Can Clozapine Cause Diarrhea? Understanding This Rare Side Effect

October 11, 2025 •

4 min read

While most people associate the antipsychotic medication clozapine with severe constipation, diarrhea is a recognized, albeit less common, adverse effect. Case studies indicate that clozapine can cause gastrointestinal issues, including colitis, which can manifest as diarrhea, particularly in the initial weeks of treatment.

Quick Summary

This article explains how clozapine, while known for causing constipation, can also induce diarrhea in rare cases. It differentiates between clozapine-induced diarrhea and the more common overflow diarrhea stemming from constipation, and discusses associated risks like colitis and eosinophilia.

Key Points

Rare, but Possible Side Effect: While far less common than constipation, clozapine can rarely cause true diarrhea, often accompanied by other systemic symptoms like fever.
Watch for Overflow Diarrhea: Diarrhea can be a sign of a more serious, life-threatening condition where constipation leads to fecal impaction, causing watery stool to leak around the blockage.
Underlying Causes: Potential mechanisms for true clozapine-induced diarrhea include hypersensitivity reactions, eosinophilic colitis, or microscopic colitis.
Monitor Bowel Habits: Healthcare providers and patients should vigilantly track bowel frequency and consistency, as subjective reporting is often unreliable due to clozapine's effects.
Seek Medical Help: Any sudden change in bowel habits, especially accompanied by fever, abdominal pain, or distension, warrants immediate medical evaluation.
Discontinue with Care: In cases of true clozapine-related colitis, discontinuation of the drug may be necessary under medical supervision, with potential for re-challenge depending on the reaction.
Avoid Anti-Diarrheals with Impaction: Using anti-diarrheal medication for overflow diarrhea is dangerous and will worsen the underlying fecal impaction.
Prophylactic Laxatives: Guidelines often recommend starting prophylactic laxatives for all patients initiating clozapine to prevent the high risk of constipation and subsequent complications.

Clozapine is a powerful second-generation antipsychotic, and while highly effective for treatment-resistant schizophrenia, it is associated with a range of potentially severe side effects. Among these, gastrointestinal issues are particularly significant and can be life-threatening if not properly managed. The most prevalent gastrointestinal complication is severe constipation, but healthcare providers must also be aware that diarrhea can occur and requires careful investigation.

Constipation vs. Diarrhea: The Critical Distinction

Clozapine's potent anticholinergic and anti-serotonergic properties significantly slow gastrointestinal motility, leading to what is known as Clozapine-Induced Gastrointestinal Hypomotility (CIGH). This effect makes constipation a very common side effect, with some studies reporting it in up to 60% of patients. However, the opposite symptom—diarrhea—can also occur, and differentiating the cause is crucial for patient safety.

True Clozapine-Induced Diarrhea: A Rare Reaction

In some rare instances, patients can experience diarrhea as a direct adverse reaction to clozapine, particularly within the first few weeks of starting treatment. The exact mechanisms are not fully understood but can include hypersensitivity reactions and inflammation. Case reports have detailed several potential causes:

Microscopic or Eosinophilic Colitis: Inflammation of the colon, which can only be seen under a microscope, has been reported in patients taking clozapine. This inflammation can be associated with eosinophilia, an increase in a type of white blood cell, suggesting an allergic component.
Hypersensitivity (DRESS-like syndrome): Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe drug reaction that can involve multiple organs. Although a full DRESS syndrome presentation is rare, a milder, localized hypersensitivity reaction may cause gastrointestinal symptoms like diarrhea.

Overflow Diarrhea: A Dangerous Mask of Constipation

One of the most dangerous scenarios is when severe constipation and fecal impaction lead to a misdiagnosis of diarrhea. With impaction, hard, dry stool blocks the large intestine, but watery, loose stool can still leak around the blockage. This phenomenon, known as overflow diarrhea, can be mistaken for true diarrhea, prompting the use of inappropriate and potentially harmful anti-diarrheal medications. Treating overflow diarrhea with agents that further slow gut motility can worsen the impaction, increasing the risk of serious complications like intestinal obstruction, bowel perforation, or toxic megacolon. Deaths from CIGH complications are a serious and recognized risk.

Comparison of Diarrhea Causes on Clozapine


Characteristic	True Clozapine-Induced Diarrhea	Overflow Diarrhea from Fecal Impaction
Incidence	Rare (observed in case reports and small studies)	Less common than simple constipation, but a serious potential complication of CIGH
Onset	Often occurs early in treatment (1–3 weeks)	Can occur at any time during treatment, often after a prolonged period of severe constipation
Stool Type	May be watery diarrhea, often accompanied by other systemic signs	Watery stool leaking around a blockage; sometimes accompanied by solid lumps of stool
Accompanying Symptoms	Can include fever, abdominal pain, nausea, and eosinophilia	Abdominal pain, bloating, nausea, vomiting, distended abdomen, lack of appetite
Primary Mechanism	Likely an allergic, hypersensitivity, or inflammatory reaction	Fecal impaction caused by severe clozapine-induced gastrointestinal hypomotility
Immediate Action	Requires medical evaluation to rule out colitis; clozapine may need to be discontinued	Requires medical evaluation and aggressive treatment of the underlying impaction; anti-diarrheal meds are dangerous

Management and Clinical Guidance

The management of diarrhea in a patient taking clozapine requires immediate medical evaluation to determine the underlying cause. Simply prescribing an anti-diarrheal can have fatal consequences if the issue is overflow diarrhea from impaction.

For suspected true clozapine-induced colitis or other inflammatory reactions, discontinuation of clozapine may be necessary. The clinical team must carefully weigh the psychiatric benefits against the medical risks. If the patient's symptoms subside upon withdrawal, it provides strong evidence of a direct drug reaction. Re-challenging with clozapine is possible in some cases, with careful monitoring, but may lead to a recurrence of symptoms.

For constipation and the risk of overflow diarrhea, proactive management is key. The U.S. Food and Drug Administration (FDA) has issued warnings about the risks of CIGH, emphasizing the importance of monitoring bowel function. Prophylactic laxatives are recommended for all clozapine patients, especially those at higher risk.

Practical Steps for Healthcare Providers and Patients

Monitor bowel habits: Keep a consistent record of bowel movements. A significant change in frequency or consistency, especially a decrease, should be immediately reported.
Recognize red flags: Any episode of diarrhea accompanied by severe or prolonged abdominal pain, bloating, or vomiting requires urgent medical attention to rule out dangerous impaction.
Stay hydrated and active: Encouraging sufficient fluid intake, fiber-rich foods, and physical activity can help promote healthy bowel function.
Avoid certain laxatives: Bulk-forming laxatives like psyllium should be avoided in patients with CIGH, as they can exacerbate blockage.
Consultation: In complex cases, especially those with severe or refractory gastrointestinal issues, consultation with a gastroenterologist is highly recommended. The mortality rate for CIGH has been reported to be higher than that of agranulocytosis, a much more well-known risk. For further reading on management guidelines, the NY.gov website offers guidance on managing clozapine-induced gastrointestinal hypomotility.

Conclusion

While constipation is the more common and well-known gastrointestinal side effect of clozapine, diarrhea is also a possibility and can indicate one of two serious issues. It could be a rare, direct drug reaction, such as colitis, or it could be a dangerous sign of fecal impaction, known as overflow diarrhea. For patients on clozapine, vigilant monitoring of bowel habits is essential. The presence of diarrhea, especially alongside other systemic symptoms or a history of constipation, should not be ignored but rather considered a medical emergency until proven otherwise. Prompt and accurate diagnosis is critical for patient safety, highlighting the need for increased awareness among both patients and healthcare providers.

Frequently Asked Questions

No, diarrhea is considered a rare side effect of clozapine. The more common and serious gastrointestinal problem is severe constipation caused by clozapine's effect on gut motility.

Yes. Diarrhea, especially after a period of constipation, can be a sign of overflow diarrhea, where watery stool leaks around a dangerous fecal impaction. This is a medical emergency and should be investigated immediately.

Clozapine-induced diarrhea is a rare, direct reaction possibly involving colitis or a hypersensitivity reaction, often appearing early in treatment. Overflow diarrhea is a complication of severe, unrecognized constipation, where liquid stool passes around a blocked bowel. It requires immediate medical attention and is treated by clearing the impaction, not with anti-diarrheals.

Beyond a change in bowel habits, warning signs include persistent abdominal pain or bloating, nausea, vomiting, reduced appetite, and fever. Seek urgent medical care if these occur.

Diagnosis requires a thorough medical evaluation, including a review of recent bowel habits, physical examination, and potentially additional tests to rule out infections, colitis, or fecal impaction.

No, you should not use anti-diarrheal medication without medical guidance. If the diarrhea is actually overflow diarrhea from impaction, these medications could worsen the blockage and lead to life-threatening complications.

Proactive management is key. This includes ensuring adequate hydration, eating a high-fiber diet, maintaining physical activity, and often involves taking prophylactic laxatives, such as docusate and senna.