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

Posted on:November 23, 2021

Last Updated: March 16, 2022

Time to read: 11–14 minutes

Constipation is a common side effect of clozapine and may cause death if severe. Unlike agranulocytosis and myocarditis, clozapine’s effects on bowel motility are both under-appreciated and under-recognised. The reported incidence of treatment-emergent constipation is 14% based on patients taking clozapine in clinical trials.[Novartis Clozaril package]

However, this may be an underestimate, with the prevalence of Clozapine induced constipation (CIC) more likely to be 30–60%. [Attard et al., 2019]

Clozapine induced GI hypomotility (CIGH) is more prevalent and affects up to 73% of users; however, self-reporting is low. [Every-Palmer et al., 2020]

CIGH has a higher mortality rate than blood dyscrasias and is more common. Serious CIGH is a medical emergency.

A study that examined all reports of clozapine-induced severe gastrointestinal hypomotility (CIGH) submitted to the Australian Therapeutic Goods Administration, and New Zealand Pharmacovigilance Centre between 1992 and 2013 [A total of 43,132 people commenced clozapine] showed that: [Every-Palmer & Ellis, 2017]

160 patients had serious gastrointestinal hypomotility with clozapine the suspected cause (37/10,000 clozapine users)
66.3% were male
Few had received laxatives
At least 29 patients died (7/10,000 clozapine users), a reported case fatality rate of 18%

There was no consistent relationship between age, dose, or duration of treatment and the onset of life-threatening CIGH, making it hard to predict which clozapine-treated patients are most at risk of serious CIGH. [Every-Palmer & Ellis, 2017]

At the end of January 2020, the FDA issued a communications statement which [strengthened] an existing warning

That constipation caused by the schizophrenia medicine clozapine can, uncommonly, progress to serious bowel complications. [FDA ]

CIC can occur at any stage of clozapine administration. In contrast to agranulocytosis and myocarditis, where the risk is highest in the first 2 months, the risk for complications from constipation is high throughout the duration of clozapine treatment. [Rege & Lafferty, 2008]

Untreated constipation can lead to severe complications, including ileus, faecal impaction, colonic obstruction, toxic megacolon, bowel ischaemia and necrosis, perforation, and sepsis, all of which can be fatal. The prevalence of life‐threatening constipation with clozapine is 0.3%, and case fatality is as high as 28%. [Palmer et al., 2008]

Below is a summary of the key points in Clozapine Induced Constipation developed by Dr Pranav Mahajan: LOOSE STOOL [Original Poster]

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.

Informed consent was obtained from the patient and his family to publish this report. All identifying information has been removed to protect patient confidentiality.

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

1. History of bowel habits before the onset of constipation.

2. History of stool frequency, consistency, and size.

Note that diarrhoea may indicate constipation with overflow
Recent changes in bowel habits may be a feature of gastrointestinal malignancy.
On an inpatient ward, consider the use of a stool chart.

3. Screen for other associated Red Flag signs

Moderate to severe abdominal pain lasting over an hour

Any abdominal pain/discomfort lasting over an hour

AND

Any one or more of the following:

abdominal distension
overflow or bloody diarrhoea
vomiting
absent or high-pitched bowel sounds
metabolic acidosis
hemodynamic instability
leukocytosis
signs of sepsis

The above should prompt an urgent referral for emergency treatment.

4. Diet (including fluid intake) and physical activity

5. Past medical history

Rule out organic causes:

Hypothyroidism
Diabetes, panhypopituitarism and phaeochromocytoma
Electrolyte abnormalities (e.g. hypercalcaemia, hypokalaemia)
Gastrointestinal obstruction (e.g. strictures or malignancy)
Neurological disorders (e.g. Parkinson’s disease, multiple sclerosis, dementia, Hirschprung’s disease, spinal cord lesions, diabetic autonomic neuropathy)
Irritable bowel syndrome (may be associated with constipation)
Previous abdominal surgery (adhesions)
Inflammatory bowel disease (strictures)
Scleroderma, myotonic dystrophy and amyloidosis
Anorexia nervosa
Pregnancy
Learning disability

5. Drug history:

Medications that increase the risk of constipation:

Some antihypertensive, e.g. calcium channel blockers (reduce smooth muscle contractility)
Medications for urinary incontinence, e.g. oxybutynin
Analgesics like opioids and nonsteroidal anti-inflammatory agents
Any drugs with anticholinergic effects: antispasmodics, some antidepressants (tricyclics, paroxetine, reboxetine), anti-Parkinsonian drugs, older sedating antihistamines (e.g. chlorphenamine), antipsychotics (especially clozapine). Venlafaxine and monoamine oxidase inhibitors such as phenelzine and isocarboxazid
Serotonin antagonists (e.g. ondansetron)
Diuretics
Oral iron supplementation
Calcium/aluminium antacids

6. Abdominal examination:

The examination may be normal.

Auscultation:

High‐pitched ‘tinkling’ bowel sounds may indicate obstruction.

Digital rectal examination may be performed to identify a faecally loaded rectum, masses, abnormal sphincter function (ask the patient to squeeze during examination), blood in stool, or fissures/haemorrhoids.

7. Investigations:

FBC (for anaemia or evidence of infection)
C‐reactive protein (infection)
U and E’s and Calcium (for evidence of dehydration, hypokalemia, or hypercalcaemia)
HbA1c
TFTs
Pregnancy test if indicated in a woman of childbearing age with abdominal pain.

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.

Intestinal Secretagogues:

Prucalopride: Selective 5‐HT4 receptor agonist that promotes gut peristalsis and thus gastrointestinal transit and can be used in chronic constipation when other laxatives fail to provide an adequate response (2 mg once daily). It has been used successfully in clozapine related constipation.[Thomas et al., 2018]
Linaclotide and Plecanatide: Oral guanylate cyclase C agonists. They have not been trialled in clozapine-induced constipation.
Lubiprostone: Prostaglandin E1 analogue has been successfully used in a patient with a history of clozapine-induced ileus and small bowel obstruction where clozapine management was continued and supplemented with docusate, lactulose, and lubiprostone. [Meyer & Cummings, 2014]

Others:

Orlistat and Bethanechol are two other agents used in CIGH at case report level evidence.[Attard et al., 2019]

While the long term use of emollient and osmotic laxatives is considered safe, there were initial concerns about the chronic use of stimulant laxatives (e.g Senna). Recent evidence suggests that these risks have been overstated and long term use is justified in patients on clozapine with monitoring for bowel habit change and ceasing if the patient develops diarrhoea. [Attard et al., 2019]

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.