Life-threatening haematemesis associated with clozapine: a case report and literature review

Abstract

Clozapine is regarded as a second-line and in some cases last-line antipsychotic known for its common life-threatening side effects, such as agranulocytosis, constipation and cardiomyopathies, but rarely haematemesis. We report a case of severe haemetemesis in a chronic schizophrenic patient managed with clozapine. The patient was a 46-year-old male being managed for chronic schizophrenia with treatment resistance who developed sudden severe haematemesis following commencement of clozapine for 6 weeks. The patient had 1.1 l of blood transfusion. The relevant literature is reviewed. Clozapine can be associated with a life-threatening haematemesis. Psychiatrists and other medical specialists need to be alert to the fatality of clozapine-induced haematemesis in the treatment of psychiatric disorders.

Introduction

Clozapine is a dibenzodiazepine known for its lesser extrapyramidal side effects compared with other antipsychotic medications. It is a second-line antipsychotic drug used in treatment-resistant psychosis, refractory mania, psychosis in mental subnormality, borderline personality and other conditions such as suicidality in psychotic patients [Meltzer et al. 1995; Raja, 2011]. Several case studies have shown various life-threatening side effects of clozapine, ranging from haematological (agranulocytosis), cardiac (cardiomyopathies, pericarditis), nervous (seizure), metabolic (diabetes, dyslipidaemia) and gastrointestinal (haematemesis, constipation, oesophagitis) complications [Fitzsimons et al. 2005; Drugs.com, 2012]. A review of the mortality effect of clozapine showed that it lowers the mortality rate in severe schizophrenia by decreasing suicide rates, while the mortality rate for less common causes of death, such as pulmonary embolism and cardiac problems, is higher [Walker et al. 1997]. Reported gastrointestinal side effects of clozapine are oesophagitis, constipation and bowel ischaemia [Laker and Cookson, 1997; Townsend and Curtis, 2006; Rege and Lafferty, 2008]. To the best of our knowledge, this is the first report of life-threatening haematemesis due to clozapine in subSaharan Africa.

Awareness of the fatality of the uncommon side effects of this last-line antipsychotic drug will go a long away to minimizing the associated mortality.

Case report

The 46-year-old single unemployed patient had the first episode of mental illness when he was 23 years old, which led to his dropping out of university. He had received treatment in various psychiatric institutions across the country and had been treated with different medications, both typical and atypical. At different times, he had been on haloperidol, chlorpromazine and olanzapine. Depot antipsychotic (fluphenazine decanoate) was also used due to poor medication adherence. The patient also had electroconvulsive therapy treatment at different times for catatonic symptoms and depression as well as treatment augmentation with carbamazepine. Improvement on all these treatment modalities was minimal. A case of treatment-resistant schizophrenia was established after necessary reviews and he was commenced on clozapine. Baseline investigations (i.e. full blood count with differentials, electrocardiography, blood electrolyte biochemistry and sugar) were all within normal limits.

He denied the use or abuse of any psychoactive substance and the pregnancy, birth and early childhood were uneventful. His physical state was good; he had no prior history of any gastrointestinal symptoms or disease and his medical history was otherwise insignificant. Significant improvement in his mental state was achieved at a daily dose of 300 mg of clozapine.

Six weeks after clozapine was commenced, he was noticed to have vomited about 200 ml of blood (on each occasion) on three occasions. During review, he complained of dull sternal and epigastric pain but the physical examinations were essentially normal. The packed cell volume (PCV) had decreased from 47% to 33%. The gastroenterology team reviewed and made an assessment of the upper gastrointestinal bleeding (query cause). The following week, he had two more episodes of haematemesis. He collapsed and was resuscitated with intravenous fluids. The PCV decreased further to 20%. The upper gastrointestinal endoscopy showed mucosal breaks alongside the oesophagus only (grade B severity on the Los Angeles classification of oesophagitis). The other investigations were within normal limits. The gastroenterologists (alongside the psychiatrists) made a diagnosis of upper gastrointestinal bleeding secondary to clozapine use as he was only on clozapine at this time. The clozapine was discontinued. He had 1.1 l of whole blood transfused and intravenous omeprazole for 24 h, which was later replaced by oral omeprazole for 1 week. He was continued with haematinics. There was no further episode of haematemesis following the discontinuation of clozapine.

Despite reassurance and an attempt at reintroducing clozapine at a lower (and slower) dose, the patient (and the care givers) refused to be recommenced on clozapine.

Discussion

The discovery of clozapine has given some hope to hitherto treatment-resistant psychosis and some other neuropsychiatric disorders. It has been shown to have a better efficacy and side-effect profile over other typical and atypical antipsychotic drugs.

The risk of causing agranulocytosis is well established and estimated to be 1%, a reason responsible for its initial withdrawal from the market before its reintroduction. Other life-threatening side effects, such as cardiomyopathies, seizures, diabetes complications, constipation, oesophagitis, have also been reported although infrequently.

The possible mechanisms by which clozapine cause oesophagitis and invariably haematemesis are unclear but may not be unrelated to its anticholinergic side effect [Tomer et al. 2002; Van Soest et al. 2008], resulting in loss of oesophageal motility, increase in lower sphincter relaxation, and loss of lower oesophageal tone and pressure. Another mechanism was described by Praharaj and colleagues in which there is impairment of swallowing arising from the effect of clozapine on the vagal regulation of oesophageal peristaltic movement as well as (apparent) hypersalivation [Praharaj et al. 2006]. Although reported cases of reflux oesophagitis are few, this is the the most common gastrointestinal complaint as a result of the use of clozapine [Laker and Cookson, 1997; Baker and Chengappa, 1998; Van Veggel et al. 2012]. To the best of our knowledge, this is the first case report of a patient in subSaharan Africa without a previous history of upper gastrointestinal disease such as peptic or duodenal ulcer.

In a report by Laker and Cookson, 4 out of 36 (11%) patients treated with clozapine developed gastrointestinal symptoms suggestive of reflux oesophagitis within 6 weeks of starting clozapine with endoscopic evidence [Laker and Cookson 1997], 2 of which did not have a prior history of gastrointestinal disease as with this patient. Taylor and colleagues reported in a cross-sectional study that patients using clozapine were more likely to be on concomitant acid-suppressant medication compared with those on those on other atypical antipsychotics [Taylor et al. 2010]. A temporal association between the use of clozapine and gastro-oesophageal reflux disease resulting in later use of acid-suppressant drugs was established in the study by Van Veggel and colleagues [Van Veggel et al. 2012].

Based on the Naranjo probability scale [Naranjo et al. 1981], clozapine is a probable cause of haematemesis in this patient (Naranjo probability score of 6). The evidence in support of this includes lack of prior history suggestive of a gastrointestinal disease, seizure or further haematemesis following discontinuation of clozapine. Furthermore, the patient was only on clozapine at the time of occurrence of the episodes of haematemesis.

Conclusion

This is the first reported case of haematemesis secondary to treatment with clozapine from this environment. There is a need for psychiatrists and other medical specialists to be aware of this life-threatening side effect of clozapine.