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 has been well controlled on , 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 , vom- no areas of stricture formation with interval iting, and and distension. decompression. CT scan of her abdomen reveals segmental The psychiatric service is consulted to in her colon with abscess formation, evaluate the possibility of clozapine-induced which leads to immediate surgery, includ- para­lytic . During initial assessment, Ms. ing ileocecostomy with primary anastomosis. X denies any psychotic symptoms, including After surgery, Ms. X suffers from gastrointes- paranoid ideations, , and auditory or tinal (GI) dysmotility. The visual , 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, . She shows no signs or symptoms which has been treated successfully for 18 that suggest . 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 , including but the drug has been associated with , thiothixene, , trifluo- life-threatening side effects, including , , and , all /, myocardi- of which were ineffective and poorly tolerated tis/cardiomyopathy, arrhythmia, , because of serious side effects. , fulminant hepatic Within 1 month of discharge, Ms. X re- failure, pulmonary embolism, and GI turns to the ED with nausea, , and complications.4 . Abdominal CT scan Clozapine-induced GI side effects in- suggests partial small and clude anorexia, nausea, vomiting, heart- significantly dilated loops of small bowel burn, abdominal discomfort, , and with decompressed 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

Class Atypical antipsychotics Clozapine, Typical antipsychotics Chlorpromazine, haloperidol, , thioridazine, thiothixene, Benztropine, , , , , ,

constipation. Clozapine-induced gastro- • comorbid medical illnesses Clinical Point intestinal hypomotility (CIGH) can lead • fever Constipation has been to 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 , 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 , and hyperthyroidism. tion (Table 1). Severe constipation can lead Her medications include , 25 mg/d; to potentially fatal GI complications such as , 40 mg/d, for negative symptoms intestinal obstruction, necrosis, perforation, and ; 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 , induced constipation has been well es- function tests, function tests, thyroid tablished. The gut is innervated mainly function profile, and serum calcium levels— by and receptors all were within normal range. (5-HT3) and these receptors are responsi- ble for . Clozapine has a potent anticholinergic effect and acts as a strong How would you address Ms. X’s GI symptoms? antagonist of 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) • 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 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 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 can inhibit clozapine metabo-

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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 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 12 hours after the Clozapine dosages should be reduced by no bedtime dose (trough levels), several days more than 25 mg/d to a maximum of 100 mg/ after clozapine initiation. Serum clozapine week levels <350 ng/mL are associated with lack Clinical Point of clinical response.13 Higher serum levels Advise patients taking (500 to 700 ng/mL) have been associated less antimuscarinic antipsychotic, such as with greater incidences of serious GI com- quetiapine or haloperidol, thereby using the clozapine to eat a plications. Serum clozapine levels also help second antipsychotic as a clozapine-sparing high fiber diet, drink guide clozapine dosage reduction because agent.9 For example, the clozapine dose adequate liquids, and of its linear kinetics—halving the dose will could be reduced by 25% by substituting 2 get regular exercise to 14 halve the serum clozapine level. mg of quetiapine for every 1 mg of clozapine. prevent constipation

OUTCOME GI symptoms improve Prevention Ms. X shows improved GI motility within few Psychiatrists who prescribe clozapine days of the first decrease in her clozapine should take a careful history of risk factors dosage. Nausea, vomiting, and abdominal that might predispose patients to clozapine- distension gradually resolve over 2 weeks induced GI side effects. Caution patients with concomitant reduction in clozapine dos- to whom you prescribe clozapine about age to 300 mg/d (50 mg in the morning and possible development of constipation and 250 mg at bedtime) without reemergence of the risk of serious GI complications. Enlist psychotic symptoms. She is able to tolerate a family members and caseworkers to keep soft diet, and conservative GI measures are no a close eye on GI side effects in patients longer required. She is discharged home with receiving clozapine. Advise patients to outpatient surgical and psychiatric follow-up. prevent constipation by eating a high fiber diet, drinking adequate fluids, and getting The authors’ observations regular exercise. Patients should be treated Successful reversal of severe clozapine- aggressively with to relieve con- induced constipation—occurring at se- stipation and educated about the warn- rum clozapine level of 490 ng/mL—has ing signs of intestinal obstruction, such as been reported in a 45-year-old man with worsening constipation, abdominal pain, treatment-resistant schizophrenia. This was vomiting, and inability to pass flatus.17 accomplished by cautious reduction of clo- Rapidly fatal bowel ischemia caused by zapine dosage (400 mg/d to 250 mg/d) over clozapine has been reported.18 Therefore, 1 week.15 Slower clozapine titration—re- urgently refer patients for medical evalu- ducing the dose by no more than 25 mg/d ation if you have any concerns about to a maximum of 100 mg/week—has been worsening constipation or observe signs recommended.16 It also has been suggested of intestinal obstruction. Vigilant consider- Current Psychiatry to replace part of the clozapine dose with a ation of clozapine as a likely culprit in se- Vol. 10, No. 7 71 Cases That Test Your Skills

2. Stahl S. Essential psychopharmacology. Cambridge, United Kingdom: Cambridge University Press; 1999. Related Resources 3. Hardman J, Limbird L, Molinoff P. Goodman & Gilman’s • Drew L, Herdson P. Clozapine and constipation: a serious issue. pharmacological basis of therapeutics. New York, NY: Aust N Z J Psychiatry. 1997;31(1):149-150. McGraw-Hill; 1996. • Winstead NS, Winstead DK. 5-step plan to treat constipation in 4. Flanagan RJ, Ball RY. Gastrointestinal hypomotility: an under-recognized life-threatening adverse effect of psychiatric patients. Current Psychiatry. 2008;7(5):29-39. clozapine. Forensic Sci Int. 2011;206(1-3):e31-36. Drug Brand Names 5. Palmer SE, McLean RM, Ellis PM, et al. Life-threatening clozapine-induced gastrointestinal hypomotility: an Amitriptyline • Elavil Nortriptyline • Aventyl, Pamelor analysis of 102 cases. J Clin Psychiatry. 2008;69(5):759-768. Benztropine • Cogentin Pimozide • Orap 6. Claghorn J, Honigfeld G, Abuzzahab F Sr, et al. The risks Bisacodyl suppository • Polyethylene glycol • MiraLax and benefits of clozapine versus chlorpromazine. J Clin Dulcolax, others Quetiapine • Seroquel Psychopharmacol. 1987;7:337-384. Chlorpromazine • Thorazine Risperidone • Risperdal 7. Perrott J. Serious gastrointestinal adverse effects of Clomipramine • Anafranil Thioridazine • Mellaril clozapine. Psychopharmacology Newsletter. 2009:1-5. Clozapine • Clozaril Thiothixene • Navane 8. Pare J, Riffand P, Baurdeix I. The clozapine in France. Docusate sodium • Colace, Trazodone • Desyrel, Oleptro Information Psychiatric. 1993;4:389-397. others Trifluoperazine• Stelazine 9. Levin TT, Barrett J, Mendelowitz A. Death from clozapine- Doxepin • Adapin, Sinequan Trihexyphenidyl • Artane, induced constipation: case report and literature review. Clinical Point Fluoxetine • Prozac Trihexane Psychosomatics. 2002;43:71-73. Fluvoxamine • Luvox Trimipramine • Surmontil 10. Centorrino F, Baldessarini RJ, Frankenburg FR, et al. Serum Refer patients for Haloperidol • Haldol Zolpidem • Ambien levels of clozapine and norclozapine in patients treated with Imipramine • Tofranil selective serotonin reuptake inhibitors. Am J Psychiatry. medical evaluation 1996;153(6):820-822. Disclosure if you have concerns 11. Sproule BA, Naranjo CA, Brenmer KE, et al. Selective The authors report no financial relationship with any company serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence. Clin Pharmacokinet. 1997; about worsening whose products are mentioned in this article or with manufactur- 33(6):454-471. ers of competing products. 12. Urichuk L, Prior TI, Dursun S, et al. Metabolism of atypical constipation antipsychotics: involvement of cytochrome p450 enzymes and relevance for drug-drug interactions. Curr Drug Metab. or intestinal 2008;9(5):410-418. obstruction 13. Perry P, Miller DD, Arndt SV, et al. Clozapine and vere GI complications in inpatient settings norclozapine plasma concentrations and clinical responses of treatment-refractory schizophrenic patients. Am J can prevent morbidity and mortality. Psychiatry. 1991;148:231-235. In our case, cautious reduction of clo- 14. Freudenreich O. Clozapine drug levels guide dosing. Current Psychiatry. 2009;8(3):78. zapine dosage, guided by serum clozapine 15. Pelizza L, De Luca P, La Pesa M, et al. Clozapine-induced intestinal occlusion: a serious side effect. Acta Biomed. levels, had obviated the need for surgery 2007;78:144-148. and prevented reemergence of psychotic 16. Hayes G, Gibler B. Clozapine-induced constipation. Am J symptoms. Psychiatry. 1995;152:298. 17. American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to References the management of chronic constipation in North America. 1. American Psychiatric Association. Treatment of patients Am J Gastroenterol. 2005;100(suppl 1):S1-4. with schizophrenia, second edition. Recommendations 18. Townsend G, Curtis D. Case report: rapidly fatal bowel for patients with schizophrenia. Arlington, VA: American ischaemia on clozapine treatment. BMC Psychiatry. Psychiatric Publishing, Inc; 2004. 2006;6:43.

Bottom Line Clozapine use can lead to constipation, intestinal obstruction, or other potentially fatal gastrointestinal complications. Cautious reduction of clozapine dosage guided by serum clozapine levels can reverse these complications without surgical morbidity or Current Psychiatry 72 July 2011 reemergence of psychotic symptoms.