Aripiprazole-induced hiccups: a case report

Available online at www.sciencedirect.com

General Hospital Psychiatry 31 (2009) 382 – 384

Aripiprazole-induced hiccups: a case report Prasenjit Ray, D.P.M., Mohammad Zia Ul Haq, D.P.M.⁎, S. Haque Nizamie, M.D., D.P.M. Central Institute of Psychiatry, Ranchi, India Received 4 July 2008; accepted 11 September 2008

Abstract Hiccups can arise from idiopathic, psychogenic and organic causes. The use of therapeutic drugs forms one of the important causes of hiccups. Although the exact pathophysiological processes involved have not yet been established, the neurotransmitters dopamine, serotonin and gamma amino butyric aid (GABA) have been documented to play a significant role in the generation of hiccups. We report a patient of organic bipolar affective disorder who developed hiccups with the atypical antipsychotic aripiprazole. The possible underlying neurotransmitter mechanisms, predisposing factors and clinical implications of this rare adverse event are discussed. © 2009 Elsevier Inc. All rights reserved. Keywords: Aripiprazole; Hiccups; Dopamine; Serotonin; GABA

1. Introduction Hiccups are the product of the simultaneous involuntary spasmodic contraction of the diaphragm and glottic closure resulting in blockade of the air entry into the trachea [1]. The hiccup reflex arc consists of the phrenic and vagus nerves, and the sympathetic chain from thoracic segments T6–T12 in the afferent limb; and the phrenic nerve and the brain stem and midbrain areas, including the respiratory centre, phrenic nerve nuclei, medullary reticular formation and hypothalamus in the efferent limb. The cervical segments C3–C5 and the brain stem probably form the central link between the afferent and the efferent limbs [2]. Although the exact pathophysiological processes involved have not yet been established, the neurotransmitters dopamine, serotonin and gamma amino butyric aid (GABA) have been documented to play a significant role in the generation of hiccups. Induction of hiccups by dopaminergic agents and their successful treatment with antidopaminergic agents have been consistently reported [3,4]. Curiously, however, hiccups have also been reported to result from antidopaminergic agents and also as a presentation of Parkinson's disease with successful treatment with levodopa ⁎ Corresponding author. Centre for Cognitive Neurosciences, Central Institute of Psychiatry, Ranchi, India. Tel.: +919234687231 (mobile); fax: +96512233668. E-mail addresses: [email protected], [email protected] (M. Zia Ul Haq). 0163-8343/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2008.09.014

[5,6]. The role of serotonin in the production of hiccups is suggested by the reports of successful treatment of hiccups by sertraline and olanzapine and, interestingly, induction of hiccups with clozapine [1,7,8]. More robust evidence comes from animal studies showing the serotonergic facilitation of phrenic motoneuronal activity at the level of the spinal cord [9,10]. The evidence for the role of GABA in the production of hiccups from animal studies showing the inhibition of the hiccup reflex arc through GABAergic inputs to the hiccupevoking site within the medullary reticular formation from nucleus raphe magnus is backed clinically by the successful treatment of hiccups by GABA-B agonists like baclofen and pregabalin [11]. Whatever the neurotransmitter mechanisms involved, hiccups can arise from idiopathic, psychogenic and organic causes. The use of therapeutic drugs forms one of the important causes of hiccups. A Medline and ScienceDirect search till June 2008 revealed only one report of aripiprazole-induced hiccups with hyponatremia as the likely etiology [12]. We here present a case of aripiprazole-induced hiccups to discuss the possible underlying mechanisms, the predisposing factors and the clinical implications of this rare adverse event. 2. Case report Mr. S.C., a 28-year-old single male with normal birth and developmental history, well-balanced premorbid personality,

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having suffered an attack of measles at 21/2 years of age, an accidental insecticide poisoning at 4 years of age and with a 4-year history of an episodic illness, was brought by his guardians to our adult psychiatry outpatient department. The illness started in August 2004 after the patient had suffered a closed head injury leaving him unconsciousness for 3 days. The patient's CT scan of the brain at that time revealed a right frontotemporal subdural hematoma with contusion of the underlying cortical areas. After regaining consciousness, the patient was found to have peritraumatic amnesia of both retrograde and anterograde type and left-sided hemiparesis, and showed behavioural problems in the form of unprovoked aggressive behavior that resolved spontaneously in around a fortnight. Behaviorally, the patient was maintaining well and showing gradual improvement in paresis till July 2005 when he experienced one depressive episode that resolved spontaneously over a month. In April 2006, the patient started having manic symptoms which resolved gradually and spontaneously over the next 6 months. The patient was brought by his guardians to our outpatient department for the first time in March 2007 with 3-week history of irritability, talkativeness, having grandiose plans, spending more than usual and having a decreased need for sleep. Physical examination revealed increased tone, Grade 4 power and exaggerated tendon jerks in the left upper and lower limbs. Mental status examination revealed a talkative, overfamiliar person with inflated self-esteem and delusions of grandiosity, having a poor insight into his illness. All the routine investigations including hemogram, liver and kidney function tests and EEG were normal. In keeping with the current nosological system (International Statistical Classification of Diseases and Health-Related Problems 10th Revision, ICD-10), the patient was diagnosed as organic bipolar affective disorder and treated with carbamazepine and olanzapine titrated to doses of 800 and 10 mg/day, respectively. The patient showed good response with resolution of symptoms over a month's time. Olanzapine had to be gradually tapered off due to excessive sedation that was interfering with his work. The patient was maintaining well on carbamazepine 800 mg/day till September 2007 when he had one depressive episode with psychotic symptoms. Carbamazepine was continued and aripiprazole 10 mg/day was added, considering its less sedating properties. Within 3–4 h of taking aripiprazole, the patient started having hiccups continuously for which he consulted a general medical practitioner who after preliminary examination advised to stop aripiprazole. The next scheduled dose of aripiprazole was omitted and the hiccups stopped a few hours later (around 30 h after the last dose), and the patient remained well for the next 2 days. The patient reported to us on the third day for further consultation. A detailed history and physical examination of the patient did not reveal any signs or symptoms of systemic involvement. Considering this, no further investigations were done and an aripiprazole rechallenge was planned. On rechallenging with aripiprazole, the hiccups recurred within a few hours. Aripiprazole was

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stopped and replaced with quetiapine. Gradual dose titration of carbamazepine and quetiapine to 1000 and 200 mg/day, respectively, resulted in complete resolution of the symptoms without the recurrence of hiccups within a month. The patient was maintaining well on a follow-up a month later.

3. Discussion Aripiprazole is a novel antipsychotic agent with a mechanism of action different from both the typical and atypical agents. It has the highest affinity for 5-HT2B, D2 and D3 dopamine receptors; significant affinity for 5HT1A, 5-HT2A, 5-HT7, α1A adrenergic and H1 histamine receptors; and the least affinity for 5-HT1D, 5-HT2C, α 1B, α 2A, α 2B, α 2C, β1 and β2 adrenergic, and H3 histamine receptors [13]. Functionally, aripiprazole is a partial agonist at the D2 and D3 dopamine receptors and 5-HT1A receptor; antagonist at 5-HT2A receptor; and an inverse agonist at 5HT 2B receptor [14,15]. The central mechanism of action of aripiprazole is believed to be the stabilization of dopamine and serotonin systems through actions mainly at the D2, 5HT1A and 5-HT2A receptors [16]. Aripiprazole has a benign side-effect profile with little extrapyramidal sideeffects, minimal or no weight gain, and a favorable metabolic profile [13,16,17]. In contrast to the previous report of aripiprazole-induced hiccups, hyponatremia seems to be an unlikely etiology in our patient for two reasons. It needs some time of the order of days for the development of hyponatremia after the drug intake and also its resolution after stopping the inciting agent as is clearly demonstrated in the previous case [12]. Secondly, the absence of any associated signs and symptoms of hyponatremia makes it an unlikely etiology in our patient. Considering these, we propose the modulation of neurotransmitters as a likely mechanism for the development of hiccups due to aripiprazole in our patient. As both hypo- and hyperdopaminergic states have been associated with the development of hiccups, the partial agonism of dopamine by aripiprazole leading to relatively increased or decreased dopaminergic states compared to the baseline seems an attractive proposition for the development of hiccups. However, the exact neuronal circuitry through which dopamine influences the hiccup reflex arc remains largely unknown at this point in time. Another possibility is through modulation of serotonin which plays an important role in the development of hiccups. Aripiprazole being a partial agonist at the 5HT1A receptor can lead to serotonergic facilitation of phrenic motoneuronal activity at the level of the spinal cord and the consequent hiccups. The brief duration and temporal relationship of hiccups with aripiprazole and the absence of any clinical signs or symptoms of gastrointestinal involvement or any recent change in the neurological status of the patient seem to rule out the possibility of a systemic cause for the hiccups. Furthermore, the follow-up of the patient after a month

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without any recurrence of the hiccups or any other signs and symptoms of systemic involvement supports this clinical assumption. Given the fact that our patient was on carbamazepine when aripiprazole was started, the possibility of an interaction between the two giving rise to hiccups needs consideration. Carbamazepine decreases the peak plasma levels of aripiprazole and its active metabolite by 66% and 68%, respectively, making the pharmacokinetic interaction between the two an unlikely possibility [18]. However, this enhanced metabolism of aripiprazole may explain the resolution of hiccups within around 30 h in our patient, considering the long half-life of aripiprazole and its active metabolite of 75 and 94 h, respectively [19]. In the absence of serum sodium measurements in our patient, all these are at best propositions and the possibility of hyponatremia leading to hiccups cannot be ruled out in our patient with certainty. Also, as both carbamazepine and aripiprazole have been reported to produce hyponatremia, the presence of an as-yet-unknown pharmacodynamic interaction may still be thought of. Though hiccup appears to be a benign side-effect, it can lead to significant distress and discontinuation of medication. Additionally, persistent hiccups can be incapacitating and can lead to esophagitis, wound dehiscence, depression, weight loss, malnutrition, insomnia and exhaustion [20]. Due to scarcity of literature, it is difficult to predict the likelihood of occurrence of this rare adverse event due to aripiprazole. However, underlying brain injury and concomitant medication seem to have predisposed our patient to this rare adverse event. As the hiccups developed shortly after starting aripiprazole, in the absence of any clinical guidelines, it seems a prudent clinical practice to replace it with another antipsychotic agent like olanzapine or quetiapine. Further studies are needed to understand the role of various neurotransmitters involved in the hiccup reflex arc and the ways different medications influence it. References [1] Alderfer BS, Arciniegas DB. Treatment of intractable hiccups with olanzapine following recent severe traumatic brain injury. J Neuropsychiatry Clin Neurosci 2006;18(4):551–2.

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