# 2003 Taylor & Francis

International Journal of Psychiatry in Clinical Practice 2003

Volume 7

Pages 277
/280 277

Granulocytopenia associated with neuroleptic

therapy in a patient with benign familial leukopenia
ILYA REZNIK1,4,
RON LOEWENTHAL2,4,
MOSHE KOTLER1,4, INNA APTER1,
ROBERTO MESTER1,4 AND
ABRAHAM WEIZMAN3,4
1

Ness-Ziona/Beer-Yakov Regional Mental Health

Center, Israel; 2Tissue Typing Unit, Haim Sheba
Medical Center, Tel-Hashomer, Israel;
3
Laboratory of Biological Psychiatry, Felsenstein
Medical Research Center, Israel; 4Sackler
Faculty of Medicine, Tel-Aviv University, RamatAviv, Israel

Correspondence Address
Dr. Ilya Reznik, Lod Community Mental Health
Center, #140 Katzenelson Street, Lod,
71226, Israel
Tel: /(972) 8 9213993
Fax: /(972) 8 9216038
E-mail: ilyarez@netvision.net.il

Received 4 March 2003; accepted for

publication 11 July 2003

Benign familial leukopenia (BFL) has been reported in several ethnic

groups, including Ethiopians of Jewish origin. To date, there are no
reported cases of patients with BFL developing granulocytopenia following
administration of neuroleptics. We report a case of a young Ethiopian Jew
suffering from schizophrenia, who exhibited premorbid benign reduced
white blood cells (WBC) count and developed leukopenia and neutropenia
following exposure to typical (zuclopentixol, perphenazine, haloperidol)
antipsychotics and the atypical antipsychotic risperidone. The diagnosis of
BFL was established and tissue typing of the patient was determined. To
the best of our knowledge, this is the first report of leukopenia with
neutropenia in an ethnically susceptible (due to BFL) schizophrenia
patient following exposure to typical and atypical antipsychotics. HLA
typing of this patient was distinct from that reported in patients
susceptible to clozapine-induced agranulocytosis. Further extensive
investigations including HLA typing in a larger cohort of schizophrenic
patients is needed in order to define the association between HLA
haplotypes and neuroleptic-induced hematological reactions and to
identify the potentially vulnerable individuals. (Int J Psych Clin Pract 2003;
7: 277
280)
/

Keywords
neuroleptic-related leukopenia
HLA

INTRODUCTION

n most instances, leukopenia and neutropenia are

considered to be risk factors for infection. An exception
to this rule is benign familial leukopenia (BFL)
/ a hereditary
phenomenon, which is transmitted as an autosomally
dominant trait and is characterized by normal or somewhat
low total leukocyte counts (49429/1354/ml), consistent
neutropenia, and, usually, relative monocytosis and lymphocytosis, sometimes with eosinophilia.1 Affected individuals
have a normal life expectancy, many are asymptomatic, but
some have histories of tendency to develop furuncles and/or
periodontal disease.1 Subjects with BFL were shown not to
have an increased incidence of infection, and their response
to infection does not differ from subjects having normal
white blood cells (WBC) count.1
3 First, BFL was described
in Afro-Americans by Huber in 19394 (cited as appearing in
Ref. 1). People of African origin and the West Indies have
been found to have this familial disorder.5
9 In the Middle

benign familial leukopenia

East, two ethnic groups with neutropenia have been

identified: native Jordanians and Yemenite Jews.1
3 The
Ethiopian Jews, a geographically and ethnically isolated
group from the Gondar region in the northern rural highlands of Ethiopia, has also been included in the list of ethnic
subpopulations with BFL.2,3 However, the risk of such
patients of developing neuroleptic-induced neutropenia is
as yet unclear.
Neuroleptic-induced agranulocytosis is an unpredictable
and life-threatening adverse event; hence the pathological
mechanisms underlying neuroleptic-induced agranulocytosis
and/or neutropenia in susceptible patients remain to be
determined. Since clozapine-induced agranulocytosis (CA)
has been associated with a characteristic HLA haplotype,10
13 tissue typing may help to identify high-risk
individuals, who are prescribed this medication.10
15 Leukopenia, induced by another antipsychotic medication,
namely olanzapine, chemically similar to clozapine, was
recently suspected having characteristic HLA-related backDOI: 10.1080/13651500310002977

278

I Reznik et al

ground.16 We report a case of leukopenia and neutropenia in

an ethnically susceptible (due to BFL) schizophrenia patient.

CASE REPORT
The patient is a 35-year-old Ethiopian male of Jewish origin
who was first hospitalized at age 30 due to an acute psychotic
episode. He was diagnosed suffering from DSM-IV paranoid
schizophrenia (F 20.0 code as per ICD-10 classification) and
was treated with perphenazine, beginning with upward
titration from 8 up to 12 mg/day (average dose, 12 mg/
day) with a good clinical response, and without adverse
events. At that time it was first noted that his WBC was
slightly low (leukocytes 3000/ml, granulocytes 1800/ml,
whereas the actual baseline WBC count remained unknown.
At that time, the diagnosis of BFL was established according
to the criteria of Shoenfeld et al.1,3
After discharge from hospital, where he had remained for
five consecutive weeks, the patient continued treatment with
perphenazine for 6 months at an outpatient clinic until he
was lost to follow-up for 2 years. When the patient returned
to the outpatient clinic, his treatment was changed to the
typical antipsychotic zuclopenthixol depot, with a regimen of
up to 100 mg/2 weeks (which is sufficient as a regular
maintenance dose); this was given over a 6-month period
(Figure 1). During this period, the WBC count was not
monitored on a regular basis. The only available WBC data
from that time indicated a significant decrease of granulocytes (1000/ml) despite an elevation of total WBC count
(3500/ml). Subsequently, administration of zuclopenthixol
depot was stopped and patient was prescribed sulpiride, as a

monotherapy, with titration from 50 up to 200 mg/day

(average dose, 100 mg/day)
/ low for ordinary maintenance
dose (400
/1200 mg/day). Within 1 month after initiation of
sulpiride treatment, WBC as well as granulocyte count were
slightly raised and the patient continued to receive this
medication for about 6 months (Figure 1).
Six months later, the patient was rehospitalized due to
psychotic relapse, following non-compliance with sulpiride
treatment, and was treated with typical antipsychotics.
Perphenazine monotherapy was given with titration from 8
up to 16 mg/day (average daily dose, 12 mg/day) for about 7
months. Due to lack of efficacy, perphenazine was gradually
stopped over 2 weeks, and he was prescribed haloperidol
from 5 up to 15 mg/day (average daily dose, 10 mg/day) for
about 1 month, together with biperiden up to 6 mg/day, as an
antiparkinsonian agent. During this treatment, a reduction of
WBC (3000/ml) and granulocytes (1000/ml) was observed.
Due to suspicion of the development of neuroleptic-induced
neutropenia, treatment with risperidone (2.5 mg/day) was
initiated and other haloperidol therapy was discontinued
abruptly. Soon after this change, both WBC and granulocytes
count were elevated to 3500/ml and 1500/ml, respectively.
However, within 4 months, a transient, but dramatic
decrease of WBC (2500/ml) and granulocytes (500/ml) count
was observed (Figure 1), and the patient was referred for
hematological assessment.
At this time, 4 months after initiation of risperidone (2.5
mg/day) administration, the patient was physically asymptomatic, with no evidence of infection or bleeding tendency,
other possible complications. Physical examination was
unremarkable. Platelet and total eosinophil counts were
normal. Hemoglobin concentration was 12.3 g/dl. Peripheral

Figure 1 Alterations in white blood and neutrophilic cells count during 5.5 years of follow-up. Neut, neutrophils; WBC, white blood cells; K, 1000.

Neuroleptic-induced granulocytopenia

279

blood smear demonstrated a normal red cell line with

neutropenia. No evidence of leukemia was noted. Tissue
typing revealed the following HLA: A2, A33, B50, B14, Bw 6
and DRB1*0304 DRB1*1302. The patients mother, who was
physically and mentally healthy, was also evaluated, and a
low WBC count (3500/ml) and granulocyte count (2500/ml)
were detected.
Risperidone was suspected as being the probable causative agent for the granulocytopenia and its dosage was
decreased to 1 mg/day. Over the next month, there was a
spontaneous rise in WBC (to a level of 4500/ml) and
granulocytes (to a level of 2500/ml) counts (Figure 1).
Hematological evaluation, performed 6 months later, revealed a WBC count of 4000/ml, a granulocyte count of 1200/
nl, with no relapse of neutropenia; hemoglobin concentration was 13.2 g/dl. The conservative treatment approach in
this patient was based on the benign nature of the familial
leukopenia as well as the lack of evidence of infection or
bleeding tendency.

tients.10 There are two suggested mechanisms that lead to

CA.23 Immune-mediated toxicity could lead to CA by
induction of the formation of antibodies in response to
covalent modification of neutrophil proteins by clozapine.24
Direct modification of critical neutrophil proteins by clozapine could also lead to neutrophil cell death.23 In this
context, HLA typing may help to identify high-risk individuals.15 In 1990, Lieberman et al reported results of the
association of CA with HLA B38 DRB1*0402 DRB4*0101
DQB1*0302 DQA1*0301 in Ashkenazi Jewish patients, and
with HLA B7 DRB1*1601 DRB5*02 DQB1*0502
DQA1*0102 in non-Jews.11 Studies by Corzo et al have
found an HSP-70 9-kb allele associated with two MHC
haplotypes as a marker for CA in different ethnic groups.25,26
These studies suggest a possible susceptibility gene for CA
located in the major histocompatibility complex.

DISCUSSION

Even though neuroleptics as a group are considered to be

relatively hematologically safe,17,18 some classical antipsychotic drugs may induce agranulocytosis.17
20 Recently,
zuclopenthixol-associated neutropenia and thrombocytopenia were described.27 Several case reports have suggested the
development of leukopenia and neutropenia under risperidone treatment.20,28
32 The relevant pathological mechanisms underlying neuroleptic-induced agranulocytosis or
neutropenia in risperidone-treated patients and their probable dose-dependency need to be clarified. Unfortunately,
and
despite
accumulated
data
for
clozapine23
20,28
32
risperidone,
there are no reports on dose-dependency of neutropenia on other neuroleptics.

To the best of our knowledge this is the first report of a

leukopenic
/neutropenic reaction in a susceptible schizophrenic patient following exposure to typical and atypical
antipsychotics.

NEUTROPENIA AND GRANULOCYTOPENIA AS A

COMPLICATION OF ANTIPSYCHOTIC THERAPY
Neutropenia is a relatively rare complication in patients
treated with neuroleptic agents, with an incidence of less
than 1%.17
20 The pathological mechanisms underlying
most forms of drug-induced neutropenia (i.e. a neutrophil
count B/1500/ml) or agranulocytosis (i.e. a neutrophil count
of B/500/ml) are unclear,21
23 although there have been
studies suggesting genetic determinants.21
23 Some druginduced cases of agranulocytosis may be regarded as
idiosyncratic drug reactions on the basis of their characteristic clinical course, such as delay between exposure and
toxicity, and a lack of correlation between the dose and risk
of toxicity.21
23

CLOZAPINE-INDUCED AGRANULOCYTOSIS
HLA HAPLOTYPING

AND

Drug-induced agranulocytosis is an unpredictable and lifethreatening, but fortunately rare, side effect. However,
historical experience with CA provides a warning that the
incidence of the condition should not be underestimated. It
took several years after the first multicenter study in Europe
before reports of an increased incidence of agranulocytosis in
patients treated with clozapine appeared in Finland. Currently, it is estimated that clozapine may cause reversible
neutropenia and agranulocytosis in about 1
/2% of pa-

NEUROLEPTICS-ASSOCIATED BLOOD
DYSCRASIAS

SUMMARY AND CONCLUSIONS

The present patient, who appeared with premorbid benign
low WBC, exhibited leukopenic
/neutropenic reactions during treatment with classical antipsychotics (zuclopenthixol,
perphenazine and haloperidol), as well as with the atypical
antipsychotic agent risperidone. The HLA profile of the
patient is different from that reported in patients susceptible
to CA. Further HLA typing is needed in a larger cohort of
neuroleptic-treated schizophrenic patients in order to determine the vulnerable individuals and to define the association
between HLA haplotypes and neuroleptic-induced reductions in the granulocyte count. The clinicians should note
that patients with underlying neutropenia, such as BFL,
should be monitored more carefully when antipsychotics are
administered. Also, further studies in different ethnic groups
could lead to identification of possible susceptibility gene(s)
for neuroleptic-induced agranulocytosis.

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I Reznik et al

ACKNOWLEDGEMENTS
Declaration of interests: No financial or material support was
received from any external resource for this work.

KEY POINTS
. This case study shows that a patient suffering from benign
familial leukopenia developed leukopenia and neutropenia under treatment with both typical and atypical
neuroleptics.
. The HLA profile of the patient is different from that
reported in patients susceptible to clozapine-induced
agranulocytosis.
. Due to the fact that this patient showed an increased risk
of developing leukopenia, this case study emphasizes the
need for careful monitoring of patients who have
increased susceptibility for underlying neutropenia.

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