Death From Clozapine-Induced Constipation
Clozapine is commonly used in the therapy of patients documented constipation and upper gastrointestinal com-
with treatment-resistant schizophrenia and schizo-
plaints. He presented with nausea and an acute abdomen,
phrenia with prominent negative symptoms. Constipation
and laparotomy revealed a grossly dilated colon. Autopsy
occurs in 14% of patients receiving clozapine and is be-
showed marked dilation and necrosis of the entire large
lieved to be an anticholinergic side effect.1 A recent edition
of the Australian Adverse Drug Reactions Bulletin2 high-
More recently, Freudenreich and Goff7 described a
lighted the common nature of this side effect. However,
49-year-old man who developed colon perforation and
this is not a trivial side effect. Of the 15 cases of serious
feculent peritonitis 6 weeks after commencing clozapine
constipation reported in Australia, 4 involved fecal impac-
(400 mg/day). The patient had complained of constipa-
tion, 2 involved subacute bowel obstruction, 1 involved
tion, but did not receive treatment. He required an emer-
rectal prolapse requiring ileostomy, and there was 1 fatality
gency hemicolectomy and perioperatively sustained a
secondary to inhalation of feculent vomitus.
The aforementioned fatality, described by Drew and
We describe a further death secondary to clozapine-
Herdson,3 occurred in a 49-year-old man with paranoid
induced constipation and fecal impaction. We believe this
schizophrenia who was treated with clozapine (500 mg/day)
is the fifth fatality described in the literature. The ramifi-
for 2 years. He died unexpectedly in a psychiatric ward.
cations of this complication for patients receiving cloza-
Postmortem examination revealed severe pulmonary
edema secondary to inhalation of feculent vomitus. Exten-sive, severe fecal impaction was found, involving the entirelarge bowel with feculent fluid extending all the way to the
stomach. There was also evidence of reflux esophagitis. Ofnote, in the month before his death, the patient had com-plained of intermittent nausea, vomiting, indigestion, and
Mr. C. is a 43-year-old man who was admitted to the hospital
chest pain, but had complained of constipation only once,
with an acute abdomen and hypotension. He had a history ofchronic paranoid schizophrenia of 20 years’ duration, which
had been treated with clozapine (750 mg/day) for the past 6
Hayes and Gibler4 described a similar death in a
years before his admission. Mr. C. was also receiving medroxy-
29-year-old man receiving clozapine (up to a dose of
progesterone acetate (Depo-Provera) for aberrant sexual behav-
400 mg/day) for 36 days, who also died of aspiration of
ior and valproate sodium (1,200 mg/day) as augmentation for
vomitus secondary to constipation and bowel obstruction.
his antipsychotic medication. He had a history of ulcerativeesophagitis and previously treated syphilis. At the time of ad-
A French report5 of 30 cases of clozapine-induced
constipation documented three cases of intestinal obstruc-
Received October 16, 2001; accepted October 16, 2001. From the De-
tion that required surgical laparotomy. One of the cases was
partment of Consultation Liaison Psychiatry, Long Island Jewish Medical
Center, New Hyde Park, NY. Address correspondence and reprint re-quests to Dr. Levin, Department of Consultation Liaison Psychiatry, Long
A further case of a 36-year-old man treated with clo-
Island Jewish Medical Center, 270-05 76th Ave, New Hyde Park, NY
zapine (600 mg/day) for 4 months was documented by
Shammi and Remington.6 Their patient had previously
Copyright ᭧ 2002 The Academy of Psychosomatic Medicine.
Psychosomatics 43:1, January-February 2002
mission, Mr. C. resided in a community mental health facility
not appreciated as heralding a possibly fatal condition.
and was treated under an involuntary community treatment
There may be a number of reasons for this, which are con-
Six months before admission, Mr. C. underwent gastros-
copy and abdominal computed tomography for investigation of
Schizophrenic patients may have altered sensitivity to
vomiting and epigastric pain. The gastroscopy revealed ulcera-
pain.8 This phenomenon may be particularly important in
tive esophagitis, and the computed tomography results were re-
diagnosis of the acute abdomen because pain is usually the
ported as “normal apart from constipation.” He was subse-
central feature.9,10 The precise degree of pain insensitivity
quently prescribed omeprazole 20 mg/day and psyllium 1 tsp.
is unclear. Neuroleptic and anticonvulsant medications
One month before admission, he saw his local doctor with
may have sedative or pain-modulating effects, and this may
complaints of vomiting and abdominal pain, and the dose of
be a confounding factor in medicated patients. It is note-
worthy, however, that the syndrome of pain insensitivity
On the morning of his admission, he was found to be un-
was well described before neuroleptic drugs were intro-
well, complaining of abdominal pain with feculent vomiting,
and was subsequently transferred to the hospital by ambulance.
On admission to the hospital, Mr. C. was conscious but
Another possibility is that pain perception is normal
confused, with cyanosis, tachycardia, tachypnea, and an un-
but that schizophrenic patients have difficulty expressing
recordable blood pressure. Examination otherwise revealed a
the pain that they feel.9 For example, the negative symp-
distended, rigid abdomen with generalized peritonitis. He was
toms of schizophrenia may affect the expression of pain,
and physicians may be misled by flattened affect and ap-
Emergency laparotomy revealed a large-bowel obstruction
secondary to severe fecal impaction affecting the entire colon,
athy into minimizing pain symptoms. Patients with a for-
especially the rectosigmoid junction. The colon, although mac-
mal thought disorder may have difficulty in organizing
roscopically intact, was grossly distended with patchy hemor-
their thoughts to express symptoms of pain. Paranoia may
rhage and necrosis. Histologic examination later confirmed se-
discourage physicians from thoroughly evaluating their pa-
vere ischemic changes and toxic dilation.
Because of the sheer fecal bulk, a manual decompression
tients. Guieu et al.12 attempted to evaluate pain perception
was carried out before a total colectomy and ileostomy were
objectively using nociceptive reflex thresholds as an index
of pain perception in neuroleptic-naive patients. Although
Despite maximal treatment in an intensive care unit, Mr.
they found no differences between the patient and control
C. died 3 weeks later with refractory septic shock and progres-
groups, the serious methodologic flaw of not using uniform
diagnostic criteria for schizophrenia casts doubt on theirfindings. For example, 4 of their group of 10 patients had
simple schizophrenia, and 1 patient had been ill for only2.4 months.
Although constipation is a common and usually benign
In the face of a florid psychotic illness, constipation
side effect of treatment with clozapine, this case highlightsthe consequences of undertreated or unrecognized, severe
may be trivialized as a minor side effect, acceptable in light
clozapine-associated constipation progressing to fatal
of the difficulty of managing an acute psychosis. Moreover,
bowel obstruction. This is perhaps the overriding and sur-
the nature of the schizophrenic illness requires a team man-
prising message of this case: that clozapine-induced con-
agement approach. Consequently, the patient may first re-
port constipation to a mental health worker who may not
This case is remarkably similar to the four previously
appreciate its implications. The psychiatrist is often the
published cases reviewed above. Clinically, there seem to
next in line to hear about the symptoms. The general phy-
be two mechanisms whereby clozapine-induced constipa-
sician or gastroenterologist, who has the expertise to deal
tion can have a fatal outcome. In the case presented and in
with the diagnosis and management of constipation, may
that of Shammi and Remington6 outlined above, bowel ob-
be involved only relatively late. Moreover, these same phy-
struction led to distention and necrosis of the bowel and
sicians, who easily investigate constipation in nonpsychi-
presented as an acute abdomen with a picture of sepsis. In
atric patients, may be challenged by the same symptom in
the remaining two cases, death was secondary to inhalation
psychotic patients. Often this seemingly simple problem
will require a coordinated and intensive multidisciplinary
Another common element is that diagnosis was often
approach. For example, administering enemas to the
difficult or delayed. Symptoms were either nonspecific or
schizophrenic Mr. C., with his residual symptoms, lack of
Psychosomatics 43:1, January-February 2002
insight and compliance, and aberrant sexual behaviors,
by substituting 2 mg of quetiapine for every 1 mg of clo-
could easily turn into a logistical nightmare.
zapine. Reinstein et al.14 used this strategy of combination
Future attention should focus on both the pathophys-
clozapine–quetiapine therapy to improve glycemic control
iology and management of this condition. The pathophys-
and reduce weight in patients previously treated with clo-
iology of clozapine-induced constipation has always been
zapine alone. There are, however, no reports of clozapine–
assumed to be due to an anticholinergic side effect of the
quetiapine combination therapy for treating clozapine-
medication, but this has never been rigorously investigated.
Cholinergic agents such as bethanechol or donepezil, for
Although we have discussed this case specifically as
example, have never been systematically tested in a con-
it relates to clozapine, other commonly used psychiatric
trolled manner for this condition. Diagnostic and treatment
medications such as thioridazine, chlorpromazine, and
protocols for clozapine-induced constipation, therefore,
benztropine, to name but a few, also present a large anti-
must be developed and tested for both the inpatient and
cholinergic burden and may cause constipation.
outpatient settings. For example, in an already severely
In conclusion, psychiatrists, general physicians, radi-
constipated patient, a bulk-forming agent may theoretically
ologists, and consultation-liaison psychiatrists, in particu-
worsen constipation, and perhaps an enema should be used
lar, should be aware of the seriousness of clozapine-induced constipation and of the risk of progression to
bowel obstruction. Psychiatrists should actively enquire
A logical strategy is to minimize the dose of clozapine.
about symptoms of constipation in this group of patients
Measurement of serum clozapine levels may be helpful in
and have a lowered threshold for investigation and treat-
this regard. If serum levels of clozapine are in the range of
ment. A patient receiving clozapine and presenting with
500–700 ng/mL or greater, then the dose can be cautiously
vomiting and abdominal pain against a background of con-
lowered. Serum levels lower than a threshold of 350 ng/mL
stipation should raise immediate concern.
are associated with a lack of clinical response.13 Anotherstrategy may be to replace part of the clozapine dose with
The authors thank Dr. Efrat Blum and Prof. Graeme C.
quetiapine, and thus use it as a clozapine-sparing agent. For
Smith for their editorial comments and assistance in the
example, the dose of clozapine could be reduced by 25%
References
1. Young CR, Bowers MB, Mazure CM: Management of adverse ef-
nomenon and some implications. Schizophr Bull 1994; 20:235–
fects of clozapine. Schizophr Bull 1988; 24:381–390
2. Mathew T, Desmond P, Isaacs D, et al: Constipation: it can be
9. Bickerstaff LK, Harris SC, Leggett RS, et al: Pain insensitivity in
severe with clozapine. Australian Adverse Drug Reactions Bulletin
schizophrenic patients. A surgical dilemma. Arch Surg 1988;
3. Drew L, Herdson P: Clozapine and constipation: a serious issue.
10. Rosenthal SH, Porter KA, Coffey B: Pain insensitivity in schizo-
phrenia. Case report and review of the literature. Gen Hosp Psy-
Hayes G, Gibler B: Clozapine-induced constipation (letter). Am J
11. Bender L, Schilder P: Unconditioned and conditioned reactions to
pain in schizophrenia. Am J Psychiatry 1930; 3:365–384
5. Theret L, Germaine ML, Burde A: Current aspects of the use of
12. Guieu R, Samuelian JC, Coulouvrat H: Objective evaluation of pain
clozapine in the Chalons-sur-Marne Psychiatric Hospital: intestinal
perception in patients with schizophrenia. Br J Psychiatry 1994;
occlusion with clozapine (French). Ann Med Psychol (Paris) 1995;
13. Kronig MH, Munne RA, Szymanski S, et al: Plasma clozapine
6. Shammi CM, Remington G: Clozapine induced necrotizing colitis.
levels and clinical response for treatment-refractory schizophrenic
J Clin Psychopharmacol 1997; 17:230–232
patients. Am J Psychiatry 1995; 152:179–182
7. Freudenreich O, Goff DC: Colon perforation and peritonitis asso-
14. Reinstein MJ, Sirotovskaya LA, Jones LE, et al: Effect of clozapine-
ciated with clozapine. J Clin Psychiatry 2000; 61:950–951
quetiapine combination therapy on weight and glycemic control. Clin
8. Dworkin RH: Pain insensitivity in schizophrenia: a neglected phe-
Psychosomatics 43:1, January-February 2002
LVVXHBOLY SR] PDJT[G 30 3DJH PROMOTiON HEALTH PROMOTION PROGRAM MANDATE & DISCLAIMER In accordance with our mandate (CROI) took place in Boston from Februaryupdate of the STARTMRK study at CROI. 27 to March 2, 2011. CROI is a scientifically-The study is comparing twice-daily raltegravirresearchers working to understand, prevent,and treat HIV/AIDS and its c
Global Research Global Investment House KSCC Equities Research Souk Al-Safat Bldg., 2nd Floor P.O. Box 28807 Safat 13149 Kuwait Tel: (965) 240 0551 Fax: (965) 240 0661 Email: research@global.com.kw http://www.globalinv.net Global Investment House stock market indices can be accessedfrom the Bloomberg page GLOHand from Reuters Page GLOBOmar M. El-Quqa, CFA Executive Vice President omar@globa