Clozapine-associated Pseudomembranous Colitis

To the Editors: Clozapine is a tricyclic dibenzodiazepine derivative, atypical antipsychotic which exhibits relatively potent antiserotonergic (5-HT2, 5-HT3), antialpha1 adrenergic, antihistaminic (H1), antimuscarinic activity, and induces preferential blockade of dopamine D1 and D4 receptors in vivo. 2–4 Various adverse gastrointestinal effects have been associated with its use including constipation, gastric outlet obstruction, prolonged postoperative ileus, as well as eosinophilic, cytomegalovirus, and necrotizing colitis. The authors are unaware of any report of clozapine-associated pseudomembranous colitis and record a case here after 9 years of clozapine therapy. A 38-year-old woman with a 20year history of organic brain syndrome secondary to chicken pox encephalitis presented with disorganized speech, disorganized behavior, aggressive episodes (smashing things and bit her mother), neglect of personal hygiene, and social withdrawal. In 1990, a computerized tomography of the brain showed cortical scars in the fronto-parietal regions with slightly prominent sulcal markings, indicating mild atrophy of the affected regions. She was started on clozapine in 1996 due to poor clinical response to various trials of conventional antipsychotics as well as atypical antipsychotic (risperidone), and the emergence of extrapyramidal side effects. The dosage of clozapine was gradually increased to 350 mg/d over time with subsequent improvement in her clinical symptoms. In 2003, she developed a tonic-clonic convulsion and, based on abnormal electroencephalography findings and consultation with her neurologist, sodium valproate was added. She was also maintained on benzhexol 6 mg/d and lorazepam 3 mg/d. During this time, she had no history of upper or lower gastrointestinal complaints. In December 2004, she was noted to pass copious amounts of soft, brown stools. Physical examination revealed hypotension with 80/60 mm Hg of systolic/ diastolic blood pressure. Two days later, she developed a distended abdomen and colonoscopy revealed colitis with plaquelike adhesions in the sigmoid and descending colon. Histologic examination of colonic biopsy showed superficial erosion of the mucosa and adherent ‘‘pseudomembranes’’ of fibrin, mucus, and inflammatory debris. Stool specimens were negative for enteric pathogens and Clostridium difficile cytotoxin. A full blood count of the patient revealed a total hemoglobin of 105 g/L, total white blood cell count of 8.3 10/L (eosinophil count of 3.1%, within normal limits of 1–6%) and platelet count of 417 10/L. As the patient remained ill and repeat colonoscopy subsequently revealed necrotic-looking areas, a surgical decision was made for colonic resection and ileorectal anastomosis. Postoperatively, the patient developed prolonged ileus which resolved 3 weeks later. The clozapine in her psychotropic regimen was stopped in December 2004. Presently, she is receiving sulpiride 100 mg/d, sodium valproate 2400 mg/d, fluvoxamine 25 mg/d, and remains psychiatrically stable. Pseudomembranous colitis often occurs in patients without a background of chronic enteric disease and has previously been associated with the use of antituberculous drugs, antibiotics, but not neuroleptics. This is the first reported case of pseudomembranous colitis in a patient after prolonged clozapine administration, which was further complicated by postoperative ileus. Although the pathogenesis of necrotizing colitis may be related to the anticholinergic properties of clozapine, it is less clear for pseudomembranous colitis, which warrants further investigation. Kang Sim, MBBS (Melbourne), MMed (Psychiatry) Tham Wai Yong, MBBS Emily Liew, BSc (Pharmacy) Hons Chua Hong Choon, MBBS, MMed (Psychiatry) Institute of Mental Health/Woodbridge Hospital, Singapore [email protected]