Cases That Test Your Skills A dangerous GI complication Amit Chopra, MD, Abhishek Rai, MBBS, Kemuel Philbrick, MD, and Piyush Das, MD How would you Ms. X, age 61, undergoes emergent surgery for intestinal obstruction. handle this case? Her paranoid schizophrenia has been well controlled on clozapine, Visit CurrentPsychiatry.com to input your answers but the drug might be causing her GI distress. What would you do? and see how your colleagues responded CASE GI surgery gastric tube decompression and total paren- Ms. X, age 61, presents to the emergency de- teral nutrition. CT enterography demonstrates partment (ED) complaining of nausea, vom- no areas of stricture formation with interval iting, and abdominal pain and distension. decompression. CT scan of her abdomen reveals segmental The psychiatric service is consulted to ischemia in her colon with abscess formation, evaluate the possibility of clozapine-induced which leads to immediate surgery, includ- para lytic ileus. During initial assessment, Ms. ing ileocecostomy with primary anastomosis. X denies any psychotic symptoms, including After surgery, Ms. X suffers from gastrointes- paranoid ideations, delusions, and auditory or tinal (GI) dysmotility. The gastroenterology visual hallucinations, and firmly believes that team recommends daily enemas along with a clozapine helps keep her stable. She also denies soft diet after she is discharged. mood symptoms that could indicate mania or Ms. X has chronic paranoid schizophrenia, depression. She shows no signs or symptoms which has been treated successfully for 18 that suggest anticholinergic delirium. years with clozapine, 500 mg/d. During acute psychotic episodes, she experienced paranoid The authors’ observations delusions and command auditory hallucina- Clozapine has proven efficacy in manag- tions telling her to kill herself. She had previ- ing treatment-resistant schizophrenia,1-3 ous trials of several antipsychotics, including but the drug has been associated with quetiapine, thiothixene, thioridazine, trifluo- life-threatening side effects, including perazine, chlorpromazine, and haloperidol, all agranulocytosis/neutropenia, myocardi- of which were ineffective and poorly tolerated tis/cardiomyopathy, arrhythmia, seizures, because of serious side effects. diabetic ketoacidosis, fulminant hepatic Within 1 month of discharge, Ms. X re- failure, pulmonary embolism, and GI turns to the ED with nausea, vomiting, and complications.4 abdominal distension. Abdominal CT scan Clozapine-induced GI side effects in- suggests partial small bowel obstruction and clude anorexia, nausea, vomiting, heart- significantly dilated loops of small bowel burn, abdominal discomfort, diarrhea, and with decompressed rectum and sigmoid co- lon. Considering her recent GI surgery and Dr. Chopra is a Fourth-Year Resident, Dr. Rai is Research Scholar, absence of abdominal pain, she is managed Dr. Philbrick is Assistant Professor, and Dr. Das is a Fourth-Year Current Psychiatry Resident, Department of Psychiatry and Psychology, Mayo 68 July 2011 with conservative measures, including naso- Clinic, Rochester, MN. Cases That Test Your Skills Table 1 Psychotropics associated with constipation Class Medications Atypical antipsychotics Clozapine, risperidone Typical antipsychotics Chlorpromazine, haloperidol, pimozide, thioridazine, thiothixene, trifluoperazine Anticholinergics Benztropine, trihexyphenidyl Antidepressants Amitriptyline, clomipramine, doxepin, imipramine, nortriptyline, trimipramine constipation. Clozapine-induced gastro- • comorbid medical illnesses Clinical Point intestinal hypomotility (CIGH) can lead • fever Constipation has been to fecalith formation, which may result in • history of surgical bowel resection, GI intestinal obstruction/pseudo-obstruction, pathology, and constipation.5 reported in 14% to intestinal distension, necrosis, perforation, 60% of patients who sepsis, aspiration from inhalation of fecu- take clozapine; other lent vomitus, or dysphagia.5 Constipation HISTORY Medical comorbidities psychotropics also can Ms. X’s medical history is significant for chron- has been reported in 14% to 60% of patients cause GI complications who take clozapine,6 although other psychi- ic constipation, hypertension, obstructive atric medications also can cause constipa- pulmonary disease, and hyperthyroidism. tion (Table 1). Severe constipation can lead Her medications include trazodone, 25 mg/d; to potentially fatal GI complications such as fluoxetine, 40 mg/d, for negative symptoms intestinal obstruction, necrosis, perforation, and insomnia; docusate sodium, 200 mg/d; and sepsis, which is associated with signifi- polyethylene glycol, 17 g/d; and bisacodyl cant morbidity due to bowel resection and a suppository, 10 mg as needed for constipa- 27.5% mortality rate.5 tion. On admission, her laboratory test re- The underlying mechanism of clozapine- sults—including complete blood count, liver induced constipation has been well es- function tests, kidney function tests, thyroid tablished. The gut is innervated mainly function profile, and serum calcium levels— by cholinergic and serotonergic receptors all were within normal range. (5-HT3) and these receptors are responsi- ble for peristalsis. Clozapine has a potent anticholinergic effect and acts as a strong How would you address Ms. X’s GI symptoms? antagonist of serotonin receptors (5-HT2, a) discontinue clozapine 5-HT3, 5-HT6, 5-HT7), which can lead to b) reduce clozapine dosage gut hypomotility.7 Risk factors associated c) continue clozapine at the same dosage with CIGH include: and add supportive GI measures • high dose of clozapine (mean dosage d) switch her to a first-generation >428 mg/d) antipsychotic • high serum clozapine levels (>500 ng/mL) The authors’ observations • coadministration of anticholinergic Because the prevalence and severity of medications clozapine-induced constipation seem to be • concomitant use of cytochrome P450 dose-dependent,8 minimizing the dosage (CYP) enzyme inhibitors (medica- is a logical management strategy.9 The life- Current Psychiatry tions inhibiting CYP1A2 enzyme) threatening nature of clozapine-induced Vol. 10, No. 7 69 Cases That Test Your Skills GI complications may require rapid dose Which can increase the risk of paralytic ileus in reduction, which could compromise a pa- patients taking clozapine? tient’s stability. There is a little evidence a) concomitant antidepressant use regarding systematic management of clo- b) clozapine serum levels >500 ng/mL zapine-induced GI complications (Table 2). c) recent GI surgery d) all of the above TREATMENT Clozapine reduction The authors’ observations We obtain a serum clozapine level, which is el- In addition to risk factors such as chronic evated at 553 ng/mL. We recommend gradual constipation and recent GI surgery, Ms. X’s reducing Ms. X’s clozapine dosage by 50 mg supra-therapeutic serum clozapine level every 3 to 4 days to reach a target dose of 300 (553 ng/mL) significantly increased her Clinical Point to 350 mg/d, to attain serum clozapine levels risk of clozapine-induced paralytic ileus. 350 to 400 ng/mL. Because of trazodone’s po- Antidepressants such as selective serotonin Minimizing the tential anticholinergic action, which could be reuptake inhibitors (SSRIs) are known to clozapine dosage is a worsening Ms. X’s constipation, we stop the increase tissue concentrations of clozapine logical management drug and begin zolpidem, 5 to 10 mg/d, to and its major metabolite, norclozapine, by strategy, but could manage her insomnia. During these medica- primarily inhibiting CYP1A2 and perhaps compromise a tion changes, we closely monitor Ms. X for re- CYP2D6.10 As a potent inhibitor of CYPA12, emerging psychotic symptoms. patient’s stability fluvoxamine can inhibit clozapine metabo- Now available at CurrentPsychiatry.com/pages_cme.asp FACULTY Differential Diagnosis of Bipolar Disorder Roger S. McIntyre, MD Medical Management of Bipolar Disorder: A Pharmacologic Perspective Matthew A. Fuller, PharmD, BCPS, BCPP, FASHP Individualizing Treatment for Patients With Bipolar Disorder: Optimizing Efficacy, Safety, and Tolerability Christoph U. Correll, MD FREE CME/CPE credit* This supplement to Current PsyChiatry was submitted by Asante Communications, LLC; supported by educational grants from Eli Lilly and Company and Janssen, *Visit www.PSYCHClinician.com/CEBDCompendium. Division of Ortho-McNeil-Janssen Pharmaceuticals Inc; and administered by Ortho-McNeil-Janssen Scientific Affairs. It was peer reviewed byC urrent PsyChiatry. This continuing education (CE) activity is jointly sponsored by Albert Einstein College of Medicine, Montefiore Medical Center, the College of Psychiatric and Neurologic Pharmacists (CPNP), and Asante Communications, LLC. Cases That Test Your Skills Table 2 lism, resulting in higher plasma concentra- tions.11 In Ms. X’s case, fluoxetine could have Clinical pearls for treating increased serum clozapine levels because of clozapine-induced constipation its ability to inhibit clozapine metabolism via CYP2D6-mediated mechanisms.12 Serum clozapine levels >500 to 700 ng/mL have been associated with increased incidence Although clozapine serum levels are not of severe GI complications routinely measured, such testing may be in- Serum clozapine levels can guide reduction of dicated in patients who do not respond to or clozapine dosage because of its linear kinetics are unable to tolerate clozapine. Clozapine (ie, halving the clozapine dose will halve the serum clozapine level) levels should be obtained