Table of Contents    
Year : 2020  |  Volume : 11  |  Issue : 4  |  Page : 140-141

Late-onset clozapine-induced agranulocytosis in a young woman with paranoid schizophrenia

1 Department of Pharmacology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
2 Department of Medicine, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India

Date of Submission07-Jun-2020
Date of Decision23-Sep-2020
Date of Acceptance21-Oct-2020
Date of Web Publication14-May-2021

Correspondence Address:
Sharath P Madhyastha
Assistant Professor, Department of Medicine, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpp.JPP_29_20

Rights and Permissions



Treatment of schizophrenia has taken so many turns, and adverse effects of the drugs still continue to remain as a hurdle in the management. Clozapine is considered to be the better promising drug in the treatment of paranoid schizophrenia with minimal side effects. Clozapine-induced agranulocytosis is one adverse event that troubles clinicians, and it requires a vigilant eye to look for the signs. In the present study, the authors discuss a case which has developed agranulocytosis in the later stages of clozapine treatment.

Keywords: Agranulocytosis, clozapine, late adverse event, paranoid, schizophrenia

How to cite this article:
Vinayaka A, Sheshadri S, Madhyastha SP, Shetty GV, Reddy CT. Late-onset clozapine-induced agranulocytosis in a young woman with paranoid schizophrenia. J Pharmacol Pharmacother 2020;11:140-1

How to cite this URL:
Vinayaka A, Sheshadri S, Madhyastha SP, Shetty GV, Reddy CT. Late-onset clozapine-induced agranulocytosis in a young woman with paranoid schizophrenia. J Pharmacol Pharmacother [serial online] 2020 [cited 2021 Oct 27];11:140-1. Available from:

   Introduction Top

Clozapine has been found to be an effective treatment in persons with schizophrenia resistant to treatment with other antipsychotic drugs. In addition, clozapine is an effective treatment for schizophrenia accompanied by persistent suicidal or self-injurious behavior. Clozapine's unique side effect profile, which includes a low rate of life-threatening agranulocytosis, gives rise to numerous considerations in prescribing, monitoring, and side effect management in the use of the drug.[1],[2]

   [Case Report Top

A 26-year-old female patient, who is a known case of paranoid schizophrenia for 6 years on treatment, came to our tertiary health-care center with the complaints of dry cough and increased fatigue for 1 week. The cough was not associated with fever or dyspnea or throat pain. Her medication history was taken which showed that she was on oral clozapine 600 mg once a day for 18 months. Her attendants revealed that she had similar complaints 2 months prior, for which she was diagnosed as a case of clozapine-induced neutropenia (CIN), and the dose of clozapine was reduced to 200 mg once a day. Her concomitant medications were oral imipramine 25 mg once a day, oral phenytoin 300 mg once a day, and atropine drops 1% sublingual.

Her vital signs were stable. General physical examination and systemic examinations were unremarkable. Psychiatric history was taken which revealed the presence of auditory hallucinations for 2 months, which was more in the morning hours with impaired recent memory. Sleep had increased in the past 4 months with decreased appetite, and bowel and bladder habits were found to be normal. On routine laboratory investigations, she was found to have leukopenia 2.4 × 103/μL and absolute neutrophil count (ANC) was 0.12 × 103/μL.

Correlating with the past history, the present complaints, and the laboratory investigations, she was diagnosed as a case of clozapine-induced severe agranulocytosis. The causality of the adverse drug reaction was analyzed using the Naranjo algorithm, which gave us a score of 9, denoting “definite” causality.

She was admitted and clozapine was stopped; throat swab revealed a culture of Staphylococcus aureus sensitive to cefepime. She was put on subcutaneous filgrastim 300 µg once daily, parenteral cefepime was started with a dose of 2 g intravenous (IV) twice daily, oral phenytoin 200 mg once a day, betadine gargles thrice a day, and oral pantoprazole 40 mg once a day. Barrier nursing was followed with contact precautions, with the use of N95 mask; consumption of raw foods was avoided and no visitors were allowed. Following which, on day 4 of admission, her ANC returned to 1.2 × 103/μL and cefepime was stopped. The cough subsided gradually, and she was shifted to oral fixed-dose combination of amoxicillin with clavulanic acid 500/125 mg for 5 days. Five doses of subcutaneous filgrastim 300 µg were given during her stay. Psychiatry consultation was sought for periodic review, and she was advised antipsychotic-free period of 2 weeks.

   Discussion Top

Clozapine remains the single medication approved by the US Food and Drug Administration (FDA) for treatment-resistant schizophrenia. It has a relatively low affinity for D2 receptors and thus is associated with a lower incidence of extrapyramidal side effects when compared with that of typical antipsychotics, but concerns about tolerability and side effects are barriers to treatment. Specifically, treatment with clozapine poses an increased risk of agranulocytosis and requires monitoring through regular blood draws examining white cell counts. Agranulocytosis is one of the most serious clozapine-induced adverse drug events. Agranulocytosis is defined as an ANC <100/mm3 in association with infectious disease.[3] Although the incidence in the Indian population is relatively lesser, the risk of agranulocytosis is 0.38% of all schizophrenia cases treated with clozapine. The risk of agranulocytosis and neutropenia is more in the initial 6–18 months of clozapine treatment.[4] The incidence falls after this period, and there have been very few reports of neutropenia and agranulocytosis in later stages.

The FDA's recently released modified blood monitoring guidelines (i.e., the monitoring of ANC only) not only grant patients access to clozapine treatment but also encourage health-care providers to take the possible side effects of clozapine into consideration.[5] Clozapine-induced agranulocytosis/granulocytopenia (CIAG) may represent two possible phenotypes: CIN (ANC <1500/mL) and clozapine-induced agranulocytosis (CIA) (ANC <500/mL).

The mechanism of CIAG is dose independent, with a significant genetic predisposition and also idiosyncratic. The most recent theory explaining CIAG is that of the immune-mediated response against haptenized neutrophils.[6] The mechanism of delayed-onset agranulocytosis is unclear. Treatment with clozapine generally lasts for months or even years. It is hypothesized that modest growth-inhibiting effects of clozapine on bone marrow may be amplified in patients undergoing long-term therapy with clozapine. N-desmethylclozapine, a metabolite of clozapine at therapeutic drug concentrations (1–3 μM), has been found to be directly cytotoxic to neutrophils or interferes with the turnover of bone marrow precursor cells.[6] The report of delayed-onset agranulocytosis in India is very rare and many cases go undiagnosed as most of the patients do not report the minor adverse effects.

In our case, the ANC levels have shown a drastic fall after the introduction of clozapine and the levels have recovered after stopping clozapine and treatment with granulocyte-stimulating factor. On analyzing the case using Naranjo's algorithm, it was observed that both dechallenge and rechallenge were positive, which gave us a score of 9, hence concluding it to be a “definite” adverse drug reaction.[7]

The patient had previous complaints which were managed with dose reduction, but the adverse effect returned as delayed onset and it was very severe requiring barrier nursing. The risk factors of female sex and young age were also present.[8] It is important to make necessary adjustments in dosage when initiating clozapine, especially in patients who have previous complaints of neutropenia. Furthermore, patients and their attenders should be advised to keep a vigilant eye on the minor adverse effects such as cold, sore throat, fever, or any sort of infection.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initial will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Jann MW, Grimsley SR, Gray EC, Chang WH. Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinet 1993;24:161-76.  Back to cited text no. 1
Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003;60:82-91.  Back to cited text no. 2
de With SAJ, Pulit SL, Staal WG, Kahn RS, Ophoff RA. More than 25 years of genetic studies of clozapine-induced agranulocytosis. Pharmacogenomics J 2017;17:304-11.  Back to cited text no. 3
Sultan RS, Olfson M, Correll CU, Duncan EJ. Evaluating the effect of the changes in FDA guidelines for clozapine monitoring. J Clin Psychiatry 2017;78:e933-9.  Back to cited text no. 4
Andres E, Mourot-Cottet R. Clozapine-associated Neutropenia and Agranulocytosis. J Clin Psychopharmacol 2017;37:749-50.  Back to cited text no. 5
Wiciński M, Węclewicz MM. Clozapine-induced agranulocytosis/granulocytopenia: Mechanisms and monitoring. Curr Opin Hematol 2018;25:22-8.  Back to cited text no. 6
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 7
Myles N, Myles H, Clark SR, Bird R, Siskind D. Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations. Aust N Z J Psychiatry 2017;51:980-9.  Back to cited text no. 8


Print this article  Email this article
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Article in PDF (277 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  

   Case Report
   [Case Report

 Article Access Statistics
    PDF Downloaded147    
    Comments [Add]    

Recommend this journal