Managing Clozapine-Induced Constipation: Practical Advice

Jonathan Meyer, MD

Clinical Professor of Psychiatry
University of California, San Diego

Last updated: July 5, 2018
Routine management of constipation is a critical part of clozapine treatment. There are case reports of fatal ileus related to clozapine therapy.

  • The first step is to minimize the use of systemic anticholinergics.
  • Docusate should be used routinely.  Bulk agents can make constipation worse and should be avoided.
  • After docusate, the next agent to add is PEG 3350.
  • Lubiprostone, a more expensive agent, can also be tried. It can be used if the combination of docusate + PEG-3350 + a stimulant is not effective.


Most people recognize that constipation is a significant problem for patients with schizophrenia, with an up to 60% incidence. The more serious problem is that some patients may develop ileus and there are case reports of fatal ileus related to clozapine therapy. So routine management of constipation is a critical part of clozapine treatment. A Danish study was published looking at 26,000 schizophrenic patients from records spanning over a decade. Treatment with clozapine increased the odds ratio for the development of ileus almost seven-fold, in a manner almost comparable to other types of anticholinergic agents. It’s this reason alone which I state that in managing sialorrhea one should use systemic anticholinergics only as drugs of last resort.

 


Here is the management plan which we have developed primarily for inpatient use, but certainly should be considered for outpatients as well. In many instances, one may want to get an abdominal x-ray just to document the baseline. Sometimes, for people who are very ill, they may not be able to report whether they’re having problems with their bowel movements. It’s something to educate people if they haven’t gone for a couple of days to let somebody know. If they’re on an inpatient unit, the staff should document this as well. And of course, we always encourage adequate fluid intake. The first step is to minimize the use of systemic anticholinergics. These contribute significantly to the problem and absolutely need to be avoided unless they cannot to the management of sialorrhea. Everybody should start on docusate routinely. If they state it gives them diarrhea, that’s fine. You can stop it. But this is rarely a problem. Docusate in and of itself is often not sufficient.

 


Then next, we will add classes of agents in order of increasing noxiousness. So the most benign agent next will be an osmotic laxative. Typically, we go to polyethylene glycol 3350 which is also called Miralax in many countries. We prefer this to lactulose as the overall evidence base, it’s a superior agent to lactulose. If the osmotic agent does not work, we will then next add a stimulant either senna or bisacodyl and max dose out as well. The idea is you’re going to continue to add agents and not take away things until you actually get what you need. One thing you’ll see here is that we do not recommend adding bulk forming laxatives. Often, our patients are already constipated and the addition of psyllium or other bulk forming laxatives could actually exacerbate the problem especially if a person does not maintain adequate water intake. These are the types of medicines which are often used for high functioning people without mental disorders who can follow the directions and know if they’re developing an ileus. This is not the population that we’re treating. At our state hospital, we actually banned the use of psyllium simply because we have a low functioning, very ill population and we have found that the use of psyllium often causes more problems than it solves.

 


So here is a summary of data looking at the effectiveness of various types of agents. The effectiveness of bulk forming agents is relatively low in terms of the quality of evidence. Again, this is something to be used for outpatients who don’t have mental illness and not for people on clozapine. We feel that the evidence for PEG 3350 or MiraLax is quite strong and we use this over lactulose. The preferred use of lactulose in our setting is to manage hyperammonemia from divalproex. But we prefer MiraLax for the management of constipation from clozapine. Then next, you have the option of either bisacodyl or senna. And then lastly, we have these two newer drugs. These are very expensive agents. It may not be routinely available. But again if your option is having to take somebody off of clozapine versus continue it, we feel that there is value in using these more expensive proprietary agents. I had published a case report several years ago about the use of lubiprostone in the state hospital system in a patient who required surgery for clozapine-induced ileus. It worked out very well and we generally will encourage people even if somebody had to have surgery or hospitalization for ileus to use lubiprostone before stopping clozapine.

 


Again, the key points are bulk agents can make constipation worse and generally should be avoided in clozapine-treated patients. After docusate, the next agent to add is going to be PEG 3350 which is MiraLax and then a stimulant and then lastly, if needed, lubiprostone.

 

References

  1. Hesketh PJ. N Engl J Med 2008 358: 2482-2494.
  2. Nielsen J and Meyer JM. Risk factors for ileus in patients with schizophrenia. Schizophrenia Bulletin 2010, 1-7
  3. Nielsen J and Meyer JM. Risk factors for ileus in patients with schizophrenia. Schiz Bull 2012; 38(3):592-8
  4. Meyer JM, Cummings MA. Lubiprostone for treatment-resistant constipation associated with clozapine use. Acta Psych Scand 2014; 130(1): 71-72.p
  5. American College of Gastroenterology Monograph on the Management of Irritable Bowel Syndrome and Chronic Constipation. American Journal of Gastroenterology 2014; 109: S2-S26.

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