The Annals of Pharmacotherapy ■
2002 June, Volume 36
tory schizophrenia or those who are intolerant of the ad-
verse effects of traditional antipsychotics.1,2In comparison
with traditional antipsychotics, clozapine has shown supe-
rior efficacy and does not cause debilitating adverse effects
such as parkinsonism, dystonia, or tardive dyskinesia.3-5
However, clozapine is not used as a first-line agent due to
an increased risk of agranulocytosis, which is defined as an
absolute granulocyte count <500/mm3.6Initially, based on
premarketing clinical research, a cumulative incidence of
risk of agranulocytosis was estimated to be between 1%
and 2%. Current estimates from the Clozaril National Reg-
istry7suggest that the incidence of risk is as low as 0.38%. In
addition to the implementation of the Clozaril National Reg-
istry, several other factors have contributed to the decrease
in mortality due to agranulocytosis. Increased knowledge
lozapine, a dibenzodiazepine derivative, is an atypical
antipsychotic indicated for use in patients with refrac-
about this reaction and its potential ramifications, as well
as successful therapy with sargramostim (granulocyte-
macrophage colony-stimulating factor; GM-CSF), have
contributed to the reduction in morbidity and mortality.8
Clozapine-induced agranulocytosis is commonly char-
acterized by a gradual decrease in white blood cell (WBC)
counts that occurs over several weeks.9Although this hema-
tologic condition is usually reversible within 14–22 days
after discontinuation of clozapine therapy,8patients with
agranulocytosis remain at risk for infections for up to 4
weeks.10Patients who have experienced clozapine-induced
agranulocytosis should not be rechallenged because of an
increased mortality risk.9
The greatest risk of developing agranulocytosis exists
during the initial 6 months of treatment with clozapine,
with the peak period of risk during the third month.11This
forms the basis for the required weekly hematologic moni-
toring in the product labeling for all clozapine products.
After 6 months of continuous clozapine therapy, the guide-
lines state that the frequency of WBC and granulocyte mon-
Sudden Late Onset of Clozapine-Induced Agranulocytosis
Nick C Patel, Peter G Dorson, and Tawny L Bettinger
OBJECTIVE: To report a patient who suddenly developed agranulocytosis after long-term clozapine therapy.
CASE SUMMARY: A 41-year-old white man suddenly developed agranulocytosis after 89 months of nearly continuous clozapine therapy.
During this time, which included the addition of risperidone to the treatment regimen, his white blood cell (WBC) and granulocyte
counts remained stable. One week after having stable hematologic counts, the patient suddenly developed agranulocytosis. WBC
and granulocyte counts returned to baseline shortly after discontinuation of all medications and administration of sargramostim.
DISCUSSION: The main factor limiting the use of clozapine as a first-line agent in mentally ill patients is the risk of agranulocytosis.
Although the greatest risk of developing this adverse reaction is during the initial 6-month exposure, clozapine-induced agranulocytosis
continues to pose a risk after years of exposure. Current product labeling requires weekly WBC and granulocyte monitoring for the
first 6 months of treatment with clozapine, which may be decreased to biweekly monitoring after 6 months. Based on the sudden
and late onset of agranulocytosis in our patient, clinicians may consider opting for weekly monitoring of hematologic function for
patients on long-term clozapine therapy. The likelihood that clozapine was the cause of the agranulocytosis was rated possible
according to the Naranjo probability scale.
CONCLUSIONS: Clinicians must remain vigilant to trends in WBC and granulocyte counts and may wish to consider weekly
hematologic monitoring regardless of duration of clozapine therapy. Patient and treatment system compliance with the registries’
protocol regarding WBC monitoring is instrumental in reducing morbidity and mortality rates associated with clozapine use.
KEY WORDS: agranulocytosis, clozapine.
Ann Pharmacother 2002;36:1012-5.
Author information provided at the end of the text.
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itoring can be decreased to biweekly. Cases of clozapine-
induced agranulocytosis occurring beyond 6 months are
rare, with some instances of delayed onset up to 43–66
months.11We report a case of a severely ill schizoaffective
patient who suddenly developed agranulocytosis after 89
months of nearly continuous clozapine therapy, which might
have been fatal with only biweekly hematologic monitoring.
A 41-year-old white man was admitted to our hospital in January
1994 with a diagnosis of schizoaffective disorder, bipolar type, with no
significant illness in his past medical history. He had a chronic history of
psychosis that was presumed to have started in his teenage years. He had
been hospitalized on multiple occasions at various institutions and tried
on numerous psychotropic medications such as haloperidol and lithium.
Records from the Clozaril National Registry indicated that the patient
had begun clozapine therapy (maximum dose 800 mg/d) in April 1991
and continued it for 33 months prior to admission. During these 33
months of clozapine therapy, his WBC count (minimum 3.8 × 103/mm3)
remained above the threshold level of 3 × 103/mm3. There were 3 inter-
ruptions in WBC monitoring of approximately 21 days each, possibly at-
tributed to patient nonadherence. It is likely that clozapine therapy was
also briefly interrupted during these periods. The patient was transferred
to our hospital from another facility due to an increase in violent and
threatening behavior toward staff and other patients.
Clozapine was started on admission and titrated to a daily dose of 700
mg. In February 1994, lithium 1350 mg/d was added. For approximately
54 months, the patient was stabilized on clozapine (maximum 900 mg/d)
and lithium. Clozapine therapy was briefly interrupted twice for trials of
risperidone (2–4 mg/d for 4 days in May 1994) and olanzapine (10–15
mg/d for 59 days from November 1996 to January 1997) monotherapy,
but each was unsuccessful as the patient became increasingly psychotic.
His WBC and granulocyte counts remained stable during this time peri-
od, averaging approximately 6.9 × 103/mm3(range 4.9–16.2) and 4.6 ×
In July 1998, low-dose risperidone (1.5 mg/d) was added to the regi-
men in an attempt to further gain symptomatic improvement for his
treatment-resistant psychosis. The dose of risperidone was gradually
titrated to 5 mg/d over a 4-month period. The patient experienced im-
provements in behavior, affect, and mood; some benefit was seen in the
psychotic symptoms. Clozapine, risperidone, and lithium therapy were
continued for the next 10 months. WBC (5.5–11.2 × 103/mm3) and gran-
ulocyte (3.0–8.7 × 103/mm3) counts fluctuated during the 10 months, but
did not display a downward trend nor decrease below threshold values
(WBC 3.0 × 103/mm3or absolute granulocyte count <1.5 × 103/mm3), af-
ter which an interruption in clozapine therapy would have been required.
On September 7, 1999, the patient’s weekly WBC (6.1 × 103/mm3)
and granulocyte (4.1 × 103/mm3) counts were within normal limits. One
week later, the values plummeted below threshold values (2.4 × 103/mm3
and 0.7 × 103/mm3, respectively), and clozapine therapy was interrupted
(Figure 1). The patient had a hematology consult at a regional cancer
center on the same day, and a diagnosis of agranulocytosis secondary to
clozapine was made. There was no concurrent medical illness or other
abnormal laboratory values at the time of this event. His counts contin-
ued to decrease despite interruption in clozapine therapy.
On September 16, the WBC and granulocyte values had decreased to
1.5 × 103/mm3and 0 × 103/mm3. At this time, all medications were dis-
continued, including risperidone, lithium, and clonazepam; no adverse
effects from the abrupt discontinuation of medications were observed.
The patient was administered sargramostim 500 µg subcutaneously once
a day. After 2 days of treatment with sargramostim, WBC and granulocyte
counts increased to 4.4 and 1.8 × 103/mm3, respectively, and returned to
baseline on September 20. Quetiapine and lithium were initiated at this
time as the patient became increasingly irritable, verbally aggressive, and
delusional. Valproic acid was added to the medication regimen in Octo-
ber because minimal improvement was seen in his symptoms with queti-
apine and lithium. In April 2000, the patient was transferred to an out-of-
state facility, per request of his family. His discharge medications were
quetiapine 500 mg twice daily, lithium carbonate 600 mg twice daily,
and valproic acid 750 mg in the morning and 1000 mg at bedtime.
The main factor limiting the use of clozapine as a first-
line agent in mentally ill patients is the risk of agranulocy-
tosis. It has been established11that the greatest risk of de-
veloping the potentially fatal condition is during the initial
6-month exposure to clozapine. Clozapine-induced agran-
ulocytosis continues to pose a risk after years of exposure.
Based on the Novartis registries, the risk of developing
agranulocytosis during the initial 6 months is 860 cases per
100000 person-years’ exposure; 70 cases per 100000 per-
son-years’ exposure during months 7–24; 40 cases per
100 000 person-years’ exposure during months 25–42;
and 20 cases per 100000 person-years’ exposure during
months 43–66. Although the risk of agranulocytosis and
possible death decreases with prolonged exposure to cloza-
pine, routine WBC and granulocyte monitoring is crucial.
Clinicians need to be sensitive to the continued risk, re-
gardless of the length of therapy. Our case is unique since,
to our knowledge, no cases occurring as late as 89 months
of treatment have been reported in the literature.
Current product labeling12requires reporting of the re-
sults of weekly WBC and granulocyte monitoring to a na-
tional registry for the first 6 months of treatment with
clozapine; after the initial 6 months of therapy, hematolog-
ic monitoring may be decreased to biweekly because the
risk of developing agranulocytosis decreases. Although the
risk of developing this blood dyscrasia decreases with
time, there has been no conclusive evidence suggesting the
manner in which clozapine-induced agranulocytosis is pre-
sented. Although some suggest that the onset of agranulo-
cytosis is gradual over several weeks, rapid declines in
WBC counts within 1 week may occur, as demonstrated in
our case. Had the hospital not had a policy requiring week-
ly hematologic monitoring regardless of duration of cloza-
pine therapy, agranulocytosis in our patient may not have
been detected and could have potentially been fatal. There
were no risk factors that could have been helpful in pre-
dicting the event, including previous episodes of leukope-
nia. Based on the sudden and late onset of agranulocytosis
in this case, clinicians may consider opting for weekly
The Annals of Pharmacotherapy ■
2002 June, Volume 36 ■
Figure 1. Sudden onset of agranulocytosis. GM-CSF = granulocyte-
macrophage colony-stimulating factor; GRAN = granulocyte count; WBC =
white blood cell count.
monitoring of hematologic function for their patients on
long-term clozapine therapy.
The likelihood that clozapine was the cause of the agran-
ulocytosis was rated possible according to the Naranjo
probability scale.13These ratings are based on previous re-
ports of delayed-onset agranulocytosis with clozapine ther-
apy, laboratory findings, and the resolution of the de-
creased granulocytes after clozapine was discontinued and
sargramostim was administered. Risperidone was also rat-
ed as a possible cause for the agranulocytosis according to
the Naranjo probability scale, but with a lower score than
that for clozapine.
There are multiple risk factors for the development of
agranulocytosis. Genetics may play a role in the develop-
ment of agranulocytosis; the presence of the alleles HLA-
B38, DR4, and DQw3 may be associated with an increased
risk.14Patients receiving clozapine concomitant with other
medications known to cause agranulocytosis or suppress
bone marrow function are placed at increased risk.12Pa-
tients with leukopenia (WBC <3.5 × 103/mm3) are also at
high risk of agranulocytosis. Patients with WBC counts
between 2–3 × 103/mm3are at a fourfold increased risk,
and up to 50% of severely leukopenic patients (WBC <2 ×
103/mm3) develop agranulocytosis.11Despite these known
risk factors, it still is difficult to determine which patients
will develop clozapine-induced agranulocytosis, as was il-
lustrated in our case.
Risperidone and olanzapine have been associated with
the development of leukopenia and agranulocytosis.15-19In
a similar case,20agranulocytosis developed 6 weeks after
the addition of risperidone to clozapine, which the patient
had been taking for 22 months. Our patient was treated
with risperidone and clozapine for 13 months. During this
time, no significant decreases in his WBC and granulocyte
counts were observed. Although there was no indication
that combination therapy increased the risk for agranulocy-
tosis, it is possible that the addition of risperidone may
have played a role in the development of this adverse reac-
tion in our patient.
Clozapine has been associated with the development of
agranulocytosis, a hematologic condition characterized by
decreased WBC and granulocyte counts. Patients who ex-
perience agranulocytosis are at increased risk of infection
and possible death. Other atypical antipsychotics, risperi-
done and olanzapine, have also been associated with induc-
ing agranulocytosis. As combination therapy with atypical
antipsychotics becomes more common, the risk of patients
developing agranulocytosis may be increased.
Our case illustrates a sudden decrease in WBCs and
granulocytes in a patient treated with clozapine therapy for
89 months. Clinicians must remain vigilant to trends in
WBC and granulocyte counts and may wish to consider
weekly hematologic monitoring regardless of duration of
clozapine therapy. In addition, patients treated with clozapine
should be educated about this condition and be advised to
inform their healthcare providers if they experience signs
and symptoms of infection. Although it may be difficult to
prevent the occurrence of clozapine-induced agranulocyto-
sis, patient and treatment system compliance with the reg-
istries’ protocol regarding WBC monitoring is instrumen-
tal in reducing morbidity and mortality rates associated
with clozapine use.
Nick C Patel PharmD, Psychiatric Pharmacy Resident, Austin State
Hospital, Texas Department of Mental Health and Mental Retardation,
Austin, TX; Resident, College of Pharmacy, The University of Texas
at Austin, Austin, TX
Peter G Dorson PharmD BCPP, Clinical Associate Professor, Col-
lege of Pharmacy, The University of Texas at Austin
Tawny L Bettinger PharmD BCPP, Clinical Assistant Professor,
Department of Psychiatry, The University of Texas Southwestern
Medical Center at Dallas, Dallas, TX
Reprints: Peter G Dorson PharmD BCPP, College of Pharmacy
PHR 5.110, The University of Texas MC#A1910, Austin, TX 78712-
1074, FAX 512/471-3756, E-mail firstname.lastname@example.org
1. Kane JM. Clinical efficacy of clozapine in treatment-refractory schizophre-
nia: an overview. Br J Psychiatry 1992;160(suppl 17):41-5.
2. American Psychiatric Association. Practice guideline for the treatment of
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3. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-
resistant schizophrenic: a double-blind comparison with chlorpromazine
(Clozaril Collaborative Study). Arch Gen Psychiatry 1988;45:789-96.
4. Lieberman JA, Kane J, Johns CA, Vital-Herne J. Clozapine: clinical evi-
dence of novel effects. Clin Neuropharmacol 1986;9(suppl 4):140-1.
5. Lieberman JA, Saltz BL, Johns CA, Pollack S, Kane JM. Clozapine ef-
fects on tardive dyskinesia. Psychopharmacol Bull 1989;25:57-62.
6. Dale DC. Abnormalities of leukocytes. In: Isselbacher K, Adams R,
Braunwald E, Petersdorf R, Wilson J, eds. Harrison’s principles of inter-
nal medicine. Tokyo, Japan: Kosaido Printing, 1980:283-290.
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8. Gerson SL. Clozapine—deciphering the risks (editorial). N Engl J Med
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12. Package insert. Clozaril (clozapine). East Hanover, NJ: Novartis Phar-
maceuticals Corporation, May 2001.
13. Naranjo CA, Busto U, Sellers P, 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.
14. Lieberman JA, Yunis J, Egea E, Canoso RT, Kane JM, Yunis EJ. HLA-
B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish pa-
tients with schizophrenia. Arch Gen Psychiatry 1990;47:945-8.
15. Finkel B, Lerner AG, Oyffe I, Sigal M. Risperidone-associated agranulo-
cytosis (letter). Am J Psychiatry 1998;155:855-6.
16. Dernovsek Z, Tavcar R. Risperidone-induced leucopenia and neutrope-
nia (letter). Br J Psychiatry 1997;171:393-4.
17. Naumann R, Felber W, Heilemann H, Reuster T. Olanzapine-induced
agranulocytosis (letter). Lancet 1999;354:566-7.
18. Benedetti F, Cavallaro R, Smeraldi E. Olanzapine-induced neutropenia
after clozapine-induced neutropenia (letter). Lancet 1999;354:567.
19. Teter CJ, Early JJ, Frachtling RJ. Olanzapine-induced neutropenia in pa-
tients with history of clozapine treatment: two case reports from a state
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The Annals of Pharmacotherapy ■
2002 June, Volume 36
NC Patel et al.
The Annals of Pharmacotherapy ■
2002 June, Volume 36 ■
OBJECTIF: Décrire un cas de patient ayant développé soudainement une
agranulocytose suite à un traitement prolongé par la clozapine.
SOMMAIRE DU CAS: Un homme de 41 ans, d’origine caucasienne, a
soudainement développé une agranulocytose après 89 mois de
traitement presque continu par la clozapine. Pendant cette période où de
la rispéridone a aussi été associée au traitement, les numérations des
globules blancs et des granulocytes sont demeurées relativement stables.
Une semaine après avoir observé des numérations toujours stables, le
patient a développé une agranulocytose. Ces résultats se sont normalisés
à nouveau peu de temps après l’arrêt de tous les médicaments et
l’administration de sargramostin.
DISCUSSION: Le principal facteur limitant l’utilisation de la clozapine
comme agent de traitement de première ligne chez des patients atteints
de maladies mentales est le risque d’apparition d’agranulocytose. Même
si le risque de développer une agranulocytose est plus grand durant les 6
premiers mois de traitement, cet effet indésirable sérieux peut se
présenter après plusieurs années de traitement. La monographie du
produit mentionne le besoin de numérations des globules blancs et des
granulocytes à chaque semaine durant les 6 premiers mois de traitement
par la clozapine et aux 2 semaines par la suite. En se basant sur
l’apparition tardive d’agranulocytose dans le cas présenté ici, les
médecins pourraient opter pour une surveillance hématologique
hebdomadaire lors de traitement au long cours. Selon l’échelle de
probabilité de Naranjo, il est possible que cet effet indésirable soit dû à
CONCLUSIONS: Les médecins doivent demeurer vigilants quant à la
surveillance de l’hématotoxicité de la clozapine et peuvent désirer
effectuer une surveillance hebdomadaire des numérations de globules
blancs et de granulocytes sans égard à la durée de traitement par la
clozapine. L’observance du patient au système de surveillance de
l’hématotoxicité de la clozapine peut permettre de réduire la morbidité
et la mortalité associées à l’utilisation de la clozapine.