East Asian Arch Psychiatry 2023;33:28-31 | https://doi.org/10.12809/eaap2233
CASE REPORT
Kenneth SW Chan, Nora BW Lai, Mimi MC Wong, PF Pang
Abstract
Clozapine is considered the most effective antipsychotic for schizophrenia, but it can cause neutropenia and even agranulocytosis. We describe the first case in Hong Kong involving the use of filgrastim, a recombinant form of human granulocyte colony-stimulating factor, to enable clozapine continuation therapy for a severely ill patient with treatment-resistant schizoaffective disorder who developed recurrent neutropenia after almost 20 years of continuous clozapine therapy. Therefore, clinical vigilance is important, regardless of clozapine treatment duration. Filgrastim can facilitate long-term clozapine therapy in patients with clozapine-induced neutropenia.
Key words: Clozapine; Filgrastim; Granulocyte colony-stimulating factor; Neutropenia; Neutrophils
Kenneth SW Chan, Department of Psychiatry, United Christian Hospital, Hong Kong
Nora BW Lai, Department of Psychiatry, United Christian Hospital, Hong Kong
Mimi MC Wong, Department of Psychiatry, United Christian Hospital, Hong Kong
PF Pang, Department of Psychiatry, United Christian Hospital, Hong Kong
Address for correspondence: Dr Kenneth SW Chan, Department of Psychiatry, United Christian Hospital, Hong Kong. Email:csw562@ha.org.hk
Submitted: 12 July 2022; Accepted: 6 February 2023
Introduction
Clozapine is considered the most effective antipsychotic for individuals with treatment-resistant schizophrenia.1 However, it can cause serious life-threatening adverse effects such as agranulocytosis and has a mortality rate of 0.012%.2 In Hong Kong, clozapine may be underutilised because of the need for frequent blood monitoring, the low tolerability, and the associated risks of medical complications.3 Approximately 2.7% of patients treated with clozapine develop neutropenia: half of the cases within the first 18 weeks of clozapine treatment and three-quarters of the cases within the first year of treatment.4 In Hong Kong, 13 of 980 clozapine recipients reportedly developed neutropenia (three of the 13 patients developed agranulocytosis). Among the 13 patients, half were aged >50 years, and three-quarters were women; half of the cases occurred in the first 18 weeks of clozapine treatment.5 However, there have been cases of late-onset neutropenia up to 66 months after treatment initiation.6 In October 2015, the United States Food and Drug Administration recommended that clozapine monitoring includes mandatory assessment of the absolute neutrophil count (ANC) and that treatment should be stopped when the ANC is <1000/mm3 or equivalent to 1×109/L.7 This enables more patients with a lower ANC to receive sustained clozapine treatment. The condition of clozapine-induced neutropenia is usually reversible within 14 to 22 days after clozapine discontinuation.8 We describe the first case in Hong Kong involving the use of filgrastim, a recombinant form of human granulocyte colony-stimulating factor (G-CSF), to enable clozapine continuation therapy for a severely ill patient with treatment-resistant schizoaffective disorder who developed recurrent neutropenia after almost 20 years of continuous clozapine therapy.
Case Presentation
In January 2022, a Chinese woman aged 53 years presented to the United Christian Hospital with sudden first-time onset of neutropenia after 20 years of uneventful clozapine treatment; her nadir neutrophil count was 0.2 ×109/L. She had been diagnosed with schizoaffective disorder at the age of 20 years. She had a family history of psychiatric illness; her mother had been diagnosed with anxiety disorder. She did not have a history of substance or alcohol abuse. She had a medical history of menorrhagia, right thyroidectomy for a right thyroid cyst, and impaired fasting glucose. She also had a history of lithium sensitivity, characterised by nausea and rash. She had no history of neutropenia before the onset of mental illness. She adhered satisfactorily to oral medication under family supervision. Her early course of mental illness was complicated by eight psychiatric admissions in 13 years because of suboptimal symptom control, for which many antipsychotic medications (eg, sulpiride 1600 mg, haloperidol 20 mg, pericyazine 40 mg, flupentixol 6 mg, perphenazine 24 mg, pimozide 8 mg, trifluoperazine 40 mg, risperidone 3 mg, and amisulpride 200 mg) had been attempted but failed despite prolonged hospitalisation before the age of 33 years; one hospitalisation episode lasted for >7 months. The patient had also required supervised placement for >5 years until she achieved full remission after initiation of clozapine treatment, which enabled her to live independently in a public housing unit. For 20 years, she had been maintained on clozapine 500 mg and sodium valproate 1000 mg; she was able to live alone independently without further psychiatric admission. She had undergone regular ANC monitoring in accordance with the clozapine prescribing guidelines, which require weekly monitoring for the first 18 weeks of treatment and monthly monitoring thereafter.
The patient underwent blood tests (for haemoglobin, white cell count, neutrophil count, platelet count, urea, creatinine, total bilirubin, alkaline phosphatase, alanine aminotransferase, prothrombin time, international normalised ratio, partial thromboplastin time, fasting glucose, fasting lipid profile, thyroid-stimulating hormone, serum valproic acid, serum rheumatoid factor, antinuclear antibody, hepatitis B surface antigen, hepatitis C antibody, hepatitis A antibody, and blood culture), sputum and saliva tests (for culture, SARS-CoV-2 RNA, influenza A, influenza B, and respiratory syncytial virus), urine culture tests, and imaging studies (chest X-ray, abdominal ultrasound) to exclude possible causes of agranulocytosis (including sepsis) and autoimmune conditions; all test results were unremarkable. In consultation with a haematologist, a bone marrow examination was not conducted because the patient’s ANC remained above the mild neutropenic range of 1 to 1.5 ×109/L following clozapine discontinuation.
The patient was diagnosed with drug-induced neutropenia by clinicians in the department of medicine. Her clozapine treatment was discontinued, and she was transferred to the department of psychiatry for further treatment. Within 4 days, she experienced a full relapse with hallucinations, delusions, irritability, pressure of speech, and sleep disturbances. During the following 4 weeks, her ANC remained marginal without clinically significant improvement (1.1-1.9 ×109/L). Her sodium valproate dose was also tapered, which led to normalisation of ANC at >2 ×109/L. This finding was presumably associated with the concurrent use of sodium valproate and an increased risk of clozapine-associated neutropenia.9 Over a 2-month interval without clozapine, the patient’s psychiatric conditions failed to respond to trials of antipsychotic medications, alone or in combination, including olanzapine up to 10 mg, haloperidol up to 20 mg, haloperidol 15 mg combined with aripiprazole 20 mg, and then haloperidol 15 mg combined with quetiapine 700 mg. Despite high-dose chemical sedation by intramuscular benzodiazepine injection (diazepam-equivalent dosage of >30 mg daily), augmented with intramuscular haloperidol injection, she remained very agitated and required frequent physical seclusion. In total, six sessions of twice-weekly electroconvulsive therapy were delivered, but the patient did not demonstrate sustained clinical improvement.
Clozapine re-challenge was initiated 8 weeks after initial discontinuation when the patient’s ANC had been stable for 3 weeks. The patient had a clinical response during gradual clozapine dose titration up to 300 mg over a period of 2 months. However, she eventually developed another neutropenic episode, with a nadir neutrophil count of 1.4 ×109/L. Considering its potential neutropenia- reversing properties,10 lithium 400 mg was initiated but was not tolerated because of generalised severe pruritis and polyuria. The haematologist was consulted again; with consent from the patient and her family, subcutaneous filgrastim (30 million units) was prescribed 2 months after clozapine re-challenge. A strategy of as-required filgrastim was adopted, based on alternate-day monitoring, until a persistently normal ANC was achieved. The as-required strategy involved a once-weekly filgrastim bolus dose of 30 million units subcutaneously when the patient’s ANC was <1.5 ×109/L and twice-weekly subcutaneous filgrastim (same dose) when the ANC was <1 ×109/L.
After six doses of filgrastim, the patient was able to continue clozapine (up to 450 mg) augmented with 20 mg of haloperidol. This combination resulted in complete symptom remission after 3 months of clozapine re- challenge. The patient was discharged after 6 months of hospitalisation. Her latest filgrastim treatment was subcutaneous injection of 30 million units at a maximum interval of 3 weeks, which appeared to normalise ANC. Considering the longer interval of normal ANC between filgrastim doses, the ANC monitoring frequency was reduced from alternate-day to once weekly, as recommended by the haematologist. Changes in the patient’s ANC according to salient management milestones are shown in the Figure.
Discussion
This report describes a difficult-to-manage clinical scenario, in which the patient presented with a rare late- onset clozapine-induced neutropenia, which differs from the usual timing (within the first year of clozapine treatment in 75% of affected patients).4 These findings highlight the importance of ongoing clinical vigilance and regular haematological monitoring, regardless of clozapine therapy duration.11 Clozapine is likely to cause drug-induced neutropenia related to toxicity affecting neutrophils and bone marrow precursors.12 The recurrent risk of clozapine- induced neutropenia can place patients at risk of infection for up to 4 weeks after clozapine discontinuation.13 Risk factors for clozapine-induced neutropenia include genetics14 and concomitant use of bone marrow suppression medications.15 Accordingly, sodium valproate was not resumed in our patient. Nonetheless, it remains difficult to identify patients who are likely to develop clozapine-induced neutropenia.11
In our patient, long-term clozapine treatment was complicated by an intolerable adverse reaction to lithium. The use of lithium can increase the neutrophil count in clozapine recipients, although the mechanism is not fully understood.16 Suggested treatments for drug-induced neutropenia include withdrawal of the offending agent, treatment of any associated infection, or the use of G-CSF.12 In our patient, clozapine discontinuation was not a good option because of severe psychotic relapse and treatment resistance when other psychotropics were used. Clozapine re-challenge may be unavoidable, despite the increased mortality risk.17 Clinicians are more likely to consider clozapine re-challenge when patients demonstrate substantial clinical improvement over an extended period of time; clinicians may be hesitant to consider re-challenge in the absence of a well-established long-term response.18
The use of G-CSF facilitates continuous clozapine therapy in patients with a history of neutropenia.18 Filgrastim, a form of G-CSF that stimulates neutrophil growth, is administered by subcutaneous or intravenous injection and widely used by haematologists to treat conditions involving low neutrophil counts (eg, chemotherapy or bone marrow transplantation). In Hong Kong, filgrastim is a formulary drug covered by the Hospital Authority. In a review of seven patients who received as-required G-CSF and 23 patients who received prophylactic G-CSF, clozapine and G-CSF co-prescription resulted in a success rate of 78%, compared with 60% after lithium and G-CSF co-prescription; no death or medication-specific adverse effects of G-CSF were reported.19 To our knowledge, this is the first case in Hong Kong involving the use of filgrastim to enable continuation of clozapine therapy, which led to symptom remission and hospital discharge. Our patient did not report adverse effects during the use of filgrastim. As-required use of filgrastim can facilitate uninterrupted clozapine therapy in patients with recurrent clozapine-induced neutropenia.
Conclusion
Late-onset neutropenia can occur after 20 years of clozapine treatment; therefore, clinical vigilance is important, regardless of clozapine treatment duration. The use of G-CSF can facilitate long-term clozapine therapy in patients with recurrent clozapine-induced neutropenia.
Contributors
All authors designed the study, acquired the data, analysed the data, drafted the manuscript, and critically revised the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
Conflicts of interest
All authors have disclosed no conflicts of interest.
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Data availability
All data generated or analysed during the present study are available from the corresponding author on reasonable request.
Ethics approval
The patient was treated in accordance with the tenets of the Declaration of Helsinki. The patient provided written informed consent for all treatments and procedures.
Acknowledgement
We thank Dr Shek Ying Lin from the Haematology Division of the Department of Medicine, United Christian Hospital for providing advice regarding the use of filgrastim in our patient.
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