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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

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