Use of Granulocyte Colony-Stimulating Factor in a Neutropenic HIV-Infected Patient on Clozapine

Psychosomatics 2016:]:]]]–]]]

& 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Case Reports Use of Granulocyte Colony-Stimulating Factor in a Neutropenic HIV-Infected Patient on Clozapine Hudson Elmore, M.D., Justin Lewin, M.D., Mark Bradley, M.D., Arthur Sinkman, M.D.

Introduction Clozapine is uniquely effective in treatment-resistant schizophrenia. However, its use in HIV-infected patients with schizophrenia is complicated by the rare but severe side effect of agranulocytosis, which poses a special problem for patients who have HIV-related leukopenias due to the bone marrow toxicity of HIV, the medications use to treat HIV or both. Consequently, many HIV-infected patients are precluded from consideration for clozapine treatment. Granulocyte colony-stimulating factor (G-CSF), traditionally used to treat chemotherapy-induced neutropenia, has also been used to facilitate clozapine therapy in patients for whom it would have been otherwise contraindicated. This includes medically compromised patients such as those developing neutropenia from chemotherapy, those with pre-existing neutropenia of varying etiologies including benign ethnic neutropenia, and those with a history of clozapineinduced granulocytopenia or agranulocytosis.1–9 We present a case of a patient with AIDS, treatment-refractory schizophrenia, and chronic neutropenia for whom G-CSF was used to facilitate clozapine administration. To our knowledge, this is the first such case in which G-CSF was used to increase the absolute neutrophil count (ANC) in a patient with HIVassociated neutropenia and refractory schizophrenia.

Case Report Mr. A, 62-year-old African-American man was living in an adult home with a history of AIDS and chronic Psychosomatics ]:], ] 2016

schizophrenia. He first received a diagnosis of schizophrenia in his early 20s and has had over 30 psychiatric hospitalizations. His history includes 1 suicide attempt by medication overdose, noncompliance with his antiretroviral medications due to persecutory delusions, and violence due to persecutory delusions. Mr. A was admitted to an inpatient psychiatry unit after he threatened several staff members and destroyed property in his adult home. At the time of admission, he had persecutory delusions about the psychiatrist and other staff members in his adult home. He demonstrated thought disorganization and thought blocking, he appeared internally preoccupied, and he reported distressing auditory hallucinations. He isolated himself in his room and did not engage in group activities. He also exhibited extrapyramidal symptoms (EPS) including decreased arm swing, bradykinesia, and a shuffling gait. Workup on admission did not indicate a medical cause of his psychosis. Upon admission, he initially was continued on his outpatient medication regimen that included high doses of an antipsychotic (oral risperidone 8 mg nightly and intramuscular injections of long-acting risperidone 75 mg every 2 weeks). A chart review indicated that Mr. A had numerous unsuccessful medication trials, including oral and depot

Received June 1, 2016; revised August 15, 2016; accepted August 16, 2016. From the Department of Psychiatry (HE, JL, MB, AS), New York University School of Medicine, New York, NY; Department of Psychiatry (MB, AS), Veterans Affairs New York Harbor Healthcare System, New York, NY. Send correspondence and reprint requests to Hudson Elmore, M.D., Department of Psychiatry, New York University School of Medicine, New York, NY; e-mail: hudson.elmore @nyumc.org & 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

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Case Reports formulations of typical and atypical antipsychotics at therapeutic doses and often in combination. Medical records indicated that even while on these medications he continued to have impairing psychotic symptoms. Mr. A’s CD4 count at the time of admission was 262 cells/μL, and viral load was 62 copies/mL, with a known lifetime CD4 count nadir of 46 cells/μL in 2011. His HIV medication regimen was darunavir, emtricitabine/tenofovir, raltegravir and ritonavir, as well as trimethoprim/sulfamethoxazole and azithromycin for Pneumocystis and Mycobacterium prophylaxis, respectively. Because of Mr. A’s multiple failed antipsychotic trials, his history of violence and suicidality, and his notable EPS, the treatment team considered a trial of clozapine. However, concerns were raised about Mr. A’s appropriateness for clozapine, as he had demonstrated chronic neutropenia. Over the past decade, his ANC was in the range of 1000– 2500 cells/μL, at times falling below the minimum ANC threshold of 1500 cells/μL as per the national clozapine registry. In light of prior literature documenting successful use of G-CSF to facilitate clozapine therapy in patients with neutropenia of other etiologies, the treatment team consulted with the hematology service to discuss using G-CSF to increase Mr. A’s ANC. Based on the his weight, the hematologist approved a subcutaneous dose of 480 μg of G-CSF with the intention that this single dose would have a sustainable effect on Mr. A’s ANC. With Mr. A’s consent, the first dose of G-CSF was administered, and the following day his ANC showed a dramatic rise to 17,700 cells/μL. Clozapine was initiated 4 days later, and Mr. A was continued on long-acting risperidone injections while oral risperidone was slowly tapered. One week after the initial dose of G-CSF, Mr. A’s ANC dropped to 1460 cells/μL, below the minimum threshold to continue clozapine therapy. Following further discussion with the hematologist and with Mr. A’s informed consent, the treatment team decided to pursue a plan of weekly G-CSF administration of 480 μg to maintain his neutrophil count above the minimum threshold on weekly blood counts and to allow for continued clozapine titration (Figure). This treatment regimen was pursued for 5 weeks after the initial G-CSF injection. Clozapine was titrated to a total daily dose of 250 mg with corresponding clozapine and norclozapine levels of 235 and 2

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FIGURE.

Mr. A’s ANC during the administration of G-CSF and clozapine. G-CSF was initiated before the first dose of clozapine, and it was stopped after 5 weeks of clozapine therapy. Clozapine was stopped after 8 weeks of therapy because of recurrent neutropenia.

120 ng/mL, respectively. Mr. A showed a gradual but marked improvement in his symptoms. His thought process became more organized with resolution of thought blocking. He no longer reported auditory hallucinations nor appeared internally preoccupied. The salience of his delusional content reduced dramatically, he began to display a brighter affect, and he began to attend group activities. He displayed no aggression, and he remained compliant with blood monitoring and medication administration throughout treatment. Further, his gait and bradykinesia showed improvement. Mild sialorrhea was his only reported side effect to clozapine. Over the course of his weekly G-CSF treatment, however, his treatment team noted with concern that after each G-CSF administration, Mr. A demonstrated consistently elevated white blood cell counts and ANCs, of more than 30,000 and 25,000 cells/μL, respectively. Additionally, by the end of each week following a G-CSF dose, his ANC consistently dropped below the 1500 cells/μL minimum threshold for continued clozapine treatment. Owing to concerns regarding his recurrent supratherapeutic bone marrow response to G-CSF followed by a return to neutropenia despite weekly G-CSF administration, the hematologist and the psychiatry team elected to discontinue G-CSF administration in week 6 of clozapine treatment. Noting his marked reduction in symptoms and hoping to explore all possible options to try and preserve his clinical gains with clozapine, the treatment team contacted the relevant national clozapine registry and collaboratively determined that, given his baseline neutropenia, he was eligible for a lower Psychosomatics ]:], ] 2016

Elmore et al. minimum ANC of 1000 cells/μL, which would enable him to remain on clozapine therapy. With Mr. A’s informed consent, clozapine was thus continued and further titrated with weekly blood monitoring. However, in week 8 of clozapine treatment, 2 weeks after the approval by the registry of the changed minimum ANC, his ANC dropped to 890 cells/μL. Following the protocol discussed with the registry, clozapine was immediately discontinued. Mr. A’s ANC subsequently returned to the previous baseline of 1500 cells/μL within 1 week. After cessation of clozapine therapy, Mr. A had a return of his psychotic symptoms, including persecutory delusions and disturbing auditory hallucinations. He has had several subsequent antipsychotic trials and psychiatric admissions. However, none of these trials has achieved the same clinical response as clozapine. Discussion This case illustrates some of the difficult treatment decisions involved in using clozapine to treat refractory schizophrenia in patients who are medically compromised, particularly those with HIV/AIDS. Clozapine remains the most effective treatment option for refractory schizophrenia. Mr. A’s poorly controlled psychotic symptoms (despite multiple highdose antipsychotic trials), his history of violence, his prior suicide attempt, and his significant EPS, all supported initiating clozapine. Under standard treatment guidelines, his pre-existing neutropenia would have precluded him from consideration for clozapine therapy, and his chronic HIV infection and the associated hematologic risks added yet more complexity to treatment decisions. Prior case reports, however, describe G-CSF administration to permit clozapine therapy in other medically compromised patients. This report thus bridges 2 literatures: that of using clozapine in patients with HIV infection8,10,11 and that of using G-CSF in medically compromised patients to permit clozapine therapy,1–4,6,7 though little work has been done in either area. G-CSF is a colony-stimulating factor that is thought to regulate production of neutrophils within bone marrow and to affect neutrophil progenitor proliferation, differentiation, and

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functional activation. Most commonly used to treat chemotherapy-induced neutropenia, G-CSF has been used in rare circumstances to permit clozapine therapy in patients with neutrophil-related contraindications. Successful use of G-CSF has been described for re-challenging patients with a history of clozapineinduced granulocytopenia or agranulocytosis,2,4,6 for continuing clozapine therapy in the setting of chemotherapy-induced neutropenia,7 and for initiating clozapine in patients with a history of benign ethnic neutropenia or idiopathic neutropenia.3,6 It was on the basis of this literature that the authors considered G-CSF use to permit clozapine therapy in Mr. A. Three general strategies for G-CSF administration to permit clozapine treatment, depending on patients’ responses to injections, have been reported in prior case reports and case series: (1) a single dose at the initiation of therapy6; (2) regular, prophylactic dosing at a specific frequency throughout treatment1,2,4,6,7; or (3) intermittent “rescue” doses when the patient’s neutrophil count drops below a designated threshold.3,6 However, dosing, frequency of administration, and white blood cell/ANC monitoring have not been established for the use of G-CSF to permit clozapine therapy. Such ambiguities reinforce the need for close consultation with a hematologist familiar with C-CSF administration to safely permit its use during clozapine therapy. Additionally, G-CSF is not without its side effects and potential complications. G-CSF injections were ultimately discontinued in our patient because of recurrent fluctuations between neutropenia and supratherapeutic response. Similar robust responses have been described in other case reports3,4 and can increase the risk for pulmonary edema, venous thrombosis, and hyperviscosity syndrome. Other serious adverse reactions to G-CSF include allergic reactions, thrombocytopenia, splenic rupture, bone pain, and hepatomegaly. Clozapine, meanwhile, remains the most efficacious medication for patients with treatment-resistant schizophrenia. In addition, as seen with Mr. A, clozapine’s relative lack of associated EPS is an important benefit to HIV-infected individuals who have higher susceptibility to EPS.12 To date, however, there is little guidance on the use of clozapine to treat schizophrenia in HIV-infected individuals. Evidence is

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Case Reports currently limited to case reports.8,10,11 However, Nejad et al. describe 2 HIV-infected patients in whom clozapine was successfully used to treat refractory schizophrenia, including one with a history of clozapine-induced granulocytopenia.8 At the same time, clozapine therapy in HIV-infected individuals is not without risks. Antiretrovirals, neoplasms, malnutrition, opportunistic infections, prophylactic antibiotics, and HIV infection itself can all cause bone marrow suppression, potentially increasing the risk of adverse hematologic consequences during clozapine therapy.8 Zidovudine, for example, has known myelosuppressive effects with neutropenia usually seen after 12–24 weeks, and trimethoprim/sulfamethoxazole, which our patient was taking for PCP prophylaxis, can cause bone marrow suppression.8,10 Furthermore, up to half of HIV-infected patients have neutropenia during the course of their illness, resulting from HIV toxicity to hematopoietic tissues.13 Thus, a combination of factors, including chronic HIV infection, baseline neutropenia, and multiple myelosuppressive medications, may have contributed to Mr. A’s recurrent neutropenia during and after G-CSF therapy.

Conclusion Our case illustrates some of the difficult clinical decisions involved in initiating clozapine in an HIVinfected patient with a history of neutropenia and in using G-CSF to facilitate clozapine therapy in any patient. Despite the prevalence of HIV in the seriously mentally ill population, there is little research and thus little guidance for clinicians considering the use of clozapine for these patients. However, G-CSF has the potential to permit clozapine administration in previously excluded patients, and the alternative use of pegfilgrastim, a pegylated form of G-CSF, may minimize potentially harmful dramatic fluctuations in white blood cell count and ANC.14 Further research, however, is needed to provide guidance for clinicians regarding clozapine use in HIV-infected individuals, and dosing, frequency, and monitoring of G-CSF administration when used to facilitate clozapine therapy. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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