Clozapine and Late-Onset Agranulocytosis: A Potential Non–Life-Threatening Etiology

Clozapine is the gold-standard antipsychotic for treatment-resistant psychosis (TRP). Agranulocytosis is an important, potentially life-threatening adverse effect of clozapine. More than half of cases of agranulocytosis occur during the first 6 months of clozapine treatment.¹ Clozapine-induced agranulocytosis is usually attributed to bone marrow suppression. The prevalence of agranulocytosis and death due to clozapine-induced agranulocytosis is 0.4% and 0.05%, respectively.² Granulocyte colony-stimulating factor (G-CSF) has been used to facilitate clozapine continuation or rechallenge in patients with severe neutropenia or agranulocytosis.³

Case Report

We recently published a case report of a patient with late-onset clozapine-induced agranulocytosis, in which the hematologic workup and clinical course suggested an etiology other than bone marrow suppression.⁴ Briefly, a 49-year-old woman with TRP experienced late-onset agranulocytosis after 8 years of clozapine treatment. She was evaluated by hematology, and her bone marrow biopsy was unremarkable. After she discontinued clozapine, her absolute neutrophil count (ANC) normalized. She was subsequently treated with high-dose olanzapine (up to 60 mg/day), but had an inadequate therapeutic response. She was rechallenged with clozapine and had a recurrence of agranulocytosis within 3 months. Thereafter, hematology prescribed a 7-day course of prednisone 10 mg daily, given the suspicion that neutropenia was due to increased neutrophil margination. One week later, her ANC increased from 500 to 1100/mm³, consistent with this hypothesis. Clozapine has since been continued with regular ANC monitoring. For the next 8 months, clozapine was maintained at 400 mg/day without interruption, and her ANCs were typically 100 to 200/mm³ (range 0-500/mm³). She did not have any severe infections. During this period, she tested positive for COVID-19 but recovered at home without complications. She has not been rechallenged with low-dose prednisone, nor has she been treated with G-CSF. This report suggests the possibility of increased neutrophil margination as a different, non–life-threatening etiology for some patients with clozapine-induced agranulocytosis. We reviewed the published literature for other similar cases.

Literature Review

We systematically searched Medline (PubMed, National Center for Biotechnology Information, US National Library of Medicine, Bethesda, Maryland), PsycInfo (via Ovid, American Psychological Association, Washington, DC), and Web of Knowledge (Science Citation Index and Social Sciences Citation Index, Thomson Reuters, Charlottesville, Virginia) in April 2026 for reports of late-onset agranulocytosis without clinical evidence of bone marrow suppression in clozapine-treated patients. The primary search strategy was “clozapine AND [‘late onset neutropenia’ OR ‘late onset agranulocytosis’].” From these sources, as well as a manual review of reference lists, we identified 26 potential case reports. The inclusion criteria were: (1) case reports of late-onset agranulocytosis, defined as after 1 year of treatment with clozapine; (2) documented ANC of less than 500/mm³; and (3) no reported fever or infection. For each case, data were extracted on: age, sex, race, duration of clozapine treatment, clozapine dose, lowest reported ANC, other psychotropic medications, whether neutropenia resolved with discontinuation of clozapine, whether the patient underwent a bone marrow biopsy, whether the patient was treated with G-CSF, and whether the patient was rechallenged with clozapine.

Thirteen case reports met the inclusion criteria, which are detailed in the Table.^4-16 The mean subject age was 44 years, and 54% (n = 7) were men. Five subjects were White (38%), 3 were Asian (23%), 2 were Black (15%), and 1 each was Hispanic, Indian, and unspecified (8%). The mean duration of clozapine treatment prior to agranulocytosis was 12 years, and the mean clozapine dose was 500 mg/day. Neutropenia resolved after discontinuation of clozapine in all subjects. Three patients (23%) underwent bone marrow biopsy. Nine patients (69%) were treated with G-CSF. Ours was the only patient challenged with prednisone. Eight patients (62%) were rechallenged with clozapine.

Discussion

Demargination is the process whereby neutrophils detach from the vascular endothelium and enter the peripheral blood. Prednisone affects neutrophil demargination by inhibiting L-selectin expression, an adhesion molecule, thereby increasing circulating neutrophils.¹⁷ Lithium¹⁸ and G-CSF³ also exhibit potential benefits for clozapine-related neutropenia. The mechanisms by which lithium increases ANC are not fully delineated but may involve: (1) stimulating G-CSF, (2) increasing neutrophil extravasation from the bone marrow into the peripheral blood, and (3) increasing neutrophil demargination.¹⁹ G-CSF increases neutrophil production in the bone marrow but may also increase neutrophil demargination.³

Our case report suggests a possible clozapine-induced “pseudoagranulocytosis.” That is, our patient has adequate neutrophils, but they are attached to the vascular endothelium and, therefore, not captured by phlebotomy. To our knowledge, no previous studies have investigated the effects of clozapine on neutrophil margination.

In what clinical scenarios might increased neutrophil margination be suspected? New-onset decline in neutrophil counts after the first year of clozapine treatment may warrant suspicion. Other medications are also associated with increased neutrophil margination, including β-blockers, which may be used to treat clozapine-associated tachycardia.²⁰ Clinicians should carefully review concomitant medications for potential effects on neutrophils.

How might these considerations guide clozapine management in similar cases? We emphasize extreme caution with these clinical suggestions, given the inherent limitations of case reports. First and foremost, clozapine treatment should be interrupted in patients with moderate or severe neutropenia. Hematology consultation is warranted, including a potential bone marrow biopsy, in such patients. Following normalization of ANC after discontinuation, clinicians and/or patients/families may request a clozapine rechallenge. Both psychiatry and hematology should concur with the proposed clozapine retrial. If neutrophil counts start to decline again during clozapine rechallenge, a short-term, low-dose corticosteroid trial could be considered, again with oversight from both psychiatry and hematology. When increased neutrophil margination is clinically suspected in the setting of clozapine-induced neutropenia, other considerations before a corticosteroid trial include: (1) absence of evidence for other hematologic disease, (2) no history of severe infections, (3) no current use of other immunosuppressive medications, (4) stable coexisting medical conditions, and (5) no history of adverse neuropsychiatric effects from corticosteroid use.

Concluding Thoughts

Our findings raise the possibility of a different, non–life-threatening etiology for some patients with clozapine-induced agranulocytosis. This is clinically relevant, as isolated moderate or severe neutropenia—in the absence of severe infections—may not require indefinite termination of clozapine treatment in patients who require it for psychiatric stability. With judiciously coordinated multispecialty care, the use of lithium, G-CSF, and potentially prednisone could help identify similar patients for whom clozapine can be safely continued or rechallenged.

References

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