as a drug class have been reported to normalize both 5HT_1A and 5HT₂ receptors in depressed patients.

Although it is a selective inhibitor of serotonin, sertraline has a varied side-effect profile, representative of its effects at various 5HT receptors. For example, the most common gastrointestinal side effects of sertraline are thought to be mediated through peripheral 5HT receptors (i.e., 5HT₃ for nausea and 5HT₄ for reduced gastric motility) potentially causing gastroparesis. Sertraline acts on 5HT_1A receptors to affect the autonomic nervous system, resulting in increased sweating, saliva, mydriasis ejaculatory failure, cold clammy skin, and dry mouth. With the above information, one could hypothesize that sertraline may affect the hiccup reflex arc by one or more ways.

1. Through its effect on peripheral 5HT₄ receptors in the gastrointestinal tract, sertraline may reduce abnormal esophageal, gastric, or diaphragmatic mobility, and, therefore, reduce hiccups.
   
2. Alternatively, sertraline may act via its effect on 5HT_1A receptors and/or 5HT₂ receptors and its effect on the autonomic nervous system to cause inhibition in the hiccup reflex arc.
   
3. Although little is known of the exact mechanism of sertraline's respiratory system side effects, it causes hypoventilation/hyperventilation, which may reduce hiccups.
   
4. Although serotonin is not directly implicated in the reflex arc, it may be hypothesized that, at an increased dose, SSRIs or sertraline may trigger other neurotransmitter systems and, therefore, affect the reflex arc.
   

A combination of the above mechanisms could also have cured Mr. A.'s hiccups.

We wondered if a reduction in Mr. A.'s hiccups was the natural course of the "hiccup." However, he reported that when he reduced the sertraline, his hiccup returned. From the available literature, there is no evidence that sertraline has been used as a remedy for intractable hiccups. Mr. A.'s success with sertraline warrants further study of SSRIs for intractable hiccups.

REFERENCES

1. Lewis J: Hiccups: causes and cures. Journal of Clinical Gastroenterology 1985; 7:539–552 [CrossRef][Medline]
2. Launois S, Bizec JL, Whitelaw WA, et al: Hiccups in adults: an overview. European Respiratory Journal 1993; 6:563–575[Abstract]
3. Friedman NL : Hiccups: a treatment review. Pharmacotherapy 1996; 16:986–995[Medline]
4. Reading P: Stopping hiccoughs. Lancet 1991; 338:187–188
5. Peabody CA, Dewitt J: Intractable hiccups treated with amitriptyline. Am J Psychiatry 1988; 145:1036
6. Burke AM: Baclofen for intractable hiccups. N Eng J Med 1988; 319:1354[Medline]
7. Williamson, BWA: Management of intractable hiccups. British Medical Journal 1977; 2:501–503
8. Grant JA, Steiner EM: Treatment of persistent hiccups (letter). J Neurol Neurosurg Psychiatry 1991; 54:468
9. PDR 1999 Zoloft pp 2443–2448
10. Leonard BE: Pharmacological differences serotonin reuptake inhibitors and possible clinical relevance. Drugs 1992; 43:3–10
11. Tollefson GD, Rosenbaum JF: Selective Serotonin Reuptake Inhibitors: The American Psychiatric Press Test Book of Psychopharmacology, Second Edition. Washington, DC, American Psychiatric Press, 1998, pp 219–237

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				H. S. Smith and A. Busracamwongs Management of hiccups in the palliative care population American Journal of Hospice and Palliative Medicine, March 1, 2003; 20(2): 149 - 154. [Abstract] [PDF]

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