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ández-Jaén et al.Journal of Attention Disorders

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Article
Journal of Attention Disorders

Efficacy of Atomoxetine for the

17(6) 497­–505
© 2011 SAGE Publications
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DOI: 10.1177/1087054711423626
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in Patients With Pervasive
Developmental Disorders:
A Prospective, Open-Label Study

Alberto Fernández-Jaén1, Daniel Martín Fernández-Mayoralas1,

Beatriz Calleja-Pérez2, Nuria Muñoz-Jareño3, María del Rosario Campos Díaz4,
and Sonia López-Arribas5

Abstract
Objective: Atomoxetine’s tolerance and efficacy were studied in 24 patients with pervasive developmental disorder and
symptoms of ADHD. Method: Prospective, open-label, 16-week study was performed, using the variables of the Clinical
Global Impression Scale and the Conners’ Scale, among others. Results: A significant difference was found between pre- and
posttreatment scores as well as a significant reduction was found on the scales used. Only five patients presented adverse
events. Conclusion: Atomoxetine therefore appears to be a useful drug, pointing to the need for larger, randomized,
controlled, double-blind studies to confirm its efficacy versus placebo and in comparison with other treatment options.
(J. of Att. Dis. 2013; 17(6) 497-505)

Keywords
ADHD, atomoxetine, autism, pervasive developmental disorder, treatment

Introduction discontinuation in at least 10% of the patient (Aman et al.,

The use of psychotropic medication to treat children with
pervasive developmental disorders is commonplace (Myers,
2007). Children and adolescents with pervasive develop-
mental disorders generally have more symptoms of ADHD
than children with normal development (Aman, Farmer,
Hollway, & Arnold, 2008; Aman, Lam, & Van Bourgondien,
2005; Brereton, Tonge, & Einfeld, 2006; McCarthy, 2007),
affecting at least half of all patients with this diagnosis
(Aman et al., 2005, 2008; Arnold et al., 2006; Hazell,
2007). In fact, these symptoms are often targeted for treat-
ment and close to 20% of these children are treated with
psychostimulants such as methylphenidate (Troost et al.,
2006), which, although useful (Aman et al., 2005), is less
effective in children with pervasive developmental disor-
ders than in children with normal development (Aman
et al., 2005, 2008; Brereton et al., 2006; McCarthy, 2007).
The percentage of adequate response is between 46%
and 62%, with an increase in side effects, the most com-
mon ones being stereotypies, asocialization, or autolytic
behaviors, tics, irritability, insomnia, and aggressive
behaviors (Aman et al., 2008). These issues lead to treatment
2008; Troost et al., 2006). Children with pervasive devel-
opmental disorders have a high incidence of anxiety dis-
orders of different types (Gadow, Devincent, Pomeroy, &
Azizian, 2005), which can worsen the response to treat-
ment with psychostimulants (Aman et al., 2008; Arnold
et al., 2006).
Atypical antipsychotics may decrease hyperactivity;
however, there are no conclusive data indicating that they
markedly improve attention and learning (Aman et al.,
2008), and the long-term side effects, especially extrapyra-
midal symptoms, are of greater concern than with drugs such
as methylphenidate or atomoxetine (Troost et al., 2006).
1
Hospital Universitario Quirón, Madrid, Spain
2
Centro de Salud “Dr. Cirajas,” Madrid, Spain
3
Hospital Infanta Leonor de Vallecas, Madrid, Spain
4
“Centro Psicoaula,” Madrid, Spain
5
Hospital Militar “Gomez Ulla,” Madrid, Spain
Corresponding Author:
Alberto Fernández-Jaén, Pediatric Neurology, Hospital Universitario
Quirón, C/Diego de Velázquez, 1, 28223 Pozuelo de Alarcón,
Madrid, Spain.
Email: aferjaen@telefonica.net

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498 Journal of Attention Disorders 17(6)
Atomoxetine is a product that has recently been incorpo-
rated in Spain and appears to be of interest in the treatment
of patients with pervasive developmental disorders and
symptoms of ADHD due to its potential effect on social
behavior (Troost et al., 2006; Tse & Bond, 2002) and its
probable anxiolytic profile (Geller et al., 2007). To date,
few studies have been published that assessed the efficacy
of this product in children with pervasive developmental
disorder and not a single one has been published with a
Spanish patient sample (Aman et al., 2008; Jou, Handen, &
Hardan, 2005; Posey et al., 2006; Troost et al., 2006).
Therefore, the objective of this work is to assess atomox-
etine’s tolerance and efficacy in a group of patients with
pervasive developmental disorder at our neuropediatrics
department with symptoms of ADHD.
Material and Method
We conducted a 16-week, prospective, open-label study in
which we recruited 24 patients with pervasive developmen-
tal disorder and symptoms of ADHD, diagnosed at the
neuropediatrics department from 2007 up to the present
time and who received atomoxetine to improve the core
symptoms of inattention, hyperactivity, and impulsivity.
The group consisted of 14 males (58%) and 10 females
(42%), with a mean chronological age of 8.8 years (SD =
3.38). One female had been previously excluded from the
study because her parents failed to follow the methodology
recommended in our department for the monitorization of
treatment efficacy.
Appropriate informed consent was obtained in all cases.
All the patients met the Diagnostic and Statistical Manual of
Mental Disorders (4th ed., text rev., DSM-IV-TR; American
Psychiatric Association, 2000) criteria for the diagnoses of
ADHD combined type and pervasive developmental disor-
der. A total of 19 cases had associated mental retardation
(80%). Of the 24 patients admitted, 17 (70%) presented an
autistic disorder, 5 (20%) Asperger’s disorder, and 2 (10%)
had a pervasive developmental disorder, not otherwise spec-
ified. The clinical diagnosis of ADHD was made by an expe-
rienced pediatric neurologist from our department, with the
same criteria for drug dosing. The diagnosis of pervasive
developmental disorder was also corroborated by a com-
plete, semistructured interview and the Childhood Autism
Rating Scale with a score of more than 30 in all cases
(Schopler, Reichler, DeVellis, & Daly, 1980). The diagnosis
of ADHD was supported by a semistructured clinical inter-
view and the scales used in this study. The etiology of the
pervasive developmental disorder was known in 4 patients
(16.6%): 2 patients with cromosomopathies, 1 patient with
Cohen’s syndrome, and 1 with sclerosis tuberosa.
The following exclusion criteria were applied: prior use
of atomoxetine; prior intolerance to selective noradrenergic
reuptake inhibitors; cardiac, liver, or kidney failure;
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associated decompensated diseases; pregnancy; psychosis;
or families–patients with known inability to follow stable
treatment schedules for the study drug or concomitant
treatments.
The final dose of atomoxetine was achieved at 3 weeks,
factoring in the child’s age and weight. All patients were
treated with an approximate initial dose of 0.4 mg/kg/day in
the 1st week, 0.8 mg/kg/day in the 2nd week, and titrating
up to 1.2 mg/kg/day in the 3rd week (M = 1.20, SD = 0.20),
taken in a single dose at breakfast, with a maximum dose of
60 mg/day.
We recorded the following variables: age at treatment
initiation, gender, vital signs and weight, prior treatments
(methylphenidate and neuroleptics), concomitant treat-
ments, situation at onset (using the variables contemplated
in the Clinical Global Impression Scale in the severity sec-
tion [CGI-S], Guy, 1976; the Conners’ Scale, Conners,
1997; and ADHD–Rating Scale [ADHDRS-IV], DuPaul,
Power, Anastopoulos, & Reid, 1998) for parents and teach-
ers, clinical status at 16 weeks measured by the same scales,
medical clinical impression of improvement (using the
improvement section of the CGI [CGI-I]), the presence of
adverse effects, and treatment retention or discontinuation
(due to intolerance or inefficacy) at the last checkup.
The CGI Scale was used to assess two variables: severity,
at baseline and after 16 weeks of treatment, and improve-
ment, according to the impression of the professional who
had initiated treatment, on the basis of the information pro-
vided by the parents as well as his or her own observation of
the patient. The CGI Severity subscale rates the severity of
the process in terms of the dysfunction it causes on a scale of
0 to 7; the higher the score, the more severe the repercus-
sions. The CGI Improvement subscale appraises the patient’s
progress after treatment, on a scale of 0 to 7; the lower the
value, the greater the clinical improvement. This scale has
been used previously in different studies that have evaluated
treatment with methylphenidate (Di Martino, Melis,
Cianchetti, & Zuddas, 2004; Network Research Units on
Pediatric Psychopharmacology Autism, 2005; Posey et al.,
2007; Santosh, Baird, Pityaratstian, Tavare, & Gringras,
2006) or atomoxetine (Arnold et al., 2006; Jou et al., 2005;
Posey et al., 2006) in patients with ADHD symptoms and
pervasive developmental disorder.
The ADHDRS-IV (DuPaul et al., 1998) scale for parents
and teachers, adapted for the Spanish population (Servera &
Cardo, 2007), with good psychometric properties, quanti-
fies two groups of core symptoms of ADHD: inattention
and hyperactivity-impulsivity. It consists of 18 items or
characteristics that correspond to the “diagnostic” symp-
toms of the disorder, according to DSM-IV-TR criteria.
Each item is scored from 0 to 3; higher score corresponds to
more frequent presence of the symptom, and hence, higher
overall scores on the scale are related to greater symptom-
atic intensity. This scale has been used previously in a study
Fernández-Jaén et al.
addressing atomoxetine treatment for the symptoms of
ADHD in patients with pervasive developmental disorder
(Troost et al., 2006).
The other scale used was the Conners’ Scale for parents
and teachers (Conners, 1997; Goyette, Conners, & Ulrich,
1978), short form, translated into Spanish, and adapted and
weighted for our country (Farre & Narbona, 1998). It quanti-
fied three symptomatic sections—inattention, hyperactivity-
impulsivity, and conduct problems—based on a 20-item
questionnaire rating each question from 0 to 3, for which
“0” corresponds to absence of said symptom or problem
and “3” marked presence or common presence of the
symptom or problem. High scores on either of the sub-
scales or on the total score correlate with greater symptom-
atic intensity. This scale has been used previously in
studies dealing with the treatment of symptoms of ADHD
in patients with pervasive developmental disorder with
methylphenidate (Birmaher, Quintana, & Greenhill, 1988;
Di Martino et al., 2004; Handen, Johnson, & Lubetsky,
2000; Quintana et al., 1995) and with atomoxetine (Jou et al.,
2005; Troost et al., 2006).
In all cases, the parents and teachers were asked to fill in
the short form of the Conners’ Scale and the ADHDRS-IV,
before beginning treatment with atomoxetine and after 16
weeks of treatment. The Conners’ Scale and ADHDRS-IV
were correctly filled in by the families of 19 (79%) and 22
(92%) of the patients, respectively. The teachers filled in
the Conners’ Scale for 11 cases (45%) and the ADHDRS-IV
for 13 patients (54%).
The statistical analysis of the data was performed using
the SPSS v17.0 software package (SPSS, Chicago). The
distribution study for each variable was conducted using the
Shapiro–Wilk test. Quantitative variables have been
expressed as mean values and standard deviations. The dif-
ferences between status at baseline and the data observed at
the following checkup (16 weeks later) on the different
scales have been compared statistically by means of the
t test for related samples or using the Wilcoxon-signed rank
test, depending on their distribution. The relationship
between qualitative or discontinuous variables with the
scores on the scales used, as well as the change in said
scores after treatment, was assessed using the Mann–
Whitney U test. Nominal data were analyzed by means of
Pearson’s chi-square test. The degrees of association
between continuous variables were calculated using
Pearson’s coefficient. A p value of less than .05 was deemed
statistically significant.
Results
The patients studied had a mean age of 8.7 years, with a
range of 5 to 17 years. All the patients received atomox-
etine doses of 25 to 60 mg (M = 39.79, SD = 12.46), taken
in a single dose.
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499
Figure 1. Mean value of severity of the ADHD (CGI-S) prior to
initiating atomoxetine treatment and again, 16 weeks later.
Note: CGI-S = Clinical Global Impression Scale in the severity section.
The most common prior treatments consisted of methyl-
phenidate and neuroleptics, used in 20 (83%) and 15 (65%)
patients, respectively. At the time of treatment initiation
with atomoxetine, 13 patients (54%) continued to take a
neuroleptic and 2 (8%) continued on methylphenidate,
without any modification whatsoever of the doses of those
drugs when introducing the new drug or in the 4 months
preceding the introduction of atomoxetine.
Insofar as the CGI-S is concerned (Figure 1), a statisti-
cally significant difference was documented between the
mean values of the pre- and posttreatment scores—baseline
CGI-S: 5.37 (SD = 0.96); posttreatment CGI-S: 4.20 (SD =
1.02); p < .001.
In terms of the results on the CGI-I Scale, of the 23
patients who completed the 16-week treatment period, 12
(52%) attained an important or very important improve-
ment (scores of 1 or 2), 5 children (22%) presented a mild
improvement, 5 children showed no significant improve-
ment (22%), and 1 child became slightly worse (4%).
Likewise, the statistical analysis confirmed a statistically sig-
nificant reduction for the variables of attention, hyperactivity-
impulsivity, and conduct problems as per the family- and
teacher-reported ADHDRS-IV and short form of the Conners’
Scale with a p value of p < .01 (Tables 1 and 2).
The intensity of the inattention and hyperactivity-
impulsivity decreased significantly, according to the pre-
and posttreatment data observed on the corresponding
subscales of the ADHDRS (Figure 2) and the short form of
the Conners’ Scale (Figure 3). As regards the change seen
in the total value of the parent-rated ADHDRS-IV, no
reduction was seen in the score for 5 of the 22 (23%) who
filled out the said scale appropriately at the beginning and end
of treatment. A symptomatic improvement was observed in
500 Journal of Attention Disorders 17(6)

Table 1. Mean Baseline and Posttreatment Values (SD)

According to Parents.

Efficacy measure Baseline Posttreatment p value

ADHDRS-IVa,b
Inattention 19.77 (3.97) 14.18 (4.37) <.001
Hyperactivity- 15.54 (4.52) 11.50 (5.26) <.001
impulsivity
Total 35.31 (6.51) 25.68 (8.47) <.001
Connersb
Inattention 10.84 (2.52) 8.10 (3.51) .003
Hyperactivity 9.84 (3.23) 6.68 (3.24) .001
Conduct 12.15 (6.39) 8.94 (5.76) .005
problems
Total 32.84 (9.77) 23.73 (10.75) .001
Note: ADHDRS = ADHD-Rating Scale.
a
Instrument on which each item corresponds to the Diagnostic and
Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) Figure 2. Mean value of the Attention and Hyperactivity-
diagnostic criteria for ADHD. Each item is rated from 0 to 3, according Inattention subscales of the ADHDRS-IV, as per parents and
to intensity. teachers.
b
Higher scores indicate greater symptomatic intensity. Note: ADHDRS = ADHD-Rating Scale; ADHDRS-I-P = mean value
of parent-rated Inattention subscale; ADHDRS-HI-P = mean value of
parent-rated Hyperactivity-Impulsivity subscale; ADHDRS-I-T = mean
value of teacher-rated Inattention subscale; ADHDRS-HI-T = mean
Table 2. Mean Baseline and Posttreatment Values (SD) value of teacher-rated Hyperactivity-Impulsivity subscale. Higher scores
indicate greater symptomatic intensity.
According to Teachers.

Efficacy measure Baseline Posttreatment p value

ADHDRS-IVa,b
Inattention 15.53 (5.50) 12.61 (5.39) .012
Hyperactivity- 15.23 (6.33) 9.84 (6.03) .003
  impulsivity
Total 30.76 (11.54) 22.46 (11.22) .003
Connersb
Inattention 9.90 (2.34) 7.72 (3.00) .009
Hyperactivity 8.36 (3.23) 6.45 (3.67) .012
Conduct 12.36 (5.31) 10.00 (5.212) .035
  problems
Total 30.63 (8.91) 24.18 (10.98) .014

Note: ADHDRS = ADHD-Rating Scale.

a
Instrument on which each item corresponds to the Diagnostic and
Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR)
diagnostic criteria for ADHD. Each item is rated from 0 to 3, according
to intensity.
b
Higher scores indicate greater symptomatic intensity.
the remaining 17 children (77%), a positive response
(symptomatic reduction greater than 25%) was seen in 12 of
the 22 patients described (54.5%), and symptomatic remis-
sion or clinical normalization (ADHDRS < 18) was noted in
3 patients (14%). None of these parameters were statisti-
cally influenced by age, gender, presence of mental retarda-
tion (Figure 4), or previous or simultaneous treatment with
neuroleptics or methylphenidate.
As concerns safety, 5 of the 24 patients (20.8%) presented
adverse events. The most common adverse events were
Figure 3. Mean value of the Attention and Hyperactivity-
Inattention subscales of the Conners’ Questionnaire, short form,
as per parents and teachers.
Note: Conners’-I-P = mean value of parent-rated Inattention subscale;
Conners’-HI-P = mean value of parent-rated Hyperactivity-Impulsivity
subscale; Conners’-I-T = mean value of teacher-rated Inattention
subscale; Conners’-HI-T = mean value of teacher-rated Hyperactivity-
Impulsivity subscale. Higher scores indicate greater symptomatic
intensity.
somnolence, gastrointestinal (GI) malaise, and/or irritability,
present in 2 (8.3%), 2 (8.3%), and 2 (8.3%) patients, respec-
tively. The adverse reactions were temporary in 2 of the 4
cases pointed out and justified discontinuing treatment in the

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Fernández-Jaén et al.
Figure 4. Decrease in the mean score versus baseline for the
scales studied, as regards the mental retardation variable.
Note: ADHDRS = ADHD-Rating Scale; ADHDRS-P = parent-rated
ADHDRS; ADHDRS-T = teacher-rated ADHDRS; Conners’-P = parent-
rated Conners’ Scale; Conners’-T = teacher-rated Conners’ Scale;
CGI-S = Severity subscale of the Clinical Global Impression Scale.
remaining 3 cases (12.5%); these 3 cases did not display
clinical improvement according to the previously named
scales. Treatment was withdrawn in another 2 patients due to
lack of efficacy (8.3%), without having exhibited associated
adverse effects of note. At the end of the study, 19 patients
(79%) continued with the treatment, 15 (78.9%) of whom
were still on the treatment 1 year after initiation. The mean
treatment time for the 19 cases was 14.3 months (SD = 6.8;
minimum of 8 months, maximum of 30 months).
Discussion
Atomoxetine is a nonstimulant drug that acts by inhibiting
noradrenaline reuptake. It is a highly selective inhibitor of
the presynaptic noradrenaline transporter with minimal
affinity for other types of noradrenergic receptors or other
neurotransmitter transporters or receptors (Vaughan, Fegert,
& Kratochvil, 2009). In experimental models, increased
concentrations of dopamine and noradrenaline have been
seen in the prefrontal cortex following atomoxetine admin-
istration. Numerous studies have demonstrated clear effi-
cacy versus placebo in children with normal psychomotor
development (Vaughan, Fegert, & Kratochvil, 2009).
Discontinuation due to complete lack of efficacy has been
reported in 10% to 19% of the cases (Vaughan et al., 2009).
In short-term studies, atomoxetine appears to be of similar
efficacy as methylphenidate, in both attention and hyperac-
tivity-impulsivity; likewise, it has a certain anxiolytic albeit
not antidepressant capacity (Vaughan et al., 2009).
Although initial studies indicated administering atomox-
etine in two divided doses, more recent studies have pointed
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501
out that it is efficacious taken once daily, in the morning or
at night (Vaughan et al., 2009). Unlike methylphenidate, its
effect is not immediate; instead, it becomes apparent after 2
to 3 weeks of treatment. Likewise, when suspended, its
effect does not disappear immediately. The recommended
doses would be 1.2 mg/kg weight and day, with no signifi-
cant clinical differences observed at higher doses (Vaughan
et al., 2009).
Like methylphenidate, adverse effects are scant and gen-
erally well tolerated, with treatment discontinuation for this
reason in fewer than 4% to 5% of the cases (Montanes-
Rada, Gangoso-Fermoso, & Martiinez-Granero, 2009). The
most common adverse events are loss of appetite, GI mal-
aise, and somnolence or fatigue. Pulse or blood pressure
(BP) may be increased, but when this does occur, they tend
to stay within nonsignificant ranges; however, caution is
advised when using atomoxetine in patients with high BP,
tachycardia, or cardiovascular or cerebrovascular disease
(Vaughan et al., 2009). Isolated cases of idiosyncratic hepa-
totoxicity have been reported; it appears that it occurred in
one patient of the four million individuals treated to date.
Systematic liver function monitoring is therefore not rec-
ommended in these patients (Montanes-Rada et al., 2009;
Vaughan et al., 2009). Likewise, one study, based on the
review of clinical histories, has suggested a possible rela-
tionship of atomoxetine with increased suicidal ideation in
these patients; this circumstance may have more to do with
the underlying process and less with the drug itself (Montanes-
Rada et al., 2009).
Individuals with pervasive developmental disorder have
been documented to be more prone to receive treatment
with atomoxetine instead of methylphenidate to improve
their symptoms of inattention and hyperactivity than people
with normal development (odds ratio = 2.00, 95% confi-
dence interval = [1.69, 2.37]; Van Brunt et al., 2005).
However, there are only four publications in MEDLINE
that appraise amoxetine’s efficacy and tolerance in patients
with pervasive developmental disorder (Arnold et al., 2006;
Goyette et al., 1978; Jou et al., 2005; Posey et al., 2006).
In 2005, Jou et al. evaluated treatment response in a ret-
rospective study of 20 patients using the CGI-I Scale and
the Conners’ Scale for parents. Half of the patients had
mental retardation; this did not condition treatment response
as it did in this study. Similarly, most of the patients were
also taking at least one concomitant medication. The treat-
ment dose was 43.3 mg (SD = 18.1), and the study duration
was 19.5 weeks (SD = 10.5). The efficacy percentages were
similar to those in the present study; 12 patients (60%)
exhibited an adequate response, defined as a score of 1 or 2
on the CGI-I Scale. The differences between the beginning
and end of the study were observed for the Behavior,
Hyperactivity, Inattention, and Learning subscales of the
Conners’ Scale scores. Side effects were documented in 6
patients (30%) and were mild, such as constipation and loss
502 Journal of Attention Disorders 17(6)
of appetite. Treatment was discontinued in one patient due
to intense emotional liability, a side effect also seen in indi-
viduals with normal development (Montanes-Rada et al.,
2009; Vaughan et al., 2009). The dose was introduced quickly
because atomoxetine treatment commenced at a dose of
18 mg/day for 1 week and was immediately raised to
1.2 mg/kg/day. The proportion of side effects was some-
what higher than that in our study, despite the fact that treat-
ment was apparently withdrawn in fewer cases; the retrospective
design or small sample size might bias the comparative
evaluation in this regard.
Arnold et al. (2006) published the only double-blind,
placebo-controlled study to date in a small, 16-patient sam-
ple (greater limitation of the study) with pervasive develop-
mental disorder and younger mental age at 18 months.
Efficacy percentages were similar to those of the present
study. A total of 9 patients (56%) responded adequately,
defined as a score of 1 or 2 on the CGI-I Scale. The effect
sizes controlled with placebo (d = 0.89-1.27) for the symp-
toms of ADHD were as good as those reported for children
with normal development (Michelson et al., 2001, 2002; d =
0.6-1.0) and somewhat better than those obtained with
methylphenidate (d = 0.5-0.89 on the parent-rated scale and
d = 0.35-0.48 on the teacher-rated scale) according to the
Research Units on Pediatric Psychopharmacology (RUPP)
Autism Network multicenter study (2005) in the same pop-
ulation (Aman et al., 2008; Network Research Units on
Pediatric Psychopharmacology Autism, 2005). Atomoxetine
exhibited a safety profile comparable with that of methyl-
phenidate and was generally better tolerated than methyl-
phenidate. The most common side effects were mild GI
symptoms and fatigue. Only 1 patient had to discontinue
treatment due to increased aggressiveness (2 dropped out of
treatment due to inefficacy), whereas in the aforementioned
study with methylphenidate in children with pervasive
developmental disorder (RUPP), treatment was withdrawn
in 18% of the children due to intolerance (Network Research
Units on Pediatric Psychopharmacology Autism, 2005). The
drug was introduced more gradually, starting with 0.25 mg/
kg/day and increasing by 0.3 to 0.4 mg/kg/day every 5 days,
which might underlie the excellent tolerance in relation to
the tolerance profile documented by our results.
Simultaneously, Posey et al. (2006) published an open-
label, prospective study on the efficacy of atomoxetine on
symptoms of ADHD in 16 highly functioning patients with
pervasive developmental disorder (nonverbal intelligence
quotient of at least 70 points). A dose of 1.2 to 1.4 mg/kg/
day was used for the 8-week follow-up period. The differ-
ences on the CGI-S (5.1 baseline to 3.9 posttreatment) were
practically identical to those presented here. A total of 12
patients (75%) responded with scores of 1 or 2 on the CGI-I
(higher than the percentage of patients who responded
in this article, 52%). Improvements were achieved on the
Swanson, Nolen, and Pelham Scale–Fourth Edition (Swanson,
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1992) and on the Aberrant Behavior Checklist (ABC;
Aman, Singh, Stewart, & Field, 1985; effect size = 1.0-1.9).
Minimal improvements were attained (effect size = 0.4-1.1)
in the areas of irritability, asociability, stereotypies, and
repetitive language. No significant improvements were
achieved on the Conners’ Continuous Performance Test
(CPT; Conners, 2000) at the 4- and 8-week time points fol-
lowing treatment initiation; perhaps the CPT is less sensi-
tive in detecting improvements than the parent- and
teacher-rated questionnaires or it may have been because
the CPT is less susceptible to bias and placebo-type effects.
In parallel with this, many individuals with pervasive devel-
opmental disorder may encounter serious difficulties in
completing this test given their language problems and
scant motivation (Posey et al., 2006). Atomoxetine was
well tolerated, although 2 patients gave up the treatment
because of excessive irritability.
Troost et al. (2006) looked at the effects of atomoxetine
on the symptoms of ADHD and autism in 12 children with
pervasive developmental disorder and absence of mental
retardation (normal or borderline intelligence quotient), by
means of an open-label study lasting 10 weeks with doses
of 1.19 ± 0.41 mg/kg/day of atomoxetine. Response was
assessed using the parent-rated and physician-rated
ADHDRS. Atomoxetine lowered scores on the ADHDRS
less markedly than in the present work (44% reduction of
the baseline score, p < .003) and the parent-rated Conners’
Scale (25% on the subscale appraising cognitive difficul-
ties, p < .028; 32% in the area of hyperactivity, p < .030; and
23% on the ADHD index, p < .023). Nevertheless, the 21%
reduction (p = .071) was not significant nor were the
changes on the Hyperactivity subscale of the ABC Scale,
although there was a clear trend toward statistical signifi-
cance. No improvements were found on any of the other
ABC subscales. In the present study, tolerance was worse
than in previous studies because almost half of the children
(42%) discontinued treatment due to side effects. The most
common of these effects were GI intolerance, irritability,
sleep problems, and fatigue. The huge difference as regards
treatment dropout between this study and the previous one
(or ours) might be due to the fact that in this last study, the
drug was introduced too quickly. Although in the study
by Troost et al. the starting dose of atomoxetine was
0.5 mg/kg/day for 4 days, followed by 0.8 mg/kg/day for
3 days, and was then titrated from this point forward up to
a final dose of 1.2 mg/kg/day, Posey et al. (2006) adminis-
tered doses of 0.5 mg/kg/day for the 1st week, 0.8 mg/kg/
day for the 2nd week, and 1.2 mg/kg/day at the beginning of
the 3rd week of treatment.
Recently, Charnsil analyzed the efficacy of atomoxetine
in children with severe autistic disorders and symptoms of
ADHD (Charnsil, 2010). Evaluation was made by using the
ABC and CGI-I Scales. A total of 12 patients were recruited,
and treatment efficacy was measured at Weeks 6 and 10.
Fernández-Jaén et al.
Only CGI-I scores showed improvement after 10 weeks of
treatment. Differences with our results could be probably
related to the size of the studied population or the severity
of the disorder. However, according to these results
(Charnsil, 2010; Troost et al., 2006), perhaps the ABC
Scale is not appropriate to measure the efficacy of atomox-
etine in these patients.
After analyzing the literature cited, as well as our own
results, we can conclude that atomoxetine can be useful in
controlling the symptoms of ADHD in patients with perva-
sive developmental disorder. Although it appears to offer a
high degree of efficacy, this may be biased by the open-label
nature of most of the studies commented on as well as this
work (Aman et al., 2008). It would appear that side effects
are tolerable, including the GI effects (Aman et al., 2008),
although symptoms of irritability can emerge, as occurs with
methylphenidate (Aman et al., 2008; Posey et al., 2006). We
should conclude by restating the need to introduce atomox-
etine treatment slowly, given that, as in patients with normal
development, tolerance is dramatically enhanced by doing
so (Prasad & Steer, 2008). Nevertheless, this is preliminary
evidence, as no randomized, placebo-controlled studies with
a large patient sample have ever been published.
In short, the current study indicates the efficacy of once-
a-day atomoxetine in improving the core symptoms of
ADHD in patients with pervasive developmental disorder.
Undoubtedly, these data have come out of an open-label,
noncontrolled study, with several limitations (known effi-
cacy of the treatments studied, presence of concomitant
treatments, poor involvement of schools, etc.). However,
duration of prospective studies does not often exceed 10
weeks (Charnsil, 2010; Posey et al., 2006; Troost et al.,
2006); despite a more prolonged control in our study (16
weeks), longer studies are necessary to confirm tolerance
and sustained effectiveness of these treatments in time.
Finally, these studies clearly reflect the symptomatic
improvement under atomoxetine treatment but not adaptive
betterment; although improvement in social and academic
performance is not conditioned by the core symptoms of the
studied disorder, especially in cases with pervasive devel-
opmental disorder, it would be also worthwhile to evaluate
this adaptive improvement in more prolonged treatments.
However, the efficacy shown time and again in open-label
studies indicates the need for larger, controlled, double-
blind, randomized studies to confirm atomoxetine’s effi-
cacy versus placebo and against other treatment options for
ADHD. These studies should probably assess atomox-
etine’s effect on cognitive-executive functions and not only
clinical improvement by means of rating scales (Aman
et al., 2008). Until such results are obtained, atomoxetine
has shown its promise as treatment for children with perva-
sive developmental disorder and ADHD, with a reasonable
safety profile, or at least similar to that of methylphenidate
in this population.
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503
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
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Author Biographies
Alberto Fernández-Jaén, MD, Chief of the Division of Pediatric
Neurology at the “Quirón” Universitary Hospital of Madrid.
Master´s degree in Neuropsychology. Medical Director of Spanish
CADE center, specialized in neurodevelopmental disorders.
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Daniel Martín Fernández-Mayoralas, MD, PhD, Neuropediatrician
of the Division of Pediatric Neurology at the “Quirón” Universitary
Hospital of Madrid. Medical co-worker of Spanish “CADE”
center, specialized in neurodevelopmental disorders.
Beatriz Calleja-Pérez, MD, Primary Health System pediatrician
of Madrid. Specialized in endocrine and metabolic disorders. She
has written many papers and books related to ADHD, autism
spectrum conditions, and mental retardation.
Nuria Muñoz-Jareño, MD, Chief of the Division of Pediatric
Neurology at the “Infanta Leonor” Hospital of Madrid.
María del Rosario Campos Díaz, PhD in Psychology.
Director of “Psicoaula” Center of Madrid. Clinical and Educative
Psychology.
Sonia López-Arribas, MD, in Psychiatry from “Gomez Ulla”
Hospital of Madrid. Medical co-worker of Spanish “CADE” cen-
ter, specialized in neurodevelopmental disorders.