Is there evidence for clozapine causing leukocytosis?

Is there evidence for clozapine causing leukocytosis?

Comment by InpharmD Researcher

A 2021 systematic review found that the incidence of leukocytosis associated with clozapine use ranges from 0.6% to 7.7% with concomitant drugs and other risk factors, such as high doses of clozapine, male gender, and smoking, possibly increasing the risk of developing leukocytosis while on treatment. Retrospective reviews and individual case reports have reported varying levels of leukocytosis.

Background

A 2021 review of 13 articles described clozapine use has been associated with a benign and transient leukocytosis with an incidence ranging from 0.6% to 7.7% in studies. More specifically, concomitant lithium use with clozapine has resulted in a more persistent form of leukocytosis. A study by Fabrazzo et al. reported leukocytosis associated with clozapine treatment in 37.8% of the patients during cohort with an incidence rate of 11.1% and 26.7% for transient and persistent types, respectively. Other risk factors are suggested to be male gender in addition to lithium concurrent use. Smoking is another risk factor for idiopathic leukocytosis as an inducer of CYP450 isoenzyme which primarily metabolizes clozapine (i.e., CYP1A2). Although the mechanism of leukocytosis induced by clozapine is not well understood, various mechanisms have been proposed to suggest an interaction between clozapine and the hematopoietic system’s cells. A dose-dependent drug effect is observed on absolute neutrophil counts, likely proportional to higher clozapine doses. Moreover, persistent neutrophilia is suggested to be associated with a loss of clozapine efficacy overtime. [1], [2], [3]

Clozapine-induced leukocytosis has been also confirmed in several studies mainly case reports, case series, and retrospective studies (see summary Tables 1, y). A case series from 2007 reported chronic leukocytosis associated with clozapine use in seven patients (all smokers) with no history of medical comorbidities (e.g., traumas, burns) that may contribute to the elevated leukocyte count. One patient case reported a leukocyte count of 19,800 units/mm^3 lasting for 2-5 years. Once the clozapine-induced leukocytosis is confirmed, treatment should be continued after ruling out the other possible alternative causes of neutrophilia. [1, 3]

Relevant Prescribing Information

Leukocytoclastic vasculitis has been reported as an adverse event in postmarketing reports.The frequency or causal relationship to drug exposure has not been established.

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is there evidence for clozapine causing leukocytosis?

Please see Tables 1-2 for your response.

Summary of studies that included leukocytosis outcomes in patients treated with clozapine
References	Patients (n)	Disease state	Treatment	Leukocytosis outcome
Sugita et al.	57	Drug-resistant schizophrenia	Long-term electroconvulsive therapy and clozapine	Bilateral modified electroconvulsive therapy is associated with changed WBC count in patients treated with clozapine
Yang et al.	1084	Various psychiatric disorders	Clozapine, clozapine plus valproate, clozapine plus lithium, clozapine plus valproate and lithium	Leukocytosis occurred in 41.8% of total populations. Clozapine daily dosage, benzodiazepine use, younger age, and combination clozapine plus lithium were associated with leukocytosis development.
Fabrazzo et al.	285	Schizophrenia and bipolar spectrum disorder	Clozapine 2-3 divided doses, dose increments of 25-50 mg every 2 days up to tolerated and effective dose.	At 18 weeks of treatment, transient leukocytosis in male and female patients occurred at 5.2% and 5.95, respectively. Persistent leukocytosis occurred in 16.3% and 10.4%, respectively
Lee et al.	101	Schizophrenia, bipolar, delusional, and schizoaffective disorder	Clozapine	At 1 year of treatment, a spike in white blood counts was observed at ~3 weeks of treatment. All elevations in cell counts were transient and resolved ~9 weeks.

References:

[1] Sugita K, Mori Y, Kanemoto K, Sugita S. Long-lasting leukocytosis in patients with schizophrenia treated with clozapine after electroconvulsive therapy : ECT stabilizes white blood cell count. Sci Prog. 2022;105(3):368504221117067. doi:10.1177/00368504221117067
[2] Yang CC, Wang XY, Chou PH, Lin CH. Valproate-related neutropenia and lithium-related leukocytosis in patients treated with clozapine: a retrospective cohort study. BMC Psychiatry. 2023;23(1):170. Published 2023 Mar 15. doi:10.1186/s12888-023-04659-2
[3] Fabrazzo M, Prisco V, Sampogna G, et al. Clozapine versus other antipsychotics during the first 18 weeks of treatment: A retrospective study on risk factor increase of blood dyscrasias. Psychiatry Res. 2017;256:275-282. doi:10.1016/j.psychres.2017.06.068
[4] Lee J, Takeuchi H, Fervaha G, et al. The Effect of Clozapine on Hematological Indices: A 1-Year Follow-Up Study. J Clin Psychopharmacol. 2015;35(5):510-516. doi:10.1097/JCP.0000000000000387

Summary of Case Reports and Clozapine use
Reference	Patient description	Disease state	Treatment	Leukocytosis outcome
Kırşavoğlu et al.	36-year-old male	Schizophrenia	Clozapine tapered to 100 mg/day	During the 18-month follow-up, leukocytes fluctuated and exceeded 10,000 units per mm3 during the period. An incident of elevated levels (17,270 units per mm3) led to clozapine dose reduction. Elevations remained stable upon last visit.
Polat et al.	41-year-old female	Schizophrenia	Clozapine 450 mg/day	White blood count (WBC) elevated to 11.9×109/L and 14.100×109/L on 8th and 16th day of treatment.
Augustin et al.	31-year-old male	Schizophrenia	Clozapine	WBC trended from 6.9 x10³/μL to 21.2 x10³/μL in two weeks. On the next routine CBC, WBC spiked to 104x10³/μL. Clozapine was discontinued and started on inotuzumuab.
Liu et al.	51-year-old male	Schizophrenia	Clozapine 300 mg daily with lorazepam 1 mg twice daily as needed for agitation	WBC dose to 16.1 1000/mm³ and the absolute neutrophil count (ANC) to 11.4 1000/mm³.
Seifritz et al.	55-year-old smoker	Major depression with psychotic and agoraphobic features	Clozapine 125-150 mg/day	Within 2 weeks, WBC counts increased and depression aggravated. Clozapine was replaced with clotiapine.

References:

[1] Kırşavoğlu, B., & Odabaşı, O. (2023). An unexpected side effect related to the use of clozapine: Neutrophilic leukocytosis and brief review of the literature. Psychiatry Research Case Reports, 2(1), 100101.
[2] Polat A, Çakir U, Gündüz N. Leukocytosis after Clozapine Treatment in a Patient with Chronic Schizophrenia. Noro Psikiyatr Ars. 2016;53(1):87-88. doi:10.5152/npa.2015.9855
[3] Augustin NB, Maroules M. Hyperleukocytosis during clozapine treatment: A rare presentation of B-cell Acute lymphoblastic leukemia [published correction appears in Leuk Res Rep. 2022 Apr 06;17:100307]. Leuk Res Rep. 2021;15:100253. Published 2021 May 31. doi:10.1016/j.lrr.2021.100253
[4] Liu F, Mahgoub N, Ferrando S. Leukocytosis associated with clozapine treatment: a case report. Psychosomatics. 2011;52(5):488-491. doi:10.1016/j.psym.2011.01.032
[5] Seifritz E, Hemmeter U, Holsboer-Trachsler E, Pöldinger W. Chronic leukocytosis and neutrophilia caused by rehabilitation stress in a clozapine-treated patient. Pharmacopsychiatry. 1993;26(3):99. doi:10.1055/s-2007-1014350