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Review
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
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.
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
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%
6 weeks
BPRS, CGAS
SAPS, SANS
BunneyHamburg
Rating Scale
Inpatient
6 weeks
Not assessed
Mean increase in
prolactin levels
HAL: 39 ng/ml
CLZ: 2 ng/ml
OLZ: 13.7 ng/ml
Retrospective
observational
Inpatient/
outpatient
6 weeks
Not assessed
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
n = 25a
Age
CLZ: 11.7 (2.3)
OLZ 12.8 (2.4)
DBRCT
Inpatient
8 weeks
CGI-S
BPRS-24
SAPS, SANS
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
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
n = 21a
Age: 14 (2.3)
DBRCT
Inpatient
n = 35a
Age: 14.1 (2.3)
Retrospective
observational
n = 40a
Age
HAL: 13.8 (1.5)
CLZ: 14.2 (2.3)
OLZ: 14.5 (3.2)
Gerbino-Rosen et al.,
2005 [18]
mean
Efcacy
measures
Study
Table 1 (Continued )
Adverse drugs reaction
(ADR)
Results summary
Not assessed
12 weeks
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
Not assessed
No difference in weight
gain between the SGAs and
FGAs groups
OLRT
Inpatient
36 weeks
CLZ: 324
FGAs: 465b
Prolactin levels
n = 11
Age: 11.3 (1.7)
OLRT
Inpatient
16 weeks
Sedation: 90%
Hypersalivation: 90%
Non-specic EEG
changes: 85%
Improvement in all
symptom scale scores; no
agranulocytosis
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
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
n = 51
Age at baseline:
16.1 (2.1)
Prospective
observational
Inpatient
26 months
Not assessed
Hypersalivation: 62.5%
Sedation: 56%
Weight gain: 56.3%
Constipation: 31.5%
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
n = 39
Age
CLZ: 15.8 (2.2)
OLZ: 15.5 (2.1)
DBRCT
Inpatient
n = 109
Age: 15.8 (1.6)
Retrospective
observational
n = 40
Age
CLZ: 19.1 (2.2)
FGAs: 18.8 (2.3)b
mean
Efcacy
measures
Study
Table 1 (Continued )
Study
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
Not assessed
Design
Setting
Duration
Medication
dosage
In mg/day
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
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
Efcacy
measures
Sample
6
Table 2
Common adverse drug reactions to clozapine.
Adverse drug reaction
Incidence (%)
Hypersalivation
8090
Sedation
5690
Worse at initiation
;ay persist throughout treatment
High doses
Constipation
1350
Low-bre diet
Inadequate uid intake
Lack of exercise
Concomitant use of anticholinergics
Enuresis
1561
Childhood enuresis
Concomitant use of a second antipsychotic
Akathisia
1531
Worse at initiation
May persist throughout treatment
Female sex
EEG abnormalities
1060
Seizures
Neutropenia
615
Female
Low baseline WBC counts
Ethnicity
Young age
Concomitant use of immunosuppressant drug
Weight gain
2064
Metabolic abnormalities
822
Weight gain
Genetic factors
Lack of physical activity
Diabetes
Genetic factors
Weight gain or metabolic syndrome on previous antipsychotics
Tachycardia
35
Hypotension
12.50
Hypertension
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).
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
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.
Suggested interventions
Hypersalivation
Sedation
Constipation
Enuresis
Akathisia
EEG abnormalities/
Seizures
Neutropenia
Weight gain /
metabolic abnormalities
Hypotension
Hypertension
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.
Absolute Neutrophil
Count/mm3
Intervention
Disclosure of interest
3500
30003500
2000
15002000
> 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
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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