The Porirua Protocol in the Treatment of Clozapine-Induced Gastrointestinal Hypomotility and Constipation: A Pre- and Post-Treatment Study

Abstract

Background: Clozapine, an antipsychotic used in treatment-resistant schizophrenia, causes slow gastrointestinal transit in 50–80% of patients. Clozapine-induced gastrointestinal hypomotility is both common and serious, and potential complications include severe constipation, ileus, bowel obstruction and related complications, with a higher mortality rate than clozapine-related agranulocytosis. Little evidence exists on its prevention and management. Method: Using a well-validated radiopaque marker (‘Metcalf’) method, we compared colonic transit times (CTTs) of clozapine-treated inpatients not receiving laxatives with their transit times when receiving laxatives, with treatment prescribed according to the Porirua Protocol for clozapine-related constipation (docusate and senna augmented by macrogol 3350 in treatment-resistant cases). Results: The median age of participants was 35 years, and median clozapine dose, plasma level and duration of treatment were 575 mg/day, 506 ng/mL and 2.5 years, respectively. Overall, 14 participants (10 male) were enrolled and all completed the study. Transit times improved markedly with laxative treatment. Median colonic transit without laxatives was 110 h (95% confidence interval [CI] 76–144 h), over four times longer than normative values (p < 0.0001). Median CTT with laxatives was 62 h (95% CI 27–96 h), a 2-day reduction in average transit time (p = 0.009). The prevalence of gastrointestinal hypomotility decreased from 86% pre-treatment to 50% post-treatment (p = 0.061). Severe gastrointestinal hypomotility decreased from 64 to 21% (p = 0.031). Subjective reporting of constipation did not correlate well with objective hypomotility, and did not change significantly with treatment. Conclusion: Treating clozapine-treated patients with docusate and senna augmented by macrogol appears effective in reducing CTTs in clozapine-induced constipation. Randomised controlled trials are the next step. Australian New Zealand Clinical Trial Registry ACTRN12616001405404 (registered retrospectively).