Daily Laxative for Clozapine-Induced Constipation
For patients on clozapine, initiate prophylactic treatment with a stimulant laxative (senna) combined with an osmotic laxative (polyethylene glycol 17g with 8 oz water twice daily), and avoid docusate as it provides no benefit.
Prophylactic Approach
Clozapine causes gastrointestinal hypomotility in 50-80% of patients, and this is a serious complication that can progress to bowel obstruction and has a higher mortality rate than clozapine-related agranulocytosis 1. Unlike other medication side effects, patients do not develop tolerance to clozapine-induced constipation, making prophylaxis essential 2.
First-Line Prophylactic Regimen
- Stimulant laxative (senna) as the foundation of therapy 2
- Polyethylene glycol (PEG): 17g (one heaping tablespoon) mixed with 8 oz water twice daily 2
- Maintain adequate fluid intake throughout treatment 2
What NOT to Use
- Docusate should NOT be used - multiple studies demonstrate it provides no benefit when added to senna and is less effective than senna alone 2
- Avoid supplemental fiber (such as psyllium) - it is ineffective for clozapine-induced constipation and may actually worsen the condition 2
Treatment Algorithm When Constipation Develops
Step 1: Assessment
- Rule out impaction and bowel obstruction through physical examination and abdominal imaging if indicated 2
- Assess for other contributing factors: hypercalcemia, hypokalemia, hypothyroidism, diabetes mellitus 2
- Goal: achieve one non-forced bowel movement every 1-2 days 2
Step 2: Escalate Laxative Therapy
If constipation persists despite prophylaxis, add:
- Bisacodyl: 10-15 mg, 2-3 times daily 2
- Alternative osmotic agents: Lactulose 30-60 mL twice to four times daily, sorbitol, or magnesium-based products (magnesium hydroxide 30-60 mL daily or magnesium citrate 8 oz daily) 2
Step 3: Advanced Interventions
The Porirua Protocol has demonstrated efficacy specifically for clozapine-induced constipation, showing a 2-day reduction in colonic transit time and reducing severe hypomotility from 64% to 21% of patients 1. This protocol uses:
- Docusate and senna as baseline
- Augmented with macrogol 3350 (polyethylene glycol) in treatment-resistant cases 1
Newer agents with emerging evidence:
- Prucalopride 2 mg once daily: Superior to lactulose in head-to-head comparison, with 85.7% of patients achieving ≥3 spontaneous complete bowel movements per week by week 4 (versus 60% with lactulose) 3
- Lubiprostone: Shows therapeutic potential with low adverse reaction risk in case series, though evidence remains limited 4
Step 4: Rescue Therapy for Impaction
- Glycerin suppositories 2
- Manual disimpaction with pre-medication using analgesics ± anxiolytics 2
- Enemas (tap water, saline, or sodium phosphate) - use sparingly due to electrolyte concerns 2
Critical Clinical Pearls
Gender considerations: Female patients experience higher rates of constipation (49.1%) compared to males (29.1%), and male patients may be undertreated 5. Maintain high vigilance regardless of patient sex.
Dose-independent effect: Constipation occurs at any clozapine dose or plasma concentration 5. Norclozapine concentrations (the metabolite) may predict constipation risk, with patients requiring laxatives having 29% higher norclozapine levels 5.
Subjective reporting is unreliable: Patients' subjective reports of constipation do not correlate well with objective gastrointestinal hypomotility 1. Do not rely solely on patient complaints; maintain prophylaxis regardless.
Common Pitfalls to Avoid
- Never wait for constipation to develop before starting prophylaxis - this is a preventable complication 2, 1
- Do not use docusate alone or in combination - it adds no benefit and wastes resources 2
- Avoid fiber supplements - they worsen clozapine-induced constipation rather than help 2
- Do not underestimate severity - this can progress to fatal bowel obstruction and perforation 6, 1
- Increase laxative doses when increasing clozapine doses to maintain prophylaxis 2