Cases That Test Your Skills

Clozapine therapy: Timing is everything

Current Psychiatry. 2003 August;2(8):70-78

References

1. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment resistant schizophrenic: a double blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45:789-96.

2. Brenner HD, Dencker SJ, Goldstein MJ, et al. Defining treatment refractoriness in schizophrenia. Schizophr Bull 1990;16:551-61.

3. Meltzer HY. Clozapine: is another view valid? Am J Psychiatry 1995;152:821-5.

4. Clozaril prescribing information. In: Physicians’ Desk Reference. (57th ed). Montvale, NJ: Thomson Healthcare, 2003.

5. Alvir JM, Lieberman JA, Safferman AZ, et al. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993;329:162-7.

6. Honigfeld G. Effects of the clozapine national registry system on incidence of deaths related to agranulocytosis. Psychiatr Serv 1996;47:52-6.

7. Scelsa SN, Simpson DM, McQuistion HL, et al. Clozapineinduced myotoxicity in patients with chronic psychotic disorders. Neurology 1996;47:1518-23.

8. Ames D, Wirshing WC, Baker RW, et al. Predictive value of eosinophilia for neutropenia during clozapine treatment. J Clin Psychiatry 1996;57:579-81.

9. Alvir JM, Lieberman JA, Safferman AZ. Do white-cell count spikes predict agranulocytosis in clozapine recipients? Psychopharmacol Bull 1995;31:311-14.

10. Sperner-Unterweger B, Czeipek I, Gaggl S, et al. Treatment of severe clozapine-induced neutropenia with granulocyte colonystimulating factor (G-CSF). Remission despite continuous treatment with clozapine. Br J Psychiatry 1998;172:82-4.

11. Chengappa KN, Gopalani A, Haught MK, et al. The treatment of clozapine-associated agranulocytosis with granulocyte colony-stimulating factor (G-CSF). Psychopharmacol Bull 1996;32:111-21.

12. Lamberti JS, Bellnier TJ, Schwarzkopf SB, Schneider E. Filgrastim treatment of three patients with clozapine-induced agranulocytosis. J Clin Psychiatry 1995;56:256-9.

13. Boshes RA, Manschreck TC, Desrosiers J, et al. Initiation of clozapine therapy in a patient with preexisting leukopenia: a discussion of the rationale of current treatment options. Ann Clin Psychiatry 2001;13:233-7.

14. Adityanjee. Modification of clozapine-induced leukopenia and neutropenia with lithium carbonate. Am J Psychiatry 1995;152:648-9.

15. Blier P, Slater S, Measham T, et al. Lithium and clozapine-induced neutropenia/agranulocytosis. Int Clin Psychopharmacol 1998;13:137-40.

16. Ahokas A, Elonen E. Circadian rhythm of white blood cells during clozapine treatment. Psychopharmacology 1999;144:301-2.

Table

Life-threatening effects of clozapine and their reported frequency of occurrence

Adverse effect	Incidence rate among clozapine users
Agranulocytosis	3/1000 person years* at 6 months
Hepatitis	Less than 1%
Hyperglycemia with ketoacidosis	Unknown, case reports
Myocarditis	5.0-96.6 cases/100,000 patient years
Neuroleptic malignant syndrome	Unknown, several case reports
Orthostasis with cardiac collapse	1/3,000 cases
Pulmonary embolism	1/3,450 person years
Seizures	5% after 1 year of therapy
* Person year = 1 person taking medication for 1 year
Source: Clozaril prescribing information. In: Physicians’ Desk Reference (57th ed). Montvale, NJ: Thomson Healthcare, 2003.

Other severe adverse effects of clozapine include myocarditis associated with cardiac failure, orthostatic hypotension with circulatory collapse, and rhabdomyolysis (Table).^4,7 Leukocytosis and eosinophilia are generally transient and self-limited but may predict agranulocytosis.^8,9 The risk of seizure occurs most commonly at dosages greater than 500 mg/d.⁴

Given these potentially fatal effects, the authors’ treatment guidelines call for potential suspension of clozapine therapy when the WBC is consistently <3,000 mm³ (Algorithm).

CONTINUED TREATMENT: A difficult decision

Ms. G was switched to quetiapine, 100 mg nightly, titrated to 800 mg/d in divided doses.

Approximately 3 weeks later, Ms. G was hospitalized for renewed severe paranoia and command-type auditory hallucinations accompanied by prominent mood lability, avolition, and thought disorganization. During her 7-week hospitalization, she underwent sequential and sometimes overlapping trials of:

ziprasidone, 160 mg bid
risperidone, 3 mg bid
trifluoperazine, 3 mg bid
haloperidol, 10 mg bid
divalproex sodium, 500 mg bid
and carbamazepine, 400 mg bid.

None of these trials significantly improved her psychosis or mood.

At this point, the treating psychiatrists faced a difficult but clear decision: Ms. G was rechallenged on clozapine, 25 mg nightly, titrated again to 300 mg nightly. After she provided informed consent, her WBC was monitored twice daily—morning and evening—for agranulocytosis and to examine WBC patterns. Her average daily WBC counts were 4,200/mm³ in the morning and 5,500/mm³ at night. No physical signs of agranulocytosis emerged.

One week after restarting clozapine, Ms. G became less paranoid and socially more appropriate. Her thought process became increasingly organized, and after 4 weeks she reached her baseline status based upon family reports and the clinician’s CGI Global Improvement rating of 2 (much improved). Her auditory hallucinations resolved, and she was discharged to her family’s care.

Twice-daily blood testing was stopped at discharge. Ms. G continues to take clozapine and receives blood tests every 2 weeks, with no apparent signs of agranulocytosis.

Algorithm Suggested guidelines for managing WBC counts during clozapine therapy

Box

Treatments for clozapine-related agranulocytosis

Two treatments for clozapine-dependent agranulocytosis have been described.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a glycoprotein that has been shown to stimulate proliferation of precursor cells in bone marrow and their differentiation into granulocytes and macrophages. Researchers have reported that GM-CSF treatment allows patients to continue taking clozapine after an episode of severe neutropenia.^10-12
Lithium salts have been reported to exploit the natural leukocytosis observed with lithium to counter clozapine-related leukopenia.¹³ Use of lithium to displace white blood cells has been debated, and anecdotal evidence suggests that combining lithium with clozapine may increase the chance of seizure and neuroleptic malignant syndrome.⁴ Still, cases reported by Adityanjee and Blier suggest that lithium augmentation is cost-effective and efficacious.^14,15

How could Ms. G’s doctors have avoided stopping her clozapine therapy and her subsequent decompensation?

The authors’ observations

Aggressive blood testing and cessation of clozapine therapy are indicated when onset of granulocytopenia and agranulocytosis are suspected. Even with early detection and discontinuation, the chance of infectious disease poses a danger for up to 4 weeks until WBC levels return to normal.⁴

Given Ms. G’s lack of response to other antipsychotics, however, we had to consider resuming clozapine therapy. Studies have described agranulocytosis management strategies that may allow patients to keep taking clozapine despite low WBC counts (Box).

We also considered the timing of Ms. G’s blood test that showed a WBC count <2,700/mm³. Ahokas¹⁶ suggests that evening WBC counts are significantly higher than those taken in the morning and that granulocytes fluctuate in a diurnal pattern. Ms. G’s evening WBC counts were on average 1,300/mm³ higher than morning levels. Allowing for this diurnal variation and comparing evening blood samples could have averted the interruption in Ms. G’s clozapine therapy and prevented relapse in a patient with highly treatment-refractory schizophrenia.

Related resources

Chong SA, Remington G. Clozapine augmentation: safety and efficacy. Schizophr Bull 2000;26:421-40.
Emsley R, Oosthuizen P. The new and evolving pharmacotherapy of schizophrenia. Psychiatr Clin North Am 2003;26:141-63.
Barnas C, Zwierzina H, Hummer M, Sperner-Unterweger B, Stern A, Fleischhacker WW. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report. J Clin Psychiatry 1992;53:245-7.

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