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      Unrecognized clozapine-related constipation leading to fatal intra-abdominal sepsis – a case report

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          Abstract

          Clozapine is the preferred antipsychotic used for the treatment of resistant schizophrenia with suicidal ideation. The drug is started at a low dose and gradually increased to a target dose of 300–450 mg/day. It is well known to cause agranulocytosis and neutropenia. Several cases of fatal sepsis have been reported in neutropenic patients and emphasis is placed on monitoring for agranulocytosis; however, clozapine also causes intestinal hypomotility and constipation, which if unrecognized can lead to intestinal obstruction, bowel necrosis, and intra-abdominal sepsis. Reduced behavioral pain reactivity in schizophrenics may alter the ability to express pain, potentially leading to a delay in the presentation for medical attention. We report a case of fatal intra-abdominal sepsis secondary to an unrecognized case of clozapine-related constipation.

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          Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy.

          Jan P A M Bogers, Dan Cohen, Bert Bakker … (2012)
          Clozapine is the preferred option for treatment-resistant schizophrenia. However, since 1975, clozapine has been known to cause agranulocytosis. In the clozapine screening guidelines, white blood cell count is mandatory. In the past 20 years, after its reintroduction, 3 other serious side effects, namely, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis have been documented but have so far failed to be incorporated in the screening guidelines. The objective of this review is to determine whether an update of the screening guidelines for serious side effects with clozapine is evidence based. The English-language literature, available via MEDLINE or PubMed, on the incidence of 4 clozapine-related side effects, using clozapine, agranulocytosis, diabetic ketoacidosis, and gastrointestinal hypomotility as keywords, that have been published over the period 1976-2010, was collected. 16 studies that provided incidence rates or data from which these rates could be calculated were included. We compared 1-year incidence rates, mortality rates in the whole study population and in the affected cases. When rates reflected longer periods of observation, the given rate was recalculated to obtain a 1-year incidence rate. The incidence of clozapine-induced agranulocytosis varies between 3.8‰-8.0‰. The mortality rate is 0.1‰-0.3‰, and the case-fatality rate is 2.2‰-4.2‰. In diabetic ketoacidosis, the incidence was calculated at 1.2‰-3.1‰, and the case-fatality rate was 20%-31%. In gastrointestinal hypomotility, the incidence was 4‰-8‰, and the case-fatality rate was 15%-27.5%. The discrepancy in incidence rates between Australia (7‰-34‰) and the rest of the world (0.07‰-0.6‰) impairs a general approach of this side effect. In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified; early detection of treatment-emergent hyperglycemia, that might-via diabetes mellitus-develop into diabetic ketoacidosis, requires obligatory monthly measurement of fasting plasma glucose. To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention. The reported incidence of myocarditis (high in Australia, low in the rest of the world) is too divergent to allow for an overall recommendation outside Australia. © Copyright 2012 Physicians Postgraduate Press, Inc.
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            Risk factors for ileus in patients with schizophrenia.

            J. Meyer, Jimmi Nielsen (2012)
            Constipation is a known side effect of psychotropics that possess high affinity for muscarinic cholinergic receptors. In severe cases, constipation progresses to ileus and bowel ischemia, with multiple fatalities related to sepsis and perforation described in the literature, primarily among patients with schizophrenia. A historical prospective database study was performed using registry data from psychiatric and somatic hospitals, combined with the prescription database to examine associations between medications and ileus. Only cases with an ICD-10 diagnosis of schizophrenia (F20) and a concurrent diagnosis of ileus in the years 1996-2007 were included in the study. A total of 26,720 patients with schizophrenia were identified with 123 cases of ileus noted in the study period. Increasing age (OR: 1.03 CI: 1.01-1.04) and female sex (OR: 1.60 CI: 1.10-2.31) were associated with an increased risk of ileus. Treatment with clozapine (OR: 1.99 CI: 1.21-3.29), high-potency first-generation antipsychotics (OR: 1.81 CI: 1.01-3.23), tricyclic antidepressants (OR: 2.29 CI: 1.29-4.09), anticholinergics (OR: 1.48 CI: 1.00-2.19), and opioids (OR: 2.14 CI: 1.36-3.36) were associated with an increased risk of ileus. The onset of ileus occurred on average more than 3 years after the first prescription of the offending drug. Aripiprazole and amisulpride were not associated with ileus. Nine of the ileus cases (7.3%) had a fatal course. Treatment with clozapine (OR: 6.73 CI: 1.55-29.17) or anticholinergics (OR: 5.88 CI: 1.47-23.58) were associated with increased risk of fatal ileus. Patients receiving psychotropics associated with significant anticholinergic properties should undergo proper monitoring and interventions in order to minimize the burden of constipation and the risk of ileus.
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              Second-generation antipsychotics and constipation: a review of the literature.

              M De Hert, H Hudyana, L Dockx … (2011)
              Antipsychotics are the cornerstone in the management of psychotic disorders and schizophrenia. They are effective agents but also have a wide range of side effects. In the recent literature constipation as possible side effect has received little attention. A review of the literature concerning constipation associated with antipsychotics was performed. Overall constipation is a rarely studied or reported side effect of antipsychotic medication. Nevertheless constipation is a common side effect. Antipsychotic agents differ in their liability to induce constipation. Constipation can be severe and can lead to serious consequences such as paralytic ileus, bowel occlusion and death. Active screening, monitoring and treatment are recommended. Further research on incidence, prevalence, underlying mechanisms and preventive measures is required. Copyright © 2010 Elsevier Masson SAS. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int Med Case Rep J
                Journal ID (iso-abbrev): Int Med Case Rep J
                Journal ID (publisher-id): International Medical Case Reports Journal
                Title: International Medical Case Reports Journal
                Publisher: Dove Medical Press
                ISSN (Electronic): 1179-142X
                Publication date Collection: 2015
                Publication date (Electronic): 11 September 2015
                Volume: 8
                Pages: 189-192
                Affiliations
                Department of Pulmonary Medicine, Interfaith Medical Center, NY, USA
                Author notes
                Correspondence: Vikram Oke, Interfaith Medical Center, 1545 Atlantic Avenue, Brooklyn, NY 11213, USA, Email vikramoke@ 123456gmail.com
                Article
                Publisher ID: imcrj-8-189
                DOI: 10.2147/IMCRJ.S86716
                PMC ID: 4573205
                PubMed ID: 26392790
                SO-VID: f93de595-fea6-4481-b975-cb99c8c00fd6
                Copyright © © 2015 Oke et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License
                License:

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Categories
                Subject: Case Report

                Keywords: antipsychotics,clozapine,schizophrenia,syncope,constipation,sepsis
                Data availability:
                Keywords: antipsychotics, clozapine, schizophrenia, syncope, constipation, sepsis

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