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Lithium to Allow Clozapine Prescribing in Benign Ethnic Neutropenia Sherry Nykiel 1, 2, David Henderson 1, Gauri Bhide 3, Oliver Freudenreich 1

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Lithium to Allow Clozapine Prescribing in Benign Ethnic Neutropenia Sherry Nykiel 1, 2, David Henderson 1, Gauri Bhide 3, Oliver Freudenreich 1 Case Reports Lithium to Allow Clozapine Prescribing in Benign Ethnic Neutropenia Sherry Nykiel 1, 2, David Henderson 1, Gauri Bhide 3, Oliver Freudenreich 1 Introduction Clozapine is the gold standard antipsychotic for spite having BEN. Lithium was used to increase his ANC in treatment-resistant schizophrenia. As life-threatening agra- a dose-dependent manner so clozapine could be adminis- nulocytosis occurs in approximately 1% of patients treated tered according to U.S. guidelines. with clozapine (1, 2), regular monitoring of white blood cell (WBC) and absolute neutrophil counts (ANC) is man- Case Report dated. Clozapine can only be prescribed if certain hema- Mr. A was a 40-year-old man who was born in Western tological parameters are met. If granulocytopenia occurs Africa and raised in the U.S. In his twenties, he developed during treatment, clozapine must be interrupted or, in the paranoid schizophrenia, complicated by incessant, insult- case of agranulocytosis, discontinued. The cutoff values for ing auditory hallucinations that told him he was worthless the treatment decisions are based on normative values from and would never be successful. Antipsychotic trials over white populations (3). These population-based values pose the decades have included haloperidol, perphenazine, flu- a problem for people of African descent as up to 50% have phenazine, olanzapine, quetiapine and ziprazidone, none of benign ethnic neutropenia (BEN) (3). This is a condition in which ever successfully eliminated the voices. Early in his which a low ANC is maintained in healthy individuals with- treatment, clozapine was considered but not pursued sec- out evidence of negative consequences such as increased ondary to his chronically low WBC and ANC (an average of risk of infections (3, 4). We describe the case of an African 4.1 mm3 and 1.3 mm3, respectively). Despite his significant immigrant with treatment-resistant schizophrenia who was psychopathology and constant hallucinations, his function- successfully treated in the United States with clozapine de- ing has often been good and he held jobs and even published some books. 1 Massachusetts General Hospital-Psychiatry However, over the years, he has had periods where it 2 McLean Hospital-OPC was difficult for him to ignore the voices, and two years ago 3 MGH/North Shore Medical Center-Cancer Center he was arrested after assaulting a stranger in response to Address for correspondence: Sherry Nykiel, MD, the voices. Prior to the assault he had been switched from McLean Hospital OPC, risperidone to aripiprazole and it was thought this may 115 Mill Street, Belmont, MA 02478 have contributed to his decompensation. The arrest led to a Phone: 617-855-3047; Fax: 617-855-3722; E-mail: [email protected] forensic hospitalization during which a clozapine trial was revisited. Given the escalation in his behavior as the result Submitted: January 22, 2009; Revised: June 1, 2009; of his symptoms and because the patient continued to suf- Accepted: June 4, 2009 fer, experiencing incessant hallucinations without reprieve, 138 • Clinical Schizophrenia & Related Psychoses July 2010 Nykiel.indd 1 6/9/10 1:28 PM Sherry Nykiel et al. Figure 1 Treatment with Lithium to Increase ANC 8 May 2006 March 2007-AH clozapine 100 mg clozapine 150 mg 7.2 daily 7.0 daily 6.9 7.0 7 6.8 6.8 6.9 June 2006 7.0 clozapine 125 mg 6.3 6.7 6.7 daily 6.5 6.5 6.3 6.3 6.4 6.3 6 6.2 6.1 6.1 5.8 5.7 May 2007 5.1 5.5 lithium 300 mg BID 5.3 5.4 5.3 5.3 5 February 2007 drooling; clozapine 100 mg daily August 2006 June 2007 clozapine 150 mg dx benign neutropenia 4 daily May 2007 3.6 3.6 3.6 Hema-onc 3.35 3.3 3.3 2.9 consult placed 3.0 3 2.7 2.8 3.0 3.2 2.1 2.6 2.0 1.9 2.4 2.3 2.3 th/cmm (thousands per cubic millimeter) 2 2.2 2.1 1.9 1.8 1.7 1.7 1.7 August 2007 1.6 1.6 lithium level 0.6 WBC 1 July 2007 ANC lithium 900 mg daily 0 Oct Oct May June July Aug Sept Nov Dec Feb Mar Apr May June July Aug Sept Nov Dec Feb Mar Apr May June July Apr-06 Jan-07 Jan-08 Time clozapine was initiated and titrated to 150 mg daily. His ini- daily and increased to 900 mg daily after eight weeks. His tial WBC and ANC were 4.9 mm3 and 2.1 mm3, respectively. average ANC, from the initiation of lithium to the present, is Within two weeks, Mr. A reported less frequent and bother- 2.8 mm3. He has continued to report decreased symptoms, some voices, as well as increased energy and concentration. does not experience extrapyramidal side effects, is gainfully Approximately three weeks after initiation, his ANC employed and has published another book since the initia- was 1.8 mm3 despite a WBC of 6.1 mm3. There was con- tion of clozapine. The addition of lithium has allowed the cern the drop was related to clozapine and the dose was de- frequency of his blood work to decrease to every other week. creased to 100 mg daily. His reported ANC one week later (See Figure 1.) was 2.1 mm3. Given his chronically low WBC and recent drop in ANC, a hematology-oncology consult was obtained Discussion to rule out any underlying pathology. This consult resulted Clozapine is known to induce neutropenia in up to 2.8% in a diagnosis of benign ethnic neutropenia (BEN). Mr. A of patients (18). While the etiology is not completely un- was continued on clozapine at 100 mg daily, but after four derstood, myeloid cells are abundant and the neutropenia is months began to complain of increasing voices and the dose thought to be secondary to a reduction in granulocyte and was returned to 150 mg daily. Over the next eight months, macrophage-colony stimulating factor (GM-CSF). In the he was unable to tolerate any dose higher than 150 mg daily much rarer case of clozapine-induced agranulocytosis, my- due to sedation. Throughout this period, his ANC was as low eloid and myeloid precursor cells are not present, possibly as 1.6 mm3, with an average of 1.98 mm3. Fourteen months as the result of an immunologically mediated response (17) into treatment, a decision was made to initiate lithium to or cytotoxic reaction that selectively affects these cells, lead- stimulate granulocytosis primarily to allow for the eventual ing to apoptosis (5). GM-CSF is a glycoprotein growth fac- decrease in monitoring frequency and to avoid intermittent tor that stimulates precursor granulocyte and macrophage treatment interruptions or increased WBC monitoring as cells in the bone marrow to form mature colonies (19) and per U.S. guidelines. Lithium was initiated at 300 mg twice enhances mature neutrophil functioning (5). It can be given Clinical Schizophrenia & Related Psychoses July 2010 • 139 Nykiel.indd 2 6/9/10 1:29 PM Clozapine and Benign Ethnic Neutropenia to treat clozapine-induced neutropenia and has been shown normative standards for WBC and ANC measurements do to increase the time of recovery from clozapine-induced not take into account ethnic differences (16). Withhold- agranulocytosis. However, the treatment is cost prohibi- ing or stopping treatment for African/African Americans tive and invasive, requiring daily or weekly injections (7), with normal physiology that does not fit guidelines based thus limiting its use. The use of lithium to boost granulocyte on largely white populations is not only unfair, but unneces- count in cases of neutropenia, including clozapine-induced sary. A low baseline WBC and African-American ethnicity neutropenia, has been previously documented (2, 5-7). are not predictors of future development of agranulocytosis Lithium is thought to exert this effect by a combination of (1). The Clozaril Patient Monitoring Service (CPMS) in the redistribution of marginated granulocytes and by stimulat- United Kingdom and Ireland has adopted a practice of con- ing granulocyte production (4). However, in this case, the sidering a lower ANC cutoff for patients with benign ethnic patient’s chronically low WBC and ANC were attributed to neutropenia (1). The U.S. should follow suit to assure that all a common condition, BEN. Lithium increased the ANC in patients have equal access to the most effective treatments. a dose-dependent manner: the average ANC during the 600 mg daily lithium dose was 2.5 mm3, increasing to 3.2 mm3 References with a daily lithium dose of 900 mg and a lithium level of 0.6. The use of lithium allowed uncomplicated prescribing 1. Munro J, O’Sullivan D, Andrews C, Arana A, Mortimer A, Kerwin R. Active monitoring of 12,760 clozapine recipients in the UK and Ireland. Beyond of clozapine, eventually lowering the blood monitoring fre- pharmacovigilance. Br J Psychiatry 1999;175:576-580. quency. 2. Boshes RA, Manschreck TC, Desrosiers J, Candela S, Hanrahan-Boshes M. Initiation of clozapine therapy in a patient with pre-existing leukopenia: a Added lithium treatment is not without risk, includ- discussion of the rationale of current treatment options. Ann Clin Psychiatry ing the possibility of inadvertent lithium toxicity and, dur- 2001;13(4):233-237. ing long-term administration, kidney and thyroid damage. 3. Haddy TB, Rana SR, Castro O. Benign ethnic neutropenia: what is a normal absolute neutrophil count? J Lab Clin Med 1999;133(1):15-22. Lithium added to antipsychotics has been associated with 4. Bray A.Ethnic neutropenia and clozapine.
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