Clozapine Induced Constipation and Gastrointestinal Hypomotility (CIC & CIGH) – Case Report and Summary of Management Principles

CASE REPORT

This case is of a 53-year-old Caucasian male who presented with severe abdominal pain and bilious vomiting to the emergency department. There was no melaena or haematemesis. He was diagnosed with schizoaffective disorder of over 10 years and was treated with clozapine 700 mg/day for the past year.

Other medications included olanzapine 10 mg twice a day, lithium carbonate 250 mg twice a day, iron tablets, multivitamins and a proton pump inhibitor which he had been taking for over 3 years. [Rege & Lafferty, 2008]

Learning points: 

• The concurrent administration of anticholinergics (e.g. tricyclic antidepressants, benztropine,  antipsychotics) or other constipating agents, such as iron supplements, may exacerbate constipation.
• Olanzapine can also exacerbate constipation due to its cholinergic antagonism. [Zhang, Jiarui et al., 2016]

He lived in a group home, and the staff reported him as stable and compliant with medications.

The patient had complained of abdominal pain and constipation on one occasion in the past. He was treated by a physician but did not receive ongoing treatment.

Examination: 

On examination in the emergency department, the patient was drowsy, sweaty, afebrile, tachycardic and hypotensive. The abdomen was distended, and the patient had severe generalised abdominal pain.

His vomitus was bilious and had an offensive odour. His investigations revealed a raised white cell count with normal urea, electrolytes and liver function tests.

His blood gases showed metabolic acidosis.

Learning points: 

The patient has several red flags (covered later), which would prompt immediate referral to the emergency department.

• Severe generalised abdominal pain
• Distended abdomen
• Metabolic acidosis
• Bilious vomiting

In some cases, the examination may be unremarkable, so clinicians should have a high index of suspicion.

Any abdominal pain/discomfort lasting over an hour should prompt further detailed history.

Abdominal Radiography

The abdominal x-ray revealed multiple fluid levels and faecal loading, mainly in his large bowel. The computed tomography scan similarly showed that his transverse and descending colon was loaded with faeces until the rectum, with resultant small bowel dilatation. There was no evidence of mechanical obstruction. He was diagnosed with sepsis due to faecal impaction.

Standing abdominal X-ray showing multiple fluid levels indicating intestinal obstruction

Supine abdominal X-ray showing dilated small bowel loop (left of spine on image)

Management: 

• Urgent exploratory laparotomy revealed severely impacted faeces in the small and large bowel.
• A manual bowel disimpaction was performed. All medications were ceased.

Relapse: 

Olanzapine and lithium were gradually re-introduced after 10 days as the patient showed signs of a relapse of their schizoaffective disorder.

The illness management was challenging because of a fluctuating mental state, with elevated mood and flight of ideas interspersed with episodes of delirium. No organic cause for his delirium was found. However, sepsis was deemed a possible contributing factor in light of his raised white cell counts.

The delirium gradually subsided over a week, but the patient continued to be elevated in mood, with flight of ideas and pressured speech.

Learning points: 

• Clozapine reintroduction may be associated with delirium. [Wilkins-Ho and Hollander, 1997], [Seoane et al., 2005], [Centorrino  et al., 2003], [Szymanski et al., 1991]
• Concurrent administration of clozapine and benzodiazepines may also cause delirium.[Jackson et al., 1995]

Clozapine Reintroduction: 

Clozapine was gradually re-introduced and increased to a dose of 350 mg/day in two divided doses. In addition, lactulose and docusate sodium (coloxyl with senna) were prescribed concurrently in liaison with a gastroenterologist.

Three weeks after the commencement of clozapine with concurrent laxative administration, the patient developed a further episode of severe constipation with faecal impaction. The clozapine was ceased.

His normal bowel movements resumed after several fleet enemas. He was commenced on risperidone 2 mg once a day. The patient continues to be thought-disordered with elevated mood. He requires a weekly fleet enema.

Learning points: 

• According to the Porirua Protocol, recent evidence shows that gastrointestinal transit times improved significantly when docusate and senna augmented by Macrogol were prescribed to clozapine-treated patients.
• Another study showed Macrogol (osmotic laxative) effectively prevented clozapine-induced constipation in psychiatric intensive care and reduced the incidence of severe constipation, especially in patients receiving clozapine and zuclopenthixol. [Bulot et al., 2016]
• Both the above strategies were not employed in our patient.
• Prophylactic laxatives at appropriate doses, along with dietary and lifestyle changes, are recommended when re-introducing clozapine in a patient with a history of clozapine-induced constipation or CIGH. Cases of successful clozapine re-challenge following bowel perforation and bowel infarction, with notably smaller doses of clozapine alongside many lifestyle changes and closer monitoring of bowel habits, have been reported. [Attard et al., 2019]
• More recent options include secretagogues (see later), orlistat and bethanechol.
• This case highlights the importance of prevention and early detection of constipation associated with clozapine treatment to prevent potentially fatal complications related to constipation. It also shows the difficulties associated with clozapine reintroduction.

In another case of severe constipation with clozapine not responding to enemas and osmotic, stimulant and emollient laxatives, prucalopride was successfully used by the author in conjunction with a physician.  Subsequently, the patient remains on docusate and senna as a prophylactic agent.

Learning point: 

• A number of secretagogues such as prucalopride, linaclotide, and plecanotide are evidence-based in treating constipation, but only prucalopride has been used in a case report with success. The other two have not been studied in CIC.
• Lubiprostone a Prostaglandin E1 analogue has also been trialled in CIC.

CLOZAPINE AND CONSTIPATION - PATHOPHYSIOLOGY

Clozapine is associated with the highest risk of causing con­stipation amongst antipsychotics. Patients are three times more likely to be constipated when treated with clozapine than other antipsychotics [Taylor et al., 2020].

Besides fatal outcomes, constipation can lead to haemorrhoids, faecal and urinary incontinence, urinary tract infections, rectal bleeding, hernias, worsening of reflux, transient ischaemic attacks and syncope.

The aetiology of clozapine-induced GI hypomotility and constipation is multifactorial :

• Strong anticholinergic effect that can delay colonic transit and relax intestinal smooth muscle. Patients on clozapine have 4 times longer colonic transit times.
• Serotonin receptor antagonism may potentiate its constipating effect.
• Anti-histaminergic effect alongside its sedative effects and resultant sedentary behaviour which increases the risk of constipation
• Hypersalivation with clozapine increases the risk of dehydration. [See management of hypersalivation with clozapine]
• Patients with schizophrenia have a poor diet characterised by high fat and low fibre intake. [McCreadie et al., 1998]
• Clozapine impairs blood glucose levels, and the development of diabetes itself can impair gut motility due to diabetic neuropathy. [Chelimsky et al., 1996], [Camilleri and Bharucha, 1996] 
• The detection of constipation may be delayed by the altered pain sensitivity in people with schizophrenia, leading to fewer complaints of abdominal pain. [Dworkin, 1994]
• Flattened affect, thought disorder, perceptual disturbances, delusions, and cognitive impairment might also contribute to impaired verbal expression of bowel symptoms.

Risk Factors for Constipation with Clozapine:

Longer duration of clozapine treatment and clozapine dose has been linked to constipation, but the literature is conflicting. The odds ratio of a fatal outcome increased by 1.21 (95% CI 1.02–1.44) for every 2 years on clozapine.[Every-Palmer & Ellis, 2017]

In clozapine-associated constipation, death can result from two main mechanisms.

• Inhalation of faeculent vomitus.
• Faecal impaction, leading to bowel necrosis and bacterial sepsis due to the translocation of bacteria from the gut.

CLINICAL ASSESSMENT OF CIGH

PREVENTION AND MONITORING

• Identify and modify risk factors for constipation before starting clozapine
• Psychoeducation to the patient about the importance of preventing constipation and alerted to the early warning signs.
• Simple advice such as increasing fibre intake, adequate fluid intake and exercise
• There is an argument that people taking clozapine should be offered prophylactic laxative treatment to prevent constipation. [Attard et al., 2019]

We challenge the status quo of reserving laxative use for those patients with identified or reported clozapine-induced constipation. Given the prevalence of clozapine-induced constipation and the high mortality rate associated with this side-effect, we are of the view that it is ethically sound to present an alternative: prophylactic use of laxatives throughout the patient’s entire treatment with clozapine. We recommend review of regular laxatives only if diarrhoea develops or a change in frequency of bowel movements necessitates their withdrawal. [Attard et al., 2019]

• The Porirua protocol recommends docusate and senna for all clozapine treated patients as part of prevention.

TREATMENT OF CLOZAPINE INDUCED CONSTIPATION

Recently the Porirua protocol and the Maudsley guidelines [which is based on the Porirua protocol with some minor differences] provides the main guidance in treating clozapine-induced constipation.

We combine the algorithms in the diagram below to provide an algorithm that can be used clinically.

In established cases of constipation, the initial management includes increased exercise, fluid intake and dietary fibre.

Where constipation occurs during clozapine initiation, a slow titration is recommended and use of the minimum effective dose (colonic transit times correlate with plasma clozapine levels). [Every‐Palmer et al., 2017]

For patients who do not respond to lifestyle measures, a trial with an osmotic laxative is recommended (e.g Macrogol / movicol). [Taylor et al., 2020], [Every-Palmer et al., 2020],  [Folden et al., 2002], [American College of Gastroenterology Chronic Constipation Task Force, 2005]

Bulk‐forming laxatives are not effective in slow‐transit constipation and should therefore be avoided.  In contrast, stimulant laxatives such as Senna (7.5-15 mg) should be used early.

Osmotic laxatives: 

• Polyethylene glycol-based laxatives (Macrogol /Movicol) provide a long-term benefit in patients with faecal impaction.
• They can be considered early (along­ side a stimulant laxative e.g Senna) instead of the emollient laxative docusate sodium.
• Docusate and senna augmented by macrogol according to the Porirua Protocol significantly improve GI transit times in clozapine-treated patients
• Macrogol also reduced the incidence of severe constipation, especially in patients receiving clozapine and zuclopenthixol. [Bulot et al., 2016]

Stimulant Laxatives: 

• Stimulant laxatives increase intestinal motility and secretion by stimulating the sensory nerve endings of the colonic mucosa.
• e.g. Senna 7.5 – 30 mg at night, bisacodyl, and sodium picosulfate
• Monitor for hypokalemia with prolonged use
• They are recommended for prevention and initial treatment of CIC and CIGH.

CONCLUSION

Constipation can be a serious side effect of clozapine and, if unrecognised or untreated, can lead to death. Psychiatrists should be proactive in asking about side effects such as constipation.

Similarly, general practitioners, physicians and surgeons need to be familiar with the seriousness of clozapine-induced constipation and bring it to the attention of the treating psychiatrist.

Clozapine serves our patients well but both patients and clinicians need to be vigilant about its side effects and it is our role to educate patients in this regard.