JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

Volume 18, Number 4, 2008

© Mary Ann Liebert, Inc.
Pp. 327–336
DOI: 10.1089/cap.2007.0138

Antipsychotic Treatment in Child and

Adolescent First-Episode Psychosis:
A Longitudinal Naturalistic Approach

Josefina Castro-Fornieles, M.D., Ph.D.,1 Mara Parellada, M.D., Ph.D.,2 César A. Soutullo, M.D., Ph.D.,3
Immaculada Baeza, M.D., Ph.D.,1 Ana Gonzalez-Pinto, M.D., Ph.D.,4 Montserrat Graell, M.D.,5
Beatriz Paya, M.D.,6 Dolores Moreno, M.D., Ph.D.,2 Elena de la Serna, Ph.D.,1
and Celso Arango, M.D., Ph.D.2

Abstract

Objective: The Child and Adolescent First-Episode Psychosis Study (CAFEPS) is a naturalistic longitudinal
study of early-onset first psychotic episodes. This report describes the antipsychotic treatment during the first
year and compares the most frequently used agents after 6 months.
Methods: Participants were 110 patients, aged 9–17 years, with a first psychotic episode attended consecutively at
six different centers. The Positive and Negative Symptom Scale (PANSS), Clinical Global Impressions (CGI), Dis-
ability Assessment Schedule (DAS), and Global Assessment of Function (GAF) scales were administered at base-
line and at 6 months and the Udvalg for Kliniske Undersøgelser (UKU) Side Effects Rating Scale only at 6 months.
Results: Diagnoses at baseline were 38.2% psychotic disorder not otherwise specified, 39.1% schizophrenia-type
disorder, 11.8% depressive disorder with psychotic symptoms, and 10.9% bipolar disorder, manic episode with
psychotic symptoms. The most frequently used antipsychotic agents were risperidone (n  50), quetiapine (n 
18), and olanzapine (n  16). Patients who were prescribed olanzapine or quetiapine had more negative and
general symptoms. Using the baseline score as covariate, no significant differences were found in the reduc-
tions on any scale in patients treated with risperidone, quetiapine, or olanzapine for 6 months. Weight increase
was greater with olanzapine than with risperidone (p  0.020) or quetiapine (p  0.040). More neurological side
effects appeared with risperidone than with olanzapine (p  0.022). All side effects were mild or moderate.
Conclusions: Second-generation antipsychotics, especially risperidone, quetiapine, and olanzapine, are the most
used in our context in first psychotic episodes in children and adolescents. These three obtain similar clinical
improvement, but differ in their side effects.

Introduction more severe than in the adult onset disorder (Schmidt et al.
1995). Although there is evidence that childhood-onset schiz-

P SYCHOTIC DISORDERS DURING CHILDHOOD and adolescence

have a negative influence on normal development and
functioning (Volkmar 1996) and the presentation may be
ophrenia bears many similarities to the adult-onset form,
child and adolescent onset of first-episode psychosis has spe-
cific features and differential diagnostic problems (Asarnow

1Department of Child and Adolescent Psychiatry and Psychology, Institut Clinic of Neurosciences. IDIBAPS. (Institut d’Investigacions

Biomèdiques August Pi Sunyer), Hospital Clínic Universitario of Barcelona, Department of Psychiatry and Psychobiology, Health Sciences
Division, University of Barcleona, CIBERsam Network, Spain.
2Adolescent Unit, Department of Psychiatry. Hospital General Universitario Gregorio Marañón, CIBERsam Network, Madrid, Spain.
3Child and Adolescent Psychiatry Unit, Department of Psychiatry and Medical Psychology, University Clinic, College of Medicine, Uni-

versity of Navarra, Pamplona, Spain.

4Stanley Institute International Mood-Disorders Research Center, 03-RC-003, Hospital Santiago Apóstol, CIBERsam Network, Vitoria,

Spain.
5Section of Child and Adolescent Psychiatry and Psychology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
6Child and Adolescent Mental Health Unit, Department of Psychiatry and Psychology, Hospital Universitario Marqués de Valdecilla,

Santander, Spain.
This study was supported by a grant from the Carlos III Institute of Health, Spanish Department of Health, Cooperative Research The-
matic Network (RETICS)-G03/032 and from the Spanish Ministry of Health, Instituto de Salud Carlos III, CIBERSAM Network.

327
328
et al. 2004; Ballageer et al. 2005). Response to antipsychotics
and side effects in children and adolescents may not be the
same as in adults. Given the influence of psychotic disorders
on cognitive development and general functioning (Bryden
et al. 2001), there is a clear need to determine the best treat-
ment for the condition at these ages. First-generation an-
tipsychotics have proved superior to placebo in improving
scores on a variety of clinical scales, but also produce more
somnolence, dizziness, and extrapyramidal symptoms (Pool
et al. 1976; Spencer and Campbell 1994).
Few well-controlled studies have assessed second-gener-
ation antipsychotics in children (Arango et al. 2004; Kumra
et al. 2007). Several open studies have been carried out with
risperidone (Grcevich et al. 1996; Armenteros et al. 1997;
Zalsman et al. 2003), olanzapine (Kumra et al. 1998; Shole-
var et al. 2000; Findling et al. 2003; Mozes et al. 2003; Ross
et al. 2003), and quetiapine (McConville et al. 2000; Shaw et
al. 2001; McConville et al. 2003) in psychotic disorders in chil-
dren and adolescents and reported acceptable rates of re-
sponse and safety. Case reports with ziprasidone (Meighen
et al. 2004) and aripiprazole (Rugino and Janvier 2005) have
been published, as have studies of olanzapine, risperidone
and haloperidol.
In an open study with children and adolescent psychotic
patients that compared these antipsychotics (Gothelf et al.
2003), the clinical improvement obtained with all three was
similar. Extrapyramidal symptoms were more frequent with
haloperidol, followed by risperidone. In a double-blind, con-
trolled study comparing risperidone, olanzapine, and
haloperidol in children and adolescents with psychotic dis-
orders, Sikich et al. (2004) obtained good therapeutic re-
sponse with all three agents. Extrapyramidal symptoms were
more frequent with haloperidol and risperidone, but weight
increase was greater with olanzapine. Open studies with
clozapine in children and adolescents with psychotic disor-
der resistant to other antipsychotics (Siefen and Remschmidt,
1986; Blanz and Schmidt 1993; Frazier et al. 1994; Turetz et
al. 1997) have reported good response. In a double-blind,
controlled study comparing clozapine with haloperidol in
psychotic children and adolescents, Kumra et al. (2006)
found a somewhat better response to clozapine, but also
more severe side effects. Comparing the efficacy and safety
of olanzapine and clozapine in child-onset schizophrenia in
a double-blind, controlled study, Shaw et al. (2006) also
found a better response in negative symptoms with clozap-
ine but worse side effects.
Many questions regarding the efficacy and safety of an-
tipsychotic medications in psychotic disorders in children and
adolescents remain to be answered. There is a need for con-
trolled studies and also for naturalistic ones in children with
psychotic symptoms within different diagnoses. The results
of studies of this kind will broaden our understanding of the
efficacy, tolerability, and safety of different drugs in children
and adolescents, an area about which little is known today
(Olfson et al. 2006). The Child and Adolescent First-Episode
Psychosis Study (CAFEPS) is a multicenter, longitudinal, fol-
low-up study designed to assess the clinical characteristics,
psychopharmacological treatment, prognostic factors, diag-
nostic specificities of findings, and pathophysiological
changes in the brain in the first 2 years after a psychotic
episode through an integrative and translational approach.
The methods, procedure, and baseline demographic and gen-
CASTRO-FORNIELES ET AL.
eral clinical characteristics of the sample have been described
in full elsewhere (Castro-Fornieles et al. 2007). The present re-
port describes the psychopharmacological treatment at the
first evaluation, after 6 months, and after 1 year of follow up,
as well as the clinical changes and side-effects at 6 months
with the three most common antipsychotic treatments.
Methods
Subjects
Subjects were recruited from child and adolescent psy-
chiatry units at six university hospitals. All patients seen at
these facilities during the 2-year recruitment period and who
met the inclusion criteria were invited to participate in the
CAFEPS (study details can be found in Castro-Fornieles et
al. 2007). The inclusion criteria were age between 7 and 17
years at the time of first evaluation and presence of positive
psychotic symptoms (within a psychotic episode) such as
delusions or hallucinations of less than 6 months’ duration.
This short duration of positive psychotic symptoms was es-
tablished to obtain a more homogeneous sample and to
avoid the influence of variables, such as prolonged psy-
chopharmacological treatment. Exclusion criteria were pres-
ence of a concomitant Axis I disorder at the time of evalua-
tion that might account for the psychotic symptoms (such as
substance abuse, autistic spectrum disorders, post traumatic
stress disorder, or acute stress disorder), mental retardation
(MR) according to Diagnostic and Statistical Manual of Mental
Disorders, 4th edition (DSM-IV) criteria (American Psychi-
atric Association 1994), including not only an intelligence
quotient (IQ) below 70 but also impaired functioning, per-
vasive developmental disorder, neurological disorders, his-
tory of head trauma with loss of consciousness, and preg-
nancy. Occasional substance use was not an exclusion
criterion if positive symptoms persisted for more than 2
weeks after a negative urine drug test. During the recruit-
ment period, 116 patients met the inclusion criteria. Six pa-
tients were excluded, three due to mental retardation (MR)
and 3 due to parents’ refusal to participate. The final sam-
ple comprised 110 children and adolescents. The study was
approved by the Institutional Review Boards (IRBs) of all
participating clinical centers. All parents or legal guardians
gave written informed consent before the study began and
all patients agreed to participate.
Procedure
A complete evaluation was performed with a structured
interview and assessment of clinical scales at baseline. The
psychopharmacological treatment was recorded at baseline,
after 6 months and after 1 year. The same clinical scales and
the Udvalg for Kliniske Undersøgelser (UKU) Side Effects
Rating Scale were also administered at 6 months.
Diagnostic interview
The Schedule for Affective Disorders and Schizophrenia
for School-Age Children–Present and Lifetime version (K-
SADS-PL; Kaufman et al. 1997), a semistructured diagnostic
interview designed to assess current and past psy-
chopathology in children and adolescents according to DSM-
IV criteria (American Psychiatric Association 1994), was used
in its Spanish translation (Ulloa et al. 2006).
ANTIPSYCHOTICS IN CHILD PSYCHOTIC EPISODES
Assessment scales
The Positive and Negative Syndrome Scale (PANSS) (Kay
et al., 1987). We used the validated Spanish version of the
PANSS (Peralta and Cuesta 1994) to assess psychopatholog-
ical symptoms of schizophrenia. It comprises a total scale
score of 30 items and three subscales (positive symptoms,
negative symptoms, and general psychopathology). The re-
liability of the different clinicians administering the scale was
evaluated and within-class correlation coefficients were
higher than 0.8.
The Clinical Global Impressions Scale (CGI) (Guy 1976)
assesses severity and improvement of global symptomatol-
ogy on a scale of 1–7. It was completed by the clinician. The
Global Assessment of Functioning Scale (GAF) (Endicot et
al. 1976), which measures the severity of symptoms and the
level of functioning on a scale from 1 to 100, was evaluated
by the clinician with the patient.
The World Health Organization Disability Assessment
Schedule (WHO-DAS) short version (Janca et al. 1996) as-
sesses difficulties in maintaining personal care, performing
occupational tasks, and functioning in family and social set-
tings. It is administered by the clinician.
The UKU Scale (Committee of Clinical Trials; Lingjaerde
et al. 1987) is a comprehensive rating scale administered by
the clinician to assess general side effects of psychotropic
drugs.
Data analysis
For descriptive purposes, continuous variables were ex-
pressed as means, standard deviations (SD), and ranges, and
categorical variables were expressed as frequencies and/or
percentages. The chi-squared test was used to compare per-
centages of discrete variables, and Fisher’s exact test was
used whenever possible. In the subgroups of patients treated
with different antipsychotics, nonparametric tests were used
due to the small sample size of each group and because the
distribution of many of these variables was skewed. We used
the Mann–Whitney test for two groups and the Kruskal–Wal-
lis test for more than two groups to compare means in dif-
ferent subgroups of patients. The Wilcoxon signed rank test
was used to compare mean scores in the scales between the
first and the second evaluation in the different antipsychotic
groups. Nevertheless, we used a group analysis of variance
with the baseline score as covariate (ANCOVA) to compare
the improvement achieved with the three antipsychotics.
Weight increase with the different antipsychotics was also
compared using an analysis of variance (ANOVA), with
weight at baseline as covariate. The Bonferroni test was used
to control for multiple comparisons. All tests were two-
tailed. Statistical analyses were carried out with the Statisti-
TABLE 1. DIAGNOSTIC SPECTRA AT BASELINE (N  110)
Diagnosis
Psychotic disorder not otherwise specified
Schizophrenia type disorder
Depressive disorder with psychotic symptoms
Bipolar disorder, manic episode with psychotic symptoms
329
cal Package for the Social Sciences, 12.0 (SPSS, Chicago, IL)
and differences of p  0.05 were considered significant.
Results
Sociodemographic and clinical characteristics
of the sample
Mean age at baseline was 15.5  1.8 years (range 9–17) and
67.3% of the sample were males. Ninety four (85.5%) patients
were Caucasian, 7 (6.4%) were Hispanic, and 9 (8.1%) were
of other ethnic backgrounds. At baseline, 92 (83.6%) patients
were hospitalized in a child psychiatric department and 18
(16.4%) were receiving outpatient treatment. The mean du-
ration of positive symptoms was 2.1  1.7 months (range 1–6
months), negative symptoms 5.2  7.1 months (range 1– 35
months), and affective symptoms 6.9  16.1 months (range
1 week to 117 months). Fifty six (50.9%) patients were al-
ready receiving psychopharmacological treatment at the
time of enrollment; the rest were drug naive. Diagnoses at
baseline and at 1 year follow up are shown in Table 1.
Psychopharmacological treatment at baseline, after 6
months and after 1 year of follow up
Table 2 shows a general description of the main treatments
administered at the three different times and the changes in
the clinical scales for patients who completed the study. At
6 months follow up, 18 (17.8%) patients were admitted at the
hospital (9 with psychotic disorder not otherwise specified,
3 with schizophrenia type disorder, and 6 with depressive
or bipolar disorder). Data regarding psychopharmacological
treatment were not obtained in 9 cases after 6 months of fol-
low up (8 patients withdrew from the study and 1 patient
did not attend this visit) and in 19 cases at 1 year of follow-
up (13 patients withdrew from the study and 6 cases did not
attend this visit). At the start of treatment, the most com-
monly used antipsychotic agent was risperidone, but the per-
centage of patients treated with this drug decreased with
time. The two other most frequently used antipsychotics
were quetiapine and olanzapine. Five patients treated with
risperidone and one with olanzapine had stopped the initial
mediction due to side effects. The shifts between medications
during the first 6 months of treatment were frequent (in 12
patients risperidone was changed to olanzapine, quetiapine,
or clozapine; in 4 patients olanzapine was changed to que-
tiapine, clozapine, ziprasidone, or aripiprazole and also in 4
patients quetiapine was changed to risperidone, olanzapine,
or aripiprazole). The number of patients treated with newer
drugs such as ziprasidone or aripiprazole increased slightly
during follow up. At 1 year follow up, 8 (8.8%) patients were
treated with clozapine.
AND AT 1 YEAR FOLLOW-UP (N  97)
At baseline At 1 year follow up
n (%) n (%)
42 (38.2) 28 (28.9)
43 (39.1) 49 (50.5)
13 (11.8) 6 (6.2)
12 (10.9) 14 (14.4)
330 CASTRO-FORNIELES ET AL.

TABLE 2. PSYCHOPHARMACOLOGICAL TREATMENT AT BASELINE, AFTER 6 MONTHS AND AFTER 1 YEAR

Baseline At 6 months At 1 year

(n  110) (n  101) (n  91)

Antipsychotics N (%) N (%) N (%)

Risperidone 50 (45.5) 38 (37.6) 31 (34.1)
Quetiapine 18 (16.4) 20 (19.8) 16 (17.6)
Olanzapine 16 (14.5) 17 (16.8) 8 (8.8)
Risperidone and quetiapine 8 (7.3) 1 (1) 0
Risperidone and olanzapine 9 (8.2) 2 (2) 0
Ziprasidone 2 (7.2) 4 (4) 4 (4.4)
Aripiprazole 2 (1.8) 3 (3) 6 (6.6)
Haloperidol 2 (1.8) 2 (2) 0
Clozapine 0 4 (4) 5 (5.5)
Clozapine and risperidone 0 0 2 (2.2)
Clozapine and olanzapine 0 0 1 (1.1)
Anxiolytics 52 (47.3) 19 (18.8) 13 (14.3)
Antidepressants 18 (16.4) 16 (15.8) 8 (8.8)
Mood Stabilizers 14 (12.7) 15 (14.9) 13 (14.3)
Anticholinergic drugs 8 (7.3) 16 (15.8) 4 (4.4)
No psychopharmacological treatment 2 (1.8) 6 (5.9) 12 (13.2)

The number of patients without psychopharmacological
treatment increased at 6 months and at 1 year of follow up.
Treatment for extrapyramidal symptoms was necessary in a
few cases at baseline, but by 6 months the number requiring
treatment had doubled. A high proportion of patients were
initially treated with anxiolytics, but this figure decreased af-
ter 6 months and 1 year of follow up. The percentages of pa-
tients treated with mood stabilizers varied little between
baseline and 6 months and the percentage of patients treated
with antidepressants decreased after 1 year of follow up.
Differences in clinical changes during the first 6 months
with the three most commonly used antipsychotics
Table 3 shows baseline data for demographic and clinical
variables in the groups of patients treated with the three most
used antipsychotics during the first 6 months of follow up.
Mean doses of antipsychotics at baseline were for 3.7  1.7
mg/day for risperidone, 183.3  122.6 mg/day for quetiap-
ine, and 11.4  5.9 mg/day for olanzapine. At 6 months fol-
low up, mean doses were 2.8  1.2 mg/day for risperidone,

TABLE 3. DEMOGRAPHIC AND CLINICAL VARIABLES AT BASELINE IN PATIENTS CONTINUOUSLY TREATED

WITH RISPERIDONE, QUETIAPINE, AND OLANZAPINE DURING THE FIRST 6 MONTHS OF FOLLOW UP

Risperidone Quetiapine Olanzapine

n  31 n  15 n  14
n (%) n (%) n (%) 2 a

Male 21 (67.7) 10 (66.7) 10 (71.4) 0.01 0.958

Diagnosis affective psychosis 2 (6.5) 7 (46.7) 5 (35.7) 10.7 0.005 Ris  Que b  0.003
Ris  Olan b  0.023
Mean (SD) Mean (SD) Mean (SD) c
Age (years) 15.1 (2.1) 16.4 (1.1) 15.7 (1.2) 5.8 0.056
Weight (kg) 60.6 (11.5) 57.6 (10.7) 66.7 (9.2) 7.1 0.048 Ris  Olan d  0.033
Que  Olan d  0.029
Body mass index 21.3 (2.8) 20.1 (3.1) 22.5 (2.4) 5.7 0.061
PANSS total 80.8 (18.0) 91.9 (16.7) 100.2 (20.7) 11.3 0.003 Ris  Que d  0.020
Ris  Olan d  0.003
PANSS positive symptoms 23.7 (5.7) 23.9 (5.4) 22.9 (5.6) 0.5 0.795
PANSS negative symptoms 16.9 (9.1) 21.2 (7.5) 25.4 (7.2) 11.5 0.003 Ris  Que d  0.028
Ris  Olan d  0.003
PANSS general symptoms 40.3 (9.3) 46.8 (9.9) 51.9 (11.8) 11.6 0.003 Ris  Que d  0.027
Ris  Olan d  0.005
Clinical Global Impressions 5.7 (0.9) 5.7 (0.8) 5.4 (0.8) 1.4 0.503
Disability Assessment Scale 10.3 (3.6) 11.5 (4.3) 11.4 (5.0) 2.2 0.330
Global Assessment Functioning 26.8 (12.0) 35.5 (14.4) 38.6 (12.5) 8.8 0.012 Ris  Que d  0.016
aChi-squared.
bFisherexact test.
cKruskal–Wallis test.
dMann–Whitney test.

SD  standard deviation; PANSS  Positive and Negative Syndrome Scale; Ris  risperidone; Que  quetiapine; Olan  olanzapine.
 TABLE 4. CHANGES IN CLINICAL SCALES AT 6 MONTHS IN PATIENTS CONTINUOUSLY TREATED WITH RISPERIDONE, QUETIAPINE, AND OLANZAPINE

Risperidone (n  31) Quetiapine (n  15) Olanzapine (n  14) Group

differences
Baseline Six months Baseline Six months Baseline Six months
Mean (SD) Mean (SD) Za p Mean (SD) Mean (SD) Za p Mean (SD) Mean (SD) Za p Fb p

PANSS total 81.8 (18.0) 56.4 (19.8) 4.5 0.001 91.9 (16.7) 59.1 (14.4) 3.4 0.001 100.2 (20.7) 63.7 (10.2) 3.3 0.001 0.13 0.876
PANSS positive symptoms 23.7 (7.7) 11.0 (5.6) 4.8 0.001 23.9 (5.4) 12.4 (4.3) 3.3 0.001 22.9 (5.6) 11.4 (3.6) 3.3 0.001 0.39 0.681
PANSS negative symptoms 16.9 (9.1) 17.5 (7.0) 0.6 0.530 21.2 (7.5) 15.6 (5.4) 2.7 0.007 25.4 (7.2) 17.9 (6.6) 2.8 0.005 1.68 0.195
PANSS general symptoms 40.3 (9.3) 27.8 (9.9) 4.4 0.001 46.8 (9.9) 31.1 (7.5) 3.3 0.001 51.9 (11.8) 34.4 (8.3) 3.2 0.001 0.30 0.741
Clinical Global Impressions 5.7 (0.9) 3.4 (1.3) 4.4 0.001 5.7 (0.8) 2.9 (1.2) 3.5 0.001 5.4 (0.8) 3.7 (0.9) 3.2 0.001 1.48 0.237
Disability Assessment Scale 10.3 (3.6) 6.8 (4.6) 3.6 0.001 11.5 (4.3) 4.7 (3.4) 3.4 0.001 11.4 (4.9) 6.8 (4.6) 2.6 0.011 2.71 0.075
Global Assessment Functioning 26.8 (11.9) 54.2 (13.4) 4.6 0.001 35.5 (14.4) 65.1 (13.9) 3.4 0.001 38.6 (12.5) 61.3 (13.6) 3.3 0.011 2.80 0.069
aWilcoxon signed rank test.
Analysis of variance with baseline score as covariate (ANCOVA).
SD  standard deviation; PANSS  Positive and Negative Syndrome Scale.
332 CASTRO-FORNIELES ET AL.

PANSS- PANSS- PANSS-

PANSS-Total Positive symp. Negative symp. General symp.
0

5

10 pa  NS

15 pa  NS

20 pa  NS

25
Risperidone
Quetiapine
30
Olanzapine

35
pa  NS
40

FIG. 1. Reductions in the scores of the PANSS subscales in patients treated with risperidone, quetiapine and olanzapine
after 6 months. aAnalysis of variance with baseline score as covariate. PANSS  Positive and Negative Syndrome Scale.

626.8  526.1 mg/day for quetiapine, and 11.7  7.0 mg/day
for olanzapine.
Differences in age and sex were not significant. Initial
weight was higher in patients treated with olanzapine. At
baseline, several clinical scales yielded differences among pa-
tients prescribed risperidone, quetiapine, or olanzapine. Pa-
tients prescribed risperidone tended to have fewer negative
and general symptoms at baseline. Mean GAF scores were
lower in patients who received risperidone. The percentage
of patients with diagnosis of depression with psychotic
symptoms, bipolar, or schizoaffective disorder was signifi-
cantly higher in patients treated with quetiapine and olan-
zapine than in those treated with risperidone.
Table 4 shows the mean scores at baseline and after 6
months on the various scales for the three most frequently
used antipsychotics. Only patients receiving the same, and
only one, antipsychotic from baseline until 6 months follow
up were included in the analysis (n  60). At 6 months fol-
low up, the percentages of patients with a positive PANSS
mean score higher than 17 (the mean score obtained at base-
line evaluation minus one standard deviation: 23.9  6.5)
were 21.2% (n  7) in the risperidone group, 13% (n  2) in
the quetiapine group, and 7% (n  1) in the olanzapine
group. The differences were not statistically significant (chi-
squared  1.5; p  0.460).
Differences between baseline and 6-month follow-up scores
were statistically significant on all the scales for the three an-
tipsychotics, except for the PANSS negative symptoms scale
in the case of patients treated with risperidone, in whom no
differences between baseline and follow up were observed.

TABLE 5. SIDE EFFECTS AT 6 MONTHS IN PATIENTS CONTINUOUSLY TREATED WITH RISPERIDONE, QUETIAPINE, AND OLANZAPINE

Risperidone Quetiapine Olanzapine

n  31 n  15 n  14
Mean (SD) Mean (SD) Mean (SD) F pa

Weight increase (kg) 6.1 (4.8) 6.0 (5.5) 11.7 (6.1) 4.5 0.015 Olan  Ris b  0.020
Olan  Que b  0.040
Body mass index increase 1.9 (1.7) 1.4 (3.2) 3.9 (2.8) 3.4 0.046
UKU scale Mean (SD) Mean (SD) Mean (SD) F a
Psychic side effects 5.3 (3.6) 4.7 (3.8) 4.0 (2.6) 1.7 0.427
Neurological side effects 1.4 (2.2) 0.6 (0.7) 0.4 (0.9) 6.9 0.031 Ris  Olan b  0.022
Autonomic side effects 0.7 (1.5) 1.1 (1.3) 1.2 (1.5) 3.8 0.147
Other side effects 2.2 (2.0) 1.5 (1.6) 1.9 (1.5) 2.0 0.376
Total 9.6 (6.1) 7.9 (5.4) 7.3 (5.0) 1.9 0.380
aAnalysisof variance with baseline weight or body mass index as covariate (ANCOVA).
bMann–Whitney test.
SD  standard deviation; UKU  Udvalg for Kliniske Undersøgelser Side Effects Rating Scale; Olan  olanzapine; Ris  risperidone;
Que  quetiapine.
ANTIPSYCHOTICS IN CHILD PSYCHOTIC EPISODES 333

Nevertheless, using the baseline score as covariate, there were Discussion

no statistically significant differences between the three an-
tipsychotics in the improvement achieved on any scale. The re-
ductions in the scores of the PANSS subscales with risperi-
done, quetiapine and olanzapine are shown in Fig. 1.
Differences in weight increase and the UKU
scale at 6 months
Again, to avoid a mixture of side effects from different
drugs, only patients receiving the same antipsychotic dur-
ing the first 6 months were included in the analysis. Table 5
shows the mean weight and body mass index (BMI) increase
and mean scores obtained on the various scales of the UKU.
Differences in weight and BMI increase were statistically sig-
nificant; olanzapine showed a greater weight and BMI in-
creases than the other two antipsychotics, even after con-
trolling for initial weight or BMI. The only UKU subscale
with significant differences between drugs was the neuro-
logical side effects scale, on which risperidone scored sig-
nificantly higher than olanzapine.
Neurological side effects were studied individually (see
Table 6). The percentage of patients with hypokinesia/aki-
nesia was significantly higher with risperidone. Dystonia
was found in only 1 patient, who was administered risperi-
done. All neurological side effects were mild or moderate.
The UKU scale scores did not show significant differences
in the percentages of patients (chi-squared  7.5; p  0.308)
and doctors (chi-squared  5.7; p  0.454) who reported
moderate or marked interference in daily functioning due to
side effects for the three drugs. Only 1 patient, treated with
olanzapine, reported a marked interference in functioning
secondary to the antipsychotic treatment.
This naturalistic study shows that second-generation an-
tipsychotics, especially risperidone, quetiapine, and olanzap-
ine, are the most frequently used drugs in children and ado-
lescents with a first psychotic episode in our context. After 6
months and 1 year of treatment, there was a small shift from
these drugs to newer ones or to clozapine. After 1 year follow
up, 8.8% of patients were treated with clozapine. Efficacy of
clozapine as a second-choice antipsychotic in children and ado-
lescents with psychosis has been already demonstrated
(Kumra et al. 2007). Other authors have pointed out that chil-
dren and adolescents are more likely to receive second-gener-
ation antipsychotics (Sikich et al. 2004), even if results from
adult studies have not shown a higher effectiveness with these
drugs in comparison with first-generation antipsychotics
(Lieberman et al. 2005). A significant general improvement on
clinical scales of positive and negative symptoms, general func-
tioning, disability, and clinical global impression was found af-
ter 6 months of treatment with the three most-used antipsy-
chotics. Clinicians seem to prefer quetiapine or olanzapine to
risperidone when there are marked affective symptoms. Que-
tiapine has proved useful in the treatment of affective symp-
toms in children and adolescents (DelBello et al. 2007), and
olanzapine has been shown to be effective in bipolar mania in
adolescents (Tohen et al. 2007).
Despite the lack of difference between olanzapine and
risperidone in negative symptom improvement in random-
ized studies with children and adolescents (Gothelf et al.
2003; Sikich et al. 2004), the present study found that clini-
cians seem to prescribe olanzapine and quetiapine more than
risperidone when negative symptoms are prominent. In
adults, the evidence for the superior efficacy of olanzapine

TABLE 6. NEUROLOGICAL SIDE EFFECTS AT 6 MONTHS (UKU SCALE) IN PATIENTS

CONTINUOUSLY TREATED WITH RISPERIDONE, QUETIAPINE, AND OLANZAPINE

Risperidone (n  31) Quetiapine (n  15) Olanzapine (n  14)

n (%) n (%) n (%) 2 p

Dystonia
0 29 (93.5) 15 (100) 13 (100) 0.9 0.622
1 or 2 1 (6.5)
Rigidity
0 25 (80.6) 15 (100) 13 (100) 5.1 0.078
1 or 2 5 (19.4)
Hypokinesia
0 15 (50) 13 (86.7) 11 (84.6) 13.4 0.001
1 or 2 15 (50) 2 (13.3) 2 (15.4)
Hyperkinesia
0 28 (93.8) 14 (93.3) 13 (100) 0.9 0.633
1 or 2 2 (6.2) 1 (6.7)
Tremor
0 26 (83.9) 11 (73.3) 11 (84.6) 1.3 0.526
1 or 2 4 (16.1) 4 (26.7) 2 (15.4)
Akathisia
0 26 (83.9) 15 (100) 13 (100) 4.0 0.135
1 or 2 4 (16.1)
Seizures
0 31 (100) 15 (100) 13 (100)
Parestesias
0 31 (100) 15 (100) 13 (100)

0  Not present or doubtfully present; 1  mild; 2  moderate.

334
in negative symptoms is conflicting (Murphy et al. 2006). In
the present study, doses of risperidone and olanzapine were
stable from baseline until 6 months follow up but quetiap-
ine doses were increased at 6 months. All scales improved
significantly at the 6-month evaluation with the three an-
tipsychotics except for negative symptoms; improvement on
this scale with olanzapine and quetiapine was significant,
but no improvement was recorded with risperidone. How-
ever, patients in the olanzapine and quetiapine groups had
higher negative symptomatology and therefore presented
more room for improvement than those treated with risperi-
done. Moreover, neurological side effects (especially hy-
pokinesia/akinesia) were more common with risperidone,
and so the effect of medication-related negative symptoms
may account, in part, for the difference.
Between baseline and 6-month follow up, there were no
significant differences between the three antipsychotics in
terms of improvement on any of the scales, using the base-
line score as a covariate. Moreover, at 6 months follow up,
the percentage of patients with positive symptoms was not
significantly different in the three groups of treatment. Other
studies have found similar clinical improvements with
haloperidol, olanzapine and risperidone in children and ado-
lescents with psychotic disorders (Gothelf et al. 2003; Sikich
et al. 2004). McConville et al. (2003) found a significant clin-
ical improvement with the Brief Psychiatric Rating Scale
(BPRS) and the CGI in an open study with 10 adolescents
with psychotic disorder treated with quetiapine, but did not
perform comparisons with other antipsychotics. To our
knowledge the present study is the first to compare risperi-
done, olanzapine, and quetiapine in children and adolescents
with psychosis.
Regarding side effects, weight and BMI gain was consid-
erable with all three drugs, but was greatest with olanzap-
ine. Previous studies comparing olanzapine with other an-
tipsychotics have reported similar findings (Sikich et al. 2004;
Fleischhaker et al. 2006; Fleischhaker et al. 2007). The weight
gain reported by those authors was lower than in our study
but this was because treatment prior to weight evaluation in
their studies lasted only 8 and 3 weeks, respectively, com-
pared with 6 months in ours. Other authors have noted the
lower weight gain obtained with quetiapine than with other
second-generation antipsychotics (Grcevich 2001; Took and
Buck 2001) in children and adolescents. Weight increase in
children raises the concern that, if treated for long periods,
these patients are at higher risk of insulin resistance, dia-
betes, hypertension or cardiovascular disease in the future.
If drugs likely to induce weight gain have to be used, com-
pensatory behavioral or pharmacological approaches should
be implemented (Correll 2007; Laita et al. 2007).
Most UKU scale items did not present differences. Only
the neurological symptoms subscale found significant dif-
ferences between risperidone and olanzapine, the former
causing more side effects. Risperidone also produced statis-
tically more hypokinesia/akinesia and, in one case, a dysto-
nia. The neurological side effects of quetiapine are more sim-
ilar to olanzapine than to risperidone. There were no overall
differences in the percentages of patients and doctors who
reported interference from side effects. In the studies by
Gothelf et al. (2003) and Sikich et al. (2004), extrapyramidal
symptoms were higher with risperidone than with olanzap-
ine. In addition, Fleischhaker et al. (2006) found rigidity and
CASTRO-FORNIELES ET AL.
dystonia in more patients with risperidone than with olan-
zapine. Those studies did not perform comparisons with
quetiapine.
Study limitations
The main limitation of this study is that it is not random-
ized and double blind. Even though chronicity was controlled,
as all patients had psychotic symptoms for less than 6 months,
the differences between antipsychotics may have been influ-
enced by selection bias. Moreover, as the percentage of patients
with mood disorders and with psychotic symptoms was higher
in the groups treated with olanzapine and quetiapine than in
the group treated with risperidone, the efficacy may be influ-
enced by the better treatment response of affective psychoses
compared with schizophrenia spectrum disorders. Neverthe-
less, this permits having more usual patients and families and
not only just the ones that are willing to participate in well-
controlled trials (Kumra et al. 2007). A second limitation is the
sample size of the subgroups of patients receiving the same
antipsychotic treatment for 6 months. The heterogeneity of the
sample might also be criticized, as patients with different di-
agnoses were included, but on the other hand this design per-
mits a greater generalization of the results to the clinical con-
text at these ages, in which heterogeneity of diagnosis in
psychotic disorders is common. Another limitation is that com-
pliance was not assessed objectively.
Conclusions
In this study, risperidone, quetiapine, and olanzapine, the
three most frequently used antipsychotics at present in clin-
ical practice for children and adolescents with a first psy-
chotic episode in our context, achieved similar degrees of
clinical improvement. Nevertheless, the side effects of the
three drugs differ: weight increase is greater with olanzap-
ine, and neurological side effects are higher with risperidone.
Even though patients and clinicians do not report marked
interference with everyday life, weight gain is a concern.
These results are in agreement with previous comparison
studies with olanzapine and risperidone, but also extend the
comparison to quetiapine and, in addition, provide a natu-
ralistic perspective on the scarce data about antipsychotics
in children and adolescents. Larger studies that permit sub-
divisions according to diagnosis and treatment are needed
to increase our knowledge of the efficacy and tolerability of
antipsychotic treatment in children.
Disclosures
The authors have no conflicts of interests or financial ties
to disclose.
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Address reprint requests to:
J. Castro-Fornieles
Department of Child and Adolescent Psychiatry and Psychology
Institut Clínic of Neuroscience
Hospital Clínic Universitari, Barcelona
Villarroel, 170, Barcelona 08036, Spain
E-mail: jcastro@clinic.ub.es