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

Mina Boazak; David R. Goldsmith; Robert O. Cotes

doi:10.4088/PCC.18l02282

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 <a id="_idTextAnchor000"></a>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%<a href="#ref1">1</a>,<a href="#ref2">2</a> of individuals taking clozapine, and agranulocytosis (defined as an ANC < 500 cells/mm3) occurs in 0.38%–0.81%.<a href="#ref3">3</a>,<a href="#ref4">4</a> To mitigate the risk of recurrent dyscrasia, lithium and granulocyte colony-stimulating factor may be added when clozapine is restarted.<a href="#ref5">5–8</a> In a systematic review, Manu et al<a href="#ref6">6</a> reported that 94% (33/35) of successful clozapine rechallenges included lithium augmentation. Although lithium may, on average, increase ANC by 88% of baseline values,<a href="#ref9">9</a> 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-seven<a href="#ref5">5–7</a>,<a href="#ref10">10–33</a> articles described reports of lithium augmentation in clozapine rechallenge after neutropenia or agranulocytosis (<a href="/pcc/article/_layouts/ppp.psych.controls/BinaryViewer.ashx?Article=/PCC/article/Pages/2018/v20n06/18l02282.aspx&Type=Supplement" target="_blank">Supplementary Table 1</a>), 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 (<a href="#" onclick="createFigure('f1'); return false;">Figure 1</a>). 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; <a href="#" onclick="createFigure('f2'); return false;">Figure 2</a>). Of the 2 agranulocytosis cases, 1 responded immediately to granulocyte-macrophage colony-stimulating factor and the other died due to infectious complications (<a href="#" onclick="createFigure('f2'); return false;">Figure 2</a>).<a href="#ref34">34</a>,<a href="#ref36">36</a> Of the 4 cases that developed neutropenia, 2 were restarted on lithium and continued clozapine treatment.<a href="#ref21">21</a>,<a href="#ref31">31</a>
 <div id="figure-2"> <a href="#" onclick="createFigure('f1'); return false;"><img src="18l02282F1.gif" alt="Figure 1" id="f1" border="0" /></a>
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 <div id="figure-2"> <a href="#" onclick="createFigure('f2'); return false;"><img src="18l02282F2.gif" alt="Figure 2" id="f2" border="0" /></a>
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 Discussion. Similar to Manu et al,<a href="#ref6">6</a> 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.<a href="#ref5">5</a>,<a href="#ref15">15</a>,<a href="#ref37">37</a> 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.<a href="#ref9">9</a> Another concern regarding ongoing use of lithium is the potential development of adverse neurologic events,<a href="#ref38">38</a> and 1 of our reviewed cases of lithium augmentation reported new-onset seizures.<a href="#ref17">17</a>
 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.<a href="#ref39">39</a> 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.
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 Mina Boazak, MDa
 <a href="mailto:mboazak@emory.edu">mboazak@emory.edu</a>
 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.
 <a title="" href="/pcc/article/_layouts/ppp.psych.controls/BinaryViewer.ashx?Article=/PCC/article/Pages/2018/v20n06/18l02282.aspx&Type=Supplement" target="_blank">Supplementary material</a>
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351

View Dependent Items

/PCC/article/_layouts/ReportServer/DependentItems.aspx?list={ListId}&ID={ItemId}

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smdl

350

Manage Clickthrough Reports

/PCC/article/_layouts/ReportServer/ModelClickThrough.aspx?list={ListId}&ID={ItemId}

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0x4

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smdl

352

Manage Model Item Security

/PCC/article/_layouts/ReportServer/ModelItemSecurity.aspx?list={ListId}&ID={ItemId}

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0x2000000

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smdl

353

Regenerate Model

/PCC/article/_layouts/ReportServer/GenerateModel.aspx?list={ListId}&ID={ItemId}

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0x4

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smdl

354

Manage Data Sources

/PCC/article/_layouts/ReportServer/DataSourceList.aspx?list={ListId}&ID={ItemId}

0x0

0x20

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smdl

351

Load in Report Builder

/PCC/article/_layouts/ReportServer/RSAction.aspx?RSAction=ReportBuilderModelContext&list={ListId}&ID={ItemId}

0x0

0x2

FileType

smdl

250

Edit in Report Builder

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rdl

250

Edit in Report Builder

/PCC/article/_layouts/ReportServer/RSAction.aspx?RSAction=ReportBuilderDatasetContext&list={ListId}&ID={ItemId}

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0x4

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rsd

250

Manage Caching Options

/PCC/article/_layouts/ReportServer/DatasetCachingOptions.aspx?list={ListId}&ID={ItemId}

0x0

0x4

FileType

rsd

350

Manage Cache Refresh Plans

/PCC/article/_layouts/ReportServer/CacheRefreshPlanList.aspx?list={ListId}&ID={ItemId}&IsDataset=true

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0x4

FileType

rsd

351

Manage Data Sources

/PCC/article/_layouts/ReportServer/DataSourceList.aspx?list={ListId}&ID={ItemId}

0x0

0x20

FileType

rsd

352

View Dependent Items

/PCC/article/_layouts/ReportServer/DependentItems.aspx?list={ListId}&ID={ItemId}

0x0

0x4

FileType

rsd

353

Compliance Details

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ContentType

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Document Set Version History

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ContentType

0x0120D520

330

Send To other location

javascript:GoToPage('{SiteUrl}/_layouts/docsetsend.aspx?List={ListId}&ID={ItemId}')

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ContentType

0x0120D520

350

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