CASE STUDY

Clozapine in the Treatment of a

Young Adolescent with Schizophrenia
LESLIE K. JACOBSEN, M.D., MARK C. WALKER, M.D., JAMES E. EDWARDS, M.D.,
PHILLIP B. CHAPPELL, M.D., AND JOSEPH L. WOOLSTON, M.D.

ABSTRACT
Although recent reports have suggested that clozapine may be efficacious in the treatment of adolescents with schizo-
phrenia, few studies have examined the use of clozapine in patients younger than 17 years of age. We describe highly
successful trials of clozapine conducted in a 13:year-old girl and her cousin, both of whom developed severe symptoms
of schizophrenia, which were refractory to neuroleptic medication, at the ages of 11 and 13 years, respectively. The
pharmacology of and clinical experience with cIozapine are reviewed. J. Am. Acad. Child Ado/esc. Psychiatry, 1994,
33, 5:645-650. Key Words: clozapine, schizophrenia, young adolescents.

To date, the pharmacological treatment of schizophre-
nia in children and adolescents has rarely been the
subject of formal research. Spencer and colleagues (in
press) are currently conducting the first double-blind,
placebo-controlled study of a neuroleptic in prepubertal
children, aged 5 to 12 years old, meeting DSM-III-R
(American Psychiatric Association, 1987) criteria for
schizophrenia. In a crossover design comparing 4 weeks
of haloperidol treatment with 4 weeks of placebo,
significant haloperidol treatment effects have been ob-
served in most of the 19 subjects who have participated
in their study. The mean optimal haloperidol dose has
been 1.8 mg/day, and side effects associated with
haloperidol have resolved during dosage maintenance
or with dosage adjustment. The one placebo-controlled
study involving adolescents was performed by Pool
and colleagues (1976), who reported that haloperidol
and loxapine were both superior to placebo in reducing
psychotic symptoms in adolescents with schizophrenia.
They found, however, that subjects receiving active
Accepted january 18, 1994.
From the Yale Child Study Center, New Haven, CT (Drs. jacobsen,
Chappell, and Woolston), Northwestern University Medical School, Chicago,
IL (Dr. Walker), and Medical University ofSouth Carolina, Charleston, SC
(Dr. Edwards). Reprint requests to Dr. jacobsen, Child Psychiatry Branch,
National Institute of Mental Health, Building 10, Room 6N240, 9000
Rockville Pike, Bethesda, MD 20892.
0890-8567/94/3305-0645$03.00/0©1994 by the Ametican Academy
of Child and Adolescent Psychiatry.
medication experienced high rates of sedation and
extrapyramidal side effects.
In 1984, Realmuto and colleagues reported a study
comparing thiothixene and thioridazine in adolescents
with schizophrenia. Only half of their sample improved,
with those who improved continuing to be quite im-
paired. Fully 40% of the total sample experienced
sedation, often to the point of requiring dose reduction.
The authors concluded that the combination of poor
prognostic indicators, including insidious onset, chro-
nicity, and poor response to medication, together with
significant vulnerability to dose-limiting side effects,
suggests that adolescents with schizophrenia may have
a poorer prognosis than individuals who develop schizo-
phrenia during adulthood.
In terms of chronicity and poor response to standard
neuroleptics, schizophrenic adolescents and those
schizophrenic adults noted by Kane and colleagues
(1988) to respond to the atypical antipsychotic cloza-
pine are similar. This has prompted some to consider
using clozapine in the adolescent schizophrenic popula-
tion. In Europe, two studies have been conducted in
which the use of clozapine in adolescents and young
adults with psychotic spectrum disorders was examined.
In 1986, Siefen and Remschmidt reported an open
trial of clozapine in 21 schizophrenic inpatients unre-
sponsive to or unable to tolerate traditional neurolep-
tics. The average age of their sample was 18 years and
the average daily dose of clozapine was 352 mg. Marked

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:5, JUNE 1994 645

JACOBSEN ET AL.
improvement or complete disappearance of psychotic
symptoms was seen in 52% of subjects, with modest
improvement noted in an additional 28% of subjects.
Side effects were usually transient.
In 1990, Schmidt and colleagues reported a retro-
spective review of 57 inpatients treated with clozapine
ranging in age from 9 to 21 years. Although 42 of
their subjects carried the diagnosis of schizophrenia,
15 carried other diagnoses (schizoaffective disorder,
affective disorder with psychosis, and autism). The
average daily dose of clozapine was 285 mg. Sixry-
seven percent of subjects significantly improved, 21 %
of subjects partially improved, 7% were unchanged,
and 5% deteriorated.
In the United States, little has been written specifi-
cally about the use of clozapine in patients younger
than 18 years of age. In 1992, Birmaher and colleagues
reported a case series of three adolescents with schizo-
phrenia, two 17-year-old males and one 18-year-old
female, whose response to standard neuroleptics had
been poor and whose negative and positive symptoms
of schizophrenia improved during treatment with clo-
zapine, 300 and 400 mg/day. Although two of these
patients continued to experience residual symptoms,
all three were able to return to school and to function
adequately. More recently, Mozes and colleagues
(1994) reported a case series of four 10- to 12-year-
old children with schizophrenia, three boys and one
girl, who improved during clozapine treatment after
failing to improve or relapsing during treatment with
standard neuroleptics. Maintenance doses of clozapine
ranged between 150 and 300 mg/day, and side effects
observed included sedation, sialorrhea, nocturnal enure-
sis, subclinical EEG changes, and, in one case, episodic
"OCD-like" behavior. In addition, Towbin and col-
leagues (1994) reported a case of a 13-year-old boy who
developed abnormal involuntary movements during
treatment with rypical neuroleptics, which were ineffec-
tive in reducing his severe symptoms of schizophrenia.
He improved moderately during treatment with cloza-
pine, 500 mg/day, and his improved state has been
maintained, with no significant or enduring side effects,
on a regimen of clozapine, 400 mg/day.
Finally, an open trial of clozapine was conducted
in 11 adolescents, 12 to 18 years ofage, with childhood-
onset schizophrenia who were unresponsive to or unable
to tolerate rypical neuroleptics (Frazier et. al., 1994).
Substantial treatment effects were observed and subjects
646
received an average daily dose of 370 mg of clozapine
by the end of the 6-week trial. Side effects were similar
to those seen in adults taking clozapine, with the
exception of greater weight gain. Currently, a double-
blind comparison of haloperidol and clozapine in 6-
to 18-year-olds with childhood-onset schizophrenia is
in progress at the National Institute of Mental Health.
The following is a case study of a young adolescent
and her cousin, both of whom were refractory to
standard neuroleptic medication but highly responsive
to clozapine. This is followed by a brief review of
clozapine.
CASE STUDY
"Robin" is a 14-year-old Asian-American girl whose
early development was normal, except for language,
which did not begin to develop until 30 to 36 months
of age. At 6.5 years of age, Robin underwent cognitive
testing, which revealed intellectual functioning in the
low average range with significant lags in receptive and
expressive language skills. She was noted to be a shy
but related girl who enjoyed playing with other chil-
dren. Robin subsequently began to receive special edu-
cation services and speech and language therapy.
At 10 years of age Robin developed secondary·sex
characteristics. During her 11 th year she gradually
began to develop frequent and intense auditory halluci-
nations, compulsive washing, echolalia, clang associa-
tions, thought disorganization, social withdrawal, and
severe psychomotor retardation. Reports of previous
psychological assessments, as well as observations by
her family members, indicated that these symptoms
were new to Robin's clinical picture. This deterioration
precipitated her first psychiatric hospitalization at age
11 years, 11 months, just before which menarche
occurred. After admission neurological examination,
EEG, computed tomographic scan of the head, routine
laboratory tests, and chromosomal studies were found
to be normal. Trifluoperazine was started and titrated
to 14 mg/day, at which point Robin's thought disorga-
nization improved modestly and she began to speak
more freely about her auditory hallucinations and con-
tamination fears.
Robin's clinical picture at this point was thought
to be most consistent with the diagnoses of obsessive-
compulsive disorder, psychotic disorder, not otherwise
specified, and pervasive developmental disorder. Fluox-
etine was added and increased to 40 mg/day with no
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:5, JUNE 1994

improvement in Robin's fears of contamination and
associated bizarre behaviors, such as scalding herself
with hot water and eating soap. Thus fluoxetine was
discontinued and clomipramine added and increased
to 75 mg/day. While taking clomipramine, Robin's
contamination fears and associated behaviors dimin-
ished. Cognitive testing during this hospitalization re-
vealed intellectual functioning in the low average range,
with relatively strong nonverbal and visual-spatial skills
and significant weaknesses in the areas of receptive and
expressive language.
Mter 4 months of inpatient treatment, Robin was
discharged with close outpatient follow-up. She began
to attend a highly structured school geared toward
severely emotionally disturbed youngsters. Despite
good medication compliance, her auditory hallucina-
tions again intensified several months after discharge
and, for the first time, she began to report bizarre,
paranoid delusions of being recorded by beepers and
of being watched by wall sockets. Clomipramine had
been maintained at the previously well-tolerated dose of
75 mg/day and had not been associated with significant
anticholinergic side effects or other signs of anticholin-
ergic delirium. Robin's prominent and bizarre delusions
and hallucinations, as well as her history of relatedness
and lack of significant psychiatric symptoms before
puberty, were inconsistent with a diagnosis of autism
or of pervasive developmental disorder. In view of this
and the absence of an organic etiology for her symp-
toms, her diagnosis was revised to schizophrenia, para-
noid type. Clomipramine was tapered, and
trifluoperazine was increased to 25 mg/day.
Despite these interventions Robin developed com-
mand-type auditory hallucinations and continued to
experience paranoid delusions. She withdrew into her
room, refused to leave her bed, and began to vomit
most of the food she ate and scrape her skin with a
knife in response to her delusional fears of contamina-
tion. These developments prompted Robin's second
psychiatric hospitalization, at 13.5 years of age. Upon
admission Robin was mute and immobile. Her clinical
picture was thought to be most consistent with the
diagnoses of schizophrenia, catatonic type, chronic with
acute exacerbation, and developmental receptive and
expressive language disorder. Shortly after admission,
trifluoperazine was discontinued and the high-potency
neuroleptic pimozide was started. Pimozide was titrated
to 16 mg/day, at which point electrocardiographic
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 33:5, JUNE 1994
CLOZAPINE IN A YOUNG ADOLESCENT
changes (prolongation of the QTC interval) prohibited
further increments. Robin's clinical picture remained
unchanged. During this period, Robin began to report
delusions of reference and suicidal ideation, particularly
when her fears of contamination became intense, in
addition to nearly constant auditory hallucinations and
paranoid delusions.
Inquiry into Robin's family history during this hospi-
talization revealed that her cousin, "Tracy," had been
diagnosed with schizophrenia at 13 years of age. Be-
tween 13 and 18 years ofage, Tracy undetwent multiple
psychiatric hospitalizations and neuroleptic trials, none
of which effectively reduced her psychotic symptoms
or her symptoms of social withdrawal. At 18 years of
age, clozapine was started and gradually increased to
600 mg/day. This was associated with remission of
Tracy's psychotic symptoms and significant improve-
ment in her negative symptoms. Furthermore, since
clozapine was started, she has not required hospitaliza-
tion, has finished high school, and has continued to
make clinical and developmental gains, such that she
is now attending a community college part-time and
working at a restaurant. With the exception of weight
gain, Tracy has not experienced enduring side effects
as a result of clozapine treatment.
Because of the now long-standing, severe, and debili-
tating nature ofRobin's positive and negative symptoms
of schizophrenia, along with the fact that these symp-
toms had not abated during trials of two different
neuroleptic medications, a trial of clozapine was pro-
posed for her. The potential risks and benefits of
clozapine were discussed with Robin's parents and were
explained to Robin in simple terms. Because of Robin's
history of having had a febrile seizure at 18 months
and a benign rolandic seizure at 10 years of age, a
neurological evaluation and an ambulatory sleep EEG
recording were obtained, which were normal. Consis-
tent with the self-limited nature of rolandic seizures,
Robin has had no recurrence of seizure activity to date.
Clozapine was started at 12.5 mg b.i.d. and was
increased by 12.5-mg increments over intervals of 5
to 7 days. Side effects that Robin experienced early in
the trial included transient tachycardia, episodic tongue
protrusion during the first 3 weeks (probable with-
drawal dyskinesia), nocturnal sialorrhea, and sedation.
Robin's weekly peripheral white blood cell counts and
differentials were, and continue to be, completely
normal.
647
JACOBSEN ET AL.
Three weeks into the clozapine trial, at a total dosage
of250 mg/day, Robin's tendency to excoriate and scald
herself was significantly diminished. Due to continued
psychotic symptoms, clozapine was gradually titrated
to a total dosage of 550 mg/day. With this titration,
Robin's auditory hallucinations and paranoid delusions
diminished, as did the bizarre behaviors associated with
these delusions. She became more socially engaged,
her affect broadened, and, perhaps most strikingly, her
gait, which had been stiff and abnormally slow since
the onset of her illness, became more fluid and normal.
After 4 months of hospitalization Robin was dis-
charged again to close outpatient follow-up and the
special educational setting she attended previously,
along with 4 hours of in-home aide services per day.
In the 14 months that have transpired since the end
of her second hospitalization, Robin has continued
to make slow, steady clinical gains. She no longer
experiences auditory hallucinations and participates
more fully in school and family activities than she has
since the onset of her illness. While important aspects
of adolescent development remain truncated in Robin,
such as the development of sexuality and of autonomy,
she has been able to forge friendships with peers at
school and has many age-appropriate interests, includ-
ing music, clothing, movies, and dancing.
Although most of the side effects Robin has experi-
enced during clozapine treatment have been transient,
she has continued to experience nocturnal sialorrhea.
In addition, her weight has increased from 100% to
127% of her ideal body weight since the time of
discharge from her second hospitalization. Approxi-
mately 1 month after discharge, Robin developed inter-
mittent nocturnal enuresis. Medical workup revealed
no organic basis for this problem, which abated with
reduction of Robin's total daily dose of clozapine to
500 mg (250 mg b.i.d.).
BRIEF REVIEW OF CLOZAPINE
Despite the well-documented efficacy of standard
neuroleptic medications, they fail to benefit up to 20%
of patients with schizophrenia (Baldessarini, 1985),
and they have significant, and at times intolerable,
neurological side effects (Van Putten and Marder,
1987). In addition, children and adolescents with
schizophrenia may respond particularly poorly to neu-
roleptics (Realmuto et al., 1984).
648
Clozapine, one of the first effective antipsychotic
medications to have few extrapyramidal side effects,
was synthesized in 1958 and patented in 1960 (Baldes-
sarini and Frankenburg, 1991). Further development
was slowed by the recognition in the 1970s of its
association with agranulocytosis (ldl1npl1m-Heikkill1 et
al., 1977). Clozapine differs pharmacologically and
biochemically from typical neuroleptics. While most
neuroleptic agents have affinity for the dopamine D 2
receptor that parallels their clinical potency, and vari-
able affinity for the D 1 receptor, clozapine has moderate
affinity for both D 1 and D 2 receptors (Baldessarini
and Frankenburg, 1991; Jann, 1991). Clozapine also
possesses potent central anticholinergic, antiadrenergic,
antiserotonergic, and antihistaminic effects Qann,
1991).
Clozapine's balanced moderate blockade of D, and
D 2 receptors, and its failure to increase dopamine
receptor density in the brain, is thought to underlie
clinical observations that clozapine is not associated
with extrapyramidal symptoms or abnormal involun-
tary movement disorders such as tardive dyskinesia, and
even reverses neuroleptic-induced tardive dyskinesia in
some patients (Gerlach and Casey, 1988; Jann, 1991;
Lieberman et al., 1991). Clozapine appears to carry
minimal or no risk of neuroleptic malignant syndrome
(Weller and Kornhuber, 1993). Clozapine selectively
activates dopamine metabolism in the hypothalamus,
which may underlie its tendency to produce increases
in serum ACTH and corticosteroid concentrations but
minimal or no elevation in serum prolactin (Gudelsky
et al., 1989).
Clozapine is metabolized in the liver and its metabo-
lites have low pharmacological activity. The elimination
half-life of clozapine is concentration dependent, aver-
aging 6 hours after a single dose and 16 hours at steady
state (Ackenheil, 1989; Lieberman et al., 1989). The
plasma levels of clozapine vary widely, both among
patients receiving the same. daily dose and within
patients maintained on the same dose over time. As
with most antipsychotic medications, the relationship
between plasma drug concentration and clinical effect
is weak (Baldessarini and Frankenburg, 1991). Plasma
levels of clozapine have been noted to be higher in
females and the elderly, and lower in smokers (Haring
et al., 1989).
To date there have been few studies comparing the
efficacy ofclozapine with placebo (Shopsin et al., 1979).
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:5, JUNE 1994

However, a number of double-blind comparisons of
the efficacy of dozapine and standard neuroleptics in
treating the symptoms of schizophrenia in adults have
been conducted, perhaps the most influential of which
was published by Kane and colleagues in 1988. They
found dozapine to be superior in efficacy to chlorprom-
azine, administered in doses approximately twice as
large, in patients 18 years of age or older with chronic
schizophrenia who had been unresponsive to treatment
with up to 60 mg/day of haloperidol.
Although dozapine is not associated with extrapyra-
midal dysfunction, it does carry the potential of agranu-
locytosis, necessitating weekly peripheral white blood
cell count monitoring. As of December 1, 1993, 394
cases of agranulocytosis had developed in the United
States out of 68,016 patients exposed to this medica-
tion, for an incidence of 0.58%. Of these 394 cases,
9 were fatal (Sandoz Pharmaceuticals Corporation). By
comparison, the risk of agranulocytosis from phenothi-
azines is estimated to be between 0.01% and 0.1 %
(Claghorn et al., 1987). Most cases of clozapine-in-
duced agranulocytosis have occurred between 6 and
18 weeks of treatment (Sandoz Pharmaceuticals Corpo-
ration, 1993). Women, the elderly, and persons of
Jewish or Finnish descent may be at increased risk of
developing agranulocytosis, which has been associated
with the haplotype HLA-B38, DR4, DQw3 (Alvir
et al., 1993; Id:tnp:t:tn-Heikkil:t et al., 1977; Lieberman
et al., 1990). While the mechanism of dozapine-
induced agranulocytosis has not been established, an
immune-mediated process is suspected.
Another important clozapine-related adverse effect
is the relatively high risk of generalized seizures, which
is dose related. In one review of 1,418 patients, the
risk of seizures was found to be 1.0% when patients
took less than 300 mg of clozapine a day, 2.7% when
patients took between 300 and 600 mg/day, and 4.4%
when patients took 600 mg/day or more (Devinsky
et al., 1991). Some clinicians prescribe an anticonvul-
sant for patients with a history of a seizure disorder or
for patients receiving 600 mg/day or more of c1ozapine.
Valproate has been recommended as it does not have
bone marrow toxicity and does not appear to alter the
metabolism of clozapine, as does phenytoin (Baldessar-
ini and Frankenburg, 1991; Gelenberg, 1991a).
Clozapine has been associated with reversible neuro-
toxicity when combined with lithium (Gelenberg,
1993), and, in rare instances, with respiratory arrest
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 33:5. JUNE 1994
CLOZAPINE IN A YOUNG ADOLESCENT
when combined with benzodiazepines (Gelenberg,
1991b). The most common adverse effects associated
with clozapine include sedation, weight gain, sialorrhea,
gastrointestinal symptoms, orthostatic hypotension,
tachycardia, and transient fever (Baldessarini and Fran-
kenburg, 1991).
To minimize side effects, the manufacturer currently
recommends that clozapine be started with a single
12.5-mg dose, followed by 25 mg once or twice daily,
and then increasing by 25 mg/day to achieve a total
daily dose of 300 mg to 450 mg/day by 2 weeks.
Limited experience with early adolescents suggests that
this population may be more sensitive to the side
effects of sedation and orthostatic hypotension and
thus may require a slower titration of dosage (C.T.
Gordon, personal communication, 1992), as both
Robin and Tracy did. Most patients respond to 300
to 600 mg/day, but children and adolescents may
require lower doses. On a milligram-for-milligram basis,
clozapine is estimated to be twice as potent as chlor-
promazine (Claghorn et al., 1987). Although many
double-blind studies ofclozapine have followed patients
for 6 weeks or less, other authors have observed late
or cumulative benefits after months of treatment with
dozapine (Kane, 1989; Lindstr{}m, 1988).
In conclusion, although dozapine is approved for
use in patients with treatment-refractory schizophrenia
16 years of age or older, the case of Robin suggests
that it has utility in the treatment of younger adoles-
cents with severe, treatment-refractory schizophrenia.
Because of the relatively high risk of agranulocytosis,
the risk of seizures at high doses, the necessity of
weekly white blood cell counts, and the high cost of
this medication in the United States, the potential
risks and benefits of starting dozapine must be carefully
weighed, and patients and their parents or guardians
should be fully informed and involved in the decision
to start this medication.
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