We obtain a serum clozapine level, which is elevated at 553 ng/mL. We recommend gradual reducing Ms. X’s clozapine dosage by 50 mg every 3 to 4 days to reach a target dose of 300 to 350 mg/d, to attain serum clozapine levels 350 to 400 ng/mL. Because of trazodone’s potential anticholinergic action, which could be worsening Ms. X’s constipation, we stop the drug and begin zolpidem, 5 to 10 mg/d, to manage her insomnia. During these medication changes, we closely monitor Ms. X for reemerging psychotic symptoms.
The authors’ observations
In addition to risk factors such as chronic constipation and recent GI surgery, Ms. X’s supra-therapeutic serum clozapine level (553 ng/mL) significantly increased her risk of clozapine-induced paralytic ileus. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are known to increase tissue concentrations of clozapine and its major metabolite, norclozapine, by primarily inhibiting CYP1A2 and perhaps CYP2D6.10 As a potent inhibitor of CYPA12, fluvoxamine can inhibit clozapine metabolism, resulting in higher plasma concentrations.11 In Ms. X’s case, fluoxetine could have increased serum clozapine levels because of its ability to inhibit clozapine metabolism via CYP2D6-mediated mechanisms.12
Although clozapine serum levels are not routinely measured, such testing may be indicated in patients who do not respond to or are unable to tolerate clozapine. Clozapine levels should be obtained 12 hours after the bedtime dose (trough levels), several days after clozapine initiation. Serum clozapine levels <350 ng/mL are associated with lack of clinical response.13 Higher serum levels (500 to 700 ng/mL) have been associated with greater incidences of serious GI complications. Serum clozapine levels also help guide clozapine dosage reduction because of its linear kinetics—halving the dose will halve the serum clozapine level.14
OUTCOME: GI symptoms improve
Ms. X shows improved GI motility within few days of the first decrease in her clozapine dosage. Nausea, vomiting, and abdominal distension gradually resolve over 2 weeks with concomitant reduction in clozapine dosage to 300 mg/d (50 mg in the morning and 250 mg at bedtime) without reemergence of psychotic symptoms. She is able to tolerate a soft diet, and conservative GI measures are no longer required. She is discharged home with outpatient surgical and psychiatric follow-up.
The authors’ observations
Successful reversal of severe clozapine-induced constipation—occurring at serum clozapine level of 490 ng/mL—has been reported in a 45-year-old man with treatment-resistant schizophrenia. This was accomplished by cautious reduction of clozapine dosage (400 mg/d to 250 mg/d) over 1 week.15 Slower clozapine titration—reducing the dose by no more than 25 mg/d to a maximum of 100 mg/week—has been recommended.16 It also has been suggested to replace part of the clozapine dose with a less antimuscarinic antipsychotic, such as quetiapine or haloperidol, thereby using the second antipsychotic as a clozapine-sparing agent.9 For example, the clozapine dose could be reduced by 25% by substituting 2 mg of quetiapine for every 1 mg of clozapine.
Prevention
Psychiatrists who prescribe clozapine should take a careful history of risk factors that might predispose patients to clozapine-induced GI side effects. Caution patients to whom you prescribe clozapine about possible development of constipation and the risk of serious GI complications. Enlist family members and caseworkers to keep a close eye on GI side effects in patients receiving clozapine. Advise patients to prevent constipation by eating a high fiber diet, drinking adequate fluids, and getting regular exercise. Patients should be treated aggressively with laxatives to relieve constipation and educated about the warning signs of intestinal obstruction, such as worsening constipation, abdominal pain, vomiting, and inability to pass flatus.17
Rapidly fatal bowel ischemia caused by clozapine has been reported.18 Therefore, urgently refer patients for medical evaluation if you have any concerns about worsening constipation or observe signs of intestinal obstruction. Vigilant consideration of clozapine as a likely culprit in severe GI complications in inpatient settings can prevent morbidity and mortality.
In our case, cautious reduction of clozapine dosage, guided by serum clozapine levels, had obviated the need for surgery and prevented reemergence of psychotic symptoms.
Related Resources
- Drew L, Herdson P. Clozapine and constipation: a serious issue. Aust N Z J Psychiatry. 1997;31(1):149-150.
- Winstead NS, Winstead DK. 5-step plan to treat constipation in psychiatric patients. Current Psychiatry. 2008;7(5):29-39.
Drug Brand Names
- Amitriptyline • Elavil
- Benztropine • Cogentin
- Bisacodyl suppository • Dulcolax, others
- Chlorpromazine • Thorazine
- Clomipramine • Anafranil
- Clozapine • Clozaril
- Docusate sodium • Colace, others
- Doxepin • Adapin, Sinequan
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Haloperidol • Haldol
- Imipramine • Tofranil
- Nortriptyline • Aventyl, Pamelor
- Pimozide • Orap
- Polyethylene glycol • MiraLax
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Thioridazine • Mellaril
- Thiothixene • Navane
- Trazodone • Desyrel, Oleptro
- Trifluoperazine • Stelazine
- Trihexyphenidyl • Artane, Trihexane
- Trimipramine • Surmontil
- Zolpidem • Ambien