Clozapine-induced Gastrointestinal Hypomotility Research Articles

(PO-186) Clozapine-induced Gastrointestinal Hypomotility (CIGH): A Case Series and Pathomechanistic Review

(PO-186) Clozapine-induced Gastrointestinal Hypomotility (CIGH): A Case Series and Pathomechanistic Review

Recognition and management of clozapine adverse effects: A systematic review and qualitative synthesis.

Clozapine is substantially underutilized in most countries and clinician factors including lack of knowledge and concerns about adverse drug effects (ADEs) contribute strongly to treatment reluctance. The aim of this systematic review was to provide clinicians with a comprehensive information source regarding clozapine ADEs. PubMed and Embase databases were searched for English language reviews concerned with clozapine ADEs; publications identified by the automated search were manually searched for additional relevant citations. Following exclusion of redundant and irrelevant reports, pertinent information was summarized in evidence tables corresponding to each of six major ADE domains; two authors reviewed all citations for each ADE domain and summarized their content by consensus in the corresponding evidence table. This study was conducted in accordance with PRISMA principles. Primary and secondary searches identified a total of 305 unique reports, of which 152 were included in the qualitative synthesis. Most clozapine ADEs emerge within 3months, and almost all appear within 6months, after initiation. Notable exceptions are weight gain, diabetic ketoacidosis (DKA), severe clozapine-induced gastrointestinal hypomotility (CIGH), clozapine-induced cardiomyopathy (CICM), seizures, and clozapine-induced neutropenia (CIN). Most clozapine ADEs subside gradually or respond to dose reduction; those that prompt discontinuation generally do not preclude rechallenge. Rechallenge is generally inadvisable for clozapine-induced myocarditis (CIM), CICM, and clozapine-induced agranulocytosis (CIA). Clozapine plasma levels >600-1000μg/L appear more likely to cause certain ADEs (e.g., seizures) and, although there is no clear toxicity threshold, risk/benefit ratios are generally unfavorable above 1000μg/L. Clozapine ADEs rarely require discontinuation.

Clozapine-induced gastrointestinal hypomotility: presenting features and outcomes, UK pharmacovigilance reports, 1992-2017.

Clozapine-induced gastrointestinal hypomotility (CIGH) affects some 75% of patients treated with clozapine. To document the incidence of potentially harmful CIGH in the UK. We studied spontaneous UK pharmacovigilance reports recorded as clozapine-related gastrointestinal adverse drug reactions, 1992-2017. There were 527 patients reported with potentially harmful CIGH; 33% (n = 172) died. Deaths averaged 1 per year 1992-1999, 5 per year 2000-2009 and 15 per year 2010-2017. Those who died were older (median 52 years v. 49 years) and had been prescribed clozapine for longer than those who recovered (median 11.3 years v. 4.8 years), but there was no difference in prescribed dose. Within the first 4 years of clozapine treatment, there were 169 reports of CIGH, of which 3% (n = 5) were fatal. At 10-14 years there were 63 reports of CIGH, of which 25% (n = 16) were fatal. Among the deaths, males were younger (median 51, range 22-89 v. median 57, range 24-89 years) with higher clozapine doses (median 450, range 100-900 v. median 300, range 12.5-800 mg/d) than females. In non-fatal CIGH, surgery was the most frequent outcome (n = 92). The procedures included appendectomy, ileostomy, total/partial colectomy, colostomy/stoma and proctosigmoidectomy. Clozapine dosage was reduced in 6 patients, stopped and restarted in 23, 'continued' in 6 and discontinued permanently in at least 76 patients. The risk of serious morbidity/mortality from CIGH is substantial. The need to actively monitor bowel function and give laxatives to patients treated with clozapine is clear.

High risk of serious morbidity, mortality from clozapine-induced gastrointestinal hypomotility

High risk of serious morbidity, mortality from clozapine-induced gastrointestinal hypomotility

Reporting of clozapine-induced gastrointestinal hypomotility and factors associated with fatal outcomes in Canada: A pharmacovigilance database study

Clozapine-induced gastrointestinal hypomotility (CIGH) is poorly understood and potentially life-threatening. Herein, we present trends of CIGH annual reporting and explore factors associated with a fatal outcome using 25-years of pharmacovigilance data in Canada. Since 1993, the number of CIGH reports increased 22-fold but the proportion of fatal reports remained relatively stable. Fatal reports of CIGH were associated with older age but not sex, clozapine dose, or clozapine duration. Concomitant use of medications used to treat CIGH (lactulose, docusate sodium) and its associated pain/discomfort (acetaminophen, lorazepam) were more commonly reported in fatal cases. Confirmatory and prospective studies of CIGH are warranted.

Constipation screening in people taking clozapine: A diagnostic accuracy study

ObjectiveClozapine is the favoured antipsychotic for treatment-refractory schizophrenia but its safe use requires careful adverse-effect management. Clozapine-induced gastrointestinal hypomotility (CIGH or ‘slow-gut’) is one of the most common and serious of clozapine's adverse effects. CIGH can lead to paralytic ileus, bowel obstruction, gastrointestinal ischaemia, toxic megacolon, and death. Enquiring about constipation is a simple and commonly used screening method for CIGH but its diagnostic accuracy has not previously been assessed. MethodsFirst, we examined the reliability of asking about constipation compared with asking about Rome constipation criteria in inpatients treated with clozapine (n = 69). Second, we examined the diagnostic accuracy of (1) self-reported constipation and (2) the Rome criteria, compared with the reference standard of gastrointestinal motility studies. ResultsAfter 30 motility tests, it was clear constipation screening had very poor diagnostic properties in this inpatient group and the study was terminated. Although 73% of participants had objective CIGH on motility testing, only 26% of participants self-reported constipation, with sensitivity of 18% (95% CI: 5–40%). Specificity and positive predictive values were higher (95% CI: 63–100% and 40–100%, respectively). Adding in Rome criteria improved sensitivity to 50% (95% CI: 28.2–71.8%), but half the cases were still missed, making this no more accurate than tossing a coin. ConclusionsCIGH is often silent, with self-reported constipation having low sensitivity in its diagnosis. Treating CIGH based on self-reported symptoms questions will miss most cases. However, universal bowel motility studies are impractical. In the interests of patient safety, prophylactic laxatives are suggested for people taking clozapine.

Clozapine: why wait to start a laxative?

SUMMARYClozapine, 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.LEARNING OBJECTIVES: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.

Clozapine-induced gastrointestinal hypomotility in Australasia

Clozapine-induced gastrointestinal hypomotility in Australasia

Clozapine-induced gastrointestinal hypomotility

Clozapine-induced gastrointestinal hypomotility

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

IntroductionClozapine is the preferred antipsychotic for treatment-resistant schizophrenia, but has significant adverse effects, including gastrointestinal hypomotility or ‘slow gut’, which may result in severe constipation, ileus, bowel obstruction, and even death. These gastrointestinal effects remain inadequately recognized.MethodsWe reviewed all reports of serious clozapine-induced gastrointestinal hypomotility (CIGH) submitted to the Australian Therapeutic Goods Administration and New Zealand Pharmacovigilance Centre between 1992 and 2013. We extracted relevant demographic, clinical, and outcome data and derived a numerator from clozapine registries. We examined whether clozapine drug safety information in Australia, New Zealand, the US, and the UK was adequate and consistent with pharmacoepidemiologic evidence.ResultsA total of 43,132 people commenced clozapine over the study period. 160 were reported as having serious gastrointestinal hypomotility with clozapine the suspected cause (37/10,000 clozapine users). Of these, 66.3% were male, age range was 17–76 years, clozapine dose range 25–1000 mg/day (mean 439 mg/day) and median duration of clozapine treatment 2.5 years. Few had received laxatives. At least 29 patients died (7/10,000 clozapine users), a reported case fatality rate of 18%. The CIGH prevalence, while similar to other smaller studies, differs significantly from clozapine prescribing information issued by regulators and pharmaceutical companies, none of which mention CIGH, and which report serious gastrointestinal complications at rates of <1/10,000, almost a 40-fold difference.ConclusionThis is the largest study to date of serious CIGH. The reported prevalence of serious CIGH was 37/10,000, a likely underestimation of true prevalence. Current prescribing guidelines provide inadequate information on CIGH. This may be contributing to poor awareness and high associated morbidity and mortality. It is time regulators and manufacturers update their guidance.

The Porirua Protocol in the Treatment of Clozapine-Induced Gastrointestinal Hypomotility and Constipation: A Pre- and Post-Treatment Study.

Clozapine, an antipsychotic used in treatment-resistant schizophrenia, causes slow gastrointestinal transit in 50-80% of patients. Clozapine-induced gastrointestinal hypomotility is both common and serious, and potential complications include severe constipation, ileus, bowel obstruction and related complications, with a higher mortality rate than clozapine-related agranulocytosis. Little evidence exists on its prevention and management. Using a well-validated radiopaque marker ('Metcalf') method, we compared colonic transit times (CTTs) of clozapine-treated inpatients not receiving laxatives with their transit times when receiving laxatives, with treatment prescribed according to the Porirua Protocol for clozapine-related constipation (docusate and senna augmented by macrogol 3350 in treatment-resistant cases). The median age of participants was 35years, and median clozapine dose, plasma level and duration of treatment were 575mg/day, 506ng/mL and 2.5years, respectively. Overall, 14 participants (10 male) were enrolled and all completed the study. Transit times improved markedly with laxative treatment. Median colonic transit without laxatives was 110h (95% confidence interval [CI] 76-144h), over four times longer than normative values (p<0.0001). Median CTT with laxatives was 62h (95% CI 27-96h), a 2-day reduction in average transit time (p=0.009). The prevalence of gastrointestinal hypomotility decreased from 86% pre-treatment to 50% post-treatment (p=0.061). Severe gastrointestinal hypomotility decreased from 64 to 21% (p=0.031). Subjective reporting of constipation did not correlate well with objective hypomotility, and did not change significantly with treatment. Treating clozapine-treated patients with docusate and senna augmented by macrogol appears effective in reducing CTTs in clozapine-induced constipation. Randomised controlled trials are the next step. Australian New Zealand Clinical Trial Registry ACTRN12616001405404 (registered retrospectively).

Clozapine-induced Gastrointestinal Hypomotility — New Objective Evidence for an Underestimated Side-effect

Clozapine-induced Gastrointestinal Hypomotility — New Objective Evidence for an Underestimated Side-effect

Clozapine-Induced Gastrointestinal Hypomotility (CIGH): An Under-recognized Serious Side Effect

Clozapine-Induced Gastrointestinal Hypomotility (CIGH): An Under-recognized Serious Side Effect

Clozapine-induced gastrointestinal hypomotility: More than just constipation

CASE A 60 y.o. male with longstanding paranoid schizophrenia was admitted from a local group home with abdominal pain and distention of several days in duration and vomiting for the previous 24 hours. He had been seen in the family practice clinic at this academic medical center on the day prior to admission for similar complaints and magnesium citrate was recommended. An abdominal plain film from that visit was consistent with ileus and moderate stool load. The patient was admitted to the emergency treatment center later that day with newonset vomiting. He was sent home after three soap suds enemas with only minimal results.

Clozapine-Induced Gastrointestinal Hypomotility

Clozapine-Induced Gastrointestinal Hypomotility

Death from Clozapine-Induced Gastrointestinal Hypomotility

Death from Clozapine-Induced Gastrointestinal Hypomotility

Life-Threatening Clozapine-Induced Gastrointestinal Hypomotility

To raise awareness of potentially lethal clozapine-induced gastrointestinal hypomotility (CIGH) by reviewing cases from the literature and unpublished pharmacovigilance data and to offer strategies aimed at prevention and early treatment. Databases (PsycINFO, 1967-2007; MEDLINE, 1950-2007; and EMBASE, 1988-2007) were searched using the term clozapine together with each of the following: gastrointestinal, dysmotility, constipation, obstipation, fecal impaction, fecaloma, paralytic ileus, adynamic ileus, subileus, ischemic colitis, colon ischemia, bowel ischemia, gastrointestinal ischemia, gut ischemia, obstruction, necrosis, gangrene, bowel perforation, micro-perforation, megacolon, toxic megacolon, acquired megacolon, pseudo-obstruction, Ogilvie, and Ogilvie's syndrome. We analyzed the electronic database entries held by the Adverse Drug Reactions Advisory Committee and the New Zealand Intensive Medicines Monitoring Program, which cited suspected clozapine-related gastrointestinal side effects, as well as all relevant published case reports. We reviewed the literature on the treatment of gastrointestinal hypomotility and constipation. We compiled a database of 102 cases of suspected life-threatening CIGH. There was a mortality rate of 27.5% and considerable morbidity, largely due to bowel resection. Within Australasia, at least 15 patients have died of CIGH. Probable risk factors are identified as recent instigation of clozapine, high clozapine dose or serum level, concomitant anticholinergic use, or intercurrent illness. The paucity of literature on CIGH suggests that the significance of this uncommon but important and frequently fatal side effect has not been recognized. Clozapine can affect the entire gastrointestinal system, from esophagus to rectum, and may cause bowel obstruction, ischemia, perforation, and aspiration. The mechanism is likely to be anticholinergic and antiserotonergic. Clozapine prescribing should be accompanied by regular physical monitoring, appropriate and timely use of laxatives, and early referral of constipated patients--before life-threatening pathologic processes develop.