Human neutrophils show decreased survival upon long‐term exposure to clozapine

Goto, Aya; Yoshimi, Akira; Nagai, Tomoko; Ukigai, Mako; Mouri, Akihiro; Ozaki, Norio; Noda, Yukihiro

doi:10.1002/hup.2629

Cited by 5 publications

(4 citation statements)

References 20 publications

(23 reference statements)

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“…However, the bioactivation/oxidation of clozapine in neutrophils produced reactive and unstable clozapine metabolites, which induced toxic oxidative stress, leading to neutrophil apoptosis. Metabolites may be cytotoxic to bone marrow stroma, potentially leading to accelerated neutrophil or myelocyte precursor apoptosis (81,82). An associated genetic susceptibility was detected in 31 patients who developed clozapine-induced agranulocytosis and 38 patients who developed neutropenia in a group of 310 clozapine users.…”

Section: Clozapinementioning

confidence: 99%

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

et al. 2020

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Atypical antipsychotics (AAP) or second-generation antipsychotics are the clinical option for schizophrenia treatment during acute psychoses, but they are also indicated for maintenance during lifetime, even though they are being used for other psychiatric conditions in clinical practice such as affective disorders and autism spectrum disorder, among others. These drugs are differentiated from typical antipsychotics based on their clinical profile and are a better choice because they cause fewer side effects regarding extrapyramidal symptoms (EPS). Even though they provide clear therapeutic benefits, AAP induce peripheral effects that trigger phenotypic, functional, and systemic changes outside the Central Nervous System (CNS). Metabolic disease is frequently associated with AAP and significantly impacts the patient's quality of life. However, other peripheral changes of clinical relevance are present during AAP treatment, such as alterations in the immune and endocrine systems as well as the intestinal microbiome. These less studied alterations also have a significant impact in the patient's health status. This manuscript aims to revise the peripheral immunological, endocrine, and intestinal microbiome changes induced by AAP consumption recommended in the clinical guidelines for schizophrenia and other psychiatric disorders.

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Section: Clozapinementioning

confidence: 99%

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

et al. 2020

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“…On the other hand, the evidence in the long run is less strong, with several studies reporting a substantial neutrophil reduction in the long run, which we have not found in our sample. 66 , 67 …”

Section: Discussionmentioning

confidence: 99%

Clozapine Management in Schizophrenia Inpatients: A 5-Year Prospective Observational Study of Its Safety and Tolerability Profile

Filippis

Gaetano

Schoretsanitis

et al. 2021

NDT

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Background Clozapine is well known for its efficacy and clinical superiority compared to other antipsychotics in treatment-resistant schizophrenia (TRS). However, it is frequently underutilized worldwide because of its acute adverse events, as well as for its long-term cardiometabolic and hematological consequences. Objective The aim of the study was to evaluate 5-year safety in chronic TRS inpatients with continuous clozapine use. Methods Patients with TRS and clozapine treatment were evaluated for 5 years. All participants were assessed using the Brief Psychiatric Rating Scale (BPRS), Glasgow Antipsychotic Side-effect Scale for Clozapine (GASS-C), Social Performance Scale (PSP) and Short Portable Mental Status Questionnaire (SPMSQ). Clinical, cardiometabolic and hematological data were collected periodically. General linear models (GLM) repeated measures controlling for CLZ dose were utilized to determine differences in variables across the time. Results Overall, 189 inpatients were screened for study participation. The final sample included twenty-one TRS patients (16 males, 76%) with an average age of 57.6 years, all with 5-year continuous use of clozapine (mean dose 266 mg/day). There was not a significant effect of time on BPRS ( p =0.774), PSP (p=0.855) and SPMSQ (p=0.066); differences remained not significant after controlling for CLZ dose (p=0.585, p=0.467 and p=0.105, respectively). No changes were found in blood and clinical parameters except for red blood cell count, which decreased over time ( p =0.024; η 2 = 0.952). Patients reported a significant BMI decrease (−8.98 kg, p =0.008) between baseline and 5 years last observation. Conclusion The findings show how the application of a structured dietary, clinical and therapeutic monitoring program in psychiatric care facilities could allow the safe and effective long-term cardiometabolic and hematological management of clozapine. The unique role that clozapine plays in the current treatment of patients with TRS requires greater clinical awareness. Although its acute and chronic side effects are notorious, its safety management is feasible and broadens its potential practical application.

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“…Clozapine (25 µM) and olanzapine (25 µM) were mixed with H 2 O 2 (5 or 10 µM) or H 2 O in the medium, immediately before addition to the cells to prepare their metabolites or their unchanged forms. The condition was adapted previous reports [19][20][21] with minor modification. Treated HL-60 cells were immediately centrifuged at 380× g (2000 rpm; Himac CT13R; HITACHI, Tokyo, Japan) for 4 min at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

A Reactive Metabolite of Clozapine Induces Hematopoietic Toxicity in HL-60 Cells Undergoing Granulocytic Differentiation through Its Effect on Glutathione Metabolism

Torii-Goto

Yoshimi

Tashiro

et al. 2022

Biological & Pharmaceutical Bulletin

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Clozapine is an atypical antipsychotic with several advantages over conventional antipsychotics, in addition to its well-known efficacy in treatment-resistant schizophrenia. However, the high risk of agranulocytosis associated with clozapine therapy limits its clinical application. Clozapine bioactivation to an unstable protein-reactive metabolite, identified as a nitrenium intermediate, has been implicated in cytotoxicity toward neutrophils. Clozapine affects myeloid precursor cells rather than neutrophils; however, the impact of its reactive metabolite on myeloid precursor cells undergoing granulocytic differentiation remains unclear. Herein, we used hydrogen peroxide (H 2 O 2 ) to generate the reactive metabolite and compared reactive metaboliteinduced cytotoxicity between HL-60 cells undergoing granulocytic differentiation and differentiated HL-60 cells. In addition, we examined the role of oxidative stress in this type of cytotoxicity. The reactive metabolite of clozapine induced rapid cytotoxicity in HL-60 cells undergoing granulocytic differentiation, but not in differentiated HL-60 cells, with the metabolite exhibiting more potent cytotoxicity than clozapine. No cytotoxicity was observed following incubation with olanzapine, a structural analog of clozapine, even after exposure of the drug to H 2 O 2 . The reactive metabolite of clozapine decreased the levels of reduced glutathione, while addition of reduced glutathione attenuated the reactive metabolite-induced cytotoxicity. These findings indicate that glutathione metabolism plays a role in the hematopoietic toxicity induced by the reactive metabolite of clozapine. Oxidative stress may potentially increase susceptibility to the hematopoietic toxicity induced by the reactive metabolite of clozapine.

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Human neutrophils show decreased survival upon long‐term exposure to clozapine

Cited by 5 publications

References 20 publications

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

Clozapine Management in Schizophrenia Inpatients: A 5-Year Prospective Observational Study of Its Safety and Tolerability Profile

A Reactive Metabolite of Clozapine Induces Hematopoietic Toxicity in HL-60 Cells Undergoing Granulocytic Differentiation through Its Effect on Glutathione Metabolism

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