Clozapine-treated Patients Have Marked Gastrointestinal Hypomotility, the Probable Basis of Life-threatening Gastrointestinal Complications: A Cross Sectional Study

•This study confirms that the antipsychotic clozapine has profound effects on bowel function•Median colonic transit time was 104.5 h if taking clozapine, > 4 times normative values or if on another antipsychotic•Right, left and rectosigmoid motility were all significantly impaired suggesting pan-colonic pathology•Colonic transit times were positively correlated with clozapine plasma level, but not other variables•This is clozapine-specific: 80% of clozapine patients and 0% of those taking other antipsychotics had abnormal GI transit•Findings may explain the clozapine-related morbidity and mortality from GI complications, such as bowel obstructionFor every thousand patients treated with clozapine, 300–600 will suffer constipation and at least four will develop serious gastrointestinal complications (including ileus, bowel obstruction, bowel ischaemia or necrosis), from which one will die. Iatrogenic mortality is higher from gastrointestinal complications than from agranulocytosis. However, the mechanism for these gastrointestinal complications has been poorly understood.This study confirms clozapine has profound effects on bowel motility, with colonic transit in clozapine-treated patients taking four times longer than normal. 80% of clozapine patients had gastrointestinal hypomotility. Self-reported constipation had low sensitivity in predicting hypomotility. Prophylactic laxative treatment is recommended in all clozapine-treated patients.

BackgroundGastrointestinal side effects are particularly common with clozapine and occur with other antipsychotics, ranging from mild constipation to fatal bowel obstruction and/or ischemia. While this adverse-effect spectrum has been attributed to ‘gastrointestinal hypomotility’, gastrointestinal transit times in antipsychotic-treated patients have not previously been measured, making this mechanism speculative.MethodsUsing standardized radiopaque marker (‘Metcalf’) methods we established colonic transit times of antipsychotic-treated psychiatric inpatients and compared them with population normative values. We analyzed results by antipsychotic type, antipsychotic dose equivalent, anticholinergic load, duration of treatment, gender, ethnicity, and age.OutcomesFor patients not prescribed clozapine, median colonic transit time was 23 h. For patients prescribed clozapine, median transit time was 104.5 h, over four times longer than those on other antipsychotics or normative values (p < 0.0001). Eighty percent of clozapine-treated patients had colonic hypomotility, compared with none of those prescribed other antipsychotics (olanzapine, risperidone, paliperidone aripiprazole, zuclopenthixol or haloperidol). In the clozapine group, right colon, left colon and rectosigmoid transit times were all markedly abnormal suggesting pan-colonic pathology. Hypomotility occurred irrespective of gender, age, ethnicity, or length of clozapine treatment. Transit times were positively correlated with clozapine plasma level (rho = 0.451, p = 0.045), but not with duration of treatment, total antipsychotic load or demographic factors.InterpretationClozapine, unlike the other antipsychotics examined, causes marked gastrointestinal hypomotility, as previously hypothesized. Pre-emptive laxative treatment is recommended when starting clozapine.