[Downloaded free from http://www.anip.co.in on Wednesday, December 18, 2019, IP: 10.232.74.

26]

Case Report

Clozapine‑Induced Massive Hematemesis: A Rare Case Report

Javed Ather Siddiqui, Shazia Farheen Qureshi, Yousef Bin Ahmed Shawosh
Department of Psychiatry, Mental Health Hospital, Taif, KSA

Abstract
Clozapine (CLZ) is a drug of choice for the treatment of resistant schizophrenia. It is always blamed probably due to its life‑threatening side
effects, such as agranulocytosis, constipation, cardiomyopathies, and rarely hematemesis. We report the case of a 65‑year‑old patient diagnosed
with resistant schizophrenia and treated with CLZ later he developed sudden massive hematemesis. The aim of our case report is to describe
the rarely seen and potentially life‑threatening side effect related to CLZ. Physician, particularly psychiatrists and medical specialists, should
not ignore, be aware, and alert or always need to be watchful to the fatality of CLZ‑induced hematemesis in the management of psychiatric
disorders and should take appropriate therapeutic measures in such a case.

Keywords: Clozapine, massive hematemesis, resistant‑schizophrenia

Introduction develop gastrointestinal symptoms similar to reflux esophagitis

Clozapine (CLZ) is a tricyclic dibenzodiazepine, antipsychotic
agent. It is first atypical antipsychotic known as the
second‑generation antipsychotic. It was first discovered in
1958, developed by Sandoz in 1961, and introduced in
Europe in 1970. It is a drug of choice and the gold standard
medication for the treatment of resistant schizophrenia,[1] but
due to complicated side effect profile, it has limited use and
needs necessary monitoring after initiation of medication.[2]
The side effects of CLZ reported could be serious and
life‑threatening and if not treated properly, can lead to
dangerous consequences. These side effects are hematological
such as agranulocytosis, cardiac side effects such as
cardiomyopathies and pericarditis, neurological such as seizure,
and metabolic such as diabetes and dyslipidemia. Other
uncommon side effects affecting the gastrointestinal system
are hematemesis, constipation, esophagitis, ischemic colitis,
paralytic ileus, gastroesophageal reflux disease, priapism,
urinary incontinence, pityriasis rosea, intertriginous erythema,
pulmonary thromboembolism, pseudopheochromocytoma,
periorbital edema, and parotitis.[3‑6] The potential reason for
discontinuing CLZ is that some of the side effects are rare, fatal,
miserable, and massive. It has been reported in the literature
and some articles that around 11% of patients treated with CLZ
Received: 19-Feb-2019  Revision: 01-Apr-2019 Accepted: 04-Apr-2019 Published: 18-Dec-2019
within 6 weeks of treatment.[4]
The pathophysiology due to which CLZ causes severe
esophagitis and subsequent hematemesis is at times difficult
to understand. Anticholinergic activity plays an important role
by causing antagonism of cholinergic receptors which may
be responsible for the reduction or abolition of esophageal
motility resulting in increased pressure in the lower sphincter
tone and an overall reduction in esophageal tone. The incidence
rate for gastrointestinal hypomotility has been reported to be
4–8/1000, which has a case fatality rate of 15%–27.5%.[7] We
wish to report a rare case of clozapine induced hematemesis.
Case Report
A 65‑year‑old male patient with good body built belonging
to low‑socioeconomic status, is admitted in a chronic
rehabilitation ward since 15 years of a psychiatric hospital.
He was diagnosed with schizophrenia 30 years back. He had
been treated with multiple typical and atypical antipsychotics.
At different times, he had been on haloperidol, olanzapine,
Address for correspondence: Dr. Javed Ather Siddiqui,
Department of Psychiatry, Mental Health Hospital, P. O. Box. 2056,
Taif 21944, KSA.
E‑mail: javedsiddiqui2000@gmail.com

This is an open access journal, and articles are distributed under the terms of the Creative
Access this article online Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to
Quick Response Code: remix, tweak, and build upon the work non‑commercially, as long as appropriate credit
Website: is given and the new creations are licensed under the identical terms.
www.anip.co.in
For reprints contact: reprints@medknow.com

DOI: How to cite this article: Siddiqui JA, Qureshi SF, Ahmed Shawosh YB.
10.4103/aip.aip_8_19 Clozapine-induced massive hematemesis: A rare case report. Ann Indian
Psychiatry 2019;3:171-2.

© 2019 Annals of Indian Psychiatry | Published by Wolters Kluwer - Medknow 171

[Downloaded free from http://www.anip.co.in on Wednesday, December 18, 2019, IP: 10.232.74.26]
Siddiqui, et al.: Clozapine‑induced massive hematemesis
chlorpromazine, amisulpride, and risperidone and depot
preparations such as fluphenazine and haloperidol decanoate,
risperidone consta for the past 30 years. Despite being treated
with multiple antipsychotics, initially, he improved for 4 years,
but as he never achieved full remission his diagnosis was
revised to treatment‑resistant schizophrenia and clozapine
was considered. Baseline investigations, such as complete
blood cell count, electrocardiography, serum electrolytes,
and liver and kidney function tests, were all within the
normal limits. There was a history of smoking since long and
subsequently patient developed chronic obstructive pulmonary
disease (COPD).
His milestones were normal . He had no substance abuse, other
medical or gastrotrointestinal symptoms except for COPD.
The patient had a significant improvement in his mental status
within a month of starting CLZ and was maintained on 300 mg
of CLZ in divided doses. 15 days later patient complained of
constipation and gastroesophageal reflux and was accordingly
treated with omeprazole and stool softener. He was noticed to
have vomited about 200 ml of coffee‑colored vomit on two
occasions by the staff nurse.
Patient had epigastric pain and was treated with intravenous
omeprazole 40 mg for 12 h and hydration was maintained.
The patient was referred to the gastroenterologist. His upper
gastrointestinal endoscopy showed evidence of esophagitis
and pangastritis. The patient was assessed on Naranjo adverse
drug reaction probability test, and the score was 7, suggesting
possible adverse drug reaction. All other investigations were
within the normal limits. The gastroenterologist made a
diagnosis of the upper gastrointestinal bleeding secondary to
CLZ use as the patient was on CLZ for 1 month. CLZ was
tapered and discontinued over 2 months. It was restarted
with caution at lower and slower dosage as the patient was
refractory to other antipsychotics. There was no further episode
of hematemesis and the patient maintained well.
Discussion
CLZ is the first‑line drug of choice for resistant schizophrenia,
due to it’s better efficacy over other typical and atypical
antipsychotic drugs but needs monitoring due to its serious and
fatal side effects, complications, and contraindications. Various
literature and case studies reported that around 17% of patient
those taking CLZ usually discontinue the treatment because
of its fatal side effects or complications.[8] The risk of causing
agranulocytosis and other life‑threatening hematemesis due
to CLZ is well established.[3] To the best of our knowledge,
there is a similar case reported in Sub‑Saharan Africa.[9] Our
patient had gastrointestinal side effects such as constipation,
gastroesophageal reflex, massive hematemesis and esophagitis
without any prior history. It is important to be aware of this
rare side effect to minimize the related mortality due to the loss
172
of esophageal motility, increase in lower sphincter relaxation,
and loss of lower esophageal tone and pressure. CLZ can also
cause impairment of swallowing due to the the vagal regulation
of esophageal peristaltic movement and hypersalivation.[10]
The gastrointestinal tract disorders, including cases of
esophagitis with constipation, hiatal hernia, and hematemesis,
have been reported with the use of CLZ, but very few articles
have been published. These gastrointestinal disturbances arise
in connection with hypomotility and changes in digestive
secretion induced by CLZ, as a result of its antiserotoninergic
and anticholinergic properties. It is the responsibility of
physicians and psychiatrist to be aware of this life‑threatening
side effect and its consequences so that the morbidity and
mortality could be prevented.
Declaration of patient consent
The authors certify that they have obtained all appropriate
patient consent forms. In the form the patient(s) has/have
given his/her/their consent for his/her/their images and other
clinical information to be reported in the journal. The patients
understand that their names and initials will not be published
and due efforts will be made to conceal their identity, but
anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
1. Schulte P. What is an adequate trial with clozapine? Therapeutic drug
monitoring and time to response in treatment‑refractory schizophrenia.
Clin Pharmacokinet 2003;42:607‑18.
2. Meltzer HY, Ranjan R, Lee MA, Kenedy J. Emerging clinical uses of
clozapine. Rev Contemp Pharmacother 1995;6:187‑96.
3. Fitzsimons  J, Berk  M, Lambert  T, Bourin  M, Dodd  S. A  review of
clozapine safety. Expert Opin Drug Saf 2005;4:731‑44.
4. Laker  MK, Cookson  JC. Reflux oesophagitis and clozapine. Int Clin
Psychopharmacol 1997;12:37‑9.
5. Townsend G, Curtis D. Case report: Rapidly fatal bowel ischaemia on
clozapine treatment. BMC Psychiatry 2006;6:43.
6. Nielsen  J, Correll  CU, Manu  P, Kane  JM. Termination of clozapine
treatment due to medical reasons: When is it warranted and how can it
be avoided? J Clin Psychiatry 2013;74:603‑13.
7. Cohen D, Bogers JP, van Dijk D, Bakker B, Schulte PF. Beyond white
blood cell monitoring: Screening in the initial phase of clozapine
therapy. J Clin Psychiatry 2012;73:1307‑12.
8. Young CR, Bowers MB Jr., Mazure CM. Management of the adverse
effects of clozapine. Schizophr Bull 1998;24:381‑90.
9. Adebayo  KO, Ibrahim  N, Mosanya  T, Eegunranti  B, Suleiman  B,
Ayankunle  A, et al. Life‑threatening haematemesis associated
with clozapine: A  case report and literature review. Ther Adv
Psychopharmacol 2013;3:275‑7.
10. Praharaj  SK, Arora  M, Gandotra  S. Clozapine‑induced
sialorrhea: Pathophysiology and management strategies.
Psychopharmacology (Berl) 2006;185:265‑73.
Annals of Indian Psychiatry  ¦  Volume 3  ¦  Issue 2  ¦  July-December 2019