European Psychiatry 29 (2014) 110

Available online at

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Review

Systematic review of the efcacy and tolerability of Clozapine in the

treatment of youth with early onset schizophrenia
C. Schneider a, R. Corrigall a, D. Hayes a, M. Kyriakopoulos a, S. Frangou b,*
a
b

Child and Adolescent Mental Health Services, South London and Maudsley NHS Foundation Trust, London, UK
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, Box 1230, 1425, Madison Avenue, New York, NY 10029, USA

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 20 May 2013
Received in revised form 20 July 2013
Accepted 11 August 2013
Available online 9 October 2013

Background: The use of clozapine (CLZ) for treatment-resistant schizophrenia is well established in
adults. However, it is seldom used in youth with early onset schizophrenia (EOS) largely because of lack
of clarity about its risk benet ratio. This review synthesises and evaluates available evidence regarding
the efcacy and tolerability of CLZ in EOS with the aim to assist clinical decision-making.
Methods: We conducted a systematic review of the primary literature on the clinical efcacy and adverse
drug reactions (ADRs) observed during CLZ treatment in EOS. We also identied relevant practice
guidelines and summarised current guidance.
Results: CLZ showed superior efcacy than other antipsychotics in treating refractory EOS patients; shortterm clinical trials suggest an average improvement of 69% on the Brief Psychiatric Rating Scale that was
sustained during long-term follow-up (up to 9 years). No fatalities linked to CLZ treatment were reported.
Sedation and hypersalivation were the most common complaints, reported by over 90% of patients. Other
common ADRs (reported in 10-60% of patients) were enuresis, constipation, weight gain, and non-specic
EEG changes. Less common ADRs (reported in 10-30% of patients) were akathisia, tachycardia and changes
in blood pressure. Neutropenia was reported in 615% of cases but was usually transient while
agranulocytosis was rare (< 0.1%). Seizures were also uncommon (< 3%). Metabolic changes were
relatively common (822%) but emergent diabetes was not frequently observed (< 6%). Overall the rate of
discontinuation was low (36%). Current guidelines recommend the use of CLZ in EOS patients who have
failed to respond to two adequate trials with different antipsychotics and provide detailed schedules of
assessments to evaluate and assess potential ADRs both prior to initiation and throughout CLZ treatment.
Conclusion: Available data although limited in terms of number of studies are consistent in
demonstrating that CLZ is effective and generally safe in the treatment of refractory EOS provided
patients are regularly monitored
2013 Elsevier Masson SAS. All rights reserved.

Keywords:
Schizophrenia
Early onset
Paediatric
Efcacy
Tolerability
Clozapine

1. Background
Schizophrenia commonly begins in adulthood, however a
substantial number of individuals experience the onset of the
disorder while they are children or adolescents [4]. The prevalence
of schizophrenia with onset before 13 years of age (childhood
onset schizophrenia; COS) is low (approximately 1 in 40,000
children) [19] but the incidence of schizophrenia rises sharply at
about 1214 years of age [21]. Approximately 5% of patients
develop schizophrenia, during their adolescent years before the
age of 18 (adolescent onset schizophrenia; AOS) [19]. In this
manuscript we will use the term early onset schizophrenia (EOS)
when we collectively refer to COS and AOS groups.

* Corresponding author.
E-mail address: sophia.frangou@mssm.edu (S. Frangou).
0924-9338/$ see front matter 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.eurpsy.2013.08.001

When schizophrenia manifests in childhood and adolescence,

the onset of clinical symptoms occurs during a critical period for
cognitive developmental thus leading to greater difculties in
acquiring basic academic skills [5]. EOS is also associated with
greater chronicity and clinical morbidity with the majority of
patients (7274%) requiring long-term psychiatric treatment
[29,11,30,45]. Psychosocial outcome is commonly worse than
in adult onset schizophrenia [39]. Patients are often unable to
sustain close relationships outside their immediate family and
remain nancially dependent either on their parents or on public
assistance [29,30]. Therefore, it is vital that the treatment and
management of EOS be based on the highest quality evidence
possible because of the long- term implications for engagement
with support services, adherence to treatment and quality of life.
Antipsychotic medication is the mainstay of pharmacological
treatment of schizophrenia regardless of age of onset. The efcacy
of antipsychotic medication in EOS patients was subjected to

C. Schneider et al. / European Psychiatry 29 (2014) 110

meta-analysis by Armenteros and Davies in 2006 [3]. The

combined sample comprised of 294 EOS patients, 209 of whom
had been treated with rst generation antipsychotics (FGA), 83
with a second generation antipsychotic (SGA), and 36 with
placebo. The median response rates across antipsychotic classes
were between 6270%. The Treatment of Early Onset Schizophrenia Spectrum Disorders Study (TEOSS) is the largest study to
date to directly compare the efcacy and safety of a FGA
(molindone) to that of two SGAs (olanzapine and risperidone)
in the acute treatment (8 weeks) of 116 young patients with EOS
or schizoaffective disorder [42]. According to this study, treatment with any antipsychotic resulted in symptomatic improvement but response rates (50% with molindone, 34% with
olanzapine, 46% with risperidone) were uniformly low. These
results suggest that the prevalence of poor treatment responders
amongst young patients is consistently high.
EOS patients are therefore likely to benet from clozapine (CLZ)
given its documented superior efcacy in adult schizophrenia [7].
However, CLZ is also associated with metabolic, neurological and
haematological adverse drug reactions (ADRs) [12] and with the
emergence of obsessive-compulsive symptoms [32]. In the UK less
that 0.4% of all CLZ prescriptions are for EOS patients; nearly 40% of
child and adolescent psychiatrists working in inpatient settings
report that they have never prescribed CLZ [6]. The most common
reasons were unfamiliarity with CLZ, fear of potential ADRs and
lack of specic information and guidance [6].
This article aims to assist clinicians in optimising treatment for
EOS using three complementary approaches:
(a) we synthesise and comment on the available evidence
regarding the efcacy and tolerability of CLZ in EOS based
on a systematic literature review;
(b) we discuss guidelines developed by national bodies on the use
of CLZ in EOS, and;
(c) we present a practical algorithm for the safe use and
monitoring of CLZ treatment in EOS.

2. Methods
We conducted a comprehensive search of English-language
studies (clinical trials, naturalistic observational trials and case
reports) published up to August 31st 2013 in electronic databases
(PubMed, MEDLINE) using both free-text and MeSH search
keywords: clozapine, schizophrenia, psychosis, childhood
OR adolescence, early onset, paediatric, antipsychotic and
their differing terminations and combinations. The search was
supplemented by a manual review of reference lists from the
identied publications. We also reviewed guidelines published by
August 31st 2013 from recognised international organisations,
societies or colleges to identify those offering specic guidance
regarding the use of CLZ in EOS.
3. Results
Our search identied 16 clinical studies, detailed in Table 1, and
four case series published since 1994. There were only two
guidelines that focused specically on the use of CLZ in young
patients. Below we present in detail the available evidence.

overlapping patient samples derived from the COS cohort of the

Child Branch of the National Institutes of Mental Health (NIMH).
One study had an open label design [16], three were double-blind
randomised controlled trials (DBRCT) [26,41,27] and one was a reanalysis of previous open label and double-blind studies [43]. In
the DBRCTs the comparator antipsychotics were haloperidol or
olanzapine. All studies focused on patients with refractory
schizophrenia, dened as failure to respond to adequate treatment with at least two antipsychotic drugs. They collectively
suggest that CLZ has superior efcacy compared to other
antipsychotic agents when used in treatment refractory COS.
After 6-8 weeks of CLZ treatment, there was an average
improvement of 69% in the Brief Psychiatric Rating Scale (BPRS),
which was the most commonly used outcome measure
[16,26,41,43,27]. Improvement was noted for all symptoms
especially negative symptoms [16,27]. As four of the ve studies
were conducted in a single centre with signicant overlap
between study samples the total population of patients from
which these observations derive is small (n = 93).
3.1.2. Long-term studies
We identied 5 studies [41,43,40,44,24] that presented data
from follow-up periods ranging for 12 weeks to 9 years (Table 1).
All long-term studies were open label trials and collectively
included a relatively small sample (n = 110). Two studies consisted
of open-label follow-up of the NIMH COS cohort mentioned above
[41,43]. The remainder were COS and/or AOS studies conducted in
three different specialist centres in Germany, Israel and South
Korea [40,44,24]. Evidence from these studies suggests that CLZ is
associated with sustained clinical improvement; compared to
previous treatment, the number and duration of hospitalization
reduced with CLZ treatment. The rate of discontinuation was very
low, averaging 6% [40,24], and was jointly accounted for by poor
efcacy and tolerability.
3.2. Tolerability
Treatment with CLZ in patients with EOS has a complex
tolerability prole. Up to 40% of patients experience more than one
ADR [24]. In Table 2, we summarise all ADRs that have been
reported during CLZ treatment in EOS and we draw attention to the
highest period of risk for each class of ADRs. Below, we discuss
ADRs in more detail and comment on the level of evidence
available regarding tolerability to CLZ in youth with EOS.
3.2.1. CNS effects
3.2.1.1. Sedation. Sedation is an almost universal complaint during
CLZ treatment. Although worse at the start of treatment, it often
persists, especially at high doses [16,13].
3.2.1.2. Seizures. The risk of seizures during CLZ treatment in EOS
is dose dependent and varies in different studies, ranging from
0.2%, at an average daily CLZ dose of 200 mg, to 4% for daily CLZ
doses of 500 mg or above [40]. EEG abnormalities were frequent
during CLZ treatment of EOS ranging from 10 to 60% [43,13] but
they were not predictive of seizure risk unless excessively severe
(i.e. EEG abnormalities indicating spike discharges or spike-andwave activity). The reported average incidence of seizures was 3%,
with most of the cases appearing after the rst year of treatment
[41,43,24,17].

3.1. Efcacy
3.1.1. Short-term studies
We identied ve studies [16,26,41,43,27] that examined the
efcacy of CLZ for periods up to 12 weeks (Table 1). All studies
came from USA centres and four [16,26,41,27] reported on

3.2.1.3. Akathisia. Akathisia in patients with EOS occurred at a rate

of 1531% both at treatment initiation and over the longer term
[40,24]. This rate is signicantly higher than the 3% commonly
reported in adults [12]; the mechanism for this is unknown but is
thought to reect greater sensitivity to dopaminergic blockade.

Table 1
Clinical studies assessing the efcacy and tolerability of clozapine in early onset schizophrenia (in chronological order).
Adverse drugs reaction
(ADR)

Results summary

CLZ: 370.5
(range: 125825)

BPRS, GAS,
SAPS, SANS

Hypersalivation 88%
Sedation 77%
Weight gain 77%

More than half of the

sample showed marked
improvement

6 weeks

CLZ: 176 (149)

HAL: 16 (8)

BPRS, CGAS
SAPS, SANS
BunneyHamburg
Rating Scale

ADR prole of CLZ and

HAL were similar
except for insomnia
(more common with
HAL); drowsiness,
hypersalivation,
neutropenia more
common with CLZ

CLZ superior to HAL on all

measures of psychosis

Inpatient

6 weeks

CLZ: 325.4 (211)

OLZ: 17 (3.5)
HAL: 15.3 (8.23)

Not assessed

Mean increase in
prolactin levels
HAL: 39 ng/ml
CLZ: 2 ng/ml
OLZ: 13.7 ng/ml

Prolactin levels remained

within the normal level
during CLZ treatment but
were elevated in 90% of HAL
and in 70% of OLZ treated
patients

Retrospective
observational

Inpatient/
outpatient

6 weeks

CLZ: 269.9 (173.3)

OLZ: 17.5 (2.8)
HAL: 15.4 (8.1)

Not assessed

Prolactin levels (rates

of hyperprolactinaemia
not reported)

Signicant correlations
between antipsychotic
plasma concentration and
prolactin levels only for the
OLZ treatment group; OLZtreated girls showed the
highest increase in
prolactin levels

n = 172
Age: 15.03 (2.13)

Retrospective
observational

Inpatient

8 weeks

431.4 (146.9)

Not assessed

Neutropenia: 13%
Agranulocytosis: 0.6%
half were successfully
rechallenged with CLZ

Incidence of
agranulocytosis similar to
that reported in the adult
literature

Shaw et al., 2006 [41]

n = 25a
Age
CLZ: 11.7 (2.3)
OLZ 12.8 (2.4)

DBRCT

Inpatient

8 weeks

CLZ: 327 (113)

OLZ: 18.1 (4.3)

CGI-S
BPRS-24
SAPS, SANS

Weight gain (kg)

CLZ: 3.8
OLZ: 3.6
Hypertension,
tachycardia
(> 100 beats/min),
enuresis

CLZ superior in efcacy

particularly for negative
symptoms; CLZ was
associated with higher
rates of hypertension,
tachycardia and enuresis

Sporn et al., 2007 [43]

n = 54a
Age: 13.5 (2.5)

Re-analyses of
data from
previous CLZtreated
patients
assessed either
BD (n = 22) or
OL (n = 32)
studies

Inpatient

6 weeks

CLZ: 298.2 (144.8)

BPRS

At 6 weeks
Tachycardia: 28%
Hypersalivation: 24%
Akathisia: 15%
Enuresis: 15%
70% of patients had
more than 1 ADR

Severity of illness at
baseline and improvement
during the rst weeks of
CLZ treatment predicted
long-term response

Sample

Design

Setting

Duration

Medication
dosage
In mg/day

n = 11a
Age: 14 (1.5)

OLRT

Inpatient

6 weeks

Kumra et al., 1996 [26]

n = 21a
Age: 14 (2.3)

DBRCT

Inpatient

Wudarsky et al., 1999 [47]

n = 35a
Age: 14.1 (2.3)

Retrospective
observational

Alfaro et al., 2002 [1]

n = 40a
Age
HAL: 13.8 (1.5)
CLZ: 14.2 (2.3)
OLZ: 14.5 (3.2)

Gerbino-Rosen et al.,
2005 [18]

Short-term (up to 12 weeks)

Frazier et al., 1994 [16]

mean

C. Schneider et al. / European Psychiatry 29 (2014) 110

Efcacy
measures

Study

Table 1 (Continued )
Adverse drugs reaction
(ADR)

Results summary

CLZ: 294.9 (133.9)

OLZ: 16.1 (6.9)
RIS: 2.9 (1.5)

Not assessed

Weight gain (kg)

CLZ: 2.5 (2.9)
OLZ: 4.6 (1.9)
RIS: 2.8 (1.3)
BMI increase (kg/m2)
CLZ: 0.8 (1)
OLZ: 1.6 (0.7)
RIS: 1.0 (0.5)

Weight gain observed for

all antipsychotics but
higher with OLZ

12 weeks

CLZ: 403.1 (201.8)

OLZ: 26.2 (6.5)

CGI, BPRS,
SANS, CGAS

Weight gain
Total serum cholesterol
Fasting triglycerides
Fasting blood glucose

Reduction in positive
symptoms was similar with
CLZ and OLZ but CLZ also
improved negative
symptoms; weight gain
higher with OLZ otherwise
no difference in ADRs

Outpatient

6 weeks

CLZ: 47.5 (118)

OLZ: 15 (6.1)
RIS: 2.7 (1.3)
HAL: 6.8 (1.1)
ZIP: 80 (0)
PER: 12 (6.9)
SUL: 50 (409.3)

Not assessed

Weight gain (kg)

SGAs: 3.4 (3.2)
FGAs 2.0 (3.9)

No difference in weight
gain between the SGAs and
FGAs groups

OLRT

Inpatient

36 weeks

CLZ: 324
FGAs: 465b

BPRS, SAPS, SANS

Prolactin levels

Prolactin levels increased

with FGA but not with CLZ;
CLZ was superior in
improving positive and
negative symptoms

n = 11
Age: 11.3 (1.7)

OLRT

Inpatient

16 weeks

CLZ: 227.3 (34.4)

CGI, BPRS, PANSS

Sedation: 90%
Hypersalivation: 90%
Non-specic EEG
changes: 85%

Improvement in all
symptom scale scores; no
agranulocytosis

Wehmeier et al., 2004 [46]

n = 36
Age range at
baseline: 921

Retrospective
observational

Not reported

2.5 to 79 months

CLZ: 219.7
Range: 12.5600

Not assessed

Eosinophilia 66.7%
Elevated AST 58.3%
Elevated CK 52.7%
Elevated LDH 44.5%
Abnormal ECG 25%

No cases of myocarditis,
pericarditis, or
cardiomyopathy

Shaw et al., 2006 [41]

n = 15a
Age at baseline
CLZ: 11.7 (2.3)
OLZ: 12.8 (2.4)

OL follow-up of
previous
randomised
trial of OLZ
andr CLZ

Outpatient

26 years

Not reported

CGI-S, BPRS-24,
SAPS, SAPS

Patients on CLZ showed

additional ADRs during
the follow-up period;
Lipid abnormalities
(n = 6) and seizure
(n = 1)

Clinical improvement was

sustained

Fleischhaker et al., 2006 [13]

n = 51
Age at baseline:
16.1 (2.1)

Prospective
observational

Inpatient

26 months

Mean dose at study

entry
CLZ: 321.9
(156.5)
OLZ: 16.6 (7.1)
RIS: 3.9 (1.7)

Not assessed

Hypersalivation: 62.5%
Sedation: 56%
Weight gain: 56.3%
Constipation: 31.5%

OLZ associated with greater

weight gain; CLZ associated
with more sedation,
hypersalivation,
constipation and
hypotension

Sample

Design

Setting

Duration

Medication
dosage
In mg/day

Fleischhaker et al.,
2008 [14]

n = 45a
Age
CLZ: 17.4 (1.7)
OLZ: 15.7 (1.3)
RIS: 15.2 (2.8)

Prospective
observational

Inpatient

6 weeks

Kumra et al., 2008 [27]

n = 39
Age
CLZ: 15.8 (2.2)
OLZ: 15.5 (2.1)

DBRCT

Inpatient

Hrdlicka et al., 2009 [22]

n = 109
Age: 15.8 (1.6)

Retrospective
observational

n = 40
Age
CLZ: 19.1 (2.2)
FGAs: 18.8 (2.3)b

Turetz et al., 1997 [44]

Long-term (more than 12 weeks)

Schultz et al., 1996 [40]

mean

C. Schneider et al. / European Psychiatry 29 (2014) 110

Efcacy
measures

Study

Table 1 (Continued )
Study

Adverse drugs reaction

(ADR)

Results summary

Mean dose at
follow-up: CLZ
360.3 (96.9)

CGAS

Discontinuation due to
ADRs: 5.5%

Sustained clinical
improvement on CLZ;
further improvement was
seen in 56% of patients who
had poor response at 6
weeks

Mean dose at study

entry
CLZ: 311.7
(137.5)
OLZ: 10.2 (3.5)
RIS: 2.6 (1.7)

Not assessed

Weight gain (kg)

CLZ: 9.5
OLZ: 16.2
RIS: 7.2
BMI increase (kg/m2)
CLZ: 2.9 (3.5)
OLZ: 5.2 (3.7)
RIS: 1.9 (1.3)

OLZ associated with greater

weight gain compared to
CLZ and RIS

Design

Setting

Duration

Medication
dosage
In mg/day

Sporn et al., 2007 [43]

n = 35a
Age at follow-up:
19 (4.1)

OL

Outpatient

26 years

Fleischhaker et al.,
2008 [14]

n = 33a
Age at baseline
CLZ: 17.2 (1.6)
OLZ: 15.7 (1.3)
RIS: 14.3 (2.6)

Prospective
observational

Inpatient/
outpatient

45 weeks

mean

Patients had fewer hospital

Neutropenia
days per year after CLZ
66.5% of males
treatment
7% of females
Discontinuation due
to ADRs after 3 years of
CLZ treatment: 6.5%
Age and dosage are shown as mean (standard deviation); weight gain and BMI are shown as mean; BMI (Body Mass Index); CLZ (clozapine); BPRS (Brief Psychiatric Rating Scale); CGAS (Child Global Assessment Scale); GCI-S (Global
Clinical Impression-Severity); DB (double-blind); DBRCT (double-blind randomised controlled trial); FGAs (rst generation antipsychotics); GAS (Global Assessment Scale); HAL (haloperidol); OL (open label); OLRT (open label
randomised trial); OLZ (olanzapine); PANNS (Positive and Negative Syndrome Scale); PER (perphenazine); RIS (risperidone); SGAs (second generation antipsychotics); SANS (Schedule for the Assessment of Negative Symptoms);
SAPS (Schedule for the Assessment of Positive Symptoms); SUL (sulpiride); ZIP (ziprasidone).
a
Overlapping samples.
b
FGAs = haloperidol (n = 9), levomepromazine (n = 5), uphenazine (n = 4), upenthixol (n = 3), chlorprothixene (n = 2), promethazine (n = 1), perazine (n = 1) and thioridazine (n = 1) 80% of patients received more than one drug.
Kim et al., 2008 [24]

n = 26
Age at baseline:
14.4 (2.1)

Retrospective
observational

Outpatient

3.6 years

Mean maintenance
dose of CLZ: 278.8
(122)

Number of
hospitalizations
per year
Hospital
days per year

C. Schneider et al. / European Psychiatry 29 (2014) 110

Efcacy
measures

Sample

C. Schneider et al. / European Psychiatry 29 (2014) 110

6
Table 2
Common adverse drug reactions to clozapine.
Adverse drug reaction

Incidence (%)

Period of highest risk

Possible risk factors

Hypersalivation

8090

Present throughout treatment

Sedation

5690

Worse at initiation
;ay persist throughout treatment

High doses

Constipation

1350

Present throughout treatment

Low-bre diet
Inadequate uid intake
Lack of exercise
Concomitant use of anticholinergics

Enuresis

1561

Highest risk at treatment initiation

Childhood enuresis
Concomitant use of a second antipsychotic

Akathisia

1531

Worse at initiation
May persist throughout treatment

Female sex

EEG abnormalities

1060

Highest risk at initiation and dose escalation

Pre-treatment seizures and/or EEG abnormalities

Brain lesions

Seizures

Highest risk after rst year of treatment

Neutropenia

615

Highest risk during the 18 rst weeks

Risk lower thereafter but persist

Female
Low baseline WBC counts
Ethnicity
Young age
Concomitant use of immunosuppressant drug

Weight gain

2064

Risk increases with length of exposure

Lack of physical activity

Race
Genetic

Metabolic abnormalities

822

Risk increases with length of exposure

Weight gain
Genetic factors
Lack of physical activity

Diabetes

Risk increased with length of exposure

Genetic factors
Weight gain or metabolic syndrome on previous antipsychotics

Tachycardia

35

Highest risk early in treatment

May persist

Rapid increase in doses

Hypotension

12.50

Highest risk early in treatment

Tolerance

Rapid increase in doses

Concomitant use of b blockers (e.g. for akathisia)

Hypertension

Highest risk early in treatment

Very common ( 1/10), common ( 1/100, < 1/10), uncommon ( 1/1000, < 1/100), rare ( 1/10,000, < 1/1000), very rare (< 1/10,000).

3.2.1.4. Obsessive-compulsive symptoms. CLZ is associated with

increased prevalence of obsessive-compulsive symptoms [32] in
adults. This association has not been systematically examined in
EOS and requires clinical vigilance.
3.2.2. Cardiovascular effects
Clinically signicant postural hypotension in CLZ-treated youth
is frequent in the rst fortnight. Tachycardia and hypertension are
also common early in the treatment and may persist [41,40,24]. In
adults, CLZ treatment is associated with an incidence of
myocarditis of up to 3% [20]. The incidence of myocarditis in
EOS is unknown. Although no cases were reported in the studies
reviewed here, there have been case reports [31], which suggest
that clinicians should remain vigilant when prescribing CLZ to
young patients.
3.2.3. Metabolic side effects
3.2.3.1. Weight gain. Weight gain is one of the most common
adverse effects reported for SGAs in adult patients [35], and this is
also the case for the pediatric population [15,9]. With regards to
CLZ, Fleischhaker et al. in 2008 [14] compared weight gain in 45
youth aged 9 to 21 years, treated for 45 weeks with olanzapine,
risperidone or CLZ. The average weight gain associated with CLZ
was 2.5  2.9 kg at 6 weeks and 9.5  10.4 kg at 45 weeks. This was
comparable to the weight gain associated with risperidone at 45

weeks (7.2  5.3 kg) while the greatest weight gain over the same
period was seen with olanzapine (16.8  8.8 kg).
3.2.3.2. Laboratory changes in lipid, triglycerides and glucose. In
children and adolescents, the diagnosis of the metabolic syndrome
requires at least three of the following: obesity (waist circumference > 90th percentile or BMI > 95th percentile), hypertriglyceridemia (fasting serum triglyceride levels > 1.24 mmol/L [110 mg/
dL]), low high-density lipoprotein (HDL) cholesterol levels (fasting
HDL cholesterol < 1.0 mmol/L [40 mg/dL]), hypertension (blood
pressure > 90th percentile for age and sex) and hyperglycaemia
(fasting glucose > 110 mg/dL) [15,9].
The prevalence of the metabolic syndrome in adults treated
with CLZ around 50% [28]. Although, the rate of metabolic
syndrome in EOS is not known, abnormalities in lipid and
glucose regulation have been reported. Hypertriglyceridemia is
the most frequent abnormality occurring in about 8-22% of CLZtreated EOS patients [16,27]. The second most frequent
abnormality is emergent diabetes, which occurs in about 6%
of CLZ-treated youth [27]. Koller et al. identied all cases with
hyperglycemia in children and adolescents treated with CLZ
that were spontaneously reported to the Food and Drug
Administration between January 1993 and March 2001 [25].
There were 11 reports of hyperglycemia in adolescents aged 13
to 18 years (seven males and four females) who had been

C. Schneider et al. / European Psychiatry 29 (2014) 110

prescribed CLZ in daily doses from 100 to 1000 mg. Eight were
newly diagnosed cases, half of whom presented within the rst
6 weeks of treatment with further cases presenting over a 6month period. CLZ was discontinued or the dose was decreased
in six patients.

could not identify any cases of severe CLZ-related gastrointestinal

ADRs in EOS, clinicians should remain vigilant and consider this
possibility in patients presenting with constipation, abdominal
distension and pain [10,36,37].
3.3. Therapeutic Dose Monitoring

3.2.4. Hematological effects

CLZ has greater propensity to cause serious hematological
adverse events (HAEs) than any other antipsychotic [12]. The most
concerning are neutropenia (absolute neutrophil count < 1,500/
mm3) and agranulocytosis (absolute neutrophil count < 500/
mm3).
3.2.4.1. Neutropenia. The annual incidence of CLZ-induced neutropenia in adults may vary from 2.3% [33] to 22% [23], if a more
liberal denition of neutropenia (absolute neutrophil count
< 2000/mm3) is used. Sporn et al. in 2007 reported a 6% rate of
neutropenia based on data from 54 COS patients from the NIMH
cohort, of whom 33 were evaluated over an average period of 4
years (range 26 years) [43]. The prevalence of neutropenia over
the period of a year was estimated at 13% based on a
retrospective chart review of 172 children and adolescents
treated with CLZ at the Bronx Childrens Psychiatric Center [18].
In this study, half of the patients who experienced neutropenia
were successfully rechallenged with CLZ. In a similar retrospective study of long-term CLZ treatment in 26 Korean children
with EOS, neutropenia developed in 34.6% of patients over a 2year period; in all cases neutropenia was transient and CLZ was
continued or re-instated successfully [24]. Overall, the data
suggest that neutropenia is relatively more common in EOS than
in adult patients but it is transient [16,40] and does not preclude
continued CLZ treatment [24].
3.2.4.2. Agranulocytosis. The risk of agranulocytosis in adults
ranges between 0.5 and 1% and is not dose-dependent [33]. The
risk of agranulocytosis in EOS is comparable ranging from 0%
[40,24] to 0.99% [18].
3.2.4.3. Fatalities. None of the studies reviewed reported any CLZrelated deaths in EOS.
3.2.5. Endocrinological effects
Unlikely, all other SGAs (olanzapine, risperidone, ziprasidone
and quetiapine) [15,9] CLZ is not associated with increased in
prolactin levels [47,1].
3.2.6. Urinary side effects
Enuresis: nocturnal enuresis has been reported in up to 15% of
the patients participating in the NIMH clinical trials [41] and up to
61.5% of patients in observational trials [24].
3.2.7. Gastrointestinal effects
3.2.7.1. Hypersalivation. Hypersalivation is the most common
side-effect of CLZ, reported in 8090% of EOS patients
[16,26,43,44,13]. Hypersalivation may be dose-related, it usually
persists throughout treatment and is more pronounced during
sleep [38].
3.2.7.2. Constipation. In adults, antipsychotic treatment is commonly associated with constipation [10] which is particularly
severe with CLZ [10,36,37]. In rare cases, constipation may
progress to paralytic ileus, faecal impaction, necrotizing colitis
and intestinal perforation, all of which can be fatal [37]. The effect
has been attributed to the peripheral anticholinergic and
antiserotinergic properties of CLZ. In EOS, constipation is common
and reported in about 30 to 50% of patients [13,24]. Although we

In adults, therapeutic drug monitoring is routinely performed to

assess adherence and toxicity and to assist in judging therapeutic
response based on plasma concentrations of CLZ and its major
metabolite, nor-clozapine. Conventionally, therapeutic plasma CLZ
concentrations range between 350 and 600 ng/mL. A specic range
that constitutes toxicity has not been established although the risk
increases with serum levels of 650 ng/mL. Couchman et al. in 2012
published the most comprehensive review of therapeutic drug
monitoring for CLZ in young patients [8]. They examined 1408
samples from the UK and Eire obtained between 1994 and 2010
from 454 patients (males = 267; females = 187), aged 817 years.
They found that plasma CLZ levels reected the prescribed dose;
median plasma CLZ increased with age up to 13 years but was
relatively stable thereafter. Generally, given the same dose, plasma
CLZ levels were approximately 30% higher in girls than boys and
higher in those with lower body weight. Interestingly, the
percentage of patients smoking cigarettes increased from 10% in
those aged 13 years to 52% in those 17 or older. This is important as
non-smokers had on average 40% higher CLZ plasma levels than
smokers. The authors concluded that the determinants of CLZ
plasma concentration in EOS are similar to those reported in CLZtreated adults.
3.4. Clinical guidelines for the use of CLZ in youths with schizophrenia
We identied two guidelines that were explicit in their
recommendations regarding the use of CLZ in EOS. The American
Academy of Child and Adolescent Psychiatry discusses CLZ in the
Practice parameters for the assessment and treatment of children
and adolescents with schizophrenia [2] and the National Institute
for Health and Clinical Excellence in the Recognition and
Management of Psychosis and schizophrenia in Children and
Adolescents [34]. Both guidelines recognise the superior efcacy
of CLZ for treatment-refractory schizophrenia in youth. Because of
signicant individual variability, they recommend that response to
any antipsychotic should be judged after patients have been
treated at an adequate dose for at least 6 weeks. They also
recommend CLZ only for patient who either failed to respond to at
least two therapeutic trials of other antipsychotics and/or
developed signicant extrapyramidal side effects. The guidelines
outline the level of monitoring for ADRs that is considered
appropriate for patients in this age group and make recommendations regarding possible interventions. We have summarised this
information in Tables 3 and 4 and Fig. 1.
4. Discussion
The evidence presented here is consistent in highlighting the
superior efcacy of CLZ in young patients with EOS. Symptomatic
improvement in CLZ-treated EOS is expected in most patients who
have failed to respond to other antipsychotics (Table 1). Moreover,
after the initial response to CLZ further clinical improvement may
be seen in the subsequent 68 months [43]. The benets of CLZ
treatment are sustained during long-term maintenance based on
studies that have followed-up patients for periods of 29 years
(Table 1).
Tolerability does not seem to present a particular challenge in
treating young patients with CLZ and this is most convincingly
demonstrated by the low discontinuation rates (36%) [40,24]. CLZ

C. Schneider et al. / European Psychiatry 29 (2014) 110

Fig. 1. Algorithm for clozapine treatment in youth with schizophrenia.

Recommendation based on references [2,34].

C. Schneider et al. / European Psychiatry 29 (2014) 110

Table 3
Interventions to ameliorate clozapine related adverse drug reactions.
Adverse drug reaction

Suggested interventions

Hypersalivation

Chewing gum (sugar free) during the day

Anticolinergic drugs (hyiscine hydrobromide,
biperiden, trihexyphenidyl)
Ophthalmologic drops (atropine) as mouthwash
before bedtime
Raising the pillow during the night

Sedation

Slow rate of titration during treatment initiation

Use minimally effective dose
Use single night time dose
Modanil co-administration

Constipation

Maintain uid intake

Healthy, bre-rich diet
Add bulk-forming laxatives

Enuresis

Fluid restriction after 6.00 pm

Double-voiding before bedtime
Avoid drinks with caffeine or bladder irritants
(citrus or cranberry drinks)
Desmopressin nasal spray before bedtime

Akathisia

Slow rate of titration during treatment initiation

Use minimally effective dose
Add long-acting benzodiazepines

EEG abnormalities/
Seizures

Use minimally effective dose

Add an anticonvulsant

Neutropenia

Monitor and discontinue treatment if

persistent (see Table 4)
Add Lithium

Weight gain /
metabolic abnormalities

Dietary education and advice

Regular physical activity
Add Metformin
Add low dose Aripiprazole

Hypotension

Slow rate of titration during treatment initiation

Use minimally effective dose

Hypertension

Dietary education and advice

Table 4
Neutropenia and agranulocytosis.

CLZ treatment was also associated with metabolic abnormalities but at a level comparable to olanzapine and other
antipsychotics SGAs [14,27,22,13,15,9].
Sedation and hypersalivation were observed in nearly every
EOS patient treated with CLZ [16,26,44,13]. Although not lifethreatening these ADRs have a negative impact on patient
experience with CLZ.
Hyperprolactinaemie was not observed during CLZ treatment
[47,1]. This is a distinct advantage of CLZ over all antipsychotics.
Hyperprolactinaemia is a particular concern in young patients
because of its potential adverse effect on development including
height, bone density, menstruation and sexual maturation.
Therapeutic drug monitoring has proved helpful in personalising CLZ treatment in adults with schizophrenia. Available evidence
[8] suggests that therapeutic drug monitoring could prove helpful
in EOS in establishing the optimal dose of CLZ in terms of risk
benet ratio, and assessing adherence.
Evidence-based recommendations are helpful in supporting
clinical decision-making but this should not diminish the value of
local support. Clinical decision making with regards to CLZ
initiation and monitoring can be enhanced through a variety of
mechanisms tailored to each clinical setting. These can take the
form of second opinion assessments by colleagues, clinical case
presentations, and consultations with senior pharmacists and
clinicians from other specialties. The latter is particularly useful in
assessing and managing neurological, metabolic, endocrine and
cardiological risk.
5. Conclusions
Systematic review of the evidence regarding the efcacy and
tolerability of CLZ in EOS conrmed the superior efcacy of CLZ in
patients that had failed to respond to two previous trials of
antipsychotic medication. Most patients experienced multiple
ADRs but life-threatening events were infrequent and the
discontinuation rate was low. Fig. 1 synthesizes the available
information on screening and monitoring patients during CLZ
treatment.

White Blood Cell

Count/mm3

Absolute Neutrophil
Count/mm3

Intervention

Disclosure of interest

 3500
30003500

 2000
15002000

CS, RC, DH and MK have no competing interests to report. SF has

received honoraria for her contribution to advisory meetings for
Enzymotec and Janssen.

> 3000

> 1500

None
Continue clozapine treatment
Twice weekly blood sampling until
counts stabilise or increase
Stop clozapine treatment
Daily blood sampling until counts
normalise
Monitor for infection

carries a higher risk of haematological ADRs compared to all other

antipsychotics which necessitates frequent monitoring. The
logistics of arranging regular venopuncture and the discomfort
associated with this procedure are possibly greater barriers than
the ADRs to prescribing CLZ. On the other hand, the necessity of
rigorous monitoring increases contact between patients, parents
and clinicians, which could enhance therapeutic relationships and
promote engagement.
Neutropenia was observed in up to 36% of patients prescribed
CLZ [24] but it was commonly transient and did not require
intervention. In contrast, agranulocytosis was a rare event (< 0.6%)
[18]. There is currently no evidence to suggest that EOS patients are
at higher risk than adults with regards to agranulocytosis.
Similarly, non-specic and clinically silent EEG changes were
common while seizures were rare (< 3%) [41].

Acknowledgments
This review has been supported by funding from the European
Communitys Seventh Framework Programme (FP7/20072013)
under grant agreement no. 279227. The funding agency has had no
input in any aspect of data review, interpretation and manuscript
writing.
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