Constipation on Clozapine

How to prevent the #1 cause of death on clozapine

We worry about a drop in white blood count (neutropenia) on clozapine, but ileus is an even bigger problem. This intestinal blockage is caused by slowing of the gut, and has a fatality rate 5-10 times higher than neutropenia (15-28% vs 2-4%).¹ Here are ways to manage it.

Preventative Treatment

Ileus is part of a spectrum of gastrointestinal hypomotility that ranges from constipation to bowel obstruction. 80% of clozapine-treated patients have some evidence of hypomotility, or slowing, in their bowels, so it’s safe to plan for the worst. Start patients on docusate (Colace) 250 mg qhs along with their first clozapine prescription.¹

Lower constipating medications

Patients with schizophrenia often take other constipating medications, such as benztropine, diphenhydramine (Benadryl), other antipsychotics, and increasingly GLP-1 agonists. Lower these whenever possible. Anticholinergics, for example, raised the risk of ileus six-fold when taken with clozapine.²

• GLP-1 agonists: Semaglutide (Ozempic, Wegovy, Rybelsus), liraglutide (Victoza, Saxenda), dulaglutide (Trulicity)
• Opioids: Oxycodone, fentanyl, hydrocodone, codeine, buprenorphine, Suboxone, tramadol, and others
• NSAID pain relievers: Ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib (Celebrex), diclofenac (Voltaren), meloxicam (Mobic)
• Anticholinergics: Cyclobenzaprine, hydroxyzine, promethazine, oxybutynin, paroxetine, and others
• Tricyclic antidepressants: Especially amitriptyline, clomipramine, doxepin, and trimipramine
• Antipsychotics: Especially clozapine, olanzapine, quetiapine, chlorpromazine, and thioridazine
• Calcium channel blockers: Verapamil, diltiazem, nimodipine
• Parkinsonian medications: Benztropine, diphenhydramine, trihexyphenidyl
• Meds for overactive bladder: Oxybutynin, tolterodine, trospium, darifenacin, solifenacin
• Iron

Caution with Bulk-forming Laxatives

Bulk-forming laxatives like psyllium (Metamucil), polycarbophil (FiberCon), and methylcellulose (Citrucel) may help general constipation, but they can be dangerous when the cause is clozapine-induced hypomotility.¹ The bulk they form can block the intestines. For the same reason, insoluble fibers should be minimized in the diet. These are the ones that don’t dissolve in water: nuts, seeds, celery, and the skin of fruits and vegetables. A slow gut does better with soft, moist foods and lots of hydration. Here is a patient-friendly guide to dietary steps for gastrointestinal hypomotility.

An Evidence Based Protocol

Constipation may be a common medical problem, but many of its treatments have surprisingly little evidence to support their use. The Porirua Protocol is the only evidence-based algorithm for managing hypomotility on clozapine. In a small study, it reduced the prevalence of gastrointestinal hypomotility from 86% to 50%.³

Beyond the Protocol

Many patients on clozapine end up needing two treatments to manage their constipation on a daily basis. In addition to the options in the Porirua Protocol, there is lactulose (30 ml qd to bid) and bisacodyl (5 mg qhs to bid). It’s best to choose options with different mechanisms of action. Patients may also require a rescue therapy for exacerbations, such as:

• Magnesium hydroxide (400 mg magnesium hydroxide per 5 ml): 5 ml po qd prn
• Magnesium citrate (17.45 g magnesium citrate per 300 ml): 300 ml po q week prn
• Mineral or water-based enemas: 1 per rectum qd prn

If impaction is suspected, magnesium should be avoided and enemas are preferred.¹

If the patient needs frequent rescue therapies, rethink their treatment. Secretogogues are good second-line options:

• Lubiprostone (8-24 mcg bid, take with food and water)
• Linaclotide (145-290 mcg qd, give > 30 min before first meal)
• Plecanatide (3 mg qd)

Emergencies

Total bowel obstruction, or ileus, is a medical emergency that necessitates referral to urgent care or an emergency department. Left untreated, ileus can progress to bowel ischemia, perforation, peritonitis, sepsis, and death. Warn patients early in the treatment to call you if they have any of the signs above.¹

Warning Signs of Ileus

• Fewer than 3 bowel movements a week
• Hard or dry stools
• Difficulty passing gas
• Moderate to severe abdominal pain lasting > 1 hour
• Nausea, vomiting
• Bloating or belly swelling
• Bloody diarrhea

The Bottom Line

Gastrointestinal hypomotility is serious and common on clozapine, but careful management can help patients stay on this life-saving therapy. Despite its daunting list of medical risks, patients who take clozapine live longer than those on other antipsychotics.⁴

References

1. Meyer JM & Stahl SM. The Clozapine Handbook. Cambridge University Press; 1 edition (May 16, 2019)
2. Nielsen J, Meyer JM. Risk factors for ileus in patients with schizophrenia. Schizophr Bull. 2012;38(3):592–598.
3. Every-Palmer S, Ellis PM, Nowitz M, et al. The porirua protocol in the treatment of clozapine-induced gastrointestinal hypomotility and constipation: a pre- and post-treatment study. CNS Drugs. 2017;31(1):75–85.
4. Vermeulen JM, van Rooijen G1, van de Kerkhof MPJ, et al. Clozapine and long-term mortality risk in patients with schizophrenia: A systematic review and meta-analysis of studies lasting 1.1-12.5 years. Schizophr Bull. 2019;45(2):315-329

—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report