This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions.

Letter to the Editor

Mask Off? Lithium Augmentation for Clozapine Rechallenge After Neutropenia or Agranulocytosis: Discontinuation Might Be Risky

Mina Boazak, MD; David R. Goldsmith, MD; and Robert O. Cotes, MD

Published: November 29, 2018

Mask Off? Lithium Augmentation for Clozapine Rechallenge After Neutropenia or Agranulocytosis: Discontinuation Might Be Risky

To the Editor: Neutropenia (defined as an absolute neutrophil count [ANC] < 1,500 cells/mm3) occurs in 3%-5%1,2 of individuals taking clozapine, and agranulocytosis (defined as an ANC < 500 cells/mm3) occurs in 0.38%-0.81%.3,4 To mitigate the risk of recurrent dyscrasia, lithium and granulocyte colony-stimulating factor may be added when clozapine is restarted.5-8 In a systematic review, Manu et al6 reported that 94% (33/35) of successful clozapine rechallenges included lithium augmentation. Although lithium may, on average, increase ANC by 88% of baseline values,9 little is known about the long-term need for lithium after clozapine rechallenge, especially given known side effects. Do individuals develop neutropenia or agranulocytosis after lithium is discontinued?

Methods. We conducted a PubMed search through December 10, 2017, using the MESH terms “clozapine” AND “lithium” AND “neutropenia” OR “agranulocytosis.”

Results. The search returned 94 articles. Twenty-seven5-7,10-33 articles described reports of lithium augmentation in clozapine rechallenge after neutropenia or agranulocytosis (Supplementary Table 1), totaling 94 individual patients. Lithium augmentation was successful in 82 of 94 cases (87.2%). We examined the outcome of individuals whose lithium was discontinued after successful clozapine rechallenge. Of 2 individuals (mean time to dyscrasia was 28 days; range, 14-42), both developed neutropenia after lithium was discontinued (Figure 1). We also examined the outcome of individuals who were coprescribed lithium and clozapine (without prior blood dyscrasias), after which lithium was discontinued. Of 6 individuals, 4 developed neutropenia and 2 developed agranulocytosis (mean time to dyscrasia was 38 days; range, 6-120; Figure 2). Of the 2 agranulocytosis cases, 1 responded immediately to granulocyte-macrophage colony-stimulating factor and the other died due to infectious complications (Figure 2).34,36 Of the 4 cases that developed neutropenia, 2 were restarted on lithium and continued clozapine treatment.21,31

Figure 1

Click figure to enlarge

Figure 2

Click figure to enlarge

Discussion. Similar to Manu et al,6 we found that lithium augmentation to clozapine can be a successful strategy after neutropenia or agranulocytosis. Our findings raise concern about lithium discontinuation after successful clozapine rechallenge, although our search was limited by a very small sample size and potential publication bias. The use of lithium in patients taking clozapine has raised a number of concerns, including lithium potentially masking impending neutropenia or agranulocytosis.5,15,37 Our finding of a short time to dyscrasia after lithium discontinuation (approximately 1 month) suggests the possibility of a masking effect, although it is possible that lithium may be protective against blood dyscrasias due to its previously established protective effects of progenitor cells, stimulation of granulocyte colony-stimulating factor production and release, and independent stimulation of progenitor proliferation.9 Another concern regarding ongoing use of lithium is the potential development of adverse neurologic events,38 and 1 of our reviewed cases of lithium augmentation reported new-onset seizures.17

Conclusion. In efforts to minimize polypharmacy, clinicians unfamiliar with lithium’s role of increasing the ANC may attempt to discontinue it, especially since it most likely does not play a significant role in augmenting the efficacy of clozapine.39 Given no reports of safe lithium discontinuation in the literature, lack of efficacy does not appear to be a reasonable consideration in deciding whether to discontinue the medication. Therefore, we would encourage caution in discontinuation of lithium after a successful clozapine initiation, especially in the setting of rechallenge. Given the limited reports on this topic, we support more active reporting on rechallenge augmented with lithium and more work to elucidate the mechanism of clozapine-induced blood dyscrasias to disentangle the putative lithium masking issue.

Mina Boazak, MDa

David R. Goldsmith, MDb

Robert O. Cotes, MDb

aDepartment of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia

bPSTAR Clinic, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia

Potential conflicts of interest: None.

Funding/support: None.

Published online: November 29, 2018.

Prim Care Companion CNS Disord 2018;20(6):18l02282

To cite: Boazak M, Goldsmith DR, Cotes RO. Mask off? lithium augmentation for clozapine rechallenge after neutropenia or agranulocytosis: discontinuation might be risky. Prim Care Companion CNS Disord. 2018;20(6):18l02282.

To share:

© Copyright 2018 Physicians Postgraduate Press, Inc.

Supplementary material


1. Sénéchal A, Landry P, Deschamps R, et al. Neutropenia in a patient treated with clozapine in combination with other psychotropic drugs [article in French]. Encephale. 2002;28(6 pt 1):567-569. PubMed

2. Lee J, Takeuchi H, Fervaha G, et al. The effect of clozapine on hematological indices: a 1-year follow-up study. J Clin Psychopharmacol. 2015;35(5):510-516. PubMed CrossRef

3. 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(3):162-167. PubMed CrossRef

4. Honigfeld G. Effects of the clozapine national registry system on incidence of deaths related to agranulocytosis. Psychiatr Serv. 1996;47(1):52-56. PubMed CrossRef

5. Kanaan RA, Kerwin RW. Lithium and clozapine rechallenge: a retrospective case analysis. J Clin Psychiatry. 2006;67(5):756-760. PubMed CrossRef

6. Manu P, Sarpal D, Muir O, et al. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? a systematic review of the published literature. Schizophr Res. 2012;134(2-3):180-186. PubMed CrossRef

7. Myles N, Myles H, Clark SR, et al. Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: a systematic review of the literature and clinical recommendations. Aust N Z J Psychiatry. 2017;51(10):980-989. PubMed CrossRef

8. Lally J, Malik S, Krivoy A, et al. The use of granulocyte colony-stimulating factor in clozapine rechallenge: a systematic review. J Clin Psychopharmacol. 2017;37(5):600-604. PubMed CrossRef

9. Focosi D, Azzarí  A, Kast RE, et al. Lithium and hematology: established and proposed uses. J Leukoc Biol. 2009;85(1):20-28. PubMed CrossRef

10. Meyer N, Gee S, Whiskey E, et al. Optimizing outcomes in clozapine rechallenge following neutropenia: a cohort analysis. J Clin Psychiatry. 2015;76(11):e1410-e1416. PubMed CrossRef

11. Aydin M, Ilhan BC, Calisir S, et al. Continuing clozapine treatment with lithium in schizophrenic patients with neutropenia or leukopenia: brief review of literature with case reports. Ther Adv Psychopharmacol. 2016;6(1):33-38. PubMed CrossRef

12. Suraweera C, Hanwella R, de Silva V. Use of lithium in clozapine-induced neutropenia: a case report. BMC Res Notes. 2014;7(1):635. PubMed CrossRef

13. Crépeau-Gendron G, L’ Heureux S. Quetiapine XR-induced neutropenia: is a clozapine trial still possible for treatment-resistant schizophrenia? a case report. Early Interv Psychiatry. 2015;9(2):151-155. PubMed CrossRef

14. Maher KN, Tan M, Tossell JW, et al. Risk factors for neutropenia in clozapine-treated children and adolescents with childhood-onset schizophrenia. J Child Adolesc Psychopharmacol. 2013;23(2):110-116. PubMed CrossRef

15. Valevski A, Modai I, Lahav M, et al. Clozapine-lithium combined treatment and agranulocytosis. Int Clin Psychopharmacol. 1993;8(1):63-65. PubMed CrossRef

16. Gagliano A, Masi G. Clozapine-aripiprazole association in a 7-year-old girl with schizophrenia: clinical efficacy and successful management of neutropenia with lithium. J Child Adolesc Psychopharmacol. 2009;19(5):595-598. PubMed CrossRef

17. Brunoni AR, Kobuti Ferreira LR, Gallucci-Neto J, et al. Lithium as a treatment of clozapine-induced neutropenia: a case report. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):2006-2007. PubMed CrossRef

18. Bray A. Ethnic neutropenia and clozapine. Aust N Z J Psychiatry. 2008;42(4):342-345. PubMed CrossRef

19. Rajagopal G, Graham JG, Haut FF. Prevention of clozapine-induced granulocytopenia/agranulocytosis with granulocyte-colony stimulating factor (G-CSF) in an intellectually disabled patient with schizophrenia. J Intellect Disabil Res. 2007;51(pt 1):82-85. PubMed CrossRef

20. Papetti F, Darcourt G, Giordana JY, et al. Treatment of clozapine-induced granulocytopenia with lithium (two observations). Encephale. 2004;30(6):578-582. PubMed CrossRef

21. Sporn A, Gogtay N, Ortiz-Aguayo R, et al. Clozapine-induced neutropenia in children: management with lithium carbonate. J Child Adolesc Psychopharmacol. 2003;13(3):401-404. PubMed CrossRef

22. 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(4):233-237. PubMed CrossRef

23. Blier P, Slater S, Measham T, et al. Lithium and clozapine-induced neutropenia/agranulocytosis. Int Clin Psychopharmacol. 1998;13(3):137-140. PubMed CrossRef

24. Silverstone PH. Prevention of clozapine-induced neutropenia by pretreatment with lithium. J Clin Psychopharmacol. 1998;18(1):86-88. PubMed CrossRef

25. Adityanjee. Modification of clozapine-induced leukopenia and neutropenia with lithium carbonate. Am J Psychiatry. 1995;152(4):648-649. PubMed CrossRef

26. Safferman AZ, Lieberman JA, Alvir JM, et al. Rechallenge in clozapine-induced agranulocytosis. Lancet. 1992;339(8804):1296-1297. PubMed CrossRef

27. Frankenburg FR, Stormberg D, Gerson SL. Unsuccessful reexposure to clozapine. J Clin Psychopharmacol. 1994;14(6):428-429. PubMed CrossRef

28. Small JG, Weber MC, Klapper MH, et al. Rechallenge of late-onset neutropenia with clozapine. J Clin Psychopharmacol. 2005;25(2):185-186. PubMed CrossRef

29. Gerbino-Rosen G, Roofeh D, Tompkins DA, et al. Hematological adverse events in clozapine-treated children and adolescents. J Am Acad Child Adolesc Psychiatry. 2005;44(10):1024-1031. PubMed CrossRef

30. Ghaznavi S, Nakic M, Rao P, et al. Rechallenging with clozapine following neutropenia: treatment options for refractory schizophrenia. Am J Psychiatry. 2008;165(7):813-818. PubMed CrossRef

31. Pinninti NR, Houdart MP, Strouse EM. Case report of long-term lithium for treatment and prevention of clozapine-induced neutropenia in an African American male. J Clin Psychopharmacol. 2010;30(2):219-221. PubMed CrossRef

32. Mattai A, Fung L, Bakalar J, et al. Adjunctive use of lithium carbonate for the management of neutropenia in clozapine-treated children. Hum Psychopharmacol. 2009;24(7):584-589. PubMed CrossRef

33. Dumas R, Bardin P, Vedie C. Long-term treatment of clozapine-induced leukopenia with lithium: fast-onset agranulocytosis following lithium discontinuation. Prim Care Companion CNS Disord. 2016;18(1):doi:10.4088/PCC.15l01841. PubMed CrossRef

34. Gerson SL, Lieberman JA, Friedenberg WR, et al. Polypharmacy in fatal clozapine-associated agranulocytosis. Lancet. 1991;338(8761):262-263. PubMed CrossRef

35. Madeb R, Hirschmann S, Kurs R, et al. Combined clozapine and valproic acid treatment-induced agranulocytosis. Eur Psychiatry. 2002;17(4):238-239. PubMed CrossRef

36. Imbarlina MJ, Sarkar S, Marwah S, et al. Leukopenia in clozapine treated patients may be induced by other drugs: a case series. Eur Psychiatry. 2004;19(8):506-509. PubMed CrossRef

37. Whiskey E, Taylor D. Restarting clozapine after neutropenia: evaluating the possibilities and practicalities. CNS Drugs. 2007;21(1):25-35. PubMed CrossRef

38. Bender S, Linka T, Wolstein J, et al. Safety and efficacy of combined clozapine-lithium pharmacotherapy. Int J Neuropsychopharmacol. 2004;7(1):59-63. PubMed CrossRef

39. Muscatello MR, Bruno A, De Fazio P, et al. Augmentation strategies in partial responder and/or treatment-resistant schizophrenia patients treated with clozapine. Expert Opin Pharmacother. 2014;15(16):2329-2345. PubMed CrossRef


Related Articles

Volume: 20

Quick Links:


Buy this Article as a PDF