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

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

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

The Author(s) 2014. This article is published with open access at Springerlink.com Objectives A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and ato-moxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactiv-ity 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 C70 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 (C25, C30 or C50 %) 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 signifi-cantly (p \ 0.05) higher among LDX-treated patient

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

Health-related quality of life of children with attention-deficit/hyperactivity disorder versus children with diabetes and healthy controls

The impact of attention-deficit/hyperactivity disorder (ADHD) on health-related quality of life (HRQoL) is reported to be similar to that of other mental health and physical disorders. In this cross-sectional study, we hypothesized that children with ADHD and children with type 1 diabetes mellitus (T1DM) would have significantly worse HRQoL compared with healthy children, and that better clinical status in ADHD and T1DM would be associated with better HRQoL. Children were recruited from three outpatient services in Scotland. Responses to two frequently used validated HRQoL instruments, the Paediatric Quality of Life Inventory (PedsQL) and Child Health and Illness Profile-child edition (CHIP-CE), were obtained from parents/carers and children (6–16 years) with/without ADHD or T1DM. Child and parent/carer-completed HRQoL measurements were evaluated for 213 children with ADHD, 58 children with T1DM and 117 healthy children (control group). Significantly lower self and parent/carer ratings were observed across most PedsQL (P < 0.001) and CHIP-CE (P < 0.05) domains (indicating reduced HRQoL) for the ADHD group compared with the T1DM and control groups. Parent/carer and child ratings were significantly correlated for both measures of HRQoL (PedsQL total score: P < 0.001; CHIP-CE all domains: P < 0.001), but only with low-to-moderate strength. Correlation between ADHD severity and HRQoL was significant with both PedsQL and CHIP-CE for all parent/carer (P < 0.01) and most child (P < 0.05) ratings; more ADHD symptoms were associated with poorer HRQoL. These data demonstrate that ADHD has a significant impact on HRQoL (as observed in both parent/carer and child ratings), which seems to be greater than that for children with T1DM

Associations between prenatal exposure to antipsychotics and attention-deficit/hyperactivity disorder, autism spectrum disorder, preterm birth and small for gestational age: a population-based cohort study

Importance: The risk of birth and neurodevelopmental complications with prenatal exposure to antipsychotics is unclear. / Objective: To evaluate the association between prenatal antipsychotics exposure and the risk of birth and neurodevelopmental problems. / Design, Setting, Participants: This population-based cohort study included children born between 2001–2015 with follow-up to 2019, identified by the Hong Kong Clinical Data Analysis and Reporting System. Pregnancies with maternal antidepressant/lithium exposure were removed. Primary analyses compared gestational-exposed and gestational non-exposed with propensity score fine-stratification. Additional analyses included gestational-exposed versus past-exposed and sibling-matched analysis to evaluate the effect of confounding by indication. / Exposures: Prenatal antipsychotic exposure. Main outcomes and measures: Preterm birth (<37 gestational weeks), small for gestational age (birth weight <2 standard deviations below the mean for gestational age), and first diagnosis of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children. / Results: The cohorts included 333,749 mother-child pairs for ADHD and 411,251 pairs for ASD/preterm birth/small for gestational age analyses. There were 13,196 children (3.95%) diagnosed with ADHD, 8,715 (2.12%) with ASD, 33,891 (8.24%) preterm, and 7,009 (1.70%) small for gestational age. The weighted hazard ratio (wHR) was 1.16 (95% confidence interval [CI]=0.83-1.61) for ADHD and 1.06 (95%CI=0.70-1.60) for ASD, while the weighted odds ratio (wOR) was 1.40 (95%CI=1.13-1.75) for preterm birth and 1.36 (95%CI=0.86-2.14) for small for gestational age, when comparing gestational-exposed to gestational non-exposed. Additional analyses showed no association when comparing gestational-exposed to past-exposed (ADHD: wHR=0.99, 95%CI=0.60-1.61); ASD: wHR=1.10, 95%CI=0.58-2.08; preterm birth: wOR=0.93, 95%CI=0.70-1.24; small for gestational age: wOR=1.21, 95%CI=0.66-2.20), and in sibling-matched analysis (ADHD: wHR=0.41, 95%CI=0.04-4.93; ASD: wHR=0.90, 95%CI=0.40-2.01; preterm birth: wOR=1.25, 95%CI=0.85-1.82; small for gestational age: wOR=0.86, 95%CI=0.32-2.31). / Conclusions and Relevance: We found no evidence that prenatal antipsychotics exposure increased the risk of ADHD, ASD or small for gestational age. In the primary analysis, there was a small increased risk of preterm birth, but additional analyses comparing gestational-exposed to past-exposed and comparing gestational exposed to gestational non-exposed siblings did not support an increased risk. Given the benefits of treating psychosis during pregnancy, our findings do not support a recommendation for women to stop their regular antipsychotic treatment during pregnancy

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)

Lateralization of infant holding by mothers: a longitudinal evaluation of variations over the first 12 weeks

The maternal preference to hold infants on the left rather than right side of the body was examined longitudinally, with attention to four explanations: maternal monitoring of infant state, maternal handedness, infant proximity to the mother’s heartbeat, and preferred infant head position. The side and site of holding were measured over the first twelve weeks of the lives of 24 infants. Information about group and individual consistency in holding side allowed novel evaluation of the theories. A strong bias to hold on the left dropped below significance when the infants were aged twelve weeks and was limited to specific holding positions. Findings were generally consistent with the monitoring hypothesis, and little support was found for the three alternative explanations

Neuropsychological characterization of aggressive behavior in children and adolescents with cd/odd and effects of single doses of medications: The protocol of the matrics_wp6-1 study

Aggressive behaviors and disruptive/conduct disorders are some of the commonest reasons for referral to youth mental health services; nevertheless, the efficacy of therapeutic interventions in real-world clinical practice remains unclear. In order to define more appropriate targets for innovative pharmacological therapies for disruptive/conduct disorders, the European Commission within the Seventh Framework Programme (FP7) funded the MATRICS project (Multidisciplinary Approaches to Translational Research in Conduct Syndromes) to identify neural, genetic, and molecular factors underpinning the pathogenesis of aggression/antisocial behavior in preclinical models and clinical samples. Within the program, a multicentre case-control study, followed by a single-blind, placebo-controlled, cross-over, randomized acute single-dose medication challenge, was conducted at two Italian sites. Aggressive children and adolescents with conduct disorder (CD) or oppositional defiant disorder (ODD) were compared to the same age (10–17 y) typically developing controls (TDC) on a neuropsychological tasks battery that included both “cold” (e.g., inhibitory control, decision making) and “hot” executive functions (e.g., moral judgment, emotion processing, risk assessment). Selected autonomic measures (heart rate variability, skin conductance, salivary cortisol) were recorded before/during/after neuropsychological testing sessions. The acute response to different drugs (methylphenidate/atomoxetine, risperidone/aripiprazole, or placebo) was also examined in the ODD/CD cohort in order to identify potential neuropsychological/physiological mechanisms underlying aggression. The paper describes the protocol of the clinical MATRICS WP6-1 study, its rationale, the specific outcome measures, and their implications for a precision medicine approach

An observational study of once-daily modified-release methylphenidate in ADHD: quality of life, satisfaction with treatment and adherence

Attention deficit hyperactivity disorder (ADHD) impacts significantly on the quality of life (QoL) of patients and their families. Choice of therapy is increasingly influenced by treatment satisfaction and patient preference, with once-daily modified-release methylphenidate (MPH-MR) formulations offering clear benefits compared with immediate-release (IR) dosage forms. The effects of MPH-MR on QoL in ADHD have not been widely investigated and need more clarity in practice. The open-label OBSEER study evaluated the effectiveness and tolerability of Equasym XL®, a MPH-MR formulation, in routine practice. Children and adolescents (aged 6–17 years) with ADHD and attending school were included if Equasym XL® treatment was planned by the treating physician. Physicians, parents and patients completed questionnaires assessing QoL (KINDL; parent, child or adolescent versions), satisfaction with medication, adherence and treatment tolerability at baseline (Visit 1), 1–3 weeks (Visit 2) and 6–12 weeks (Visit 3) over a maximum 3-month observation period. Data from 822 consecutively referred patients were analysed. QoL and medication satisfaction increased from Visit 1 to Visit 3, with both patients and parents rating therapy with Equasym XL® as better than previous drug therapy. KINDL total score effect sizes were 0.67 (parents’ ratings), 0.52 (children’s ratings) and 0.51 (adolescents’ ratings; all p < 0.001). All KINDL subscores also increased: both parents and patients had the greatest improvement for school. Adherence to Equasym XL® was frequently rated as superior to prior treatment, particularly compared with MPH-IR repeated dosing. Treatment was generally well tolerated; approximately 3% of the patients discontinued treatment due to adverse events. Equasym XL® improved QoL compared with prior therapy, and resulted in good medication satisfaction and adherence in drug-naïve and previously treated patients