Braz J Psychiatry. 2022 Jan-Feb;44(1):21-25
doi:10.1590/1516-4446-2021-1765
Brazilian Psychiatric Association
0 0 0 0 -0 02-7316-1 85
ORIGINAL ARTICLE
Risk of neutropenia among clozapine users and
non-users: results from 5,847 patients
André Akira Sueno Goldani,1,2,3,4*0 0 -0 0 -0 0 -0 0 Francisco Diego Rabelo-da-Ponte,1,2,3,4*0 0 -0 0 -0 0 -0 0 Jacson Gabriel
Feiten,1,2,3,4*0 0 -0 0 -0 0 -0 0 Maria Ines R. Lobato,40 0 -0 0 -0 0 -0 0 Paulo S. Belmonte-de-Abreu,40 0 -0 0 -0 0 -0 0 Clarissa S. Gama1,2,3,40 0 -0 0 -0 0 -0 0
1
Laboratório de Psiquiatria Molecular, Centro de Pesquisa Experimental, Hospital de Clı́nicas de Porto Alegre (HCPA), Universidade Federal
do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. 2Laboratório de Psiquiatria Molecular, Centro de Pesquisa Clı́nica, HCPA, UFRGS,
Porto Alegre, RS, Brazil. 3Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, UFRGS, Porto Alegre, RS, Brazil. 4Programa
de Pós-Graduac¸ão em Psiquiatria e Ciências do Comportamento, Departamento de Psiquiatria, Faculdade de Medicina, UFRGS, Porto
Alegre, RS, Brazil. * These authors have contributed equally to this manuscript.
Objective: Clozapine is underprescribed due to neutropenia risk. Blood tests every 3 months in those
on continuous treatment for 4 1 year who have never had an absolute neutrophil count (ANC)
o 2,000/mL has been proposed as a monitoring strategy; however, there are no South American data
to support this recommendation. This study sought to investigate whether clozapine use and other
variables could explain the occurrence of ANC o 1,000/mL in patients with severe mental disorders.
Methods: A total of 5,847 subjects were included, 1,038 on clozapine. We performed a Cox
regression considering the outcome as ANC o 1,000/mL at any time point. Predictors were sex, age,
ethnicity, clozapine use, ANC 4 2,000/mL during the first year of blood monitoring, and presence of a
severe medical condition.
Results: In the Cox regression model, ethnicity (white) (hazard ratio [HR] 0.53; 95%CI 0.29-0.99,
p o 0.05) and ANC 4 2,000/mL (HR 0.04; 95%CI 0.01-0.10, p o 0.001) were protective factors, while
presence of a severe medical condition (HR 69.35; 95%CI 37.45-128.44, p o 0.001) was a risk factor
for ANC o 1,000/mL. Other variables were not significant, including clozapine use (HR 1.33; 95%CI
0.74-2.39, p 4 0.05).
Conclusions: These findings suggest that clozapine does not increase the risk of neutropenia in
subjects with ANC 4 2,000/mL during the first year of use and in the absence of a severe medical
condition. These results could help guide clinical and public-health decisions regarding clozapine
blood monitoring guidelines.
Keywords: Clozapine; neutropenia; hematological monitoring; hemogram; absolute neutrophil count
Introduction
Clozapine, an atypical antipsychotic, distinguishes itself
among its class for higher efficacy in several chronic
mental health disorders, such as schizophrenia, bipolar
disorder, and Parkinson’s disease psychosis.1-3 Particularly in schizophrenia, its use is associated with better
outcomes in treatment resistance, with lower suicidality
rates and lower long-term mortality.4-6 However, clozapine is underused due to prescribers’ concern for the risk,
albeit rare, of developing neutropenia and subsequent
agranulocytosis.7
Initially made available in the 1970s, clozapine was
withdrawn after the report of eight fatal cases of
agranulocytosis.8 It was later returned to market under
strict absolute neutrophil count (ANC) monitoring, but
there are discrepancies among countries regarding
Correspondence: Clarissa S. Gama, Centro de Pesquisa Experimental, Hospital de Clı́nicas de Porto Alegre, Universidade Federal
do Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Prédio Anexo,
CEP 90035-903, Porto Alegre, RS, Brazil.
E-mail: cgama@hcpa.edu.br
Submitted Jan 21 2021, accepted Jul 10 2021, Epub Oct 29 2021.
required surveillance regimens.9,10 Currently, in the
United States, the prescribed regimen involved weekly
ANC monitoring during the first 6 months; every other
week for the second 6 months; and every 4 weeks after
1 year of treatment, with monthly monitoring thereafter for
the duration of treatment (Clozapine REMS Program11).
In Brazil and several other countries, the stipulated
regimen is weekly during the first 18 weeks and monthly
thereafter.10 In some settings, the prescription of clozapine is further withheld on account of this burdensome
long-term monitoring.12
Recently, the literature has been challenging the
requirement of monthly ANC follow-up after the first
18 weeks. In a meta-analysis of 425,774 individuals on
clozapine therapy, neutropenia-related mortality was rare
and neutropenia incidence rates were low after 1 year of
treatment.13 In another report, the same authors did not
How to cite this article: Goldani AAS, Rabelo-da-Ponte FD, Feiten
JG, Lobato MIR, Belmonte-de-Abreu PS, Gama CS. Risk of
neutropenia among clozapine users and non-users: results from
5,847 patients. Braz J Psychiatry. 2022;44:21-25. http://dx.doi.org/
10.1590/1516-4446-2021-1765
22
AAS Goldani et al.
observe a difference in incident neutropenia between
clozapine users and users of other atypical antipsychotics.14 Moreover, reports in Japan and Chile corroborate
low long-term incidence rates of neutropenia, with 90.2%
occurring in the first year and 80% in the first 18 weeks of
treatment respectively.15,16
Furthermore, a more flexible long-term monitoring
approach has been debated in order to prevent unnecessary exposure of at-risk patients during the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The latest consensus is to monitor every 3 months
patients who fulfill the following criteria: continuous
treatment for 4 1 year; never had an ANC o 2,000/mL
(or o 1,500/mL if history of benign ethnic neutropenia);
no safe or practical access to ANC testing.17 The Latin
American population is one of the most ethnically diverse
worldwide, because of miscegenation of native groups
with European, African, and Asian migrants. There are
no large-scale studies describing the characteristics of
the Brazilian population regarding clozapine blood monitoring, and few reports in other Latin American countries.16,18 Thus, our general aim was to investigate
whether clozapine use and other variables could explain
the occurrence of ANC o 1,000 in a large sample of
patients with severe mental disorders in several settings
of a general university hospital in Porto Alegre, the capital
of the southernmost state of Brazil.
absolute and relative frequencies, as appropriate. Participants were separated into two groups for descriptive
analyses: clozapine users and non-users. The ShapiroWilk test was used to assess normality of data distribution,
the chi-square test to analyze categorical data, the MannWhitney U test to analyze nonparametric continuous
variables, and Student’s t test for parametric continuous
variables. We performed a multivariable Cox proportionalhazards regression to assess independent risk factors
for moderate and severe neutropenia (ANC o 1,000/mL),
including sex, age (years), ethnicity, clozapine use, ANC
above 2,000/mL during the first year of clozapine blood
monitoring records or beyond, and the presence of a
severe medical condition (i.e., human immunodeficiency
virus [HIV], hepatitis C virus [HCV], cancer). Hazard ratios
(HR) with 95% confidence intervals (95%CIs) and p-values
from a Wald test were reported. A two-tailed p-value
o 0.05 was considered as significant. The statistical
analysis was performed using R software (version 4.0.2),
RStudio (version 1.3), and the ‘survival’ R package (version
3.2.7) for Cox regression.
Ethics statement
Methods
Our study was approved by the local ethics committee
and conducted in accordance with the Declaration of
Helsinki. Informed consent was waived since there was
no more than minimal risk to privacy or harm of the
individuals studied.
Participants
Results
We included 5,847 patients with severe mental disorders
in several settings (i.e., inpatient and outpatient clinics)
of a tertiary mental health referral service, Hospital de
Clı́nicas de Porto Alegre (HCPA). Participants who had
at least one ANC value entered into their electronic
medical record (EMR) during the years 2005-2020 were
included.
Participants’ information was obtained from the HCPA
EMR. The inpatient subgroup is characterized by adult
patients (age 4 18 years) in acute brief hospitalization
without a substance use disorder as the main diagnosis.
The outpatient subgroup mainly comprised patients
diagnosed with a chronic psychotic disorder (i.e., schizophrenia), bipolar disorder, or other major functional
impairment due to psychiatric disorders. Patients who
were prescribed clozapine at least once during their
follow-up at HCPA were identified as clozapine users.
Demographic characteristics were collected by the hospital’s administrative staff members, who are instructed to
check official identification documents and enter ethnicity
as self-declared (white non-Hispanic, black, native Brazilian,
Asian, or other). The population of the state of Rio Grande
do Sul, the southernmost state of Brazil, is composed
mainly of white non-Hispanics.
Sociodemographic and clinical features are described in
Table 1. The clozapine user and non-user groups differed
in terms of sex, age, ethnicity, and educational status.
Additionally, clozapine users underwent more blood tests
and, consequently, had a higher number of follow-up days
than non-clozapine users. Most individuals on clozapine
had a diagnosis of schizophrenia or a severe mental
condition (diagnosis not reported). The exact date of
clozapine initiation was assumed from the first available
ANC of patients that were identified to be on clozapine. In
our sample of 1,038 clozapine users, during a median
follow-up of 1,071 days (36 months), the absolute risk of
severe neutropenia was 0.77% (ANC o 500/mL), and the
risk of overall neutropenia (ANC o 1,500/mL) was 5.3%.
There was no reported mortality due to neutropenia in
either clozapine users or non-users.
In the multivariable Cox proportional-hazards regression model (Wald test [6] = 237.6, p o 0.001), we found
that ethnicity (white) (HR 0.53 [95%CI 0.29-0.99], p o
0.05), ANC above 2,000/mL during the first year of
clozapine blood monitoring records or beyond (HR 0.04
[95%CI 0.01-0.10], p o 0.001), and the presence of a
severe medical condition (HR 69.35 [95%CI 37.45128.44], p o 0.001) were significantly associated with
development of moderate and severe neutropenia (ANC
o 1,000/mL), the first two as protective factors and the
latter as a risk factor (Figure 1). Other variables, including
clozapine use, did not show any significant effect on
outcome.
Data analysis
We reported descriptive analyses as mean (standard
deviation [SD]), median (interquartile range [IQR]), or
Braz J Psychiatry. 2022;44(1)
Neutropenia among clozapine users and non-users
23
Table 1 Sociodemographic and clinical variables of inpatients and outpatients with severe mental illness who underwent at
least one ANC measurement from 2005 to 2020
Sociodemographic and clinical variables
No clozapine (n=4,809)
Clozapine (n=1,038)
p-value
Gender: male
2,098 (43.6)
672 (64.7)
o 0.001w
Age in years, mean (SD)
43.5 (16.3)
40.1 (14.7)
o 0.001=
Ethnicity: white non-Hispanic
4,116 (85.5)
921 (88.7)
0.012w
Education
Primary
Secondary
Tertiary
Missing
2,196 (45.6)
1,411 (29.3)
981 (20.3)
221 (4.5)
466
320
208
44
(44.8)
(30.8)
(20.0)
(4.2)
o 0.001=
2 (1-3)
17 (6-57)
o 0.001y
3 (0-122)
1,071 (68-3,283)
o 0.001y
Diagnosis
Schizophrenia
Bipolar disorder
Severe mental illness (not otherwise specified)
451 (9.3)
631 (13.1)
3,727 (77.5)
452 (43.5)
100 (9.6)
486 (46.8)
o 0.001w
Documented antipsychotic use (%)
Absolute risk ANC o 2,000/mL
Absolute risk ANC o 1,500/mL
Absolute risk ANC o 1,000/mL
Absolute risk ANC o 500/mL
1,891 (39.3)
10.67
4.24
0.79
0.17
1,048 (100,00)
13.97
5.30
1.64
0.77
Number of blood tests, median (IQR)
Follow-up days, median (IQR)
Data presented as n (%), unless otherwise specified.
ANC = absolute neutrophil count; IQR = interquartile range; SD = standard deviation.
w
Chi-square test.
=
Student t test.
y
Mann-Whitney U.
Figure 1 Multivariate Cox proportional-hazards regression model to assess independent risk factors for moderate and severe
neutropenia (absolute neutrophil count [ANC] o 1,000/mL). Data are expressed as hazard ratio (HR) and 95% confidence
interval (95%CI). Bars represent 95%CI. Square is the value of hazard ratio. * p o 0.05; ** p o 0.001.
Discussion
Brazil is a large, populous country without a centralized
registry for clozapine use. In the last 5 years, other
South American countries have reported neutropenia
prevalence and incidence in their national registries
of clozapine use (i.e., Chile, Argentina, and Colombia).16,18,19 However, our study is the first to assess the
risk of neutropenia in a severe mental illness sample
with both clozapine and non-clozapine users in a
treatment-as-usual setting in the subcontinent. Our
analysis corroborates a recent meta-analysis which
demonstrated non-different neutropenia rates when
clozapine was compared to other antipsychotics in
randomized clinical trials.14 In our study, despite both
groups not being statistically matched as in a casecontrol design, pooled analysis is still relevant, since it
comprises patients on an array of psychiatric medications in a naturalistic context, allowing higher external
validity.
Braz J Psychiatry. 2022;44(1)
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AAS Goldani et al.
Our findings demonstrated that ANC above 2,000/mL
during the first year of clozapine blood monitoring records
or beyond was a significantly protective factor (HR 0.04;
95%CI 0.01-0.10) for neutropenia risk o 1,000/mL at any
time in a population with severe mental illness, regardless
of clozapine use. The rationale of investigating this
subgroup of patients is the largely reported low risk of
neutropenia after the first year of clozapine use. Therefore, our results substantiate the recent recommendation
for more flexible ANC monitoring strategies during the
SARS-CoV-2 pandemic for clozapine users with a stable
ANC above 2,000/mL for at least 1 year.17 There are
presumably other advantages of a lower frequency of
ANC tests for clozapine users, such as lower COVID-19
exposure and a lighter resource burden for healthcare
systems. Also, it could facilitate clozapine prescription for
patients in whom it would be otherwise withheld due to
safety and monitoring feasibility concerns.12 Ultimately,
this could contribute to a higher proportion of treatmentresistant schizophrenia patients being adequately treated,
thus improving symptom control and life expectancy.20
However, within the subgroup of patients who developed neutropenia, the presence of a medical comorbidity
had a significantly elevated HR for this outcome. This is
interpreted as the co-occurrence of lower neutrophil counts
due to certain medical conditions and/or their respective
treatments, such as malignant neoplasia, AIDS, and active
viral hepatitis. Consequently, patients presenting with a
potential neutrophil-lowering condition or treatment should
undergo a more stringent monitoring regimen, regardless
of clozapine use.
Another significant protective factor for neutropenia
o 1,000/mL was white non-Hispanic ethnicity (HR 0.53;
95%CI 0.29-0.99). This finding could be explained by
the higher incidence of benign ethnic neutropenia in
the African American population,21 and is thus aligned
with Centers for Disease Control and Prevention (CDC)
monitoring guidelines with a lower diagnostic criterion for
neutropenia.
Sex and age were not associated with a higher risk of
neutropenia. A major difference between clozapine users
and non-users is the longer follow-up of the former
compared to the latter. This discrepancy is probably due
to the differential monitoring regimen for clozapine users,
as evidenced also by the higher number of blood tests in
the clozapine group.
Although not the main objective of this study, we also
reported on overall absolute risk of neutropenia. In our
sample of 1,038 clozapine users, during a median followup 1,071 days (36 months), the absolute risk of severe
neutropenia (ANC o 500/mL) was 0.77%, similar to those
reported by a meta-analysis and a naturalistic study
(respectively 0.9 and 0.61%).13,16 However, the absolute
risk of overall neutropenia (ANC o 1,500/mL) was 5.3%,
higher than reported in previous studies.13,16 The higher
overall neutropenia rate could be explained by a number
of reasons. First, our sample was composed exclusively
of patients seen in tertiary care, derived in part from acute
psychiatric inpatient settings. Although some clozapine
users might initiate the medication in this treatment
setting, it is usually reserved for more severe and acute
Braz J Psychiatry. 2022;44(1)
condition, which are likely to involve higher use of
concomitant medications and comorbid non-psychiatric
conditions. Age was not a significant risk or protective
factor in our sample. However, is was directly correlated
with risk of neutropenia in others.13 Our sample was older
than that of the Chilean registry, a possible explanation
for the different risk of overall neutropenia in this study.
Another possible explanation for the discrepancy is the
different composition of ethnic groups between our
population and the Chilean one.16 Specifically, benign
ethnic neutropenia is more associated with African
descent.21 The higher proportion of white non-Hispanics
in our sample notwithstanding (88.7%), the other 11.3%
could explain the higher rate. Finally, socioeconomic
factors (i.e., low educational levels) could be involved.
Our results must be interpreted considering the
limitations of this study. The main constraint was limited
data retrieval because of the query-based nature of
collection. Although all patients on clozapine were accounted for, variables such as clozapine dose and other
medications in use were scant. Certainty of antipsychotic
use was obtained for 39.3% for the non-clozapine group,
though more were assumed to be in use. However, all
patients were derived from clinics caring for refractory
psychotic, manic, and high-suicidality disorders, which
allow us to assume that most were on antipsychotics or
other psychiatric medications.
In conclusion, the present study provides consistent
evidence in support of more flexible blood monitoring in
those patients on clozapine with ANC 4 2,000/mL during
the first year of monitoring and in the absence of a severe
medical condition (defined in this sample as HIV, HCV, or
cancer). These results add compelling information from
the South American population and could help guide
clinical and public-health decisions towards flexibilizing
blood monitoring guidelines for clozapine users.
Disclosure
The authors report no conflicts of interest.
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