Granulocytopenia associated with neuroleptictherapy 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

1Ness-Ziona/Beer-Yakov Regional Mental Health

Center, Israel; 2Tissue Typing Unit, Haim Sheba

Medical Center, Tel-Hashomer, Israel;3Laboratory of Biological Psychiatry, Felsenstein

Medical Research Center, Israel; 4Sackler

Faculty of Medicine, Tel-Aviv University, Ramat-

Aviv, Israel

Correspondence Address

Dr. Ilya Reznik, Lod Community Mental Health

Center, #140 Katzenelson Street, Lod,

71226, Israel

Tel: /(972) 8 9213993Fax: /(972) 8 9216038E-mail: ilyarez@netvision.net.il

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 benign familial leukopenia

HLAReceived 4 March 2003; accepted for

publication 11 July 2003

INTRODUCTION

I n most instances, leukopenia and neutropenia areconsidered to be risk factors for infection. An exceptionto this rule is benign familial leukopenia (BFL) / a hereditaryphenomenon, which is transmitted as an autosomally

dominant trait and is characterized by normal or somewhat

low total leukocyte counts (49429/1354/ml), consistentneutropenia, and, usually, relative monocytosis and lympho-

cytosis, 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.13 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.59 In the Middle

East, two ethnic groups with neutropenia have been

identified: native Jordanians and Yemenite Jews.13 The

Ethiopian Jews, a geographically and ethnically isolated

group from the Gondar region in the northern rural high-

lands 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 hap-

lotype,1013 tissue typing may help to identify high-risk

individuals, who are prescribed this medication.1015 Leu-

kopenia, induced by another antipsychotic medication,

namely olanzapine, chemically similar to clozapine, was

recently suspected having characteristic HLA-related back-

# 2003 Taylor & Francis International Journal of Psychiatry in Clinical Practice 2003 Volume 7 Pages 277/280 277

DOI: 10.1080/13651500310002977

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 paranoidschizophrenia (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 accordingto 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 regularmaintenance 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 granulo-

cytes (1000/ml) despite an elevation of total WBC count(3500/ml). Subsequently, administration of zuclopenthixoldepot 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 maintenancedose (400/1200 mg/day). Within 1 month after initiation ofsulpiride 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) countwas 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 asympto-

matic, 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.

278 I Reznik et al

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 causa-tive 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) andgranulocytes (to a level of 2500/ml) counts (Figure 1).Hematological evaluation, performed 6 months later, re-

vealed a WBC count of 4000/ml, a granulocyte count of 1200/nl, with no relapse of neutropenia; hemoglobin concentra-

tion was 13.2 g/dl. The conservative treatment approach inthis patient was based on the benign nature of the familial

leukopenia as well as the lack of evidence of infection or

bleeding tendency.

DISCUSSION

To the best of our knowledge this is the first report of aleukopenic/neutropenic reaction in a susceptible schizo-phrenic patient following exposure to typical and atypical

antipsychotics.

NEUTROPENIA AND GRANULOCYTOPENIA AS ACOMPLICATION OF ANTIPSYCHOTIC THERAPY

Neutropenia is a relatively rare complication in patientstreated with neuroleptic agents, with an incidence of less

than 1%.1720 The pathological mechanisms underlying

most forms of drug-induced neutropenia (i.e. a neutrophil

count B/1500/ml) or agranulocytosis (i.e. a neutrophil countof B/500/ml) are unclear,2123 although there have beenstudies suggesting genetic determinants.2123 Some drug-

induced cases of agranulocytosis may be regarded as

idiosyncratic drug reactions on the basis of their character-istic clinical course, such as delay between exposure and

toxicity, and a lack of correlation between the dose and risk

of toxicity.2123

CLOZAPINE-INDUCED AGRANULOCYTOSIS ANDHLA HAPLOTYPING

Drug-induced agranulocytosis is an unpredictable and life-threatening, 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. Cur-

rently, it is estimated that clozapine may cause reversible

neutropenia and agranulocytosis in about 1/2% of pa-

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 cloza-

pine could also lead to neutrophil cell death.23 In this

context, HLA typing may help to identify high-risk indivi-

duals.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.

NEUROLEPTICS-ASSOCIATED BLOODDYSCRASIAS

Even though neuroleptics as a group are considered to be

relatively hematologically safe,17,18 some classical antipsy-

chotic drugs may induce agranulocytosis.1720 Recently,

zuclopenthixol-associated neutropenia and thrombocytope-

nia were described.27 Several case reports have suggested the

development of leukopenia and neutropenia under risper-

idone treatment.20,2832 The relevant pathological mechan-

isms underlying neuroleptic-induced agranulocytosis or

neutropenia in risperidone-treated patients and their prob-

able dose-dependency need to be clarified. Unfortunately,

despite accumulated data for clozapine23 and

risperidone,20,2832 there are no reports on dose-depen-

dency of neutropenia on other neuroleptics.

SUMMARY AND CONCLUSIONS

The present patient, who appeared with premorbid benign

low WBC, exhibited leukopenic/neutropenic reactions dur-ing 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 deter-

mine the vulnerable individuals and to define the association

between HLA haplotypes and neuroleptic-induced reduc-

tions 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.

Neuroleptic-induced granulocytopenia 279

ACKNOWLEDGEMENTS

Declaration of interests: No financial or material support was

received from any external resource for this work.

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KEY POINTS

. This case study shows that a patient suffering from benignfamilial leukopenia developed leukopenia and neutrope-

nia under treatment with both typical and atypical

neuroleptics.

. The HLA profile of the patient is different from thatreported in patients susceptible to clozapine-inducedagranulocytosis.

. Due to the fact that this patient showed an increased riskof developing leukopenia, this case study emphasizes the

need for careful monitoring of patients who have

increased susceptibility for underlying neutropenia.

280 I Reznik et al