Hiccups in an Adult Case with Schizophrenia due to Aripiprazole: A Case Report

Abstract

Neurotransmitters and neuroreceptors involved in the pathophysiology of hiccups are not well defined. However, dopamine and serotonin are reported to have roles in activating hiccups, and recent case reports suggest that some psychopharmacologic medications –such as antipsychotics– may trigger hiccups in many cases.

Our case describes the activation of hiccups in a young male with schizophrenia while being treated with aripiprazole. The patient was switched from risperidone to aripiprazole due to excessive sedation, hiccups started within 48 hours of initiation of treatment with aripiprazole at a dosage of 15 mg/day, and no change in the hiccups was observed despite a dose reduction. Discontinuation of aripiprazole treatment resulted in complete relief from hiccups.

This case report shows that antipsychotics may trigger hiccups.

INTRODUCTION

A hiccup is a sudden and involuntary contraction of the diaphragm and inspiratory muscles, which are followed immediately by inspiration and glottis closure leading to a “hic” sound (1, 2). Hiccups are generated by a reflex arc consisting of the vagal and sympathetic pathways, brain stem, midbrain areas, and cervical spine –which coordinate the rhythmic movement of the diaphragm (3, 4). Neurotransmitters such as dopamine, serotonin and gamma-aminobutyric acid are also involved in the pathophysiology of hiccups (2, 5).

There are multiple causes in the etiology, including rapid stomach distension, neck diseases, myocardial ischemia, stroke, herpes infection, irritation of phrenic and vagal nerves, gastroesophageal reflux disease, and medications like –steroids, chemotherapeutics, antiparkinsonian drugs and antipsychotic drugs (2).

Aripiprazole is one of the antipsychotics that is reported to generate transient or persistent hiccups in adult and adolescent patients (6–9). Here we report a case of activation of hiccups within 48 hours of administration of aripiprazole in a young male with schizophrenia.

CASE REPORT

The patient presented in this study was a 27-year-old male who was diagnosed with schizophrenia, according to DSM-5. Initially, he was admitted to hospital because of symptoms including bizarre thoughts –ideas of persecution and reference. He complained about having uncontrolled thoughts of being homosexual and believed others around him were aware of his thoughts. He thought that the movements and gazes of people around him were meant to warn him about danger and potential threats of harm. As a result, he was socially isolated.

As per his medical history, he had improvement and reduction of delusions when prescribed risperidone (6 mg/day). He had taken risperidone treatment for four months regularly. However, because of excessive sedation, he stopped taking risperidone several days before being admitted to hospital. His treatment was started with 5 mg aripiprazole at an inpatient unit, and the dose was increased gradually to 15 mg/day after two weeks.

Hiccups were activated as early as the second day after administering aripiprazole 15 mg/day. Due to the potential role of aripiprazole in inducing persistent hiccups, the dose was reduced to 10 mg/day initially and 5 mg/day subsequently in one week. A neurologist and an internist consulted the patient, and his physical examination, all routine blood investigations, plain chest X-ray, and EEG were evaluated as normal. Both specialists ruled out systemic causes of hiccups. As the patient continued having hiccups, aripiprazole was discontinued, and 2 mg risperidone was prescribed with gradual increase of dosage to 4 mg/day. Relief from hiccups was observed within 12 hours of discontinuation of aripiprazole. 4 mg of risperidone was prescribed again and no hiccups were observed. In addition, Naranjo algorithm evaluations demonstrated a score of 7, indicating probable adverse drug reaction (10).

DISCUSSION

Aripiprazole exerts its unique function through modulating different molecular and pharmacological mechanisms compared to other typical/atypical antipsychotic agents. In fact, aripiprazole acts as a partial agonist for D2 and D3 dopamine receptors as well as 5-HT1A receptors, although functioning as an antagonist for 5-HT2A receptors. The main mechanism of action for aripiprazole was identified to act via stabilization of dopamine and serotonin signaling pathways (11). Complementing these findings, aripiprazole is shown to function as an antagonist with elevated levels of dopamine, though acting as an agonist when dopamine levels were depleted (11).

The mechanism of aripiprazole inducing hiccups remains as poorly understood as the pathophysiology of a hiccup. Accordingly, both hypodopaminergic and hyperdopaminergic conditions have been shown to generate hiccups (6–9). The partial agonism of D2 dopamine receptors by aripiprazole can lead to increased or dimished dopaminergic tones that may trigger hiccups and plethora of reports analyzing hiccups associated with dopamine agonists demonstrating increased D3 dopamine receptors affinity underscores the contribution of D3 receptors in the pathogenesis of hiccups by a similar mechanism to antiparkinsonian drugs (4, 11). In our case, the expression of D2 receptors might be increased in response to risperidone administration previously and subsequent initiation of aripiprazole treatment might trigger agonistic activity on the D2 receptors. Consequently, dysregulated dopaminergic system induces hiccups.

Besides, modulation of serotonin by aripiprazole points toward its role in the induction of hiccups. Aripiprazole, functioning as a partial agonist for 5-HT1A receptor, could trigger hiccups by serotonergic stimulation of phrenic motor neuronal activity at the level of the spinal cord (5, 6, 9).

Our case demonstrated a sudden and definite induction of hiccups shortly after aripiprazole intake at the inpatient unit. Based on these observations, it is hypothesized that sensitization and stimulation of neurotransmitters by aripiprazole can cause hiccups. This significant case will help clinicians be aware of the possibility of unwanted induction of hiccups during any therapy which involves intake of aripiprazole. More research studies should be planned to delineate the mechanism of action of aripiprazole in the hiccup reflex arc, as this unavoidable side effect is being increasingly reported in many cases worldwide.