BJPsych Advances (2019), vol. 25, 377–386 doi: 10.1192/bja.2019.42 Clozapine: why wait to start a ARTICLE laxative? Azizah Attard , Andrew Iles, Stephen Attard, Nathan Atkinson & Anita Patel most prominent of these are blood dyscrasias, dia- Azizah Attard is a lead specialist SUMMARY betic ketoacidosis and myocarditis, for each of pharmacist with West London NHS Trust, UK. Andrew Iles is a con- Clozapine, the antipsychotic of choice for treat- which there are strictly enforced monitoring guide- ment-resistant schizophrenia, has a number of sultant forensic psychiatrist with lines (Cohen 2012). Clozapine can also cause consti- side-effects, some of which are potentially life- Surrey and Borders Partnership NHS pation (the difficult, incomplete or infrequent Foundation Trust, UK. Stephen threatening. Historically viewed as a relatively Attard is a consultant forensic minor side-effect, there is increasing awareness evacuation of dry hardened faeces), which affects – psychiatrist with Central and North of the potentially severe sequalae of constipation 30 60% of patients (De Hert 2011a; Shirazi 2016; West London NHS Foundation Trust, secondary to clozapine-induced gastrointestinal Taylor 2019; also, clozapine SmPC: Box 1). UK. Nathan Atkinson is a consult- hypomotility (CIGH). These include ileus, intestinal Historically, clinicians have viewed antipsychotic- ant gastroenterologist and endosco- obstruction, bowel ischaemia, gastrointestinal induced constipation as a troublesome but mild pist with North Shore and Waitakere Hospital, Auckland, New Zealand. necrosis, toxic megacolon and death. CIGH is sig- adverse effect of antipsychotic therapy. However, Anita Patel is an assistant nificantly more common than clozapine-induced today we are overwhelmed with evidence that consti- researcher with Derbyshire blood dyscrasias and has a higher mortality rate. pation can in fact lead to ileus, intestinal obstruction, Healthcare NHS Foundation Trust, Although strict criteria must be followed to assert- bowel ischaemia, gastrointestinal necrosis or toxic UK. ively monitor, detect and treat blood dyscrasias in Correspondence megacolon, the consequences of which can be fatal patients taking clozapine, no such framework Dr Stephen Attard, Consultant (Schwartz 1993;Erickson1995;Hayes1995;Drew exists for CIGH. We recommend that prescribing Forensic Psychiatrist, HMP Woodhill, Tattenhoe Street, guidelines, regulatory agencies and information 1997;Levin2002; Townsend 2006; Rondla 2007; Palmer 2008;Hibbard2009;DeHert2011a; Milton Keynes MK4 4DA, UK. from manufacturers should more clearly highlight Email: [email protected] the risks identified in the literature. Furthermore, Flanagan 2011; Nielsen 2012;Oke2015;Every- we recommend that, in people taking clozapine, Palmer 2017a; West 2017). First received 22 Jan 2019 constipation should be prevented by prophylactic Constipation caused by clozapine-induced gastro- Final revision 6 May 2019 Accepted 22 May 2019 treatment with laxatives rather than treated only intestinal hypomotility (CIGH) is much more when clinically identified. common than clozapine-induced blood dyscrasias Copyright and usage and has a higher mortality rate (Cohen 2012; © The Royal College of Psychiatrists LEARNING OBJECTIVES: Every-Palmer 2016; Ingimarsson 2018). When pre- 2019 After reading this article you will be able to: scribing clozapine, strict criteria must be followed to • understand the mechanism of gastrointestinal assertively monitor, detect and treat related blood hypomotility in those taking clozapine • improve the monitoring of clozapine-induced dyscrasias (clozapine SmPC: Box 1). No such frame- constipation work exists for the monitoring of constipation, even • understand prophylactic laxative treatment and though CIGH may also lead to death. In a recent and the use of less commonly prescribed laxatives in large pharmacovigilance study in Australia and New patients who experience clozapine-induced Zealand, 160 patients (37/10 000) on clozapine constipation. were reported as having serious gastrointestinal hypomotility. Of these, 29 (7/10 000) are known DECLARATION OF INTEREST: to have died – a fatality rate of 18% (Every-Palmer None. 2017a). The case-fatality rate reported by the US KEYWORDS Food and Drug Administration (De Hert 2011b) was nearly identical to this, at 21.9% (7 of 32 Drug interactions and side-effects; clozapine; fi clozapine-induced hypomotility; in-patient patients). Despite the prevalence and signi cant treatment; community mental health teams. mortality associated with CIGH, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK does not mention CIGH specifically in its drug information for prescribers (clozaril: Clozapine remains the gold-standard antipsychotic http://www.mhra.gov.uk/spc-pil/); rather, the for treatment-resistant schizophrenia, but its use summary of product characteristics for the drug comes with a significant number of potentially life- lists intestinal obstruction/paralytic ileus/faecal threatening side-effects (Taylor 2017). Among the impaction as ‘very rare’ (Clozapine SmPC last 377 Downloaded from https://www.cambridge.org/core. 29 Sep 2021 at 03:49:56, subject to the Cambridge Core terms of use. Attard et al accessed 2019). The term ‘very rare’ is defined as are often not reported and are not easily objectively ‘isolated case reports or occurring in less than one recognised by clinicians, given the private nature of in 10 000 users’. patients’ bowel functions. Patient under-reporting Aside from the fatal consequence of constipation could also be due to inherent cognitive deficits, caused by CIGH, it has been repeatedly shown core symptoms of schizophrenia, reduced pain sensi- that chronic constipation can have a negative tivity or reduced ability to communicate (Bickerstaff impact on the patient’s quality of life (Damon 1988; Dworkin 1994; De Hert 2011c; Stubbs 2004; Dennison 2005; Wald 2007). Symptoms of 2015). Clozapine itself causes side-effects that can delayed colonic transit time include reduced fre- exacerbate such pre-existing risk factors: sedation quency of defecation, lack of urgency to defecate, (through antihistaminergic properties), increased abdominal distension, bloating and feelings of appetite and hypersalivation (which can worsen incomplete evacuation (Koch 1997). One study dehydration) (clozaril at http://www.mhra.gov.uk/ reported that median colonic transit time for spc-pil/; clozapine SmPC: Box 1). Clozapine is patients prescribed clozapine was 104.5 h, which thought to reduce gastrointestinal motility through is over four times longer than for those on other anti- its gut peripheral muscarinic anticholinergic effects psychotics (23 h; P < 0.0001) (Every-Palmer 2016). and antagonism at serotonin receptors (Meltzer Eighty per cent of clozapine-treated patients had 1991; Chengappa 2000; Crowell 2001; Abrams colonic hypomotility, compared with none of those 2006). These multifaceted risk factors for constipa- treated with other antipsychotics (olanzapine, ris- tion – schizophrenia itself, inherent under-reporting peridone, paliperidone, aripiprazole, zuclopenthixol and under-detection, clozapine side-effects, together or haloperidol). with reduced gastric motility – put this subgroup of This article will highlight the need for enhanced patients at a degree of risk that necessitates either a identification and treatment of constipation asso- challenge to the ethics behind most current ‘wait and ciated with clozapine and will challenge the status treat’ constipation guidance or an overhaul of the quo of reserving treatment for patients with identi- way clinicians view the prescribing of laxatives. fied or reported clozapine-induced constipation. Opinions differ about the relationship between We will emphasise the importance of prophylactic clozapine dose, plasma levels and rates of CIGH or use of laxatives in patients who are taking clozapine, ileus. A subgroup analysis in a 22-year bi-national describing both commonly prescribed laxatives and pharmacovigilance study in Australia and New less well-known agents. Zealand showed that those with fatal outcomes had Despite the recommendation that monitoring significantly longer duration of clozapine treatment and treatment of constipation caused by CIGH (median 4.2 years, IQR = 1.5–8.6years)thanthe should be brought in line with the strict framework rest of the group (median 1.9 years, IQR = 0.2–5 in place to detect blood dyscrasias (Cohen 2012), years) (Every-Palmer 2017a). The odds ratio of there has been no such coordinated provision. a fatal outcome increased by 1.21 years (95% CI Although we uphold the need for a systematised 1.02–1.44) for every 2 years on clozapine. Age, approach to monitoring clozapine-induced consti- female gender, dose and receiving other constipat- pation, we recommend interim improvement to ing medications had a positive, but non-significant local practice. association with fatal outcomes. A study focusing Given the life-threatening severe nature of severe on ileus alone (Nielsen 2012) found an increased clozapine-induced constipation, readers’ attention risk with increasing age (OR = 1.03, 95% CI is drawn to Box 2, which lists symptoms of sus- 1.01–1.04), female gender (OR = 1.60, 95% CI pected acute CIGH. A low threshold for referral to 1.10–1.23) and duration of clozapine treatment an emergency department is warranted, as there (OR = 1.99, 95% CI 1.21–3.29). The onset of are cases in which death occurred only hours after ileus occurred on average more than 3 years