Clozapine re-challenge under the cover of Filgrastim
R Gopalakrishnan, TP Subhalakshmi, A Kuruvilla, KS Jacob
Department of Psychiatry, Christian Medical College, Bagayam, Vellore, Tamil Nadu, India
Department of Psychiatry, Christian Medical College, Bagayam, Vellore, Tamil Nadu
Rechallenge with clozapine, despite a history of clozapine-induced neutropenia is considered in patients with a good response to the drug in the past, for whom no other treatments are effective, and in cases where the risks of withholding treatment are greater than the risks of rechallenge. Dyscrasias that occur during rechallenge are reportedly earlier in onset and longer lasting. Strategies advocated during rechallenge include frequent monitoring of white blood counts, the use of lithium or Granulocyte-Colony Stimulating Factors. We report a case of a patient with treatment-resistant schizophrenia who developed neutropenia with clozapine as a result of which the drug was discontinued. However poor response to other first and second-generation antipsychotic medication and the persisting risk of harm to himself and others necessitated the reconsideration of clozapine. The patient was re-challenged with clozapine under the cover of Filgrastim, a Granulocyte-Colony Stimulating Factor.
|How to cite this article:|
Gopalakrishnan R, Subhalakshmi T P, Kuruvilla A, Jacob K S. Clozapine re-challenge under the cover of Filgrastim.J Postgrad Med 2013;59:54-55
|How to cite this URL:|
Gopalakrishnan R, Subhalakshmi T P, Kuruvilla A, Jacob K S. Clozapine re-challenge under the cover of Filgrastim. J Postgrad Med [serial online] 2013 [cited 2022 May 19 ];59:54-55
Available from: https://www.jpgmonline.com/text.asp?2013/59/1/54/109496
Clozapine is considered the most effective antipsychotic drug, which can have beneficial effects in several areas in people with schizophrenia including reduction in severity of psychotic symptoms and suicidal behavior, reduction in hospitalization rates and health care costs, and increase in the potential for social and occupational rehabilitation. However, it is generally reserved for patients who fail to respond to treatment with other antipsychotics in view of adverse effects with life-threatening potentials such as neutropenia, agranulocytosis, and myocarditis. The occurrence of these side-effects warrants discontinuation of the drug. However, when alternate treatment strategies fail, psychiatrists are sometimes compelled to restart patients on clozapine despite the past history of adverse effects.
Re-challenge is inherently fraught with the risk of re-occurrence of these side-effects. Reports of re-challenging patients with the drug following a history of clozapine-induced neutropenia or agranulocytosis are not common. The strategies suggested for such a re-challenge include the use of intensive monitoring or the addition of lithium or colony-stimulating factor analogs like Filgrastim. ,, Lithium causes a reversible leukocytosis which can antagonize clozapine-induced neutropenia.  Filgrastim is a human granulocyte colony-stimulating factor (G-CSF) manufactured by recombinant DNA technology and is thought to regulate production of neutrophils within the bone marrow. It also affects neutrophil progenitor proliferation, differentiation, and selected cell functional activation. Filgrastim is commonly used in the treatment of neutropenia associated with cytotoxic chemotherapy, myeloblastic therapy followed by bone marrow transplantation, congenital causes and in advanced HIV infections, and mobilization of peripheral blood progenitor cells. 
This report describes a patient with treatment-resistant schizophrenia who developed neutropenia with clozapine as a result of which the drug was discontinued. However, the patient's poor response to other first-and second-generation antipsychotic medications and the persisting risk of harm to himself and others necessitated the reconsideration of clozapine. The patient was re-challenged with clozapine under the cover of Filgrastim.
Mr. A, a 37-year-old Asian male was diagnosed to have schizophrenia in 2003. He underwent unsuccessful trials of different antipsychotic agents, including risperidone and olanzapine. He was considered treatment resistant and commenced on clozapine in 2005. Within a period of 3 weeks of initiation of the drug, he developed neutropenia (total white blood cell count, 2100/cu mm; absolute neutrophil count, 546/cu mm) and subsequently a lower respiratory tract infection.  Clozapine was discontinued. He was restarted on first-and second-generation antipsychotic medications and received consecutive therapeutic trials of aripiprazole, 30 mg/day; quetiapine, 800 mg/day; amisulpride, 800 mg/day; zotepine, 350 mg/day; haloperidol, 20 mg/day; depot fluphenazine decanoate (100 mg once a fortnight) and sodium valproate (1000 mg/day), each over a 3-6 month period, both individually and in combinations. He also received two courses of Electro Convulsive Therapy (ECT). However, there was no significant reduction in psychotic symptoms and he continued to have delusions of persecution and infidelity with a significant risk of harm to self and others. His Positive And Negative Syndrome Scale (PANSS) score was 23, 28, and 33 on positive, negative, and general psychopathology subscales, respectively.
The option of re-challenging the patient with clozapine was considered in view of persistent psychopathology and homicidal risk. Written informed consent was obtained from the patient and his father prior to commencing clozapine. Treatment plans were made in consultation with a clinical hematologist. As the risk of neutropenia is greater when clozapine is used in conjunction with other psychotropic medications, all medications, except for haloperidol, were tapered and stopped; haloperidol was continued to avoid being without antipsychotic cover. Along with thrice-weekly injections of Filgrastim (0.9 mg/week), clozapine was commenced and the dose gradually increased to 450 mg per day over the next few weeks. Blood cell counts were monitored twice a week for the first 8 weeks and later once a week. Filgrastim was discontinued after 3 weeks as counts remained high. The patient continues to be followed up regularly and white blood cell counts have remained normal 12 months after re-challenge with clozapine. Psychotic symptoms gradually reduced (total PANSS scores dropped from 84 at admission to 47 at discharge) along with an improvement in personal and social functioning. His PANSS score at 12-month follow-up was 46.
Clozapine re-challenge has been considered an option despite a history of clozapine-induced neutropenia in patients with a good response to the drug in the past, for whom no other treatments are effective, and in cases where the risks of withholding treatment are greater than the risks of re-challenge. However, it is advised that monitoring is more frequent (twice a week for 3 months) to detect emergent dyscrasias as neutropenia or agranulocytosis tends to appear earlier and in a more severe form than during the initial treatment with clozapine. , The risk factors associated with clozapine-induced white cell dyscrasias include increasing age, female gender, Asian ethnicity, concomitant use of other medications, and past history of medication-induced dyscrasias.  Mr. A has two of these risk factors (Asian ethnicity and past history of dyscrasias); however, non-response to other antipsychotics and significant risk issues prompted the treating team to consider a re-challenge with clozapine. To the best of our knowledge, there are no published reports of re-challenge with clozapine from this region.
Past reports of re-challenge in patients with clozapine-induced neutropenia have been under the cover of lithium or with G-CSF analogs like Filgrastim. Filgrastim has been commenced either after the onset of dyscrasias or simultaneously along with clozapine; we employed the second strategy. Although the addition of Filgrastim helped to prevent granulocytopenia in this patient, this strategy does not always prove to be successful. , There is no consensus about the dose or duration of Filgrastim to be used; however, it has been suggested that a dose of more than 0.3 mg/week may prevent against a blood dyscrasia.  Our patient received a higher dose than reported previously which may have played a role in the successful re-challenge. We suggest that the simultaneous commencement of Filgrastim may be a useful option while re-challenging patients who have experienced mild to moderate neutropenia with clozapine.
|1||Manu P, Sarpal D, Muir O, Kane JM, Correll CU. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res 2012;134:180-6.|
|2||Ghaznavi S, Nakic M, Rao P, Hu J, Brewer JA, Hannestad J, et al. Rechallenging with clozapine following neutropenia: Treatment options for refractory schizophrenia. Am J Psychiatry 2008;165:813-8.|
|3||Hägg S, Rosenius S, Spigset O. Long-term combination treatment with clozapine and filgrastim in patients with clozapine-induced agranulocytosis. Int Clin Psychopharmacol 2003;18:173-4.|
|4||Kanaan RA, Kerwin RW. Lithium and clozapine rechallenge: A retrospective case analysis. J Clin Psychiatry 2006;67:756-60.|
|5||Gascon P. Presently available biosimilars in hematology-oncology: G-CSF. Target Oncol 2012;7:S29-34.|
|6||Thangadurai P, Jyothi KS, Gopalakrishnan R, Kuruvilla A, Jacob KS. Reversible neutropenia with olanzapine following clozapine-induced neutropenia. Am J Psychiatry 2006;163:1298.|
|7||Dunk LR, Annan LJ, Andrews CD. Rechallenge with clozapine following leucopenia or neutropenia during previous therapy. Br J Psychiatry 2006;188:255-63.|
|8||Lertxundi U, Sanchez P, Hernandez R, Elizagarate E. A case of agranulocytosis secondary to rechallenge with clozapine following severe neutropenia during previous therapy. J Clin Psychiatry 2011;72:1659.|
|9||Joffe G, Eskelinen S, Sailas E. Add-on filgrastim during clozapine rechallenge in patients with a history of clozapine-related granulocytopenia/agranulocytosis. Am J Psychiatry 2009;166:236.|
|10||Majczenko TG, Stewart JT. Failure of filgrastim to prevent severe clozapine-induced agranulocytosis. South Med J 2008;101:639-40.|