Clozapine-induced paralytic ileus: a case report

Introduction

Ileus is the disruption of the normal propulsive ability of the gastrointestinal tract and it represents 20% of acute abdominal pain cases. Renal failure, hypovolemic shock, organ hypoperfusion, bowel perforation, peritonitis and sepsis, are serious and potentially fatal consequences of ileus. All of the psychotropic drugs with anticholinergic side effects can result in a change in bowel movements which may result in paralytic ileus. Paralytic ileus cases have been reported related to the anticholinergic side effects in the use of antidepressants such as amitriptyline, clomipramine and imipramine; and first-generation antipsychotics such as chlorpromazine, thioridazine and flupenthixol. Second-generation antipsychotics can cause a very rare paralytic ileus [Luzny et al. 2010; Rondla and Crane 2007; Giordano et al. 1975; Gaszner et al. 2004; Hayes et al. 1987; Fayad and Brujinzeel, 2012; Ramamourthy et al. 2013]. In the literature, advanced age, female gender, first-generation antipsychotics, tricyclic antidepressants, anticholinergics and opioids are reported as risk factors for ileus in patients with schizophrenia [Nielsen and Meyer, 2012]. The main reason for ileus being associated with clozapine is the muscarinic anticholinergic activity of clozapine. It has been also suggested that clozapine may induce an infection or ileus may develop depending on the dose of the toxicity [Rondla and Crane 2007; Nielsen and Meyer, 2012; Darling and Huthwaite, 2011; Solanki et al. 2007]. Indeed, after the treatment of animal models with antipsychotics, bowel structure inflammation, edema and bleeding have been reported in the intestinal structure [Luzny et al. 2010; Rondla and Crane, 2007]. Another present mechanism is the immobility caused by the H1 antagonism. 5HT receptors which are effective in gastrointestinal motility may also be effective in the etiology [Nielsen and Meyer, 2012].

A schizophrenic patient who developed paralytic ileus after the use of clozapine has been presented as a case study below.

Case

A 33-year-old single woman was admitted to the emergency department complaining of an inability to pass a stool for 10 days, abdominal pain and nausea. Her temperature was 37.2°C, pulse was 88 beats/min and blood pressure was 110/70 mmHg. The patient was diagnosed with paranoid schizophrenia 6 years ago, and she had been treated only with clozapine at a dose of 200 mg/day for the past year. She did not have any other known organic disease and had not experienced a similar situation before. There was no record of alcohol and drug use. Family history was unremarkable. Her examination showed distended abdomen and decreased bowel sounds. The patient’s blood count, biochemistry, electrolytes, urinalysis, and inflammatory markers were normal. Abdominal ultrasonography revealed dilated bowel loops. Emergency laparoscopic surgery was performed as an air–fluid level was observed in direct abdominal radiography of the patient. There was no mechanical reason which would explain the obstruction. Paralytic ileus was diagnosed, which may be caused by trauma, an operation, hypokalemia, electrolyte imbalance, uremia or toxemia, although not in this case. The symptoms of the patient were thought to be due to the use of clozapine, therefore oral intake was stopped and feeding was provided by a nasogastric tube. The balance of potassium and sodium was managed with rehydration. On the third day, the patient’s symptoms improved. Clozapine treatment of 150 mg/day was continued in the follow up of the patient, gastrointestinal side effects were observed closely, high-fiber food was increased in the diet, and physical exercise was also increased. Gastrointestinal problems were not experienced during the 6-month follow up.

Conclusion

Clozapine is a highly effective second-generation antipsychotic known to reduce suicide rates and it is used for treatment-resistant schizophrenia. Clozapine is weakly dopaminergic 2, strong dopaminergic 1,3,4, and is also noradrenergic, and a cholinergic muscarinic, histaminergic receptor antagonist [Solanki et al. 2007]. The rare but well-known side effects of clozapine are agranulocytosis, myocarditis, cardiomyopathy and prolongation of the QTc interval. Gastrointestinal side effects of clozapine include nausea, vomiting and constipation. Constipation is seen in 14–60% of patients. The Adverse Drug Reactions Advisory Board has reported 5 cases of colitis, 2 of ileus, 3 of paralytic ileus, 14 intestinal obstructions, 1 bowel perforation, 1 case of peritonitis and 2 cases of small bowel obstruction associated with clozapine treatment in Australia. It has also reported that 5 of these cases resulted in death [Feszczur, 2004].

Autonomic dysfunction of the enteric nervous system has been reported in people with schizophrenia and their first-degree relatives and specifically dysmotility of gastrointestinal tract due to abnormal sympathetic reflexes [Ramamourthy et al. 2013; Peupelmann et al. 2009; Berger et al. 2010]. The anticholinergic and antiserotonergic effects of antipsychotics are known to contribute to the onset of paralytic ileus [Ramamourthy et al. 2013; Lemyze et al. 2009]. In our case study, paralytic ileus was considered to be due to the use of clozapine. Other contributory factors can include hypothyroidism and electrolyte imbalance following postoperative procedures, which were not present in this case. In our case study, we did not use anticholinergic drugs other than clozapine. The patient did not have a long history of constipation. Clozapine, muscarinic anticholinergic activity, H1 antagonism and 5HT2A antagonism caused ileus. There was discussion with the family as to whether an alternative treatment to clozapine should be used. However, they felt that it was better to continue with clozapine as the benefits in treating the patient’s psychiatric illness outweighed the risks. Therefore, the dosage was reduced and close follow up will be continued.

It is important to continue the follow up of patients using antipsychotic drugs, and to make sure they are taking standard precautions to avoid constipation. Slowly increasing the dose of medications and starting the anticholinergic drugs carefully are all very important. Caution should be taken in cases of ileus, as typical clinical symptoms can be masked or may vary especially in those with psychiatric disorders. Also, the pain detection threshold may vary in each person, patients can come to ignore the symptoms of pain, and the physician may misinterpret it as a symptom of pain of the psychiatric disorder which would lead to an incorrect identification of cases of ileus. All of these factors should be taken into account in the decision-making process.