by Nicholas D. McKinnon, MD, Capt, USAF, MC; Alvi Azad, DO, Capt, USAF, MC; Brian M. Waters, MD, Capt, USAF, MC; and Kaustubh G. Joshi, MD, Maj, USAF, MC, FS

Drs. McKinnon and Azad are general psychiatry residents with US Air Force (Wilford Hall Medical Center, Lackland AFB, Texas) and the University of Texas Health Science Center at San Antonio, Texas; Dr. Waters is inpatient staff psychiatrist with US Air Force (Wilford Hall Medical Center, Lackland AFB, Texas); and Dr. Joshi is Psychiatry Department Chairman and Chief of Consultation-Liaison Psychiatry with US Air Force (Wilford Hall Medical Center, Lackland AFB, Texas).

Psychiatry (Edgemont) 2009;6(3):30–35


The opinions expressed in this paper do not necessarily reflect those of the United States Air Force or the Department of Defense.

Financial disclosure

The authors report no relevant conflicts of interest or commercial ties with respect to this material.


Resistant schizophrenia is often treated with clozapine after other conventional atypical antipsychotics have failed or have resulted in intolerable side effects. Clozapine is generally reserved for secondary use due to its propensity to cause serious side effects, such as life-threatening agranulocytosis and the necessity for life-long blood monitoring. In this case report we present a 40-year-old female patient who suffered from chronic constipation and bowel infarctions after long-term use with clozapine. Although the use of this medication resulted in multiple abdominal surgeries with subtotal colonic resections, the patient’s schizophrenic symptoms only responded to clozapine after several repeat failures with other medications; ultimately, she was continued on this medication.

Key Words

clozapine, ischemic colitis, atypical antipsychotic, schizoaffective disorder, constipation, bowel surgery


The US Food and Drug Administration (FDA) has approved the atypical antipsychotic clozapine for use in patients who have severe schizophrenia and who are either intolerant or refractory to other antipsychotic medications. Compared to conventional neuroleptics, clozapine has been found superior in the treatment of refractory schizophrenia and has been found to have utility in the treatment of suicidal behavior in schizophrenic patients, childhood schizophrenia, affective disorders, neurological complaints to include movement disorders precipitated by other antipsychotic medications, aggressive behavior, and comorbid substance use disorders in dually diagnosed patients.[1–7]

Structurally, clozapine consists of a dibenzodiazepine derivative with a piperazinyl side chain (Figure 1). Through brain imaging studies, clozapine has shown a weaker binding affinity for dopamine D1 and D2 receptors (20–30%) than the typical antipsychotics and a greater binding affinity for cortical D3 and D4 receptors. Clozapine has binding affinity 100 times more selective for serotonin (specifically 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT3) than dopamine receptors and exhibits more pronounced adrenergic (alpha 1 and 2), muscarinic, cholinergic, and histaminergic (H1) antagonist properties.[7,11–13]

Few reports of extrapyramidal side effects with clozapine exist, likely secondary to the drug’s weaker D2 receptor affinity, and until recently, no case reports of tardive dyskinesia had been published.[14,15] Up to 17 percent of patients must discontinue treatment with clozapine because of adverse effects.[16]

Agranulocytosis is the major, life-threatening, adverse effect classically associated with clozapine use and occurs in 1 to 2 percent of patients who take the drug. Patients administered clozapine are therefore required to submit to routine phlebotomy and participate in a national registry designed to monitor for agranulocytosis, a fact that has limited both the availability and appeal of clozapine therapy.

Besides agranulocytosis, other potentially chronic and disabling adverse effects that have been reported with clozapine include weight gain, hyperglycemia, dyslipidemia, seizure, delirium, sedation, obsessive compulsive symptoms, tachycardia, cardiac abnormalities, myocarditis, both hypertension and hypotension, hepatic injury, fever, neuromuscular effects, neuroleptic malignant syndrome, sialorrhea, urinary incontinence, nausea, and constipation.[7,11,13,16,17]

Gastrointestinal side effects associated with clozapine include constipation, gastric outlet obstruction, prolonged postoperative ileus, and peritonitis with bowel perforation; there have even been fatalities reported.[25] The prevalence of developing intestinal side effects while a patient is on clozapine has been reported to be as high as 33 percent.[25,26] Although bowel infarction is a rare occurrence, this particular side effect has lethal consequences.[23] Causes of bowel infarction include (but are not limited to) venous or arterial occlusion, obstructions, nonocclusive or occlusive mesenteric ischemia, and splanchnic vasoconstrictive agents (e.g., sympathomimetics, digitalis).

Case Report

The following is the complicated medical course of a 40-year-old Caucasian woman who was admitted to the hospital from the emergency department following four days of progressively worsening right-sided abdominal pain. She also complained of a two-week history of worsening urinary incontinence and has a permanent cystostomy with in-dwelling suprapubic catheter for management of sporadic urinary incontinence that became bothersome to the patient approximately three years prior to this admission. She has a history of treatment-resistant schizoaffective disorder treated with clozapine for the past nine years. Her medications at the time of admission were clozapine 200mg twice daily and 300mg at bedtime; topirimate 100mg twice daily and 50mg at bedtime; alprazolam 1mg in the morning, 0.5mg in the evening, and 0.5mg at bedtime; venlafaxine XR 225mg daily; oxybutynin 5mg three times daily; amlodipine 5mg daily; zolpidem 20mg at bedtime.

Her past medical history was significant for bilateral congenital hearing loss and hypertension. Previous surgeries included bilateral stapes replacement, suprapubic catheter placement for urinary incontinence, appendectomy, and both large and small bowel resections. At the time of admission, the patient was residing independently and was adherent with her care. There were no substance use issues.

Approximately eight years prior to this admission, the patient underwent surgery to resect a portion of her large bowel and undergo colostomy formation. At that time, two segments of descending colon measuring 17.0×7.0x7.0cm and 12.0×5.0cm were resected, and specimens submitted for both gross and microscopic pathology were found to exhibit evidence of extensive mucosal necrosis consistent with localized infarction. Following that hospitalization, clozapine was discontinued for eight months out of concern that it may have contributed to her initial bowel infarction. Records from that time indicate patient insistence that, given the refractoriness of her mental illness and the perceived psychiatric benefit of her medication, clozapine be restarted despite the possible contribution to her gastrointestinal problems.

Once back on clozapine the patient’s constipation persisted and proved refractory to medical treatment. Subsequently, one year following the first surgery, she underwent a subtotal colectomy to remove a 105cm segment of markedly dilated and dusky-appearing large intestine followed by an intraoperative ileorectal anastomosis. The operative diagnosis at that time was atonic colon with chronic constipation.

Over the next several years the patient continued to struggle with constipation and with on and off complaints of abdominal pain and bloating. Approximately two years prior to her current presentation, an extraperitoneal end-ileostomy was created due to patient complaints of constipation with intermittent bouts of fecal incontinence. Notably, minimal intra-abdominal adhesions were found during the operative procedure.

On the day of admission, she was complaining of four days of worsening right-sided abdominal pain, nausea without emesis, decreased stool output into her colostomy, and a two-week exacerbation of recurrent urinary incontinence. She was hypertensive (158/103) upon admission. Physical examination revealed a soft, nondistended abdomen with normoactive bowel sounds. She had tenderness around the ileostomy site with the ostomy bag filled with liquid stool. There was no erythema or pus around the ileostomy site. Abdominal x-rays and a computed tomography (CT) scan (Figure 2) revealed multiple dilated air/fluid loops of small and large bowel with possible ileus or obstruction without a definite point. Abdominal ultrasound showed hepatomegaly with a normal pancreas. Laboratory studies did not reveal significant abnormalities. Bowel rest and nasogatric suction were initiated.

On the day following admission, she vomited a significant amount of foul-smelling and bilious-appearing material and proceeded into respiratory arrest requiring mechanical ventilation. Aspiration of gastric contents was suspected as the cause of her respiratory distress. Once stabilized and pulmonary embolus was ruled out, the patient was taken to surgery where approximately 130.0cm of gangrenous bowel with an average diameter of 8.0cm was resected.

Grossly, the resected bowel was found to be significantly dilated by fecal material without evidence of a mechanical source of obstruction. Microscopic pathology revealed extensive mucosal necrosis consistent with localized infarction secondary to massive fecal dilatation (Figure 3). The patient’s medical course was complicated by septic shock, with the abdominal cavity as the suspected source. She subsequently required ventilator assistance for two and half weeks and dialysis for six weeks.

After the patient was medically stabilized, psychiatry was consulted to address patient complaints of episodic paranoia and hallucinations. Over the course of several weeks, efforts were made to treat her psychotic symptoms with an alternative antipsychotic agent (quetiapine) without symptomatic improvement. The patient insisted on continuing clozapine. Low-dose clozapine was reintroduced with fluctuating but gradual symptomatic improvement. Her outpatient psychiatrist was notified of the potential dangers of continued treatment with high-dose clozapine and the patient was discharged on 75mg clozapine per day.


There are a number of case reports linking clozapine with constipation and at least seven published cases of death secondary to clozapine-induced constipation resulting in either: frank bowel necrosis, paralytic ileus, gastric outlet obstruction, colonic perforation with fecal peritonitis, with fatal aspiration of feculent vomitus as a result of bowel obstruction, postoperative ileus or eosinophilic colitis.[18–29] Constipation associated with clozapine is thought to be mediated by the drugs’ pronounced dose-dependent cholinergic and serotonergic antagonism.[6,12,18,19,23–25,30]

Constipation can be further compounded by the administration of pharmacologic agents, which may interact with or potentiate the effects of other medical or environmental factors promoting slowed bowel motility. The patient presented in this article was also maintained on as-needed narcotic analgesic (dextropropoxyphene). Although these medications are well known for their effects on contributing to constipation, she had been taking this medication for a shorter period of time than she was taking clozapine and had not been taking this medication regularly. She had been taking oxybutynin as an outpatient, which has anticholinergic properties. However, there are no published case reports of this medication resulting in significant bowel complications. In addition, there is no evidence of overuse of oxybutynin in this patient. She had also been on this medication for a shorter period of time compared to clozapine. It is possible that in combination with the anticholinergic properties of clozapine, oxybutynin increased hindrance to gastric motility.

It is worth mentioning that clozapine has been reported to cause disturbances in urinary function in six percent and specifically enuresis in 0.23 percent of patients treated with this drug.[31,32] The highly anticholinergic antispasmodic oxybutynin, as was utilized in the presented patient, is among the agents that may be used for treatment of urinary incontinence.[33]

The patient in this case report also had prior abdominal procedures, which can result in adhesions and possible denervation as risk factors for future gastrointestinal complications. However, at the time of surgery, there was no evidence of adhesions or other mechanical obstruction, aside from abundant fecal material. There was also no evidence of arterial or venous occlusion and no evidence of mesenteric ischemia during the course of her hospitalization. She was not prescribed sympathomimetic agents as an outpatient or during her hospitalization. After considering the additional causes of infarction and excluding them during the course of her hospitalization, clozapine was eventually determined to be the culprit.

Clozapine is hepatically metabolized primarily by cytochrome P450 1A2. A further consideration particularly in the schizophrenic patient population is the possible contribution of substrates of P450 1A2 and their impact on drug-drug interactions.[25] Though the above presented patient is a nonsmoker, tobacco use rates among individuals diagnosed with schizophrenia have been estimated as high as 80 percent.[34] Cigarette smoke is a potent inducer of P450 1A2 and may cause clinically significant reductions in medications such as clozapine.[35] Clozapine-treated individuals who abruptly stop smoking are therefore at increased risk of significant anticholinergic side effects as a consequence of increased serum drug levels.

Although the risk of neutropenia is relatively well-known, clozapine is reported to be associated with a number of other syndromes which may be rapidly fatal, including not only constipation and bowel obstruction but also cardiovascular collapse, seizures, and ketoacidosis. Patients taking clozapine should pay attention to abdominal pain, constipation, feculus vomitus, and distended abdomen as signs and symptoms of possible complications of clozapine use. However, these signs and symptoms are nonspecific. Psychiatrists working with such patients should remain vigilant of the possibility of such complications and should communicate those risks to other clinicians caring for the patient.[19]

The new generations of atypical antipsychotics and clozapine in particular, have the potential to ameliorate profound psychotic disabilities. Clozapine use has become widespread, and a survey conducted at a major university inpatient facility in the mid-1990s found that after haloperidol and perphenazine, clozapine was the antipsychotic most often prescribed to their patients.[36] With the introduction and widespread availability of newer atypical antipsychotic agents with more favorable side effect profiles, the use of clozapine has declined in recent years; still with appropriate monitoring it remains a useful adjunct in the treatment of highly refractory psychotic patients.


The author would like to thank the patient for her permission to present this case. Additional thanks to Haakon Nygaard, MD, and Eric E. Santos, MD, for their assistance with the abdominal CT and anatomical images.

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