Examining the pharmacological and psychological treatment of child and adolescent ADHD in Australia: Protocol for a retrospective cohort study using linked national registry data.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder which affects 5% of children globally. In Australia, it is estimated that 4.1% of children and adolescents have ADHD. While research has examined the treatment and outcomes of children with ADHD attending public mental health services during their time in the public system in Australia, it is not known what treatment they received before and after these treatment episodes, which will provide a more complete understanding of these children's treatment journey. METHODS AND ANALYSIS: We will link clinical data from cohorts of children and adolescents treated in the public child and youth mental health and/or child development services in Brisbane, Melbourne and Sydney to the Medicare Benefits Schedule (MBS), Pharmaceutical Benefits Scheme (PBS) and National Death Index. MBS data will demonstrate the treatment journey with respect to clinicians seen, and treatment episodes from the public health service data sets will be examined to assess if the type and intensity of treatment are related to treatment outcomes. PBS data will reveal all psychotropic medications prescribed, allowing an examination of not just ADHD medications, but also other psychotropics which may indicate co-occurring conditions (eg, anxiety and mood disorders). Statistical analyses will include descriptive statistics to describe the rates of specific medications and clinician specialties seen. Linear and logistic regression will be used to model how treatment and sociodemographic variables relate to routinely collected outcome measures in the public health system while controlling for covarying factors. ETHICS AND DISSEMINATION: This study has been approved by the following institutional ethics committees: (1) Children's Health Queensland Hospital and Health Service (HREC/21/QCHQ/76260), (2) The University of Queensland (2021/HE002143) and (3) The Australian Institute of Health and Welfare (EO2021/4/1300). Findings will be disseminated through peer-reviewed journals, conferences, professional associations and to public mental health services that treat ADHD.

Functional impairment outcomes in clinical trials of different ADHD medications: post hoc responder analyses and baseline subgroup analyses.

Several recent phase 3 clinical trials of attention-deficit/hyperactivity disorder (ADHD) medications have used the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). Here, we assess WFIRS-P response in individual patients in two pivotal trials of lisdexamfetamine dimesylate (LDX) and guanfacine extended release (GXR). We also analysed pooled WFIRS-P data from seven phase 3 studies of ADHD medications to shed light on factors associated with baseline functional impairment. The proportion of patients with a change in WFIRS-P score that exceeded the minimal important difference (MID) criteria for response was greater for LDX than placebo in the Family, Learning and School, and Risky Activities domains, and was greater for GXR than placebo in the Social Activities, Learning and School, and Family domains. Responders had significantly worse baseline scores in all WFIRS-P domains (all p < 0.001) than non-responders. In the pooled analyses, baseline WFIRS-P scores in all domains were significantly worse in participants with oppositional defiant disorder (ODD) than in those without ODD. Having combined type or hyperactive-impulsive type ADHD, being enrolled into a study in Europe, being male and being younger also had modest negative effects on baseline WFIRS-P scores. The present analysis of WFIRS-P response shows that previously reported group-level improvements in WFIRS-P functional impairment score translated into clinically relevant improvements in many individual participants. Functional impairment is a diverse and subjective construct that is influenced by multiple factors. Optimal management of individuals with ADHD should involve monitoring improvements in functioning and quality of life, as well as symptomatic improvement.

Post hoc analyses of response rates to pharmacological treatments in children and adolescents with attention-deficit/hyperactivity disorder.

INTRODUCTION AND OBJECTIVES: Lack of consensus regarding how best to define treatment response hinders translation from trials to the clinic. These post hoc analyses examine three commonly used response criteria in six trials of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: Data from four short-term randomised controlled trials (RCTs) and two long-term open-label studies were analysed. Children and adolescents with ADHD received either dose-optimised (30-70 mg/day) or fixed-dose (70 mg/day) LDX. The RCTs included osmotic-release oral system methylphenidate (OROS-MPH) or atomoxetine (ATX) as a head-to-head comparator or as a reference treatment. Three definitions of response were used in these analyses: reductions of ⩾30% or ⩾50% in ADHD Rating Scale IV (ADHD-RS-IV) total score plus a Clinical Global Impressions - Improvement (CGI-I) score of 1 or 2, or an ADHD-RS-IV total score of ⩽18. RESULTS: At the end point, LDX response rates for the least stringent criterion of ⩾30% reduction in ADHD-RS-IV total score plus a CGI-I score of 1 or 2 ranged from 69.6% to 82.6%. The proportion achieving the more stringent criterion of a reduction in ADHD-RS-IV total score of ⩾50% plus a CGI-I score of 1 or 2 at the end point ranged from 59.8% to 74.8%. An ADHD-RS-IV total score of ⩽18 at the end point was achieved by 56.7-79.9% of participants. Response rates remained stable throughout the long-term open-label studies. CONCLUSIONS: Response rates were similar for the two more stringent response criteria. The less stringent criterion resulted in higher response rates and may include partial responders.

Weight and Height in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Longitudinal Database Study Assessing the Impact of Guanfacine, Stimulants, and No Pharmacotherapy.

Objectives: To assess the impact of long-term pharmacotherapy with guanfacine immediate- or extended-release (GXR), administered alone or as an adjunctive to a stimulant, on weight and height in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Methods: Data were extracted from U.S. Department of Defense medical records for patients 4-17 years of age at index date (initiation of any study medication following a year without ADHD medications, or diagnosis if unmedicated) with weight/height measurements for the analysis period (January 2009-June 2013) and the previous year (baseline). Longitudinal weight and height z-scores were analyzed using multivariable regression in three cohorts: guanfacine (initial period of guanfacine exposure), first-line stimulant monotherapy (initial period of exposure), and unmedicated. Guanfacine cohort subgroups were based on previous/concurrent stimulant exposure. Results: The weight analyses included 47,910 patients (66.8% male) and the height analyses 41,248 (67.2% male). Mean initial exposure in the weight analyses was 237 days (standard deviation [SD] = 258, median = 142) for guanfacine and 257 days (SD = 284, median = 151) for first-line stimulant monotherapy, and was similar in the height analyses. Modeling indicated that guanfacine monotherapy was not associated with clinically meaningful deviations from normal z-score trajectories for weight (first-line, n = 943; nonfirst-line, n = 796) or height (first-line, n = 741; nonfirst-line, n = 644). In patients receiving guanfacine adjunctive to a stimulant, modeled weight (n = 1657) and height (n = 1343) z-scores followed declining trajectories. In this subgroup, mean standardized weight/height had decreased during previous stimulant monotherapy. For first-line stimulant monotherapy, modeled weight (n = 32,999) and height (n = 28,470) z-scores followed declining trajectories during year 1. In the unmedicated cohort, modeled weight (n = 11,515) and height (n = 10,050) z-scores were stable. Conclusions: Guanfacine monotherapy (first-line or nonfirst-line) was not associated with marked deviations from normal growth in this modeling study of children and adolescents with ADHD. In contrast, growth trajectories followed an initially declining course with stimulants, whether given alone or with adjunctive guanfacine.

Correlations Between Clinical Trial Outcomes Based on Symptoms, Functional Impairments, and Quality of Life in Children and Adolescents With ADHD.

OBJECTIVE: To assess relationships between treatment-associated changes in measures of ADHD symptoms, functional impairments, and health-related quality of life in children and adolescents with ADHD. METHOD: Pearson correlation coefficients were calculated post hoc for changes from baseline to endpoint in outcomes of one randomized, placebo- and active-controlled trial of lisdexamfetamine (osmotic-release methylphenidate reference) and one of guanfacine extended-release (atomoxetine reference). RESULTS: Changes in ADHD Rating Scale IV (ADHD-RS-IV) total score generally correlated moderately with changes in Child Health and Illness Profile-Child Edition: Parent Report Form (CHIP-CE:PRF) Achievement and Risk Avoidance ( r ≈ .4), but weakly with Resilience, Satisfaction, and Comfort ( r ≈ .2); and moderately with Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) total score ( r ≈ .5). CHIP-CE: PRF Achievement and Risk Avoidance correlated moderately to strongly with WFIRS-P total score ( r ≈ .6). CONCLUSION: The ADHD-RS-IV, CHIP-CE:PRF, and WFIRS-P capture distinct but interconnected aspects of treatment response in individuals with ADHD.

Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1: a study protocol for a randomised placebo-controlled crossover trial.

INTRODUCTION: Dopamine dysregulation has been identified as a key modulator of behavioural impairment in neurofibromatosis type 1 (NF1) and a potential therapeutic target. Preclinical research demonstrates reduced dopamine in the brains of genetically engineered NF1 mouse strains is associated with reduced spatial-learning and attentional dysfunction. Methylphenidate, a stimulant medication that increases dopaminergic and noradrenergic neurotransmission, rescued the behavioural and dopamine abnormalities. Although preliminary clinical trials have demonstrated that methylphenidate is effective in treating attention deficit hyperactivity disorder (ADHD) symptoms in children with NF1, its therapeutic effect on cognitive performance is unclear. The primary aim of this clinical trial is to assess the efficacy of methylphenidate for reducing attention deficits, spatial working memory impairments and ADHD symptoms in children with NF1. METHODS AND ANALYSIS: A randomised, double-blind, placebo-controlled trial of methylphenidate with a two period crossover design. Thirty-six participants with NF1 aged 7-16 years will be randomised to one of two treatment sequences: 6 weeks of methylphenidate followed by 6 weeks of placebo or; 6 weeks of placebo followed by 6 weeks of methylphenidate. Neurocognitive and behavioural outcomes as well as neuroimaging measures will be completed at baseline and repeated at the end of each treatment condition (week 6, week 12). Primary outcome measures are omission errors on the Conners Continuous Performance Test-II (attention), between-search errors on the Spatial Working Memory task from the Cambridge Neuropsychological Test Automated Battery (spatial working memory) and the Inattentive and Hyperactivity/Impulsivity Symptom Scales on the Conners 3-Parent. Secondary outcomes will examine the effect of methylphenidate on executive functions, attention, visuospatial skills, behaviour, fine-motor skills, language, social skills and quality of life. ETHICS AND DISSEMINATION: This trial has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12611000765921.

Growth and Puberty in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Stimulant medications for the treatment of attention-deficit/hyperactivity disorder have a history of safe and effective use; however, concerns exist that they may adversely affect growth trajectories in children and adolescents. OBJECTIVE: The objective of this study was to evaluate the longer-term effects of lisdexamfetamine dimesylate on weight, height, body mass index and pubertal development in children and adolescents with attention-deficit/hyperactivity disorder. METHODS: Children and adolescents aged 6-17 years with attention-deficit/hyperactivity disorder took open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) in this open-label 2-year safety and efficacy study. Safety evaluations included treatment-emergent adverse events, measurement of weight, height and body mass index, and self-reported pubertal status using Tanner staging. RESULTS: The safety analysis population comprised all enrolled participants (N = 314) and 191 (60.8%) completed the study. Weight decrease was reported as a treatment-emergent adverse event in 63 participants (20.1%) and two participants (0.6%) discontinued the study as a result of treatment-emergent adverse events of weight decrease. Growth retardation of moderate intensity was reported as a treatment-emergent adverse event for two participants. From baseline to the last on-treatment assessment, there were increases in mean weight of 2.1 kg (standard deviation 5.83) and height of 6.1 cm (standard deviation 4.90), and a body mass index decrease of 0.5 kg/m2 (standard deviation 1.72). Mean weight, height and body mass index z-scores decreased over the first 36 weeks of the study and then stabilised. Changes from baseline to the last on-treatment assessment in mean z-scores for weight, height and body mass index were significantly less than zero (- 0.51, - 0.24 and - 0.59, respectively; nominal p < 0.0001). The proportion of participants with a z-score of < - 1 ranged from 5.1% (baseline) to 22.1% (week 84) for weight, 8.2% (baseline) to 12.6% (week 96) for height, and 8.3% (baseline) to 28.8% (week 96) for body mass index. Thirteen participants (4.1%) shifted to a weight below the fifth percentile at the last on-treatment assessment from a higher weight category at baseline. At the last on-treatment assessment, most participants remained at their baseline Tanner stage or had shifted higher. CONCLUSIONS: Findings from this comprehensive examination of growth outcomes associated with lisdexamfetamine dimesylate treatment over 2 years were consistent with previous studies of stimulant medications. Whilst mean weight and height increased over the course of the study, there was a small but transient reduction in mean weight, height and body mass index z-scores. A small increase in the proportion of participants in the lowest weight and body mass index categories highlights the importance of the regular monitoring of weight and height. There was no evidence of delayed onset of puberty. CLINICALTRIALS. GOV IDENTIFIER: NCT01328756.

Developing the Symptoms and Functional Impairment Rating Scale: A Multi-Dimensional ADHD Scale.

OBJECTIVE: This research developed a practical, multi-dimensional attention deficit hyperactivity disorder (ADHD) rating scale (i.e., the Symptoms and Functional Impairment Rating Scale, SFIRS) for Chinese children, aged 6-12 years, with ADHD. METHODS: The structural validity, criterion validity, internal consistency, and test-retest reliability of the scale were evaluated. Item screening was conducted with 412 ADHD patients and 322 developmentally typical controls. RESULTS: The scale includes 44 items, divided among Hyperactivity-Impulsivity, Self-Control, Inattention, Self-Management, Academic Performance, and Social Interaction. The six-factor model showed good data fit, with each factor significantly correlated with its corresponding criterion (r=0.690-0.841). The Cronbach's α of the full scale was 0.976. Total score test-retest reliability was r=0.816 (p<0.01). CONCLUSION: The SFIRS thus demonstrated good reliability and validity and may be used to assess ADHD among children aged 6-12 years in China.

Cognitive Function of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate.

BACKGROUND: SPD489-404 was the first 2-year safety study of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. In accordance with advice from the European Medicines Agency, assessment of cognitive function was a predefined safety outcome in SPD489-404. OBJECTIVE: The objective of this study was to assess cognitive function over 2 years in study SPD489-404, using the Cambridge Neuropsychological Test Automated Battery (CANTAB). METHODS: Participants aged 6-17 years received dose-optimised open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) for 104 weeks. Cognition was assessed using four CANTAB tasks; Delayed Matching to Sample (DMS), Spatial Working Memory (SWM), Stop Signal Task (SST) and Reaction Time (RTI). Key and additional variables were pre-specified for each CANTAB task; groupwise mean percentage changes in key variables from baseline of > 5% were considered potentially clinically significant. RESULTS: All 314 enrolled participants received lisdexamfetamine dimesylate and were included in the safety population, and 191 (60.8%) completed the study. No potentially clinically significant deteriorations from baseline were observed in any key CANTAB variable over the 2 years of the study. Based on predefined thresholds, potentially clinically significant improvements from baseline were observed at 6 months (DMS median reaction time, mean per cent change, - 6.6%; SWM total between-search errors, - 22.8%; SST stop signal reaction time, -18.9%), and at the last on-treatment assessment (DMS median reaction time, - 6.5%; SWM total between-search errors, - 32.6%; SST stop signal reaction time, - 25.7%). CONCLUSIONS: Lisdexamfetamine dimesylate treatment for 2 years was not associated with deterioration of cognitive function in children and adolescents with attention-deficit/hyperactivity disorder. Although improvements in some cognitive measures were observed, lack of a control group makes interpretation of the findings difficult. Further studies of the impact of stimulants on cognition are required. CLINICALTRIALS. GOV IDENTIFIER: NCT01328756.

Long-Term Safety and Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents with ADHD: A Phase IV, 2-Year, Open-Label Study in Europe.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized as a persistent disorder requiring long-term management. OBJECTIVES: Our objective was to evaluate the 2-year safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD. METHODS: Participants (aged 6-17 years) with ADHD received open-label, dose-optimized LDX 30, 50, or 70 mg/day for 104 weeks. Safety monitoring included treatment-emergent adverse events (TEAEs), vital signs, electrocardiography, and growth. The TEAEs decreased appetite, weight decrease, insomnia events (including insomnia, initial insomnia, middle insomnia, and terminal insomnia), headache, and psychiatric TEAEs were pre-defined as being of special interest. Efficacy was assessed as a secondary objective using the ADHD Rating Scale IV (ADHD-RS-IV), the Clinical Global Impressions-Improvement (CGI-I) scale, and the CGI-Severity (CGI-S) scale. RESULTS: Of 314 participants enrolled, 191 completed the study. TEAEs were reported in 89.8% of participants, led to discontinuation in 12.4%, and were reported as serious in 8.9%. TEAEs that were reported by ≥5% of participants and considered by investigators as related to LDX were decreased appetite (49.4%), weight decrease (18.2%), insomnia (13.1%), initial insomnia (8.9%), irritability (8.6%), nausea (6.7%), headache (5.7%), and tic (5.1%). The median time to first onset and duration, respectively, of TEAEs of special interest were as follows: decreased appetite, 13.5 and 169.0 days; weight decrease, 29.0 and 225.0 days; insomnia, 17.0 and 42.8 days; and headache, 22.0 and 2.0 days. Reports of decreased appetite, weight decrease, insomnia, and headache were highest in the first 4-12 weeks. Psychiatric TEAEs were infrequent: psychosis and mania (n = 1), suicidal events (suicidal ideation, n = 2; suicide attempt, n = 1), and aggression events (aggression, n = 14; anger, n = 2; hostility, n = 1). At the last on-treatment assessment (LOTA), mean increases from baseline in vital signs were as follows: pulse rate, 7.0 bpm (95% confidence interval [CI] 5.7-8.2); systolic blood pressure (SBP), 3.4 mmHg (95% CI 2.2-4.5); and diastolic blood pressure (DBP), 3.2 mmHg (95% CI 2.2-4.2). Pre-defined thresholds for a potentially clinically important (PCI) high pulse rate were met at one or more visits by 22 participants (7.0%), for PCI high SBP were met by 45 children (22.4%) and 17 adolescents (15.2%), and for PCI high DBP were met by 78 children (38.8%) and 24 adolescents (21.4%). The mean QT interval corrected using Fridericia's formula (QTcF) decreased from baseline to LOTA (-0.6 ms [95% CI -2.3 to 1.2]; range -50 to +53). Mean changes in growth from baseline to LOTA were weight, 2.1 kg (95% CI 1.5-2.8); height, 6.1 cm (95% CI 5.6-6.7); and body mass index (BMI), -0.5 kg/m2 (95% CI -0.7 to -0.3). There was a general shift to lower z score categories for height, weight, and BMI from baseline to LOTA. The mean change in ADHD-RS-IV from baseline to LOTA was -25.8 (95% CI -27.0 to -24.5) for total score, -12.6 (95% CI -13.4 to -11.9) for the hyperactivity/impulsivity subscale score, and -13.1 (95% CI -13.8 to -12.4) for the inattention subscale score. At LOTA, 77.9% of participants had a CGI-I score of 1 or 2. In addition, 77.3 and 69.2% of participants were classified as treatment responders, based on a CGI-I score of 1 or 2 and a ≥30% or ≥50% reduction from baseline in ADHD-RS-IV total score, respectively. CONCLUSIONS: The safety profile of LDX in this longer-term study was similar to that reported in previous studies. The efficacy of LDX was maintained throughout the 2-year study period. CLINICALTRIALS. GOV IDENTIFIER: NCT01328756.

Systematic review of quality of life and functional outcomes in randomized placebo-controlled studies of medications for attention-deficit/hyperactivity disorder.

Children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD) experience functional impairment and poor health-related quality of life (HRQoL) in addition to symptoms of inattention/hyperactivity-impulsivity. To synthesize qualitatively the published evidence from randomized, double-blind, placebo-controlled trials of the effectiveness of pharmacotherapy on functional impairment or HRQoL in patients with ADHD, a systematic PubMed searching and screening strategy was designed to identify journal articles meeting pre-specified criteria. Post hoc analyses and meta-analyses were excluded. HRQoL outcomes, functional outcomes and the principal ADHD symptom-based outcome were extracted from included studies. An effect size of 0.5 versus placebo was used as a threshold for potential clinical relevance (unreported effect sizes were calculated when possible). Of 291 records screened, 35 articles describing 34 studies were included. HRQoL/functioning was usually self-rated in adults and proxy-rated in children/adolescents. Baseline data indicated substantial HRQoL deficits in children/adolescents. Placebo-adjusted effects of medication on ADHD symptoms, HRQoL and functioning, respectively, were statistically or nominally significant in 18/18, 10/12 and 7/9 studies in children/adolescents and 14/16, 9/11 and 9/10 studies in adults. Effect sizes were ≥0.5 versus placebo for symptoms, HRQoL and functioning, respectively, in 14/16, 7/9 and 4/8 studies in children/adolescents; and 6/12, 1/6 and 1/8 studies in adults. Effect sizes were typically larger for stimulants than for non-stimulants, for symptoms than for HRQoL/functioning, and for children/adolescents than for adults. The efficacy of ADHD medication extends beyond symptom control and may help reduce the related but distinct functional impairments and HRQoL deficits in patients with ADHD.

The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research.

Atomoxetine is a noradrenergic reuptake inhibitor prescribed for attention-deficit/hyperactivity disorder (ADHD) that first gained approval in the USA in 2002 and has been authorized in 97 countries worldwide. The aim of this paper is to comprehensively review publications that addressed one or more of seven major safety topics relevant to atomoxetine treatment of children and adolescents (aged ≥6 years) diagnosed with ADHD. While the review focuses on children and adolescents, publications in which data from patients aged >18 years and from 6 to 18 years were analyzed in the same dataset were included. Using a predefined search strategy, including agreement of two reviewers when selecting papers, reduced the potential for bias. Using this process, we identified 70 eligible papers (clinical trials, epidemiological studies, and case reports) across the seven topics. We also referred to the European Summary of Product Characteristics (SPC) and US label. We found 15 papers about suicidality, three about aggression/hostility, seven about psychosis/mania, six about seizures, seven about hepatic effects, 29 about cardiovascular effects, and 28 about growth and development. The main findings (i.e., those from the largest and most well-conducted studies/analyses) are as follows. A large register-based study of pediatric and adult patients (6818 received atomoxetine) calculated a hazard ratio of 0.96 for suicide-related events during treatment with atomoxetine, and a meta-analysis of 23 placebo-controlled studies (N = 3883), published in 2014, found no completed suicides and no statistically significant association between atomoxetine and suicidality. The frequency of aggression/hostility was not statistically significantly higher with atomoxetine, e.g., experienced by 1.6 % (N = 21/1308) of atomoxetine-treated patients versus 1.1 % (N = 9/806) of placebo-treated patients in one meta-analysis. Symptoms of psychosis and mania were mainly observed in patients with comorbid bipolar disorder/depression. Based on spontaneous reports, during a 2-year period when 2.233 million adult and pediatric patients were exposed to atomoxetine, the reporting rate for seizures was 8 per 100,000 patients. In the manufacturer's database, atomoxetine was a "probable cause" of three hepatic adverse events (AEs) (all reversible hepatitis), and 133 hepatic AEs had possible confounding factors and were "possibly related" to atomoxetine, during 4 years when atomoxetine exposure had reached about 4.3 million patients. Rare cases of severe liver injury are described in the US label and European SPC; a case requiring liver transplantation is described in the US label. In a comprehensive review of a clinical trials database (N = 8417 received atomoxetine), most pediatric patients experienced modest increases in heart rate and blood pressure, and 8-12 % experienced more pronounced changes (≥20 bpm, ≥15 to 20 mmHg). However, in three long-term analyses (≥2 years), blood pressure was within age norms, and few patients discontinued due to cardiovascular AEs. As described in the European SPC, QT interval prolongation is uncommon, e.g., in an open-label study, 1.4 % of 711 children and adolescents had prolonged QTc intervals (≥450 ms in males, ≥470 ms in females) that were not clinically significant at ≥3 years of treatment with atomoxetine. The European SPC warns about potential QT interval prolongation in patients with a personal or family history, or if atomoxetine is administered with other drugs that potentially affect the QT interval. Decreases in growth (weight and height gain) occurred and were greatest in patients of above average weight and height, but appeared to recover over 2-5 years of atomoxetine treatment. In conclusion, suicidality, aggression/hostility, psychosis, seizures, liver injuries, and prolonged QT interval are uncommon or rare in children and adolescents treated with atomoxetine, based on data from the predefined search and from the European SPC. Overall, the data that we assessed from our search do not suggest that associations exist between atomoxetine and suicidality or seizures. The data also suggest that an association may not exist between atomoxetine and aggression/hostility. While atomoxetine may affect the cardiovascular system, the data suggest these effects are not clinically significant in most patients. Reductions in growth appear to be reversible in the long term.

Functional outcomes from a head-to-head, randomized, double-blind trial of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder and an inadequate response to methylphenidate.

Attention-deficit/hyperactivity disorder (ADHD) is associated with functional impairments in multiple domains of patients' lives. A secondary objective of this randomized, active-controlled, head-to-head, double-blind, dose-optimized clinical trial was to compare the effects of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) on functional impairment in children and adolescents with ADHD. Patients aged 6-17 years with an ADHD Rating Scale IV total score ≥ 28 and an inadequate response to methylphenidate treatment (judged by investigators) were randomized (1:1) to once-daily LDX or ATX for 9 weeks. Parents/guardians completed the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) at baseline and at week 9 or early termination. p values were nominal and not corrected for multiple comparisons. Of 267 randomized patients, 200 completed the study (LDX 99, ATX 101). At baseline, mean WFIRS-P total score in the LDX group was 0.95 [standard deviation (SD) 0.474; 95% confidence interval (CI) 0.87, 1.03] and in the ATX group was 0.91 (0.513; 0.82, 1.00). Scores in all WFIRS-P domains improved from baseline to endpoint in both groups, with least-squares mean changes in total score of -0.35 (95% CI -0.42, -0.29) for LDX and -0.27 (-0.33, -0.20) for ATX. The difference between LDX and ATX was statistically significant (p < 0.05) for the Learning and School (effect size of LDX vs ATX, 0.43) and Social Activities (0.34) domains and for total score (0.27). Both treatments reduced functional impairment in children and adolescents with ADHD; LDX was statistically significantly more effective than ATX in two of six domains and in total score.

Post hoc analyses of the impact of previous medication on the efficacy of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in a randomized, controlled trial.

BACKGROUND: Following the approval of lisdexamfetamine dimesylate (LDX) in several European countries for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents with an inadequate response to methylphenidate (MPH) treatment, the aim of the present analysis was to establish the response to LDX in subgroups of patients with different ADHD medication histories. METHODS: This was a post hoc subgroup analysis of data from a 7-week, European, double-blind, dose-optimized, Phase III study. Patients aged 6-17 years were randomized 1:1:1 to LDX, placebo, or osmotic-release oral system methylphenidate (OROS-MPH). OROS-MPH was included as a reference arm rather than as a direct comparator. Efficacy was assessed in patients categorized according to their ADHD medication history using the ADHD Rating Scale IV and Clinical Global Impressions-Improvement (CGI-I) scores. RESULTS: The difference between active drug and placebo in least-squares mean change from baseline to endpoint in ADHD Rating Scale IV total score (95% confidence interval) was similar between the overall study population (n=317; LDX, -18.6 [-21.5, -15.7]; OROS-MPH, -13.0 [-15.9, -10.2]) and treatment-naïve individuals (n=147; LDX, -15.1 [-19.4, -10.9]; OROS-MPH, -12.7 [-16.8, -8.5]) or patients previously treated with any ADHD medication (n=170; LDX, -21.5 [-25.5, -17.6]; OROS-MPH, -14.2 [-18.1, -10.3]). In addition, similar proportions of patients receiving active treatment were categorized as improved based on CGI-I score (CGI-I of 1 or 2) in the overall study population and among treatment-naïve individuals or patients previously treated with any ADHD medication. CONCLUSION: In these post hoc analyses, the response to LDX treatment, and to the reference treatment OROS-MPH, was similar to that observed for the overall study population in subgroups of patients categorized according to whether or not they had previously received ADHD medication.

Health-related quality of life and functional outcomes from a randomized-withdrawal study of long-term lisdexamfetamine dimesylate treatment in children and adolescents with attention-deficit/hyperactivity disorder.

BACKGROUND: The stimulant prodrug lisdexamfetamine dimesylate (LDX) is an effective and generally well tolerated treatment for the symptoms of attention-deficit/hyperactivity disorder (ADHD). Positive impacts of LDX on health-related quality of life and functional impairment have previously been demonstrated in a 7-week, randomized, double-blind, placebo-controlled, phase III study in children and adolescents in Europe. Maintenance of these broad benefits, as well as symptomatic control, is a key goal of long-term management of ADHD. OBJECTIVE: Secondary objectives of this multinational study in children and adolescents with ADHD were to assess the long-term maintenance of effectiveness of LDX in improving health-related quality of life and reducing functional impairment, as gauged using the Child Health and Illness Profile-Child Edition: Parent Report Form (CHIP-CE: PRF) and the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P), respectively. METHODS: Patients aged 6-17 years with diagnosed ADHD and a baseline ADHD Rating Scale IV total score of at least 28 were enrolled from the previous European study and from US sites. Patients who completed an open-label LDX treatment period of at least 26 weeks were randomized (1:1) to continue on their optimized dose of LDX or to switch to placebo for a 6-week, double-blind, withdrawal period. Parents completed CHIP-CE: PRF and WFIRS-P questionnaires at weeks 0, 8 and 26 of the open-label period and at weeks 0 and 6 of the randomized-withdrawal period, or at early termination. The endpoint of each period was defined as the last visit with valid data. Effect sizes were the difference (LDX minus placebo) in least-squares (LS)-mean change from baseline to endpoint divided by root-mean-square error. P values were nominal and not adjusted for multiple comparisons. RESULTS: The open-label and randomized full analysis sets comprised 262 and 153 (LDX n = 76; placebo n = 77) patients, respectively. Mean pretreatment CHIP-CE: PRF T-scores were more than one standard deviation below the normative mean in four of the five domains, and there was significant improvement across all domains from baseline to endpoint of the open-label period. In the randomized-withdrawal period, LS-mean CHIP-CE: PRF T-scores deteriorated in all domains in the placebo group, but not in the LDX group. Compared with placebo, the effect of LDX was significant in the Risk Avoidance (effect size 0.829; p < 0.001), Achievement (0.696; p < 0.001) and Satisfaction (0.636; p < 0.001) domains. Mean pretreatment WFIRS-P scores were lowest in the Family domain and the Learning and School domain. WFIRS-P total score and scores in all domains improved significantly from baseline to endpoint of the open-label period. In the randomized-withdrawal period, LS-mean scores deteriorated in the placebo group but not in the LDX group. Compared with placebo, the effect of LDX was significant in the Family, Learning and School, and Risky Activities domains and in total (effect size 0.908; p < 0.001). CONCLUSIONS: Using parent-rated instruments, long-term maintenance of the beneficial effect of LDX in multiple domains of health-related quality of life and functional impairment was demonstrated by comparison of treatment continuation and withdrawal under randomized, double-blind, placebo-controlled conditions.

Treatment response and remission in a double-blind, randomized, head-to-head study of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit hyperactivity disorder.

OBJECTIVES: A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactivity disorder (ADHD) and an inadequate response to methylphenidate (MPH). The primary efficacy and safety outcomes of the study, SPD489-317 (ClinicalTrials.gov NCT01106430), have been published previously. METHODS: In this 9-week, double-blind, active-controlled study, patients aged 6-17 years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70 mg/day) or ATX (patients <70 kg: 0.5-1.2 mg/kg/day, not to exceed 1.4 mg/kg/day; patients ≥70 kg: 40, 80 or 100 mg/day). Treatment response was a secondary efficacy outcome and was predefined as a reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score of at least 25, 30 or 50 %. Sustained response was predefined as a reduction from baseline in ADHD-RS-IV total score (≥25, ≥30 or ≥50 %) or a Clinical Global Impressions (CGI)-Improvement (CGI-I) score of 1 or 2 throughout weeks 4-9. CGI-Severity (CGI-S) scores were also assessed, as an indicator of remission. RESULTS: A total of 267 patients were enrolled (LDX, n = 133; ATX, n = 134) and 200 completed the study (LDX, n = 99; ATX, n = 101). By week 9, significantly (p < 0.01) greater proportions of patients receiving LDX than ATX met the response criteria of a reduction from baseline in ADHD-RS-IV total score of at least 25 % (90.5 vs. 76.7 %), 30 % (88.1 vs. 73.7 %) or 50 % (73.0 vs. 50.4 %). Sustained response rates were also significantly (p < 0.05) higher among LDX-treated patients (ADHD-RS-IV ≥25, 66.1 %; ADHD-RS-IV ≥30, 61.4 %; ADHD-RS-IV ≥50, 41.7 %; CGI-I, 52.0 %) than among ATX-treated individuals (ADHD-RS-IV ≥25, 51.1 %; ADHD-RS-IV ≥30, 47.4 %; ADHD-RS-IV ≥50, 23.7 %; CGI-I, 39.3 %). Finally, by week 9, 60.7 % of patients receiving LDX and 46.3 % of those receiving ATX had a CGI-S score of 1 (normal, not at all ill) or 2 (borderline mentally ill), and greater proportions of patients in the LDX group than the ATX group experienced a reduction from baseline of at least one CGI-S category. CONCLUSIONS: Both LDX and ATX treatment were associated with high levels of treatment response in children and adolescents with ADHD and a previous inadequate response to MPH. However, within the parameters of the study, LDX was associated with significantly higher treatment response rates than ATX across all response criteria examined. In addition, higher proportions of patients in the LDX group than the ATX group had a CGI-S score of 1 or 2 by week 9, indicating remission of symptoms. Both treatments were generally well tolerated, with safety profiles consistent with those observed in previous studies.

Maintenance of efficacy of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder: randomized-withdrawal study design.

OBJECTIVE: In this phase 3 extension study, the long-term maintenance of efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) was evaluated using a randomized-withdrawal study design. METHOD: European and US patients (6-17 years; N = 276) with ADHD were entered into a 26-week open-label trial of LDX treatment. Those who completed the open-label period (n = 157) were randomized 1:1 to their optimized dose of LDX (30, 50, or 70 mg per day) or placebo for a 6-week randomized-withdrawal period (RWP). The primary efficacy measure was the proportion of patients meeting treatment failure criteria (≥50% increase in ADHD Rating Scale IV total score and ≥2-point increase in Clinical Global Impressions-Severity of Illness [CGI-S] score, compared with RWP start point). Safety and tolerability were also evaluated. RESULTS: During the RWP (LDX, n = 78; placebo, n = 79), significantly fewer patients receiving LDX met treatment failure criteria (15.8%) compared with those receiving placebo (67.5%; difference = -51.7%; 95% confidence interval = -65.0, -38.5; p < .001 ). Most treatment failures occurred at or before the week 2 visit after randomization. Treatment-emergent adverse events were reported in 39.7% and 25.3% of patients receiving LDX and placebo, respectively, during the RWP. CONCLUSIONS: These data demonstrate the maintenance of efficacy of LDX during long-term treatment in children and adolescents with ADHD. The rapid return of symptoms on LDX withdrawal demonstrates the need for continuing treatment. The safety profile of LDX was consistent with that of other stimulants. Clinical trial registration information-Double-Blind, Placebo-Controlled, Randomized Withdrawal, Extension, Safety and Efficacy Study of LDX in Children and Adolescents Aged 6-17; http://clinicaltrials.gov; NCT00784654.

A systematic review of the safety of lisdexamfetamine dimesylate.

BACKGROUND: Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS: A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). RESULTS: In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25-39 % of patients and insomnia by 11-19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non-medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. CONCLUSIONS: The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants.

Efficacy of lisdexamfetamine dimesylate throughout the day in children and adolescents with attention-deficit/hyperactivity disorder: results from a randomized, controlled trial.

Lisdexamfetamine dimesylate (LDX) is a long-acting, prodrug stimulant therapy for patients with attention-deficit/hyperactivity disorder (ADHD). This randomized placebo-controlled trial of an optimized daily dose of LDX (30, 50 or 70 mg) was conducted in children and adolescents (aged 6-17 years) with ADHD. To evaluate the efficacy of LDX throughout the day, symptoms and behaviors of ADHD were evaluated using an abbreviated version of the Conners' Parent Rating Scale-Revised (CPRS-R) at 1000, 1400 and 1800 hours following early morning dosing (0700 hours). Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference treatment, but the study was not designed to support a statistical comparison between LDX and OROS-MPH. The full analysis set comprised 317 patients (LDX, n = 104; placebo, n = 106; OROS-MPH, n = 107). At baseline, CPRS-R total scores were similar across treatment groups. At endpoint, differences (active treatment - placebo) in least squares (LS) mean change from baseline CPRS-R total scores were statistically significant (P < 0.001) throughout the day for LDX (effect sizes: 1000 hours, 1.42; 1400 hours, 1.41; 1800 hours, 1.30) and OROS-MPH (effect sizes: 1000 hours, 1.04; 1400 hours, 0.98; 1800 hours, 0.92). Differences in LS mean change from baseline to endpoint were statistically significant (P < 0.001) for both active treatments in all four subscales of the CPRS-R (ADHD index, oppositional, hyperactivity and cognitive). In conclusion, improvements relative to placebo in ADHD-related symptoms and behaviors in children and adolescents receiving a single morning dose of LDX or OROS-MPH were maintained throughout the day and were ongoing at the last measurement in the evening (1800 hours).

Effects of methylphenidate on cognitive functions in children and adolescents with attention-deficit/hyperactivity disorder: evidence from a systematic review and a meta-analysis.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of neuropsychological impairments. The relationship between these neuropsychological deficits and the defining symptoms of ADHD seems more complex than originally thought. Methylphenidate (MPH) is an effective treatment for ADHD symptoms, but its impact on cognition is less clearly understood. METHODS: With a common systematic search strategy and a rigorous coding and data extraction strategy across domains, we searched electronic databases to identify published placebo controlled trials that compared MPH and placebo on executive and nonexecutive memory, reaction time, reaction time variability and response inhibition in children and adolescents (5-18 years) with a formal diagnosis of ADHD. RESULTS: Sixty studies were included in the review, of which 36 contained sufficient data for meta-analysis. Methylphenidate was superior to placebo in all five meta-analyses: executive memory, standardized mean difference (SMD) .26, 95% confidence interval (CI): -.39 to -.13; non-executive memory, SMD .60, 95% CI: -.79 to -.41; reaction time, SMD .24, 95% CI: -.33 to -.15; reaction time variability, SMD .62, 95% CI: -.90 to -.34; response inhibition, SMD .41, 95% CI: -.55 to -.27. CONCLUSIONS: These data support the potentially important effects of MPH on various aspects of cognition known to be associated with ADHD. Consideration should be given to adding cognitive outcomes to the assessment of treatment outcome in ADHD, considering the complexity of the relationship between ADHD symptoms and cognition.