The evidence-based pharmacological treatment of paediatric ADHD.

Attention deficit hyperactivity disorder (ADHD) is common in children, adolescents, and adults, with extensive research establishing it as a valid neurobiological disorder. Without intervention, ADHD can result in significant impairment throughout the lifespan for the individuals it afflicts. Fortunately, multiple evidence-based options are available for the treatment of ADHD, including several efficacious pharmacotherapies. The role of medication, including stimulants as well as non-stimulants, is well-documented by an extensive body of literature. Although there may be less enthusiasm for behavioural and other psychosocial interventions as stand-alone treatments for moderate to severe ADHD, they are recommended as first-line treatment for ADHD management in preschool-aged children, for those patients with mild symptoms, and as an adjunct to medication in patients with comorbid disorders or suboptimal responses to pharmacotherapy. When planning treatment for individuals with ADHD, the potential risks associated with the available interventions must be carefully balanced against the risks of not treating, or not treating adequately. The treatment plan must also include ongoing re-assessment of the effectiveness of and the need for continued therapy. Recent practice parameters provide further specific guidance for the evidence-based assessment and treatment of children and adolescents with ADHD

An open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder.

OBJECTIVE: To collect pilot data assessing the safety, tolerability, and efficacy of tomoxetine, a nonstimulant norepinephrine enhancer, in pediatric attention deficit hyperactivity disorder (ADHD). METHODS: An open-label trial of tomoxetine in pediatric ADHD was conducted as part of a multisite clinical trial. Following a baseline assessment, an ascending dose titration was completed during 10 weekly visits. RESULTS: Ten subjects were enrolled at baseline, with eight completing the study. Seven of the eight remaining subjects met efficacy criteria. Significant decreases in symptom severity ratings by parents and study investigators were found. The medication was well tolerated, with transient appetite suppression the most frequently reported side effect. However, subjects\u27 weights remained stable across study visits. DISCUSSION: These preliminary findings suggest that tomoxetine may hold promise as a treatment for pediatric ADHD

Antidepressant prescribing practices for the treatment of children and adolescents.

OBJECTIVE: This study evaluates pediatric antidepressant prescribing practices of Nebraska clinicians. METHODS: Surveys were sent in July, 2005, to 1,521 prescribing clinicians throughout Nebraska to assess pediatric antidepressant use along with any practice changes following the U.S. Food and Drug Administration (FDA) black box warning issued in October, 2004. RESULTS: Over half (n = 866) of the clinicians responded to the survey, of which 96.8% reported awareness of the FDA black box warning. Of the respondents, 76.9% (n = 666) were prescribing antidepressants to children and/or adolescents. Clinicians reported decreased prescribing frequency for both children (15.5%) and adolescents (36.6%), with 36% having increased referrals to specialists. While 31.9% reported seeing patients more frequently upon initiation of antidepressants, only 7.5% reported weekly visits for the first month of treatment, as recommended by the FDA. Over one fifth (21.9%) reported a caregiver or patient had refused antidepressant medication treatment due to the FDA\u27s warning. CONCLUSION: Clinicians in Nebraska report changes in clinical practice due to the issuance of the FDA black box warning, with a decrease in prescribing antidepressants to pediatric patients and an increase in referrals to specialists. Although awareness of the FDA\u27s warning was evident among clinicians and patients, adherence to recommended guidelines was low

Atomoxetine treatment in children and adolescents with attention-deficit hyperactivity disorder: what are the long-term health-related quality-of-life outcomes?

OBJECTIVE: Numerous investigations have examined the efficacy of pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD) in children. However, relatively few studies have addressed the impact of treatment on long-term subjective, psychosocial outcomes, such as health-related quality of life (HRQL). This study examines the long-term effects of pharmacological treatment with atomoxetine on HRQL in children and adolescents with ADHD. METHODS: Participants included 6- to 17-year-old children and adolescents (n = 912) with ADHD enrolled in a 24-month, multicenter, open-label trial of atomoxetine. Outcomes included clinician ratings of ADHD, parent ratings of ADHD, and a widely used measure of HRQL (The Child Health Questionnaire (CHQ)). Treatment response rates were calculated based on a CHQ improvement of at least 1 standard error of measurement. RESULTS: Significant improvements in HRQL were found following both acute and long-term treatment for psychosocial but not physical health. Of participants who completed treatment (n = 312 or 34.2% of those enrolled), 81% responded to acute treatment and 78% responded to long-term treatment. Improvements noted after acute treatment were maintained during long-term treatment with the majority of participants (86%) continuing to respond to treatment. CONCLUSIONS: Atomoxetine is associated with improvements in HRQL, and the improvements are generally stable over time

Emotional expression during attention-deficit/hyperactivity disorders treatment: initial assessment of treatment effects.

OBJECTIVE: The purpose of this research was to provide an initial examination of the effects of atomoxetine and stimulants on emotional expression using a newly developed scale for assessing emotional expression in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: The parent-rated Expression and Emotion Scale for Children (EESC) was collected during two studies. During a cross-sectional validation study, the EESC was completed to assess the child\u27s current treatment and retrospectively for previous medication. In a randomized, placebo-controlled trial of atomoxetine, the EESC was collected at baseline and endpoint. RESULTS: In the validation study, no statistically significant differences in EESC scores were found between groups taking atomoxetine (n = 74) and stimulants (n = 105). Patients who switched from a stimulant to atomoxetine (n = 40) had greater improvement in emotional expression than those switched to another stimulant (n = 21) (p = 0.008). In the clinical trial, no difference in rates of worsening of emotional expression were observed (atomoxetine 8.8%, placebo 12.3%; p = 0.440). CONCLUSION: No treatment differences in emotional expression were observed based on current medications. However, stimulant patients needing to switch medications may have greater improvements in emotional expression by switching to atomoxetine

Selective serotonin reuptake inhibitors in pediatric depression: is the balance between benefits and risks favorable?

Recent controversies surrounding the use of selective serotonin reuptake inhibitors (SSRIs) have highlighted the need to reassess potential benefits, as well as potential risks of this class of medications in the treatment of pediatric depression. The recent availability of data from meta-analyses of published and unpublished antidepressant trials, epidemiological studies, and the Treatment for Adolescents with Depression Study (TADS) has facilitated a reanalysis of this risk/benefit relationship. Despite reviewing similar data, various regulatory agencies have arrived at rather disparate conclusions regarding the data, resulting in continued controversy. Although all groups appear to agree that careful assessment, education regarding risks, and closer monitoring are essential for SSRIs, only the U.S. Food and Drug Administration (FDA) and the U.K. Medicine and Health Care Products Regulatory Agency maintain that an acceptable risk/benefit relationship exists for fluoxetine. The European Medicines Agency concluded that the SSRIs should not be used in the treatment of depression in children and adolescents. The authors of this review have taken into consideration many of these same data and offer a critical discussion of the pros and cons of SSRIs in pediatric depression. The authors have concluded that SSRIs -- in particular, fluoxetine -- do have a role in the treatment of pediatric depression

Neural Responses to Fluoxetine in Youths with Disruptive Behavior and Trauma Exposure: A Pilot Study

Objective: A preliminary investigation of the impact of a serotonergic agent (fluoxetine) on symptom profile and neural response in youths with disruptive behavior disorders (DBDs) and a history of trauma exposure. Methods: There were three participant groups: (i) Youths with DBDs and trauma exposure who received fluoxetine treatment for 8 weeks (n = 11); (ii) A matched group of youths with DBDs and trauma exposure who received routine regular follow-up in an outpatient clinic (n = 10); and (iii) Typically developing youths (n = 18). All participants conducted an expression processing functional magnetic resonance imaging task twice, 8 weeks apart: (pretreatment and post-treatment for youths with DBDs). Results: Youths with DBDs and trauma exposure who received fluoxetine treatment compared to the other two groups showed: (i) significant improvement in externalizing, oppositional defiant disorder, irritability, anxiety-depression, and trauma-related symptoms; (ii) as a function of fearful expression intensity, significantly decreased amygdala response and increased recruitment of regions implicated in top-down attention control (insula cortex, inferior parietal lobule, and postcentral gyrus) and emotional regulation (ventromedial prefrontal cortex [vmPFC]); and (iii) correlation between DBD/irritability symptom improvement and increased activation of top-down attention control areas (inferior parietal lobule, insula cortex, and postcentral gyrus) and an emotion regulation area (vmPFC). Conclusions: This study provides preliminary evidence that a serotonergic agent (fluoxetine) can reduce disruptive behavior and mood symptoms in youths with DBDs and trauma exposure and that this may be mediated by enhanced activation of top-down attention control and emotion regulation areas (inferior parietal lobule, insula cortex, and vmPFC)

Dysfunctional attitudes scale perfectionism: a predictor and partial mediator of acute treatment outcome among clinically depressed adolescents.

The effect of perfectionism on acute treatment outcomes was explored in a randomized controlled trial of 439 clinically depressed adolescents (12-17 years of age) enrolled in the Treatment for Adolescents with Depression Study (TADS) who received cognitive behavior therapy (CBT), fluoxetine, a combination of CBT and FLX, or pill placebo. Measures included the Children\u27s Depression Rating Scale-Revised, the Suicidal Ideation Questionnaire-Grades 7-9, and the perfectionism subscale from the Dysfunctional Attitudes Scale (DAS). Predictor results indicate that adolescents with higher versus lower DAS perfectionism scores at baseline, regardless of treatment, continued to demonstrate elevated depression scores across the acute treatment period. In the case of suicidality, DAS perfectionism impeded improvement. Treatment outcomes were partially mediated by the change in DAS perfectionism across the 12-week period

Structural Atrophy of the Right Superior Frontal Gyrus in Adolescents With Severe Irritability

Severe irritability is common in youths with psychiatric disorders and results in significant dysfunction across domains (academic, social, and familial). Prior structural MRI studies in the pediatric population demonstrated that aberrations of cortical thickness (CT) and gray matter volume (GMV) in the fronto-striatal-temporal regions which have been associated with irritability. However, the directions of the correlations between structural alteration and irritability in the individual indices were not consistent. Thus, we aim to address this by implementing comprehensive assessments of CT, GMV, and local gyrification index (LGI) simultaneously in youths with severe levels of irritability by voxel-based morphometry and surface-based morphometry. One hundred and eight adolescents (46 youths with severe irritability and 62 healthy youths, average age = 14.08 years, standard deviation = 2.36) were scanned with a T1-weighted MRI sequence. The severity of irritability was measured using the affective reactivity index. In youths with severe irritability, there was decreased CT, GMV, and LGI in the right superior frontal gyrus (SFG) compared to healthy youths, and negative correlations between these indices of the SFG and irritability. Our findings suggest that structural deficits in the SFG, potentially related to its role in inhibitory control, may be critical for the neurobiology of irritability

Acute atomoxetine treatment of younger and older children with ADHD: A meta-analysis of tolerability and efficacy

<p>Abstract</p> <p>Background</p> <p>Atomoxetine is FDA-approved as a treatment of attention-deficit/hyperactivity disorder (ADHD) in patients aged 6 years to adult. Among pediatric clinical trials of atomoxetine to date, six with a randomized, double-blind, placebo-controlled design were used in this meta-analysis. The purpose of this article is to describe and compare the treatment response and tolerability of atomoxetine between younger children (6–7 years) and older children (8–12 years) with ADHD, as reported in these six acute treatment trials.</p> <p>Methods</p> <p>Data from six clinical trials of 6–9 weeks duration were pooled, yielding 280 subjects, ages 6–7 years, and 860 subjects, ages 8–12 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-diagnosed ADHD. Efficacy was analyzed using the ADHD Rating Scale-IV (ADHD-RS), Conners' Parent Rating Scale-revised (CPRS-R:S), and the Clinical Global Impression of ADHD Severity (CGI-ADHD-S).</p> <p>Results</p> <p>Atomoxetine was superior to placebo in both age categories for mean (SD) change in ADHD-RS total, total T, and subscale scores; 3 CPRS-R:S subscales; and CGI-ADHD-S from baseline. Although there were no significant treatment differentials between the age groups for these efficacy measures, the age groups themselves, regardless of treatment, were significantly different for ADHD-RS total (younger: ATX = -14.2 [13.8], PBO = -4.6 [10.4]; older: ATX = -15.4 [13.2], PBO = -7.3 [12.0]; p = .001), total T (younger: ATX = -15.2 [14.8], PBO = -4.9 [11.2]; older: ATX = -16.4 [14.6], PBO = -7.9 [13.1]; p = .003), and subscale scores (Inattentive: younger: ATX = -7.2 [7.5], PBO = -2.4 [5.7]; older: ATX = -8.0 [7.4], PBO = -3.9 [6.7]; p = .043; Hyperactive/Impulsive: younger: ATX = -7.0 [7.2], PBO = -2.1 [5.4]; older: ATX = -7.3 [7.0], PBO = -3.4 [6.3]; p < .001), as well as the CGI-ADHD-S score (younger: ATX = -1.2 [1.3], PBO = -0.5 [0.9]; older: ATX = -1.4 [1.3], PBO = -0.7 [1.1]; p = .010). Although few subjects discontinued from either age group due to adverse events, a significant treatment-by-age-group interaction was observed for abdominal pain (younger: ATX = 19%, PBO = 6%; older: ATX = 15%, PBO = 13%; p = .044), vomiting (younger: ATX = 14%, PBO = 2%; older: ATX = 9%, PBO = 6%; p = .053), cough (younger: ATX = 10%, PBO = 6%; older: ATX = 3%, PBO = 9%; p = .007), and pyrexia (younger: ATX = 5%, PBO = 2%; older: ATX = 3%, PBO = 5%; p = .058).</p> <p>Conclusion</p> <p>Atomoxetine is an effective and generally well-tolerated treatment of ADHD in both younger and older children as assessed by three recognized measures of symptoms in six controlled clinical trials.</p> <p>Trial Registration</p> <p>Not Applicable.</p