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Clozapine: why wait to start a laxative?

  • Azizah Attard (a1), Andrew Iles (a2), Stephen Attard (a3), Nathan Atkinson (a4) and Anita Patel (a5)...


Clozapine, the antipsychotic of choice for treatment-resistant schizophrenia, has a number of side-effects, some of which are potentially life-threatening. Historically viewed as a relatively minor side-effect, there is increasing awareness of the potentially severe sequalae of constipation secondary to clozapine-induced gastrointestinal hypomotility (CIGH). These include ileus, intestinal obstruction, bowel ischaemia, gastrointestinal necrosis, toxic megacolon and death. CIGH is significantly more common than clozapine-induced blood dyscrasias and has a higher mortality rate. Although strict criteria must be followed to assertively monitor, detect and treat blood dyscrasias in patients taking clozapine, no such framework exists for CIGH. We recommend that prescribing guidelines, regulatory agencies and information from manufacturers should more clearly highlight the risks identified in the literature. Furthermore, we recommend that, in people taking clozapine, constipation should be prevented by prophylactic treatment with laxatives rather than treated only when clinically identified.


After reading this article you will be able to:

  • understand the mechanism of gastrointestinal hypomotility in those taking clozapine
  • improve the monitoring of clozapine-induced constipation
  • understand prophylactic laxative treatment and the use of less commonly prescribed laxatives in patients who experience clozapine-induced constipation.




Corresponding author

Correspondence Dr Stephen Attard, Consultant Forensic Psychiatrist, HMP Woodhill, Tattenhoe Street, Milton Keynes MK4 4DA, UK. Email:


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Abrams, P, Andersson, KE, Buccafusco, JJ, et al. (2006) Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. British Journal of Pharmacology, 148: 565–78.
Bell, TJ, Panchal, SJ, Miaskowski, C, et al. (2009) The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European patient survey (PROBE 1). Pain Medicine, 10: 3542.
Bickerstaff, LK, Harris, SC, Leggett, RS, et al. (1988) Pain insensitivity in schizophrenic patients: a surgical dilemma. The Archives of Surgery, 123: 4951.
British National Formulary (2018) Constipation. BMJ Group & Pharmaceutical Press ( Accessed March 2019.
Byers, RJ, Marsh P, Parkinson D, et al. (1997) Melanosis coli is associated with an increase in colonic epithelial apoptosis and not with laxative use. Histopathology, 30: 160–4.
Chengappa, KN, Pollock, BG, Parepally, H, et al. (2000) Anticholinergic differences among patients receiving standard doses of olanzapine or clozapine. Journal of Clinical Psychopharmacology, 20: 311–6.
Chukhin, E, Takala, P, Hakko, H, et al. (2013) In a randomised placebo-controlled add-on study orlistat significantly reduced clozapine-induced constipation. International Clinical Psychopharmacology, 28: 6870.
Cohen, D, Bogers, J, van Dijk, D, et al. (2012) Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy. Journal of Clinical Psychiatry, 73: 1307–12.10.4088/JCP.11r06977
Cohen, D (2017) Clozapine and gastrointestinal hypomobility. CNS Drugs, 31: 1083–91.10.1007/s40263-017-0481-5
Crowell, MD (2001) The role of serotonin in the pathophysiology of irritable bowel syndrome. American Journal of Managed Care, 7: s25260.
Damon, H, Dumas, P, Mion, F (2004) Impact of anal incontinence and chronic constipation on quality of life. Gastroenterologie Clinique et Biologique, 28: 1620.
De Hert, M, Dockx, L, Bernagie, C, et al. (2011a) Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive study. BMC Gastroenterology, 11 : 17.
De Hert, M, Hudyana, H, Dockx, L, et al. (2011b) Second-generation antipsychotics and constipation: a review of the literature. European Psychiatry, 26: 3444.
De Hert, M, Correll, CU, Bobes, J, et al. (2011c) Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry, 10: 52–7.10.1002/j.2051-5545.2011.tb00014.x
Dennison, C, Prasad, M, Lloyd, A, et al. (2005) The health-related quality of life and economic burden of constipation. Pharmacoeconomics, 23: 461–76.
Drew, L, Herdson, P (1997) Clozapine and constipation: a serious issue. Australian and New Zealand Journal of Psychiatry, 31: 149–50.
Ducrotté, P, Milce, J, Soufflet, C, et al. (2017) Prevalence and clinical features of opioid-induced constipation in the general population: a French study of 15,000 individuals. United European Gastroenterology Journal, 5: 588600.10.1177/2050640616659967
Dworkin, RH (1994) Pain insensitivity in schizophrenia: a neglected phenomenon and some implications. Schizophrenia Bulletin, 20: 235–48.
Erickson, B, Morris, DM, Reeve, A (1995) Clozapine-associated postoperative ileus: case report and review of the literature. Archives of General Psychiatry, 52: 508–9.
Every-Palmer, S, Newton-Howes, G, Clarke, MJ (2014) Pharmacological treatment for antipsychotic-related constipation (protocol). Cochrane Database of Systematic Reviews, 5: CD011128.
Every-Palmer, S, Nowitz, M, Stanley, J, et al. (2016) Clozapine-treated patients have marked gastrointestinal hypomotility, the probable basis of life-threatening gastrointestinal complications: a cross sectional study. EBioMedicine, 5: 125–34.10.1016/j.ebiom.2016.02.020
Every-Palmer, S, Ellis, PM (2017a) Clozapine-induced gastrointestinal hypomotility: a 22-year bi-national pharmacovigilance study of serious or fatal ‘slow gut’ reactions, and comparison with international drug safety advice. CNS Drugs, 31: 699709.
Every-Palmer, S, Ellis, PM, Nowitz, M, et al. (2017b) The Porirua protocol in the treatment of clozapine-induced gastrointestinal hypomotility and constipation: a pre- and post-treatment study. CNS Drugs, 31: 7585.10.1007/s40263-016-0391-y
Fitzsimons, J, Berk, M, Lambert, T, et al. (2005) A review of clozapine safety. Expert Opinion on Drug Safety, 4: 731–44.10.1517/14740338.4.4.731
Flanagan, RJ (2011) Gastrointestinal hypomobility: an under-recognised life-threatening adverse effect of clozapine. Forensic Science International, 206: e316.
Foxx-Orenstein, A, McNally, MA, Odunsi, ST (2008) Update on constipation - one treatment does not fit all. Cleveland Clinic Journal of Medicine, 75: 813–24.
Guarino, AH (2005) Treatment of intractable constipation with orlistat: a report of three cases. Pain Medicine, 6: 327–8.10.1111/j.1526-4637.2005.00053.x
Haddad, PM, Fleischhacker, WW, Peuskens, J, et al. (2014) SMARTS (Systematic Monitoring of Adverse events Related to TreatmentS): the development of a pragmatic patient-completed checklist to assess antipsychotic drug side effects. Therapeutic Advances in Psychopharmacology, 4: 1521.
Hayes, G, Gibler, B (1995) Clozapine-induced constipation. American Journal of Psychiatry, 152: 298.
Hibbard, KR, Propst, A, Frank, DE, et al. (2009) Fatalities associated with clozapine-related constipation and bowel obstruction: a literature review and two case reports. Psychosomatics, 50: 416–9.
Hynes, C, Keating, D, McWilliams, S, et al. (2015) Glasgow Antipsychotic Side-effect Scale for Clozapine: development and validation of a clozapine-specific side-effects scale. Schizophrenia Research, 168: 505–13.
Ikai, S, Suzuki, T, Uchida, H, et al. (2013) Reintroduction of clozapine after perforation of the large intestine: a case report and review of the literature. Annals of Pharmacotherapy, 47: e31.10.1345/aph.1S117
Ingimarsson, O, MacCabe, JH, Sigurdsson, E, et al. (2018) Constipation, ileus and medications use during clozapine treatment in patients with schizophrenia in Iceland. Nordic Journal of Psychiatry, 72: 497500.
Karmacharya, R, et al. (2005) Clozapine-induced eosinophilic colitis. American Journal of Psychiatry, 162: 1386–7.
Khalili, B, Bardana, EJ Jr, Yunginger, JW (2003) Psylium associated anaphylaxis and death: a case report and review of the literature. Annals of Asthma, Allergy and Immunology, 91: 579–84.10.1016/S1081-1206(10)61538-4
Koch, A, Voderholzer, WA, Klauser, AG, et al. (1997) Symptoms in chronic constipation. Diseases of the Colon & Rectum, 40: 902–6.
Kune, GA (1993) Laxative use not a risk for colorectal cancer: data from the Melbourne Colorectal Cancer Study. Zeitschrift für Gastroenterologie, 31: 140–3.
Lacy, BE, Mearin, F, Chang, , et al. (2016) Bowel disorders. Gastroenterology, 150: 1393–407 (
Leng-Peschlow, E (1992) Senna and its rational use. Pharmacology, 44: S152.
Leong, QM, Wong, KS, Koh, DC (2007) Necrotising colitis related to clozapine? A rare but life threatening side-effect. World Journal of Emergency Surgery, 2: 21.
Levin, TT, et al. (2002) Death from clozapine-induced constipation: case report and literature review. Psychosomatics, 43: 71–3.
Lewis, SJ, Heaton, KW (1997) Stool form scale as a useful guide to intestinal transit time. Scandinavian Journal of Gastroenterology, 32: 920–4.
McKinnon, ND, Azad, A, Waters, BM, et al. (2009) Clozapine-induced bowel infarction: a case report. Psychiatry, 6: 30–5.
Meltzer, HY, Nash, JF (1991) Effects of antipsychotic drugs on serotonin receptors. Pharmacological Reviews, 43: 587604.
Meyer, JM, Cummings, MA (2014) Lubiprostone for the treatment-resistant constipation associated with clozapine use. Acta Psychiatrica Scandinavica, 130: 71–2.
Morales, MA, Hernández, D, Bustamante, S, et al. (2009) Is senna laxative use associated to cathartic colon, genotoxicity, or carcinogenicity? Journal of Toxicology, 2009: 287247.
Muller-Lissner, SA (1988) Effect of wheat bran on weight of stool and gastrointestinal transit time: a meta analysis. BMJ (Clinical Research Edition), 296: 615–7.
Muller-Lissner, S, Bassotti, G, Coffin, B, et al. (2017) Opioid-induced constipation and bowel dysfunction: a clinical guideline. Pain Medicine, 18: 1837–63.
National Institute for Health and Care Excellence (2017) Constipation (CKS Clinical Knowledge Summary). NICE ( Accessed March 2019.
National Prescribing Centre (2011) The management of constipation. Medical Record Bulletin, 21: 18.
NHS Choices (2013) Physical Activity Guidelines for Adults. NHS UK (
Nielsen, J, Meyer, JM (2012) Risk factors for ileus in patients with schizophrenia. Schizophrenia Bulletin, 38: 592–8.
Nusko, G, Schneider, B, Schneider, I, et al. (2000) Anthranoid laxative use is not a risk factor for colorectal neoplasia: results of a prospective case control study. Gut, 46: 651–5.
Oke, V, Schmidt, F, Bhattarai, B, et al. (2015) Unrecognized clozapine-related constipation leading to into-abdominal sepsis - a case report. International Medical Case Reports Journal, 8: 189–92.
Palmer, SE, McLean, RM, Ellis, PM, et al. (2008) Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases. Journal of Clinical Psychiatry, 69: 759–68.10.4088/JCP.v69n0509
Poetter, CE, Stewart, JT (2013) Treatment of clozapine-induced constipation with bethanechol. Journal of Clinical Psychopharmacology, 33: 713–4.10.1097/JCP.0b013e3182a1160d
Rondla, S, Crane, S (2007) A case of clozapine-induced paralytic ileus. Emergency Medicine Journal, 24: e12.
Schwartz, BJ, Frisolone, JA (1993) A case report of clozapine-induced gastric outlet obstruction. American Journal of Psychiatry, 150: 1563.
Shammi, CM, Remington, G (1997) Clozapine-induced necrotizing colitis. Journal of Clinical Psychopharmacology, 17: 230–2.10.1097/00004714-199706000-00021
Shirazi, A, Stubbs, B, Gomez, L, et al. (2016) Prevalence and predictors of clozapine-associated constipation: a systematic review and meta-analysis. International Journal of Molecular Sciences, 17: E863.
Stubbs, B, Thompson, T, Acaster, S, et al. (2015) Decreased pain sensitivity among people with schizophrenia: a meta-analysis of experimental pain induction studies. Pain, 156: 2121–31.10.1097/j.pain.0000000000000304
Taylor, DM (2017) Clozapine for treatment-resistant schizophrenia: still the gold standard? CNS Drugs, 31: 177–80.
Taylor, DM, Barnes, TRE, Young, AH (2019) The Maudsley Prescribing Guidelines in Psychiatry (13th edn). Wiley.
Townsend, G, Curtis, D (2006) Case report: rapidly fatal bowel ischaemia on clozapine treatment. BMC Psychiatry, 6: 43.
Vaswani, SK, Hamilton, RG, Valentine, MD, et al. (1996) Psylium laxative-induced anaphylaxis, asthma, and rhinitis. European Journal of Clinical Immunology, 51: 266–8.
Wald, A, Scarpignato, C, Kamm, MA, et al. (2007) The burden of constipation on the quality of life: results of a multinational survey. Alimentary Pharmacology of Therapeutics, 26: 227–36.
Weinstein, M (2001) First do no harm. The dangers of mineral oil. Paediatric Child Health, 6: 129–31.
West, S, Rowbotham, D, Xiong, G, et al. (2017) Clozapine induced gastrointestinal hypomotility: a potentially life-threatening adverse event: a review of the literature. General Hospital Psychiatry, 46: 32–7.10.1016/j.genhosppsych.2017.02.004
Wilson, N, Schey, R (2015) Lubiprostone in constipation: clinical evidence and place in therapy. Therapeutic Advances in Chronic Disease, 6: 4050.
Xing, JH, Softer, EE (2001) Adverse effects of laxatives. Diseases of the Colon and Rectum, 44: 1201–9.
Young, CR, Bowers, MB Jr, Mazure, CM (1998) Management of the adverse effects of clozapine. Schizophrenia Bulletin, 24: 381–90.10.1093/oxfordjournals.schbul.a033333
Yu, SC, Chen, HC, Lee, SM (2013) Rapid development of fatal bowel infarction within 1 week after clozapine treatment: a case report. General Hospital Psychiatry, 35: 679.10.1016/j.genhosppsych.2013.03.002
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Clozapine: why wait to start a laxative?

  • Azizah Attard (a1), Andrew Iles (a2), Stephen Attard (a3), Nathan Atkinson (a4) and Anita Patel (a5)...
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