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

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

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

[email protected]

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: https://doi.org/10.4088/PCC.18l02282

© Copyright 2018 Physicians Postgraduate Press, Inc.

Supplementary material

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