Clozapine-induced intestinal occlusion: a serious side effect.
ABSTRACT Aim of this article is to describe the first italian case reported in literature of a clozapine-induced intestinal occlusion with previous severe constipation in a 45-year-old male patient who had been treated with daily clozapine for 5 months because of treatment-resistant residual schizophrenia. When conservative treatment (intravenous fluids, fleet enema and rectal washout) was used and clozapine therapy was decreased, gastrointestinal symptoms rapidly improved and the patient had regular bowel motions within a week. Preventive measures (high-fiber diet, adequate fluid intake, stool softeners and exercise) was also used to ensure that clozapine therapy could be safely continued. Although constipation is a common and usually benign side effect of treatment with clozapine, this case-report highlights the consequences of undertreated and unrecognized marked constipation progressing to severe bowel obstruction (a complication which deserves more attention because it can lead to hospitalization and might be potentially fatal).
- Journal of clinical psychopharmacology 08/2010; 30(4):463-5. · 5.09 Impact Factor
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ABSTRACT: Cardiac autonomic dysfunction has been reported in patients suffering from schizophrenia. The aim of the present study was to evaluate gastric electrical activity in unmedicated patients suffering from acute schizophrenia in relation to their symptoms. Electrogastrography was performed before and after test meal ingestion in 26 patients suffering from schizophrenia and 26 matched controls. The non-linear measure approximate entropy (ApEn) was calculated for the first time from the obtained signal in addition to standardized measures. Results were correlated with the scales for the assessment of positive symptoms and negative symptoms. In addition, autonomic and abdominal symptoms were assessed by the autonomic symptom score. We found a significantly increased amount of tachygastria and arrhythmia within the signal of the activity of the gastric pacemaker before and after test meal digestion in patients compared to controls, indicating increased sympathetic modulation within the enteric nervous system. A significant difference was observed for slow wave, which represents the dominant frequency of gastric pacemaker activity, indicating gastric dysmotility in our patients. The elevated ApEn measure points to increased complexity and dysregulation. In addition, we have observed a correlation between delusions and tachygastria. Sympathetic function seems to be altered in the enteric nervous system of patients suffering from schizophrenia. Future studies need to explore the influence of the disease on different branches of the autonomic nervous system and clinical consequences of enteric dysfunction. Our findings point to a possible systemic autonomic imbalance that needs to be studied in respect to the neurobiology of schizophrenia.Progress in Neuro-Psychopharmacology and Biological Psychiatry 08/2009; 33(7):1236-40. · 3.55 Impact Factor
- Journal of clinical psychopharmacology 08/2013; · 5.09 Impact Factor
Clozapine is an atypical antipsychotic drug com-
monly used in the therapy of patients with treatment-
resistant schizophrenia (1-3). Despite its demonstra-
ted efficacy in psychotic disorders (it can result in dra-
matic improvements in many refractory schizophre-
nics, where it has been found to be superior to tradi-
tional neuroleptics) (4-6), the widespread use of clo-
zapine has been limited by its potential adverse effects
(such as life-threatening agranulocytosis, seizures, hy-
potension, weight gain, sialorrhea) (7-10).
Constipation is a common, albeit less known, si-
de effect of clozapine which occurs in 14-60% of trea-
ted patients (11-16). It is attributed to the combina-
tion of poor bowel habits (low-fiber diet, inadequate
fluid intake, diminished exercise) (17) and clozapine’s
strong anticholinergic properties (18, 19). In this way,
clozapine appears to be the most antimuscarinic of the
antipsychotic medications (it is an antagonist at M3
and M5 receptors and a partial agonist of M1 and M2
receptors) (20, 21). Its anticholinergic properties are
comparable in strength to those of amitriptyline and
benztropine,which have the most potent antimuscari-
nic effects among the psychotropic drugs (22, 23).
Other associated medications with antimuscarinic ac-
tivity (such as traditional neuroleptics,tricyclic antide-
pressants and antiparkinson drugs) may also increase
clozapine’s anticholinergic burden and exacerbate
constipation (1, 10, 17).
Clozapine-induced constipation is one such side
effect which must be taken seriously (24). In fact, it
may result in intestinal occlusion, paralytic ileus and
death (11, 25-27). A recent edition of the Australian
Adverse Drug Reactions Bulletin (18) highlighted the
common (but not trivial) nature of constipation. Of
the 15 cases of this serious side effect reported in Au-
stralia between 1992 and 1999,nine involved fecal im-
paction, two involved sub-acute bowel obstruction
and there was one fatality (24) secondary to inhalation
of feculent vomiting after occlusion of the transverse
colon. This fatal case is remarkably similar to the five
previously published cases reviewed by Levin et al
(25). Clinically, there seem to be two mechanisms
whereby clozapine-induced constipation can have a
fatal outcome. In three cases (28-30), intestinal ob-
Clozapine-induced intestinal occlusion:a serious side effect
Lorenzo Pelizza, Pasquale De Luca, Maurizio La Pesa, Daniela Borella
Casalmaggiore Psychiatric Operative Unit n. 25 - “Oglio Po” General Hospital, Cremona Hospital Institutes, Italy
Abstract. Aim of this article is to describe the first italian case reported in literature of a clozapine-induced
intestinal occlusion with previous severe constipation in a 45-year-old male patient who had been treated
with daily clozapine for 5 months because of treatment-resistant residual schizophrenia. When conservative
treatment (intravenous fluids,fleet enema and rectal washout) was used and clozapine therapy was decreased,
gastrointestinal symptoms rapidly improved and the patient had regular bowel motions within a week. Pre-
ventive measures (high-fiber diet, adequate fluid intake, stool softeners and exercise) was also used to ensure
that clozapine therapy could be safely continued.Although constipation is a common and usually benign side
effect of treatment with clozapine, this case-report highlights the consequences of undertreated and unrec-
ognized marked constipation progressing to severe bowel obstruction (a complication which deserves more
attention because it can lead to hospitalization and might be potentially fatal). (www.actabiomedica.it)
Key words:Clozapine, constipation, intestinal occlusion, schizophrenia
C A S E
R E P O R T
ACTA BIOMED 2007; 78: 144-148© Mattioli 1885
Clozapine-induced intestinal occlusion: a serious side effect
struction led to distention and necrosis of the bowel
and presented as an acute abdomen with a picture of
feculent peritonitis and sepsis. In the remaining two
cases (11, 26), postmortem examinations revealed se-
vere pulmonary edema secondary to inhalation of fe-
culent vomiting due to an extensive fecal impaction
involving the entire large bowel.
Herein, we describe the first italian case reported
in literature of clozapine-induced intestinal occlusion
with previous severe constipation to highlight how it
is important for prescribers to recognise and treat (as
soon as possible) constipation in patients taking cloza-
pine in order to prevent the development of more se-
A 45-year-old male patient with a 27-year history
of treatment-resistant residual schizophrenia (with
much institutional care) and excellent past physical
health (he had no prior history of constipation or other
gastrointestinal symptoms or diseases) had been trea-
ted with clozapine (400 mg/die) for the past 5 months
before his admission in our hospital, obtaining a signi-
ficant psychopathological benefit. At the time of ho-
spitalization, he resided in a community mental health
facility and was also receiving lorazepam (2.5 mg/die)
for a recurrent starting insomnia and sertraline (100
mg/die) as augmentation for his antipsychotic (negati-
ve symptoms) medication. His plasma clozapine levels
were within therapeutic limits (490 ng/mL for cloza-
pine and 280 ng/mL for norclozapine) (31, 32).
On admission, the patient reported a three-week
history of severe constipation and subjective abdomi-
nal distention (without pain), followed by two episo-
des of biliary vomiting on the same day. In the week
before his hospitalization,he also complained of inter-
mittent fever (temperature > 38° C) and coughing fits
probably due to his marked sialorrhea (chest X-ray ap-
pearance, in fact, was normal and ECG showed no
pathological findings). Physical examination revealed
diffuse abdominal tenderness which was soon accom-
panied by marked abdominal distention (without
pain), colon cord sensation in the right iliac fossa and
decreased bowel sounds. Rectal examination also re-
vealed the existence of a fecaloma. A slight leukocyto-
sis (10760 white cells per mL [87% neutrophils, 9%
lymphocytes,2% monocytes and 2% eosinophils) with
a neutrophilia of 8100 cells per mL and a lymphope-
nia of 700 cells per mL were the only abnormal labo-
ratory findings (creatinine, urea and electrolytes, in
fact,were normal and liver function values were within
the normal range). Abdominal X-ray appearance
showed dilated loops of the small and large bowel
(with no evidence of air-fluid levels) and a loaded co-
lon (megacolon) with extensive severe fecal impaction
mainly involving its transverse and descending por-
tions. A contrast enema also revealed no gross struc-
tural lesions. Based on those findings, a diagnosis of
intestinal occlusion was made.
Over the following week, the ileus resolved with
conservative treatment (intravenous fluids, fleet ene-
ma and rectal washout), while clozapine therapy had
been decreased to a dose of 250 mg/die. After the in-
testinal obstruction had resolved, the patient fully re-
covered within four days of treatment, had regular
bowel motions within a week and preventive measures
(high-fiber diet, adequate fluid intake, stool softeners
and exercise) were used to ensure that clozapine the-
rapy could be safely continued.
Although constipation is a common and usually
benign side effect of treatment with clozapine (it oc-
curs in 14-60% of treated schizophrenics) (10-16),
this case-report highlights the consequences of under-
treated and unrecognized marked clozapine-associa-
ted constipation progressing to severe bowel obstruc-
tion. This is perhaps the overriding and important
message of this article: clozapine-induced constipa-
tion and its clinical complications are not rare and
they deserve more attention since they can lead to ho-
spitalization and death (24, 27). Schizophrenic pa-
tients on clozapine should be warned of these pro-
blems and be asked (regularly) concerning their bowel
function. Due to the increasing number of psychiatric
subjects taking clozapine that are treated in the com-
munity, psychiatrists as well as other specialists and
general practitioners ought to be aware of clozapine-
L. Pelizza, P. De Luca, M. La Pesa, D. Borella
associated constipation and its complications (particu-
larly, of the possible development of an intestinal oc-
clusion).With regard to this severe consequence,eight
cases (0.13%) of paralytic ileus were found in 8000
Chinese psychiatric patients (33) and two cases
(0.25%) of bowel sub-occlusion were found in 929
German schizophrenics (7). Three cases of intestinal
occlusion (10%), one of them fatal, were also reported
among 30 clozapine-treated psychotic subjects in a
French hospital (26). According to Hayes and Gibler
(11), most constipated patients on clozapine were
mild to moderate in severity and adequately respon-
ded to stool softeners or bulk-forming laxatives, while
only 12% required repeated use of enemas to relieve
Another common element to highlight is that the
diagnosis of constipation and its complications was
often difficult or delayed in schizophrenic subjects
treated with clozapine (25). Their gastrointestinal
symptoms were either nonspecific (i.e.“false diarrhea”
of constipated patients) or not appreciated as heral-
ding a possibly fatal condition. There may be a num-
ber of reasons for this,which are briefly considered be-
low. Schizophrenics can have altered sensitivity to
pain (34-36) (this phenomenon may be particularly
important in the diagnosis of the acute abdomen, be-
cause pain is usually the central feature). The precise
degree of pain insensitivity is unclear.Neuroleptic me-
dications can have sedative or pain-modulating effects
and this may be a confounding factor in medicated pa-
tients. It is noteworthy, however, that the syndrome of
pain insensitivity was well described before antipsy-
chotic drugs were introduced (37).Another possibility
is that pain perception is normal but that schizophre-
nic subjects show difficulty in expressing the pain that
they feel (36). For example, the negative symptoms of
schizophrenia may affect the expression of pain and
physicians may be misled by flattened affect and
apathy into minimizing pain symptoms. Moreover,
psychotic patients with a formal thought disorder can
have difficulty in organizing their thoughts to express
symptoms of pain. Paranoia (i.e. persecutory or hypo-
chondriac delusions) may also discourage physicians
from thoroughly evaluating their patients.Furthermo-
re, in the face of a florid psychotic illness, constipation
may be trivialized as a minor side effect, acceptable in
light of the difficulty of managing an acute psychosis.
Moreover,the nature of the schizophrenic disorder re-
quires a team management approach. Consequently,
the patient can first report constipation to a mental
health worker who may not appreciate its implica-
tions.The psychiatrist is often the next in line to hear
about the symptoms. The general physician and ga-
stroenterologist, who have the expertise to deal with
the diagnosis and management of constipation, may
be involved only relatively late.
Future attention should focus on both the
pathophysiology and management of constipation and
its complications. The pathophysiology of clozapine-
induced constipation and intestinal occlusion have
always been assumed to be due to an anticholinergic
side effect of the medication (an atropinic reaction
causing a diffuse bowel hypomotility and the possible
formation of fecalomas), but this has never been rigo-
rously investigated or systematically tested in a con-
trolled manner (25). Diagnostic and treatment proto-
cols for clozapine-induced constipation, therefore,
must be developed and tested for both inpatient and
outpatient settings (11).
Since bowel obstruction seems to be preceded by
a (more or less) long time of constipation, standard
measures to prevent fecal impaction are strongly re-
commended (10, 27). In addition, since the prevalen-
ce and severity of constipation seem to be dose-de-
pendent (38), a logical strategy is to minimize the do-
se of clozapine (25). Measurement of serum clozapine
levels may be helpful in this regard. If serum levels of
clozapine are in the range of 500-700 ng/mL or grea-
ter,then the dose can be cautiously lowered (serum le-
vels lower than 350 ng/mL are associated with a lack
of clinical response) (31). Another strategy suggested
by Levin et al (25) is to replace part of the clozapine
dose with a less antimuscarinic antipsychotic drug (su-
ch as quetiapine or haloperidol) and thus use it as a
clozapine-sparing agent (this strategy of combination
therapy has demonstrated to improve glycemic control
and reduce weight gain in schizophrenic patients pre-
viously treated with clozapine alone) (39). Moreover,
Hayes and Gibler (11) have recommended a slower
clozapine titration schedule with small increments in
the dose of medication by no more than 25 mg/die to
a maximum of 100 mg/week.
Clozapine-induced intestinal occlusion: a serious side effect
In conclusion, psychiatrists, general physicians
and radiologists should be aware of the seriousness of
clozapine-induced constipation and of the risk of pro-
gression to bowel occlusion (particularly, in those
schizophrenics with a long history of high-dose anti-
psychotic treatment before clozapine therapy [which
may have contributed to less bowel motility] and in
those psychotic subjects with prolonged inpatient ho-
spitalization [who are less likely to be active]). Psy-
chiatrists should actively question about symptoms of
constipation in this group of patients and have a lowe-
red threshold for investigation and treatment (a pa-
tient receiving clozapine and presenting with abdomi-
nal pain or vomiting against a background of consti-
pation should raise immediate concern). Prophylactic
treatment and prompt intervention for constipation
along with slower clozapine titration appear to have
been successfull in decreasing the prevalence and seve-
rity of clozapine-induced constipation in this psychia-
tric population, where this adverse drug reaction may
lead to bowel occlusion (needing of an hospitaliza-
tion) and can be potentially fatal (as well as agranu-
1. American Psychiatric Association (APA).Treatment recom-
mendations for patients with schizophrenia. Washington
DC, APA Press, 2004.
2. Stahl S. Essential psychopharmacology. Cambridge, Cam-
bridge University Press, 1998.
3. Hardman J, Limbird L, Molinoff P. Goodman & Gilman’s
pharmacological basis of therapeutics. New York, McGraw-
4. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for
treatment-resistant schizophrenia: a double-blind compari-
son with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789-
5. Baldessarini R, Frankenburg F. Clozapine: a novel antipsy-
chotic agent. New Eng J Med 1991; 324: 746-54.
6. Meltzer H. Treatment of schizophrenia. Washington DC,
APA Press, 1995.
7. Grohmann R, Ruther E, Sassim N, Schmidt L. Adverse ef-
fects of clozapine. Psychopharmacol 1989; 99: 101-4.
8. Safferman A, Lieberman J, Kane J, Szymanski S, Kinon B.
Update on the clinical efficacy and side effects of clozapine.
Schizophr Bull 1991; 17: 247-61.
9. Marinkovic D, Timtijevic I, Babinsky T, Totic S. The side
effects of clozapine: a four year follow-up study. Prog Neu-
ropsychopharmacol 1994; 18: 537-44.
10. Young C, Bowers M, Mazure C. Management of the ad-
verse effects of clozapine. Schizophr Bull 1998; 24: 381-90.
11. Hayes G, Gibler B. Clozapine-induced constipation. Am J
Psychiatry 1995; 152: 2.
12. Claghorn J, Honigfeld G, Abuzzahab F. The risks and be-
nefits of clozapine versus chlorpromazine. J Clin Psy-
chopharmacol 1987; 7: 337-84.
13. Fitton A, Heel R. Clozapine: a review of its pharmacologi-
cal properties and therapeutic use in schizophrenia. Drugs
1990; 5: 722-747.
14. Potter W, Ko G, Liang D. Clozapine in China: a review
and preview of US/PRC collaboration. Psychopharmacol
1989; 99: 87-91.
15. Singer K, Lam C. Evaluation of clozapine in schizophrenia
with acute symptomatology. J Int Med Res 1973; 1: 622-9.
16. Lieberman M, Safferman A, Pollack S. Clinical effects of
clozapine in chronic schizophrenia: response to treatment
and predictors of outcome. Am J Psychiatry 1994; 151:
17. Mathew T, Desmond P, Isaacs D. Constipation: it can be
severe with clozapine. Aust Adverse Drug Reactions Bull
1999; 18: 2.
18. Jann M, Grimsley S, Gray E, Chang W. Pharmacodyna-
mics and pharmacokinetics of clozapine. Clin Pharmacoki-
net 1993; 24: 161-76.
19. Chengappa K, Pollock B, Parepally H, Levine J. Anticholi-
nergic differences among patients receiving standard clini-
cal doses of olanzapine and clozapine. J Clin Psychopharma-
col 2000; 20: 311-6.
20. De Leon J, White A, Josiassen R, Diaz F, Simpson G. Se-
rum antimuscarinic activity during clozapine treatment. J
Clin Psychopharmacol 2003; 23: 336-41.
21. Ichikawa J, Dai J, O’Laughlin I. Atypical, but not typical,
antipsychotic drugs increase cortical acetylcholine release
without an effect in the nucleus accumbens and striatum.
Neuropsychopharmacol 2002; 26: 325-39.
22. Bloom F, Kupfer D. Psychopharmacology, the fourth gene-
ration in progress. New York, Raven Press, 1994.
23. De Leon J, Canuso C, White A. A pilot effort to determi-
ne benztropine equivalents of anticholinergic medications.
Hosp Comm Psychiatry 1994; 45: 606-7.
24. Drew L, Herdson P. Clozapine and constipation: a serious
issue. Aust NZ J Psychiatry 1997; 31: 149-50.
25. Levin T, Barrett J, Mendelowitz A. Death from clozapine-
induced constipation. Psychosomatics 2002; 43: 71-3.
26.Theret L, Germaine M, Burde A. Current aspects of the
use of clozapine in the Chalons-sur-Marne Psychiatric Ho-
spital: intestinal occlusion with clozapine. Ann Med Psychol
(Paris) 1995; 153: 474-7.
27.Tang W,Ungvari G.Clozapine-induced intestinal obstruc-
tion. Aust NZ J Psychiatry 1999; 29: 660.
28. Shammi C, Remington G. Clozapine-induced necrotizing
colitis. J Clin Psychopharmacol 1997; 17: 230-2.
29. Commitee on Safety of Medicines/Control Agency.Cloza-
L. Pelizza, P. De Luca, M. La Pesa, D. Borella
pine and gastrointestinal obstruction. Curr Prob Pharmaco-
vigilance 1999; 25: 1.
30. Freudenreich O, Goff D. Colon perforation and peritonitis
associated with clozapine.J Clin Psychiatry 2000; 61: 950-1.
31. Perry P, Miller D, Arndt S, Cadoret R. Clozapine and nor-
clozapine plasma concentrations and clinical responses of
treatment-refractory schizophrenic patients. Am J Psychia-
try 1991; 148: 231-5.
32. Kronig M, Munne R, Szymanski S, Safferman A. Plasma
clozapine levels and therapeutic response for treatment-re-
fractory schizophrenic patients. Am J Psychiatry 1995; 152:
33. Lu M. Clinical analysis of the main side effects of clozapi-
ne. Chinese J Neurol Psychiatry 1991; 24: 71-4.
34. Dworkin R. Pain insensitivity in schizophrenia: a neglected
phenomenon and some implications. Schizophr Bull 1994;
35. Rosenthal S, Porter K, Coffey B. Pain insensitivity in schi-
zophrenia: case-report and review of the literature.Gen Ho-
sp Psychiatry 1990; 12: 319-22.
36. Bickerstaff L, Harris S, Leggett R. Pain insensitivity in
schizophrenic patients: a surgical dilemma. Arch Surg 1988;
37. Bender L,Schilder P.Unconditioned and conditioned reac-
tions to pain in schizophrenia.Am J Psychiatry 1930;3:365-
38. Pare J, Riffand P, Baurdeix I. The clozapine in France.
Information Psychiatric 1993; 4: 389-97.
39. Reinstein M, Sirotovskaya L, Jones L. Effect of clozapine-
quetiapine combination therapy on weight and glycemic
control. Clin Drug Invest 1999; 18: 99-104.
40. Klimke A, Kleiser E. Side effects and efficacy of clozapine
in the treatment of acute schizophrenia. Pharmacopsychiatr
1992; 25: 107.
Accepted: 24thApril 2007
Correspondence: Pelizza Lorenzo, MD
c/o Centro Salute Mentale Guastalla
Via Salvo D’Acquisto n. 7
42016 Guastalla (RE)
Fax number: 0522/838980
E-mail: email@example.com, www.actabiomedica.it