Atomoxetine hydrochloride in the treatment of children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: a placebo-controlled italian study

European Neuropsychopharmacology (2009) 19, 822–834 Atomoxetine hydrochloride in the treatmentof children and adolescents withattention-deficit/hyperactivity disorder and comorbidoppositional defiant disorder: A placebo-controlledItalian study Grazia Dell'Agnello a, Dino Maschietto b, Carmela Bravaccio c,Filippo Calamoneri d, Gabriele Masi e, Paolo Curatolo f, Dante Besana g,Francesca Mancini a, Andrea Rossi a, Lynne Poole h,Rodrigo Escobar i, Alessandro Zuddas j,⁎for the LYCY Study Group a Medical Department, Eli Lilly Italia, Italyb Operative Unit of Child Neuropsychiatry, Azienda USL n 10 Veneto Orientale, San Donà di Piave, Venezia, Italyc Department of Pediatrics, University of Naples "Federico II", Italyd Clinic of Child Neuropsychiatry, University Policlinic of Messina, Italye Department of Child Neuropsychiatry, IRCCS Fondazione Stella Maris, Calambrone, Pisa, Italyf Department of Child Neuropsychiatry, Tor Vergata University of Rome, Italyg Operative Structure of Child Neuropsychiatry, Hospital of Alessandria, Italyh Eli Lilly and Co. UKi European Medical Department, Eli Lilly and Co. Alcobendas, Madrid, Spainj Department of Neuroscience, Section of Child Neuropsychiatry, University of Cagliari, Italy Received 3 January 2009; received in revised form 2 July 2009; accepted 23 July 2009 Objective: The primary aim of this study was to assess the efficacy of atomoxetine in improving hyperactivity disorder; ADHD and ODD symptoms in paediatric patients with ADHD and comorbid oppositional defiant Oppositional defiant disorder (ODD), non-responders to previous psychological intervention with parent support.
Methods: This was a multicentre, randomised, placebo-controlled trial conducted in patientsaged 6–15 years, with ADHD and ODD diagnosed according to the DSM-IV criteria by a structured ⁎ Corresponding author. Centre for Pharmacological Therapies in Child and Adolescent Neuropsychiatry, Department of Neuroscience, University of Cagliari, via Ospedale, 46, 09124 Cagliari, Italy. Tel.: +39 070 609 3509/3510; fax: +39 070 669591.
E-mail address: (A. Zuddas).
0924-977X/$ - see front matter 2009 Elsevier B.V. and ECNP. All rights reserved.
Treatment with atomoxetine of children and adolescents with ADHD and ODD clinical interview (K-SADS-PL). Only subjects who are non-responders to a 6-week standardizedparent training were randomised to atomoxetine (up to 1.2 mg/kg/day) or placebo (in a 3:1 ratio)for the following 8-week double blind phase. Results: Only 2 of the 156 patients enrolled for theparent support phase (92.9% of males; mean age: 9.9 years), improved after the parent trainingprogram; 139 patients were randomised for entering in the study and 137 were eligible for efficacyanalysis. At the end of the randomised double blind phase, the mean changes in the Swanson,Nolan and Pelham Rating Scale-Revised (SNAP-IV) ADHD subscale were −8.1 ± 9.2 and −2.0 ± 4.7,respectively in the atomoxetine and in the placebo group (p b 0.001 between groups); changes inthe ODD subscale were −2.7 ± 4.1 and −0.3 ± 2.6, respectively in the two groups (p = 0.001 betweengroups). The CGI-ADHD-S score decreased in the atomoxetine group (median change at endpoint:−1.0) compared to no changes in the placebo group (pb0.001 between groups). Statisticallysignificant differences between groups, in favour of atomoxetine, were found in the CHIP-CEscores for risk avoidance domain, emotional comfort and individual risk avoidance subdomains.
An improvement in all the subscales of Conners Parents (CPRS-R:S) and Teacher (CTRS-R:S)subscales was observed with atomoxetine, except in the cognitive problems subscale in the CTRS-R:S. Only 3 patients treated with atomoxetine discontinued the study due to adverse events. Noclinically significant changes of body weight, height and vital signs were observed in both groups.
Conclusions: Treatment with atomoxetine of children and adolescents with ADHD and ODD, whodid not initially respond to parental support, was associated with improvements in symptoms ofADHD and ODD, and general health status. Atomoxetine was well tolerated.
2009 Elsevier B.V. and ECNP. All rights reserved.
Longitudinal data suggest that ADHD predicts academicoccupational dysfunction, earlier sexual intercourse, and Attention-deficit/hyperactivity disorder (ADHD) is charac- early parenthood ( terised by a persistent high level of hyperactive, inattentive ), whereas the presence of ODD may modulate persistence and impulsive behaviour, which can be prevalent in both child of associated disorders ) and may and adolescent populations. Although information on preva- predispose affected children to the subsequent development lence and incidence of ADHD in Europe is scarce and depending conduct disorders, delinquent behaviour and substance misuse on the used definition, a range from 2 to 5% (for subjects aged 6–16 years) has been reported in most of studies based on the ICD-10 and DSM-IV diagnostic criteria, respectively Clinical studies evaluating the effects of stimulants in (A few different epidemiological studies treating children with ADHD and comorbid ODD reported conducted in Italy estimated a frequency of ADHD in the inconclusive results. Some of these studies that investigate paediatric population ranging from 4% to 7% children with mental retardation, were conducted either in laboratory conditions or very specific settings such as gender ratio of 7:1 between males and females, aligned with partial hospitalization programs or strictly academic situa- data from international literature ). Factor analysis of ADHD and ), so that the generalization oppositional defiant symptoms reports by both Italian parents of their findings does not necessarily extend to the home and teachers indicate a structure similar to that observed in environment or more natural conditions. Others, without the US and Northern Europe ).
specifically assessing oppositional-defiant symptoms, ADHD may be associated with additional psychiatric reported the efficacy of methylphenidate for CD symptoms disorders such as mood and anxiety disorders and disruptive in ADHD patients with comorbid CD, also indicating that behaviour disorders. In particular, oppositional defiant disor- the presence of a diagnosis of ODD or CD diminished the der (ODD) is among the most common comorbid psychiatric effect size of the drug disorders in patients with ADHD, occurring in up to 67% of ). The Multicenter Treatment clinically referred populations () and Study of Children with ADHD (MTA study) showed that the representing a serious clinical problem. ODD is characterized presence of ODD did not alter the expected pattern of ADHD by a pattern of developmentally inappropriate negativistic, symptom response and suggested that ODD symptoms may hostile and defiant behaviour causing clinically significant show greater improvement with pharmacological treatment impairment in social, familiar or academic functioning.
than with behavioural management ( Genetic, family environment and psychometric studies indi- cate that they have separate aetiologies and pathophysio- Atomoxetine hydrochloride is a potent inhibitor of the logical mechanisms presynaptic norepinephrine transporters, and has minimal affinity for other neurotransmitter transporters or receptors.
ADHD combined with ODD tend to have more severe ADHD In comparative placebo-controlled studies conducted in symptoms, more peer problems, and more family distress children, adolescents and adults, atomoxetine consistently compared to children with ADHD alone ().
reduced symptoms of ADHD ( G. Dell'Agnello et al.
cant laboratory or ECG abnormalities; medical conditions likely to and positive outcomes have also been reported in family and increase sympathetic nervous system activity or regular intake of social functioning of children and adolescents with ADHD and sympathomimetic drugs; narrow-angle glaucoma; uncontrolled in their quality of life thyroid dysfunction; likelihood of start of structured psychotherapyat any time during the study; pregnant or breastfeeding females, or Moreover, atomoxetine seems to females at risk of pregnancy.
exert positive effects on additional psychiatric conditions,such as other disruptive behaviour disorders, mood andanxiety disorders, which are often associated with ADHD 2.2. Study design (An analysis of data from placebo-controlled studies in The entire study consisted of 4 study periods ( children and adolescents provided evidence on the efficacyof atomoxetine in reducing symptoms and improving social a) Study period I (screening phase): this was a screening and and family functioning in patients with ADHD and comorbid assessment/evaluation period, ranging from 3 to 28 days, to ensure eligibility for the study, and was started after parent's ally, a recent review has shown that atomoxetine reduces consent was obtained.
ADHD symptoms in both ODD-comorbid and non-comorbid b) Study period II (open-label, parent support phase): during this subjects to similar extents and that reduction in ODD 6-week phase, the investigators provided a standardized symptoms is highly related to the magnitude of ADHD management for the parental support. Parents received weeklyseries of advice on the management of the behavioural problems response, indicating that the presence of ODD symptoms of their children from qualified psychologists or child neuro- does not affect the clinical effectiveness of atomoxetine in psychiatrists, based on standardized procedures ( ADHD subjects Relapse of ADHD With this program, parents were trained to provide clear, symptoms is also not influenced by the presence of comorbid consistent expectations, directions and limits to their children, to use modification principles to reinforce positive behaviours In a recent placebo-controlled study conducted in Europe and to eliminate or reduce negative behaviours that create and Australia on children with ADHD and comorbid ODD, no problems for their children. Additionally, the training helped significant differences between atomoxetine and placebo parents to become able to assist their children in making friends were found for ODD symptoms, although atomoxetine and learning to work cooperatively with others. Response significantly improved ADHD symptoms criteria were defined as an improvement in CGI-S score of 2 ormore from baseline and at least a 30% decrease from baseline suggesting that the social and cultural environment may in 18 items of the ADHD subscale score of investigator-rated play a role in modulating the atomoxetine effects on ODD SNAP-IV. Only patients who did not reach both mentioned criteria were randomised to the study period III.
The present study was carried out to evaluate the efficacy c) Study period III (randomised, double blind, placebo-controlled of atomoxetine in improving ADHD and ODD symptoms in an phase). This was an 8-week period of double blind treatment. At Italian population of children and adolescents initially not the beginning of this period, patients who did not respond to the responding to a parent training intervention, and to assess 6-week period of parent support were randomly assigned to the extent of improvements in health status and level of treatment with atomoxetine or placebo in a ratio of 3:1 (i.e. with approximately 75% of patients receiving atomoxetine and 25% ofpatients receiving placebo). Patients randomised to atomoxetinewere titrated, in 7 days, from 0.5 mg/kg/day (dose ranging from 0.5 to 0.8 mg/kg/day) to the target dose of 1.2 mg/kg/day (rangefrom 1.0 to 1.4 mg/kg/day), to be administered for the first 2.1. Patient population 8 weeks of the study once daily in the morning. In case of onset offatigue or somnolence during the day, the investigator coulddecide to administer the dose in the evening.
The study group included patients of both sexes aged 6–15 years, d) Study period IV (long-term, open-label extension phase). This was with ADHD and ODD diagnosed according to the DSM-IV criteria. The an optional, open-label, long-term extension phase for patients Kiddie Schedule for Affective Disorders and Schizophrenia for School who had completed study period III. At the end of the 8-week Aged Children-Present and Lifetime Version (K-SADS-PL), a semi- double blind period, all patients had the choice to receive open structured diagnostic interview that includes supplements for label atomoxetine treatment for a long-term period until the drug affective disorders, anxiety, and behavioural disorders (including became commercially available. During this phase information on ADHD) was completed at screening for each subject.
efficacy, health outcomes and safety were collected.
To be eligible in the study, patients were required to have a score of at least 1.5 SD above the age norm for the ADHD subscale of theSNAP-IV, a CGI-S ≥4 at both screening and baseline, a SNAP-IV ODD The study periods I–III included 14 visits: visit 1 was the screening subscale score of at least 15, and a normal intelligence, i.e. a score visit, weekly visits were placed during the study period II (parent of ≥70 on an Intelligence Quotient (IQ) test. Patients with any of support phase, visits 2–8) and during the initial 4 weeks of the phase the following conditions were excluded from study participation: III (randomised double blind phase, visits 8–12); the remaining visits body weight b20 kg; history of bipolar I or II disorder, or history of (13 and 14) took place every 2 weeks. As study period IV is already psychosis or pervasive development disorder; history of any seizure ongoing, this article refers to data measured up at the end of the disorder (other than febrile seizures) or past/concomitant intake of randomised double blind phase.
anticonvulsants for seizure control; serious risk of suicide; history of Antipsychotics, antidepressants, anticonvulsants, anorexics, severe drug allergies; current or past (within 3 months) alcohol or anticoagulant, benzodiazepines and monoamine oxidase inhibitors drug abuse; clinically significant cardiovascular disease (including were not permitted at any time during the study. Concomitant hypertension) or other conditions that could be worsened by an administration of CYP2D6 inhibitors was not permitted, and in any increased heart rate or increased blood pressure; clinically signifi- case they could be used only after consultation and permission of

Treatment with atomoxetine of children and adolescents with ADHD and ODD Study design and study phases.
study staff physicians. Formal individual or family psychotherapy rated instrument measures presence and severity of depression.
was excluded for the entire duration of the study.
A total score below 20 indicates an absence of depression, a scoreof 20–30 indicates borderline depression and a score of 40–60indicates moderate depression. The SCARED-Parent Version is a 41- 2.3. Outcome measures item parent self-report questionnaire (),which measures symptoms of DSM-IV linked anxiety disorders in Efficacy variables were measured at the start and at the end of children, aimed at screening for panic disorder, general anxiety period I–III. The primary efficacy measure for this study is the 18 disorder, separation anxiety disorder, social phobia, and the items of the ADHD subscale score of the SNAP-IV. The SNAP-IV is a 26- presence of a relevant simple phobia, and the school phobia in item scale (0–3 score for each item) that includes 1 item for each of clinical () and community samples ( the 18 symptoms contained in the DSM-IV diagnosis of ADHD and 1 item for each of the 8 symptoms contained in the DSM-IV diagnosis of The Health Related Quality of Life (HRQOL) was measured by ODD. The SNAP-IV is a widely used measure of the symptoms of ADHD means of the Child Health and Illness Profile-Child Edition (CHIP-CE).
and ODD. It has been validated and normalized in a sample of school- It is a 76-item parent-rated assessment of a child's health status and aged children from the US ( level of functioning (and examines the following The SNAP-IV yields scores in three domains: inattention (items 1–9), domains and sub domains: satisfaction (satisfaction with health, hyperactivity/impulsivity (items 10–18), and oppositional (items satisfaction with self), comfort (physical comfort, emotional 19–26). The inattention, hyperactivity/impulsivity, and combined comfort, limitation of activity), risk avoidance (individual risk scores were considered as the primary efficacy measure while the avoidance, threats to achievement, peer influences), resilience ODD subscale score was considered a secondary measure in this (family involvement, physical activity, social problem solving), and achievement (academic performance, peer relations). Most of the The CGI-S ) was used to assess the severity of the items assess frequency of activities or feelings using a 5-point patient's ADHD symptoms, in relation to clinician's total experience response format.
of ADHD patients, on a 7-point scale (from 1 = normal, not ill at all, to Adverse events were recorded at any time during the study. Body 7 = among the most extremely ill patients).
weight, height, heart rate and blood pressure were measured at Other outcome measures of the study included the Conners' screening and at any visit during the randomised phase.
Parent Rating Scale-Revised: Short Form (CPRS-R:S) and the Conners'Teacher Rating Scale-Revised: Short Form (CTRS-R:S). The CPRS-R:S) is a 27-item rating scale completed by the parents to 2.4. Statistical analysis assess problem behaviours related to ADHD. The CTRS-R:S is a 28-item rating scale completed by a teacher to assess The sample size was based on the primary outcome variable, i.e. the problem behaviours related to ADHD in the school setting. Both 18 items of the ADHD subscale score of the investigator-rated SNAP- scales include the oppositional, cognitive problems, hyperactivity IV. Using an estimate of the common standard deviation of 13 points, ADHD Index subscales. In the cases of administration outside of the a sample of 130 patients (in a 3:1 ratio atomoxetine:placebo) gave school sessions, the CTRS-R:S had to be administered at the earliest about 80% power to detect a difference between groups of 8 points next time point of school-time or at the last visit prior to the school on the SNAP-IV, that can be considered as clinically significant. The break in the final assessment.
sample size was determined using a two-sided test with alpha = 0.05 Patients' depression and anxiety were scored by means of the and assumed that up to 10% of patients discontinued the study Children's Depression Rating Scale-Revised (CDRS-R) and the Screen without providing post-baseline efficacy data in the randomised for Child Anxiety Related Emotional Disorders (SCARED)-Parent Version, respectively. The CDRS-R () The analysis of primary and secondary efficacy endpoints, and of was based on the Hamilton Depression Rating Scale (HAMD) for vital signs, was carried out using an analysis of covariance (ANCOVA) adults, but also includes questions about school. This clinician- model on the last observation carried forward (LOCF) change from

G. Dell'Agnello et al.
Disposition of patients in the study.
baseline to endpoint, in the double blind randomised phase of the therapy. ADHD diagnosis and anxiety/affective diagnoses at study. The baseline score was included in the model as one of the baseline, according with DSM IV, are summarized in .
covariates. The results of the ADHD subscale were also expressed as The mean (± standard deviation) starting atomoxetine dose response rate, where response was defined as at least 25%, 30% or was 0.61 ± 0.08 mg/kg/day (range 0.44–0.80) and was titrated 40% improvement (reduction) from the start to the end of the to 1.10 ± 0.13 mg/kg/day (range 0.85–1.33) at the end of the randomised treatment phase of the study.
randomised phase of the study, a dose slightly below the one Raw scores of CHIP-CE were converted in T scores based on established standardized scores (mean of a healthy population, 50; recommended (SPC Strattera).
standard deviation from this mean, 10) ().
Adverse events were coded using the MedDRA dictionary. Events were considered treatment emergent adverse events (TEAE) if they started or worsened after the first intake of study medicationcompared to the pre-baseline period. Rates of patients with TEAE in A slight non-significant decrease in all SNAP-IV subscales scores the double blind phase of the study were compared between groups was observed during the parent support phase: the mean scores using the Fisher's exact test.
at the start and at the end of this phase were, respectively, 43.3 ±6.6 and 42.1 ± 6.9 for the ADHD subscale (i.e. the 18 items ofinattention, hyperactivity/impulsivity, and combined domains), A total of 156 patients (mean age: 9.9 years, 92.9% males) werescreened and entered the parent support phase. The patients' Demographic data by treatment group at baseline.
disposition is shown in Seventeen patients discontinuedthe study during the parent support phase, before randomization (mainly due to patient/caregiver's or Investigator's decision).
All 139 remaining patients were analysed for safety and 137 Demographic data: for efficacy (two did not have post-baseline data). In the atomoxetine group, 5 patients discontinued the study during mean ± SD (range) the double blind randomised phase. Only two patients (1.3% of screened) responded to the parent psychological intervention and were not randomised.
Patients' demographics are shown in No statisti- mean ± SD (range) cally significant differences between groups were found at baseline (visit 8). Previous psychotherapy (of any type) was mean ± SD (range) (110–174) used in 18 patients (17.1%) in the atomoxetine group and in 6 (18.8%) in the placebo group, while 21 (20.0%) and 4 (12.5%) mean ± SD (range) patients, respectively in the two groups, used previous drug

Treatment with atomoxetine of children and adolescents with ADHD and ODD DSM-IV ADHD diagnosis and anxiety/affective During the randomized phase, the mean changes from visit 8 diagnoses at baseline.
to the last visit in the ADHD subscale were −8.1 ± 9.2 and −2.0 ±4.7, respectively in the atomoxetine and in the placebo group (p b 0.001 between groups). The corresponding changes in the ODD subscale were −2.7 ± 4.1 and −0.3 ± 2.6, respectively in the DSM-IV ADHD subtype two groups (p = 0.001 between groups) (An analysis in Inattentive, number (%) response rate, defined as at least 25%, 30% or 40% improvement Hyperactive, number (%) (reduction) from visit 8 to the last visit in SNAP-IV ADHD Combined, number (%) subscale score, showed statistically significant differences Age at onset of ADHD symptoms, between groups, in favour of atomoxetine compared to years, mean ± SD (range) placebo, in 25% response (39.0% vs. 9.4%, respectively in thetwo groups, p = 0.001), in 30% response (31.4% vs. 6.3%, Anxiety diagnoses from K-SADS: p = 0.004) and in 40% response (18.1% vs. 3.1%, p = 0.043). A Generalised anxiety disorders, decrease of mean scores from visit 8 to the last visit was also observed in any subscale for atomoxetine treated patients, compared to no substantial changes with placebo (p b 0.001 between groups for inattention and p = 0.005 for hyperactivity/ Panic disorder, number (%) impulsivity) ).
Separation anxiety disorder, The median CGI-ADHD-S score did not change from the start to the end (median score: 5.0 at both visits) of the parent support Specific phobias, number (%) phase. A statistically significant decrease in the atomoxetinegroup was observed during the randomised double-blind phase Affective diagnoses from K-SADS: (median change at endpoint: −1.0), compared to no changes in Adjustment disorder, number (%) the placebo group (p b 0.001 between groups). The cumulative Dysthymia, number (%) distribution of CGI-ADHD-S scores shows that patients in the Major depressive disorders, placebo group have a similar distribution between baseline and last visit, while almost 50% of patients treated with atomoxetine Seasonal pattern disorders, were moderately ill or mildly ill at last visit The results of the CPRS-R:S and the CTRS-R:S in the parent Any other depressive disorders, support phase showed small decreases from baseline in all subscales (except for unchanged mean values in the cognitiveproblems subscale in the CTRS-R:S): the mean changes in theADHD index were −1.5 in the CPRS-R:S and −1.1 in the CTRS-R:S.
The results of the CPRS-R:S and the CTRS-R:S in the randomised 21.9 ± 3.3 and 21.3 ± 3.6 for the inattention subdomain, 21.4 ± 4.2 phase are summarised in An improvement in all CPRS-R:S and 20.8 ± 4.3 for the hyperactivity/impulsivity subdomain, and and CTRS-R:S subscales was observed following treatment with 18.1 ± 2.5 and 17.2 ± 3.3 for the ODD subdomain.
atomoxetine, except in the cognitive problems subscale in the Results of the SNAP-IV subscales during the randomised double blind phase (atomoxetine: full diamonds; placebo: empty circles). Values are mean scores.

G. Dell'Agnello et al.
(+ 3.3) and peer relations (+ 2.1). The comparisons betweengroups showed statistically significant differences, in favour ofatomoxetine, for risk avoidance domain (p = 0.013), and foremotional comfort (p = 0.007) and individual risk avoidance(p = 0.007) subdomains.
shows the TEAEs reported in at least 5% of patients in anygroup during the randomised double blind phase of the study. Themost commonly involved system organ classes by MedDRAdictionary were gastrointestinal disorders (mainly nausea,vomiting and abdominal pain), which were reported in 45.8% Frequency of CGI-ADHD-S score by treatment group — of patients in the atomoxetine group and 21.9% in the placebo study period III.
group, and metabolism and nutrition disorders (anorexia/decreased appetite), which were reported in 43.0% and 9.4% ofpatients, respectively in the two groups.
CTRS-R:S. Statistically significant differences vs. placebo were Almost all adverse events (except in 5 cases) were of mild or found in all subscales of the CPRS-R:S and in the oppositional moderate severity and only 3 patients treated with atomoxetine subscale of the CTRS-R:S, while the p value was at the limit of discontinued the study due to adverse events. No serious significance level in the hyperactivity subscale and in the AHDH adverse events were reported in both groups. No substantial index of the CTRS-R:S.
changes of mean body weight and height were observed during The mean total scores of CDRS-R and SCARED were below the the parent support phase, while the results in the randomised clinical threshold at baseline and did not change in the parent phase showed a small increase (+ 0.5 kg) of body weight with support phase: the mean changes from baseline to the end of placebo and a small decrease (−1.2 kg) with atomoxetine this phase were −0.6 ± 4.1 and −0.3 ± 7.5, respectively. The (p b 0.001), as well as mean height increased slightly more mean changes of CDRS-R total score from visit 8 to the last visit markedly in the placebo group (+ 1.5 cm) than in the were −0.5 ± 4.4 in the atomoxetine group and −0.1 ± 5.0 in the atomoxetine group (+ 1.0 cm) (p = 0.021). The mean changes in placebo group (p = 0.870 between groups). The corresponding vital signs from visit 8 to the end of randomised phase in the changes of SCARED were −2.1 ± 7.6 and −1.7 ± 6.5, respectively atomoxetine group and in the placebo group were, respectively, in the two groups (p = 0.836 between groups).
1.0 and 5.1 mmHg in systolic blood pressure (p = 0.482), −0.2 The mean CHIP-CE total, domain and subdomain scores did and 2.3 mmHg in diastolic blood pressure (p = 0.557), and 3.7 not change during the parent support phase. shows the and 1.5 bpm in heart rate (p = 0.312). No difference was ob- CHIP-CE total and domain T scores during the randomised served in body temperature, between study groups at any time double blind phase. The mean changes of CHIP-CE total score and at endpoint.
from visit 8 to the last visit were 3.6 with atomoxetine and 1.2with placebo (p = 0.071 between groups). Improvements in meanscores of all domains were observed in the atomoxetine group.
The results of CHIP-CE subdomains in the atomoxetine groupshowed marked improvements from visit 8 to the last visit in ADHD treatment guidelines suggest that pharmaco-therapy satisfaction with self (mean change: + 4.2), emotional comfort should be used as part of a multi-modal treatment package (+ 2.1), individual risk avoidance (+ 2.7), threats to achievement including parent training, family or school interventions Results of the CPRS-R:S and the CTRS-R:S in the randomised double blind phase.
Cognitive problems Cognitive problems Values are means ± standard deviation. p values refer to comparisons between groups in changes from visit 8 to the last visit.

Treatment with atomoxetine of children and adolescents with ADHD and ODD CHIP-CE total and domains scores during the randomised double blind phase (atomoxetine: full diamonds; placebo: empty circles). Values are mean scores.
and psychotherapy. In Europe, pharmaco-therapy is largely significant compared to placebo not only in the primary through psycho-stimulant medications such as methylpheni- variable 18 items of the ADHD subscale score of the SNAP-IV, date and dexamphetamine NICE, but also in each of the three examined domains (inattention, Although the Italian guidelines of diagnosis and treatment of hyperactivity/impulsivity and oppositional). A significantly ADHD recommend the use of pharmaco-therapy for children higher number of patients on atomoxetine compared to and adolescents with severe and disabling ADHD (SINPIA, placebo showed various degrees of response to therapy, ), psychotherapy and psychosocial intervention is still consistently with the improvement observed in the ADHD the main (often the only) type of treatment, for both ADHD and ODD. In this trial only subjects who failed to respond to a It should be highlighted that, despite that the results did 6-week validated and standardized behavioural management not show initial response to the psychoeducational phase, training for the parents of all the eligible patients were the duration of the parental support phase was relatively randomised to atomoxetine or placebo.
short and, therefore, potential carry-on positive effects of This study included only paediatric patients meeting this training program effect might have been produced criteria for ADHD and comorbid ODD, and used a wide during the randomized phase of the study: an informal non- spectrum of validated outcome measures, including ADHD structured psychoeductional support to the parents was symptoms, ODD symptoms, comorbid anxiety and depres- provided during the pharmacological double blind phase of sion, problem behaviours related to ADHD (including the the study. In the present study, treatment with atomoxetine school setting), and emotional and social well-being of the or placebo could be considered as an ‘add-on' therapy given patient and the family.
in combination with the psychoeducational support. This The manualized psychological intervention with parental particular design might explain the, minimal or no placebo support resulted in a very low rate of response and the mean effects observed in the present study. With this respect, the values of all efficacy outcome measures of the study did not results of a recently published study conducted in Europe and vary in this phase accordingly. In non-responder patients, Australia (in which treatment with treatment with atomoxetine was associated with improve- atomoxetine or placebo of children with ADHD and comorbid ments of symptoms of both ADHD and ODD, which resulted ODD was not preceded by psychotherapy, showed that ADHD G. Dell'Agnello et al.
Treatment-emergent adverse events reported in at least 5% of patients in any group during the randomised double blind phase of the study.
Atomoxetine (n = 107) Abdominal pain upper Decreased appetite n = number of patients; p values refer to comparisons between groups.
symptoms in the atomoxetine arm improved in a similar the tricyclics may be mediated by the improvement in extent to that of the present trial, whereas no significant symptoms of ADHD. On the other hand, Spencer et al. differences between atomoxetine and placebo were found showed that improvements by amphetamine salts on ODD on ODD symptoms due to a placebo effect. Similarly, in a subscale of the SNAP-IV can be measured, even in subjects Northern American study (), atomoxetine with pure ODD, suggesting that the improvement in symptoms was effective for the treatment of ADHD symptoms but of oppositionality may be independent of any change in appeared to not significantly reduce oppositional symptoms ADHD symptoms. Moreover, it has also been suggested that compared to placebo; in another study environment can also play a crucial role on the effects of ADHD significant improvements vs. placebo in ADHD, ODD, medication on ODD symptoms. showed and quality-of-life measures in patients with concomitant that methylphenidate appears to improve symptoms of hy- ODD symptoms were obtained at a dose level (1.8 mg/kg/ peractivity and impulsivity in a traditional classroom setting day) higher than that of the present trial. It should also be without significant effects on symptoms of oppositionality.
considered that although severity of ADHD and ODD Contrarily, in a structured program of therapeutic, educa- symptoms was similar in all the studies published (Newcorn tional, and recreational activities, subjects appeared to et al., ; Kaplan et al., ; Bangs et al., ; improve with methylphenidate treatment in both their Biederman et al., and in the present study, patients hyperactive/impulsive and oppositional symptoms. Taken of the Newcorn study were older (mean age 11 compared 9 of together, these findings further suggest the independence of the other studies), with a higher proportion of inattentive oppositional and hyperactive/impulsive symptoms to treat- subtype (about 30% compared to the 10% of other studies) ment, and the crucial effect that psychoeducation interven- and with medication administered twice a day, in compari- tion can play on clinical efficacy of ADHD medication on ODD son to the single daily dose of the other studies.
In the present study, pre-selected children and adoles- In the patients with dysthymia, cents meeting the DSM-IV diagnostic criteria for ADHD (any generalized or separation anxiety, showed a smaller reduc- subtype) and ODD were shown to benefit from an 8-week tion in ODD symptoms during atomoxetine treatment, treatment with atomoxetine (and significantly compared although excluding these patients from the overall LOCF to a placebo control group) not only in ADHD, but also in analysis had no effect because their small number. In the oppositional symptoms. Additionally, the effects on ODD present study, only few patients (approximately 20% of symptoms were obtained at a mean atomoxetine dose (final patients in total) presented evidence of comorbid anxiety or dose: 1.10 ± 0.13 mg/kg/day) that approximates the mean affective disorders, and the mean baseline scores of CDRS-R dose used with success in ADHD symptoms in children and SCARED were indicative of no or borderline symptoms in and that is recommended most of the participants. Consequently, the mean total scores for the maintenance of symptoms' control of both scales did change neither in the parent support phase, nor in the randomised treatment phase in both groups.
Patients with ADHD and comorbid oppositional symptoms The assessment of the problem behaviours related to exhibit significantly greater ADHD symptom severity and social ADHD, as measured by parents with the CPRS-R:S, showed that dysfunction than ADHD patients without such comorbidity treatment with atomoxetine was associated with improve- A recent metanalysis ( ments in all subscales (oppositional, cognitive problems, ) suggests that much of the improvement in oppositional hyperactivity and AHDH index) and significantly compared symptoms by atomoxetine, pemoline, psychostimulants, or to placebo. Similarly, patients treated with atomoxetine Treatment with atomoxetine of children and adolescents with ADHD and ODD experienced improvements of the problem behaviours related down during the initial 6 months of treatment, but increases to ADHD in the school environment (by teacher-rated CTRS-R: to values close to those predicted by age and gender norms at S), except in the cognitive problems subscale. Consistently the end of the 2 years of observation ).
with previous published data these The results of the open-label extension phase will provide findings suggest that both parents and teachers are able to further insight on the long-term safety of atomoxetine on detect improvements in a wide spectrum of functional growth and cardiovascular effects.
behaviours, including the school setting.
In conclusion, the results of this study indicate that, in The mean CHIP-CE total score at the start of the ran- children and adolescents with ADHD and ODD, who initially domised phase was indicative of a moderate impairment of did not respond to short term psychological intervention with HRQOL, which was lower than that reported in another trial parental support, the treatment with atomoxetine was conducted in the UK that used the same scale associated with improvements on symptoms of both ADHD ). Although this previous study ( and ODD measured by both parents and teachers, as well as showed greater improvements than those observed in our in specific aspects of quality of life and general health.
study, caution should be used in the interpretation of the Atomoxetine exhibited a satisfactory safety profile, with results due to the open-label design of this study and to low incidence of dropouts and no serious adverse events possible cross-cultural differences in the perception of observed. The results in the open-label extension phase will quality of life. Moreover, another analysis of effects of assess whether the benefits observed after 8 weeks of atomoxetine on HRQOL that used a different scale pointed treatment are maintained in a long-term exposure to into evidence that the likelihood of obtaining improvements in physical functioning correlates with a worse baselineperception of HRQOL (The results of Role of the funding source our study showed that an HRQOL improvement was observedin some subdomains; other scores improved but did not reach The study is fully sponsored by Eli Lilly Italy.
statistical significance maybe because of the small samplesize due to the study design based on SNAP-IV improvement.
Importantly, patients treated with atomexetine greatly G. Dell'Agnello has written the study protocol, coordinated research benefited in domains, such as risk avoidance or achievement, activities and substantially contributed to data analisis and which are considered as the most impacted ones in this interpretation. D. Maschietto, A. Pascotto, F. Calamoneri, G. Masi, patient population ).
P. Curatolo, D. Besana, have given their contribution to study design The safety results of this study are consistent with those and data collection. F. Mancini has coordinated study activities and of previous reports. In all trials atomoxetine resulted safe A. Rossi has contributed to data analysis and interpretation of the and well tolerated, with discontinuations among children results and coordinated publication's activities; L. Poole has and adolescents due to adverse events typically less than 5% contributed to data analysis and interpretation of the results. R.
() and with a spectrum of adverse Escobar has contributed to study design, data interpretation and events that are mostly mild to moderate and transient general study coordination. A. Zuddas has substantially contributed (; see also ). The typology of to study design, data collection, analysis and interpretation andgeneral study coordination. All authors have critically revised the adverse events most frequently reported in this study article and approved the manuscript before submission.
(anorexia, somnolence and gastrointestinal complaints) andtheir severity, coupled with the lack of serious adverseevents, are in line with the known safety profile of Conflict of interest atomoxetine in children and adolescents over variable G. Dell'Agnello, F. Mancini, A. Rossi are full time employees at Eli extents of exposure Lilly Italy. L. Poole and R. Escobar are full time employees at Eli Lilly Atomoxetine has also been previously & Co. D. Maschietto is a consultant for Eli Lilly and Shire, has associated with mild increases in blood pressure and pulse received research grants from Eli Lilly. C.Bravaccio has received that plateau during treatment and resolve upon discontin- research grants from Eli Lilly, Shire and Astra Zeneca. F.Calamoneri uation The noradrenergic activity of has received research grants from Eli Lilly. G. Masi is a consultant for atomoxetine accounts for these effects. In this study, the Eli Lilly and Shire, has received research grants from Eli Lilly, and hasbeen speaker for Eli Lilly and Sanofi-Aventis. D. Besana is a mean blood pressure did not vary following treatment with consultant for Eli Lilly, has received research grants from Eli Lilly atomoxetine, while a small increase in heart rate from the and Janssen Cilag and has been speaker for Eli Lilly. P. Curatolo is a start to the end of the randomised phase has been reported consultant for Eli Lilly, and has received research grants from in patients receiving atomoxetine, however not significantly Janssen Cilag and Eli Lilly. D. Besana is a consultant for Eli Lilly, has compared to placebo.
received research grants from Eli Lilly and Janssen Cilag and has A small decrease of body weight and a slightly lower been a speaker for Eli Lilly. A. Zuddas has an advisory or consulting height gain compared to placebo were observed in patients relationship with Eli Lilly, Shire, UCB and Astra Zeneca, has received receiving atomoxetine. This could be an expected finding research grants from Eli Lilly and Shire, and has been a speaker for based on previous experiences, which showed that atomox- Eli Lilly and Sanofi-Aventis.
etine may have a modest initial effect on growth rates.
However, this apparent growth-lowering effect does not persist on a long-term exposure: a pooled analysis of data onweight and height from 13 trials in children and adolescents The authors thank Luca Cantini and Andrea Rossi for their support in treated with atomoxetine at usual doses for at least 2 years medical writing of this article, Pierluigi Crisà and Roberto Pino for has shown that mean growth rates may moderately slow their contribution in the study organization.
G. Dell'Agnello et al.
The LYCY study group is: effects on quality of life and school functioning. Clin. Pediatr.
Dino Maschietto, Unità Operativa di Neuropsichiatria Infantile, (Phila) 45, 819–827.
Azienda USL 10 Veneto orientale, San Donà di Piave, Venezia; Bukstein, O.G., Kolko, D.J., 1998. Effects of methylphenidate on Carmela Bravaccio, Departimento di Pediatria, Università di Napoli aggressive urban children with attention-deficit hyperactivity "Federico II", Napoli; Filippo Calamoneri, Clinica di Neuropsichiatria disorder. J. Clin. Child. Psychol. 27, 340–351.
Infantile, Policlinico Universitario, Messina; Gabriele Masi, Divisione Camerini, G., Coccia, M., Caffo, E., 1996. Il Disturbo da Deficit di Neuropsichiatria Infantile, IRCCS Fondazione Stella Maris, dell'Attenzione-Iperattività: analisi della frequenza in una Calambrone, Pisa; Antonio Condini, Unità Operativa Autonoma di popolazione scolastica attraverso questionari agli insegnanti.
Neuropsichiatria infanzia e adolescenza ULSS 16, Padova; Amerigo Psichiatria. dell'infanzia. e. dell'adolescenza 63, 587–594.
Zanella, IRCCS Eugenio Medea, San Vito al Tagliamento, Pordenone; Christman, A.K., Fermo, J.D., Markowitz, J.S., 2004. Atomoxetine, a Giovanni Lanzi, Fondazione Mondino, Dipartimento di Clinica novel treatment for attention-deficit–hyperactivity disorder.
Neurologica e Psichiatrica dell'Età Evolutiva, Pavia; Lucia Margari, Pharmacotherapy 24, 1020–1036.
Clinica Neurologica 2°, Sezione di Neuropsichiatria Infantile, Conners, C.K., 1997. Conners' Rating Scales-Revised, Technical Policlinico di Bari, Bari; Paolo Curatolo, Neuropsichiatria Infantile, Manual. MultiHealth Systems Inc, Toronto.
Policlinico di Tor Vergata, Clinica Sant'Alessandro, Roma; Edwige Connor, D., Glatt, S.J., Lopez, I.D., Jackson, D., Melloni, R.H., 2002.
Veneselli, Ospedale Giannina Gaslini, Genova; Dante Besana, Psychopharmacology and aggression: I: a meta-analysis of Struttura Operativa Complessa di Neuropsichiatria Infantile, Ospe- stimulant effects on overt/covert aggression-related behaviors dale Infantile, Azienda Ospedaliera Nazionale di Alessandria, in ADHD. J. Am. Acad. Child. Adolesc. Psychiatry 41, 253–262.
Alessandria; Anna Fabrizi, Dipartimento di Scienze Neurologiche e Corman, S.L., Fedutes, B.A., Culley, C.M., 2004. Atomoxetine: the Psichiatriche dell'Età Evolutiva, Università La Sapienza, Roma; first nonstimulant for the management of attention-deficit/ Alessandro Zuddas, Clinica di Neuropsichiatria Infantile, Azienda hyperactivity disorder. Am. J. Health. Syst. Pharm. 61, 2391–2399.
Ospedaliero-Universitaria di Cagliari, Cagliari.
Escobar, R., Soutullo, C.A., Hervas, A., Gastaminza, X., Polavieja, P., Gilaberte, I., 2005. Worse quality of life in children newlydiagnosed with Attention Deficit/Hyperactivity Disorder (ADHD) compared with asthmatic and healthy children. Pediatrics 116,e364–369.
Aman, M.G., Kern, R.A., Osborne, P., Tumuluru, R., Rojahn, J., del Fergusson, D.M., Horwood, L.J., Lynskey, M.T., 1993. The effects of Medico, V., 1997. Fenfluramine and methylphenidate in children conduct disorder and attention deficit in middle childhood on with mental retardation and borderline IQ: clinical effects. Am.
offending and scholastic ability at age 13. J. Child. Psychol.
J. Ment. Retard. 101, 521–534.
Psychiatry 34, 899–916.
Bangs, M.E., Emslie, G.J., Spencer, T.J., Ramsey, J.L., Carlson, C., Fergusson, D.M., Lynskey, M.T., Horwood, L.J., 1997. Attentional Bartky, E.J., Busner, J., Duesenberg, D.A., Harshawat, P., difficulties in middle childhood and psychosocial outcomes in Kaplan, S.L., Quintana, H., Allen, A.J., Sumner, C.R., 2007.
young adulthood. J. Child. Psychol. Psychiatry 38, 633–644.
Efficacy and safety of atomoxetine in adolescents with attention- Gallucci, F., Bird, H.R., Berardi, C., Gallai, V., Pfanner, P., deficit/hyperactivity disorder and major depression. J. Child.
Weinberg, A., 1993. Symptoms of attention-deficit hyperactivity Adolesc. Psychopharmacol. 17, 407–420.
disorder in an Italian school sample: findings of a pilot study. J.
Bangs, M.E., Hazell, P., Danckaerts, M., Hoare, P., Coghill, D.R., Am. Acad. Child. Adolesc. Psychiatry 32, 1051–1058.
Wehmeier, P.M., Williams, D.W., Moore, R.J., Levine, L., 2008.
Gaub, M., Carlson, C.L., 1997. Behavioral characteristics of DSM-IV Atomoxetine for the treatment of attention-deficit/hyperactivity ADHD subtypes in a school-based population. J. Abnorm. Child.
disorder and oppositional defiant disorder. Pediatrics 121, e314–320.
Psychol. 25, 103–111.
Barkley, R.A., Fischer, M., Smallish, L., Fletcher, K., 2004. Young Geller, D., Donnelly, C., Lopez, F., Rubin, R., Newcorn, J., Sutton, adult follow-up of hyperactive children: antisocial activities and V., Bakken, R., Paczkowski, M., Kelsey, D., Sumner, C., 2007.
drug use. J. Child. Psychol. Psychiatry 45, 195–211.
Atomoxetine treatment for pediatric patients with attention- Barkley, R.A., Fischer, M., Smallish, L., Fletcher, K., 2006. Young deficit/hyperactivity disorder with comorbid anxiety disorder.
adult outcome of hyperactive children: adaptive functioning in J. Am. Acad. Child. Adolesc. Psychiatry 46, 1119–1127.
major life activities. J. Am. Acad. Child. Adolesc. Psychiatry 45, Guy, W., 1976. ECDEU assessment manual for psychopharmacology, revised. Bethesda (MD), US Dept. of Health, Education and Welfare.
Biederman, J., Heiligenstein, J.H., Faries, D.E., Galil, N., Dittmann, Hazell, P., Zhang, S., Wolanczyk, T., Barton, J., Johnson, M., Zuddas, R., Emslie, G.J., Kratochvil, C.J., Laws, H.F., Schuh, K.J., 2002.
A., Danckaerts, M., Ladikos, A., Benn, D., Yoran-Hegesh, R., Efficacy of atomoxetine versus placebo in school-age girls with Zeiner, P., Michelson, D., 2006. Comorbid oppositional defiant attention-deficit/hyperactivity disorder. Pediatrics 110, e75.
disorder and the risk of relapse during 9 months of atomoxetine Biederman, J., Spencer, T.J., Newcorn, J.H., Gao, H., Milton, D.R., treatment for attention-deficit/hyperactivity disorder. Eur.
Feldman, P.D., Witte, M.M., 2007. Effect of comorbid symptoms Child. Adolesc. Psychiatry 15, 105–110.
of oppositional defiant disorder on responses to atomoxetine in Hinshaw, S.P., Hencker, B., Whalen, C.K., Erhardt, D., Dunnington children with ADHD: a meta-analysis of controlled clinical trial Jr, R.E., 1989. Aggressive, prosocial and non-social behavior in data. Psychopharmacology 190, 31–41.
hyperactive boys: dose effects of methylphenidate in naturalistic Birmaher, B., Khetarpal, S., Brent, D., Cully, M., Balach, L., Kaufman, settings. J. Consult. Clin. Psychol. 57, 636–643.
J., Neer, S.M., 1997. The Screen for Child Anxiety Related Hinshaw, S.P., Heller, T., Mc Hale, J.P., 1992. Covert antisocial Emotional Disorders (SCARED): scale construction and psycho- behavior in boys with attention-deficit hyperactivity disorder: metric characteristics. J. Am. Acad. Child. Adolesc. Psychiatry 36, external validation and effects of methylphenidate. J. Consult.
Clin. Psychol. 60, 274–281.
Birmaher, B., Brent, D., Chiappetta, L., Bridge, J., Monga, S., Kaplan, S., Heiligenstein, J., West, S., Busner, J., Harder, D., Baugher, M., 1999. Psychometric properties of the Screen for Dittmann, R., Casat, C., Wernicke, J.F., 2004. Efficacy and safety Child Anxiety Related Emotional Disorders Scale (SCARED): a of atomoxetine in childhood attention-deficit/hyperactivity replication study. J. Am. Acad. Child. Adolesc. Psychiatry 38, disorder with comorbid oppositional defiant disorder. J. Atten.
Disord 8, 45–52.
Brown, R.T., Perwien, A., Faries, D.E., Kratochvil, C.J., Vaughan, B.S., Kelsey, D.K., Sumner, C.R., Casat, C.D., Coury, D.L., Quintana, H., 2006. Atomoxetine in the management of children with ADHD: Saylor, K.E., Sutton, V.K., Gonzales, J., Malcolm, S.K., Schuh, K.J., Treatment with atomoxetine of children and adolescents with ADHD and ODD Allen, A.J., 2004. Once-daily atomoxetine treatment for children Perwien, A.R., Faries, D.E., Kratochvil, C.J., Sumner, C.R., Kelsey, with attention-deficit/hyperactivity disorder, including an assess- D.K., Allen, A.J., 2004. Improvement in health-related quality of ment of evening and morning behavior: a double-blind, placebo- life in children with ADHD: an analysis of placebo controlled controlled trial. Pediatrics 114, 1–8.
studies of atomoxetine. J. Dev. Behav. Pediatr. 25, 264–271.
Kirley, A., Lowe, N., Mullins, C., McCarron, M., Daly, G., Waldman, Perwien, A.R., Kratochvil, C.J., Faries, D.E., Vaughan, B.S., Spencer, I., Fitzgerald, M., Gill, M., Hawi, Z., 2004. Phenotype studies of T., Brown, R.T., 2006. Atomoxetine treatment in children and the DRD4 gene polymorphisms in ADHD: association with adolescents with attention-deficit hyperactivity disorder: what oppositional defiant disorder and positive family history. Am. J.
are the long-term health-related quality-of-life outcomes? Med. Genet. B. Neuropsychiatr. Genet 131, 38–42.
J. Child. Adolesc. Psychopharmacol. 16, 713–724.
Klein, R.G., Abikoff, H., Klass, E., Ganeles, D., Seese, L.M., Pollack, Polanczyk, G., de Lima, M.S., Horta, B.L., Biederman, J., Rohde, L.A., S., 1997. Clinical efficacy of methylphenidate in conduct disorder 2007. The worldwide prevalence of ADHD: a systematic review and with and without attention-deficit hyperactivity disorder. Arch.
metaregression analysis. Am. J. Psychiatry 164, 942–948.
Gen. Psychiatry 54, 1073–1080.
Poznanski, E., Mokros, H.B., 1999. Children's Depression Rating Kolko, D.J., Bukstein, O.G., Barron, J., 1999. Methylphenidate and Scale, Revised. Western Psychological Services, Los Angeles.
behavior modification in children with ADHD and comorbid ODD Prasad, S., Harpin, V., Poole, L., Zeitlin, H., Jamdar, S., Puvanendran, or CD: main and incremental effects across settings. J. Am. Acad.
K., The SUNBEAM Study Group, 2007. A multi-centre, randomised, Child. Adolesc. Psychiatry 38, 578–586.
open-label study of atomoxetine compared with standard current Kuhne, M., Schachar, R., Tannock, R., 1997. Impact of comorbid therapy in UK children and adolescents with attention-deficit/ oppositional or conduct problems on attention-deficit hyper- hyperactivity disorder (ADHD). Curr. Med. Res. Opin. 23, 379–394.
activity disorder. J. Am. Acad. Child. Adolesc. Psychiatry 36, Ralston, S.J., Lorenzo, M.J., 2004. ADORE — Attention-Deficit Hyperactivity Disorder Observational Research in Europe. Eur.
Lavigne, J.V., Cicchetti, C., Gibbons, R.D., Binns, H.J., Larsen, L., Child. Adolesc. Psychiatry. 13 (Suppl 1), 36–42.
De Vito, C., 2001. Oppositional defiant disorder with onset in Riley, A.W., Forrest, C.B., Starfield, B., Karig, M., Ensminger, M.E., preschool years: longitudinal stability and pathways to other 1998. A taxonomy of adolescent health need: reliability and disorders. J. Am. Acad. Child. Adolesc. Psychiatry 40, validity of the adolescent health and illness profiles. Med. Care 36, 1237–1248.
Michelson, D., Faries, D., Wernicke, J., Kelsey, D., Kendrick, K., Riley, A.W., Forrest, C.B., Starfield, B., Rebok, G.W., Robertson, J.A., Sallee, F.R., Spencer, T., 2001. Atomoxetine in the treatment of Green, B.F., 2004. The parent report form of the CHIP-Child children and adolescents with attention-deficit/hyperactivity Edition: reliability and validity. Med. Care 42, 210–220.
disorder: a randomized, placebo-controlled, dose–response Satake, H., Yamashita, H., Yoshida, K., 2004. The family psychosocial study. Pediatrics 108, E83.
characteristics of children with attention-deficit hyperactivity Michelson, D., Allen, A.J., Busner, J., Casat, C., Dunn, D., Kratochvil, disorder with or without oppositional or conduct problems in C., Newcorn, J., Sallee, F.R., Sangal, R.B., Saylor, K., West, S., Japan. Child. Psychiatry Hum. Dev. 34, 219–235.
Kelsey, D., Wernicke, J., Trapp, N.J., Harder, D., 2002. Once- Società Italiana di NeuroPsichiatria dell'Infanzia e dell'Adolescenza daily atomoxetine treatment for children and adolescents with (SINPIA), 2004. Linee guida per il disturbo da deficit attentivo attention deficit hyperactivity disorder: a randomized, placebo- con iperattività (ADHD) in età evolutiva. I: Diagnosi e terapia controlled study. Am. J. Psychiatry 159, 1896–1901.
farmacologica. Giornale di Neuropsichiatria dell'età evolutiva 24 MTA Cooperative Group, 1999. Moderators and mediators of treat- (Suppl. 1), 41–87.
ment response for children with attention-deficit/hyperactivity Spencer, T., Biederman, J., Wilens, T., Prince, J., Hatch, M., Jones, J., disorder. Arch. Gen. Psychiatry 56, 1088–1096.
Harding, M., 1998. Effectiveness and tolerability of atomoxetine Mugnaini, D., Masi, G., Brovedani, P., Chelazzi, C., Matas, M., in adults with attention deficit hyperactivity disorder. Am. J.
Romagnoli, C., Zuddas, A., 2006. Teacher reports of ADHD Psychiatry 155, 693–695.
symptoms in Italian children at the end of first grade. Eur.
Spencer, T.J., Newcorn, J.H., Kratochvil, C.J., Ruff, D., Michelson, Psychiatry 21, 419–426.
D., Biederman, J., 2005. Effects of atomoxetine on growth after Muris, P., Merckelbach, H., Brakel, A., Mayer, B., Dongen, L., 1999.
2-year treatment among pediatric patients with attention- The Revised Screen for Child Anxiety Related Emotional Disorders deficit/hyperactivity disorder. Pediatrics 116, 74–80.
(SCARED-R): factor structure in normal children. Person. Indiv.
Spencer, T.J., Abikoff, H.B., Connor, D.F., Biederman, J., Pliszka, S.R., Diff. 26, 99–112.
Boellner, S., Read, S.C., Pratt, R., 2006. Efficacy and safety National Institute for Clinical Excellence, 2000. Guidance on the use of mixed amphetamine salts extended release (Adderall XR) in of methylphenidate (ritalin, equasym) for attention deficit/ the management of oppositional defiant disorder with or without hyperactivity disorder (ADHD) in childhood. Technology Appraisal, comorbid attention-deficit/hyperactivity disorder in school-aged Guidance No. 13.
children and adolescents: a 4-week, multicenter, randomized, Newcorn, J.H., Spencer, T.J., Biederman, J., Milton, D.R., double-blind, parallel-group, placebo-controlled, forced-dose-es- Michelson, D., 2005. Atomoxetine treatment in children and calation study. Clin. Ther. 28, 402–418.
adolescents with attention-deficit/hyperactivity disorder and Steinhausen, H.C., Novik, T.S., Baldursson, G., Curatolo, P., Lorenzo, comorbid oppositional defiant disorder. J. Am. Acad. Child.
M.J., Rodrigues Pereira, R., Ralston, S.J., Rothenberger, A., 2006.
Adolesc. Psychiatry 44, 240–248.
Co-existing psychiatric problems in ADHD in the ADORE cohort. Eur.
Newcorn, J.H., Michelson, D., Kratochvil, C.J., Allen, A.J., Ruff, D.D., Child. Adolesc. Psychiatry 15 (suppl 1), 25–29.
Moore, R.J., Atomoxetine Low-dose Study Group, 2006. Low-dose Strattera SPC (last updated on the eMC: 20/11/2008) atomoxetine for maintenance treatment of attention-deficit/ hyperactivity disorder. Pediatrics 118, 1701–1706.
Oosterlaan, J., Scheres, A., Sergeant, J.A., 2005. Which executive Swanson, J., 1992. School-Based Assessment and Interventions for functioning deficits are associated with AD/HD, ODD/CD and ADD. KC Publishing, Irvine, p. 184.
comorbid AD/HD+ODD/CD? J. Abnorm. Child. Psychol. 33, 69–85.
Taylor, E., Dopfner, M., Sergeant, J., Asherson, P., Banaschewski, Pelham, W.E., Bender, M.E., Caddell, J., Booth, S., Moorer, S.H., 1985.
T., Buitelaar, J., Coghill, D., Danckaerts, M., Rothenberger, A., Methylphenidate and children with attention-deficit disorder: dose Sonuga-Barke, E., Steinhausen, H.C., Zuddas, A., 2004. European effects on classroom academic and social behavior. Arch. Gen.
clinical guidelines for hyperkinetic disorder — first upgrade. Eur.
Psychiatry 42, 948–952.
Child. Adolesc. Psychiatry 13 (Suppl 1), I7–30.
G. Dell'Agnello et al.
van Lier, P.A., van der Ende, J., Koot, H.M., Verhulst, F.C., 2007.
Wernicke, J.F., Kratochvil, C.J., 2002. Safety profile of atomoxetine Which better predicts conduct problems? The relationship of in the treatment of children and adolescents with ADHD. J. Clin.
trajectories of conduct problems with ODD and ADHD symptoms Psychiatry 63 (Suppl 12), 50–55.
from childhood into adolescence. J. Child. Psychol. Psychiatry Wernicke, J.F., Faries, D., Girod, D., Brown, J., Gao, H., Kelsey, D., 48, 601–608.
Quintana, H., Lipetz, R., Michelson, D., Heiligenstein, J., 2003.
Vio, C., Offredi, G., Marzocchi, G.M., 1999. Il bambino con deficit di Cardiovascular effects of atomoxetine in children, adolescents, attenzione/iperattività. Trento, Edizioni Erickson.
and adults. Drug. Saf. 26, 729–740.
Weiss, M., Tannock, R., Kratochvil, C., Dunn, D., Velez-Borras, J., Zuddas, A., Marzocchi, G.M., Oosterlaan, J., Cavolina, P., Ancilletta, Thomason, C., Tamura, R., Kelsey, D., Stevens, L., Allen, A.J., B., Sergeant, J., 2006. Factor structure and cultural factors of 2005. A randomized, placebo-controlled study of once-daily disruptive behaviour disorders symptoms in Italian children. Eur.
atomoxetine in the school setting in children with ADHD. J. Am.
Psychiatry 21, 410–418.
Acad. Child. Adolesc. Psychiatry 44, 647–655.

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