Explore the vast range of titles available.

ADHD is the most common neurodevelopmental disorder presenting to child and adolescent mental health, paediatric, and primary care services. Timely and effective interventions to address core ADHD symptoms and co-occurring problems are a high priority for healthcare and society more widely. While much research has reported on the benefits and adverse effects of different interventions for ADHD, these individual research reports and the reviews, meta-analyses and guidelines summarizing their findings are sometimes inconsistent and difficult to interpret. We have summarized the current evidence and identified several methodological issues and gaps in the current evidence that we believe are important for clinicians to consider when evaluating the evidence and making treatment decisions. These include understanding potential impact of bias such as inadequate blinding and selection bias on study outcomes; the relative lack of high-quality data comparing different treatments and assessing long-term effectiveness, adverse effects and safety for both pharmacological and non-pharmacological treatments; and the problems associated with observational studies, including those based on large national registries and comparing treatments with each other. We highlight key similarities across current international clinical guidelines and discuss the reasons for divergence where these occur. We discuss the integration of these different perspective into a framework for person/family-centered evidence-based practice approach to care that aims to achieve optimal outcomes that prioritize individual strengths and impairments, as well as the personal treatment targets of children and their families. Finally, we consider how access to care for this common and impairing disorder can be improved in different healthcare systems.

ObjectivesAs part of the ‘Suicidality: Treatment Occurring in Paediatrics (STOP)’ study, we developed and performed psychometric validation of an electronic-clinical-outcome-assessment (eCOA), which included a patient-reported-outcome (ePRO), an observer-rated-outcome (eObsRO) for parents/carers and a clinician-reported-outcome (eClinRO) that allows identification and monitoring of medication-related suicidality (MRS) in adolescents.DesignSTOP: Prospective study: A two phase validation study to assess the impact of medication on suicidal ideations.SettingSix participating countries: Netherlands, UK, Germany, France, Spain and Italy that were part of the Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 261411.ParticipantsCohort 1 consisted of 41 adolescent-completions, 50 parent-completions and 56 clinician-completions. Cohort 2 consisted of 244 adolescent-completions, 198 parent-completions and 240 clinician-completions from across the six countries. The scale was administered only to participants who have screened positive for the STOP-Suicidality Assessment Scale (STOP-SAS).ResultsA total of 24 items for the development of the STOP-Medication Suicidality Side Effects Scale (STOP-MS3) were identified and three versions (for patients, parents and clinicians) of the STOP-MS3 were developed and validated in two separate study cohorts comprising of adolescents, their parents and clinicians. Cronbach’s α coefficients were above 0.85 for all domains. The inter-rater reliability of the STOP-MS3 was good and significant for the adolescent (ePRO), clinician (eClinRO) (r=0.613), parent (eObsRO) versions of the scale (r=0.394) and parent and clinician (r=0.347). Exploratory factor analysis identified a 3-factor model across 24 items for the adolescent and parent version of the scale: (1) Emotional Dysregulation, (2) Somatic Dysregulation and (3) Behavioural Dysregulation. For the clinician version, a 4-factor model defined the scale structure: (1) Somatic Dysregulation, (2) Emotional Dysregulation, (3) Behavioural Dysregulation and (4) Mood Dysregulation.ConclusionThese findings suggest that the STOP-MS3 scale, a web-based eCOA, allows identification and monitoring of MRS in the adolescent population and shows good reliability and validity.

Background Low recruitment in clinical trials is a common and costly problem which undermines medical research. This study aimed to investigate the challenges faced in recruiting children and adolescents with obsessive-compulsive disorder and autism spectrum disorder for a randomized, double-blind, placebo-controlled clinical trial and to analyze reasons for non-participation. The trial was part of the EU FP7 project TACTICS (Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes). Methods Demographic data on pre-screening patients were collected systematically, including documented reasons for non-participation. Findings were grouped according to content, and descriptive statistical analyses of the data were performed. Results In total, n  = 173 patients were pre-screened for potential participation in the clinical trial. Of these, only five (2.9%) were eventually enrolled. The main reasons for non-inclusion were as follows: failure to meet all inclusion criteria/meeting one or more of the exclusion criteria ( n  = 73; 42.2%), no interest in the trial or trials in general ( n  = 40; 23.1%), and not wanting changes to current therapy/medication ( n  = 14; 8.1%). Conclusions The findings from this study add valuable information to the existing knowledge on reasons for low clinical trial recruitment rates in pediatric psychiatric populations. Low enrollment and high exclusion rates raise the question of whether such selective study populations are representative of clinical patient cohorts. Consequently, the generalizability of the results of such trials may be limited. The present findings will be useful in the development of improved recruitment strategies and may guide future research in establishing the measurement of representativeness to ensure enhanced external validity in psychopharmacological clinical trials in pediatric populations. Trial registration EudraCT 2014-003080-38 . Registered on 14 July 2014.

Background Many children and adolescents with attention deficit/hyperactivity disorder (ADHD) are treated with stimulant and non-stimulant medication. ADHD medication may be associated with cardiovascular effects. It is important to identify whether mean group effects translate into clinically relevant increases for some individual patients, and/or increase the risk for serious cardiovascular adverse events such as stroke or sudden death. Objectives To evaluate potential cardiovascular effects of these treatments, we conducted a systematic review and meta-analysis of the effects of methylphenidate (MPH), amphetamines (AMP), and atomoxetine (ATX) on diastolic and systolic blood pressure (DBP, SBP) and heart rate (HR) in children and adolescents with ADHD. Methods We conducted systematic searches in electronic databases (PsychINFO, EMBASE and Medline) to identify published trials which involved individuals who were (i) diagnosed with ADHD and were aged between 0–18 years; (ii) treated with MPH, AMP or ATX and (iii) had their DBP and SBP and/or HR measured at baseline (pre) and the endpoint (post) of the study treatment. Studies with an open-label design or a double-blind randomised control design of any duration were included. Statistical analysis involved calculating differences between pre- and post-treatment measurements for the various cardiovascular parameters divided by the pooled standard deviation. Further, we assessed the percentage of clinically relevant increased BP or HR, or documented arrhythmias. Results Eighteen clinical trials met the inclusion criteria (10 for MPH, 5 for AMP, and 7 for ATX) with data from 5837 participants (80.7% boys) and average duration of 28.7 weeks (range 4–96 weeks). All three medications were associated with a small, but statistically significant pre–post increase of SBP (MPH: standard mean difference [SMD] 0.25, 95% confidence interval [CI] 0.08–0.42, p  < 0.01; AMP: SMD 0.09, 95% CI 0.03–0.15, p  < 0.01; ATX: SMD 0.16, 95% CI 0.04–0.27, p  = 0.01). MPH did not have a pre–post effect on DBP and HR. AMP treatment was associated with a small but statistically significant pre–post increase of DBP (SMD 0.16, CI 0.03–0.29, p  = 0.02), as was ATX treatment (SMD 0.22, CI 0.10–0.34, p  < 0.01). AMP and ATX were associated with a small to medium statistically significant pre–post increase of HR (AMP: SMD 0.37, CI 0.13–0.60, p  < 0.01; ATX: SMD 0.43, CI 0.26–0.60, p  < 0.01). The head-to-head comparison of the three medications did not reveal significant differences. Sensitivity analyses revealed that AMP studies of <18 weeks reported higher effect sizes on DBP compared with longer duration studies ( F (1) = 19.55, p  = 0.05). Further, MPH studies published before 2007 reported higher effect sizes on SBP than studies after 2007 ( F (1) = 5.346, p  = 0.05). There was no effect of the following moderators: type of medication, doses, sample size, age, gender, type of ADHD, comorbidity or dropout rate. Participants on medication reported 737 (12.6%) other cardiovascular effects. Notably, 2% of patients discontinued their medication treatment due to any cardiovascular effect. However, in the majority of patients, the cardiovascular effects resolved spontaneously, medication doses were changed or the effects were not considered clinically relevant. There were no statistically significant differences between the medication treatments in terms of the severity of cardiovascular effects. Conclusions Statistically significant pre–post increases of SBP, DBP and HR were associated with AMP and ATX treatment in children and adolescents with ADHD, while MPH treatment had a statistically significant effect only on SBP in these patients. These increases may be clinically significant for a significant minority of individuals that experience larger increases. Since increased BP and HR in general are considered risk factors for cardiovascular morbidity and mortality during adult life, paediatric patients using ADHD medication should be monitored closely and regularly for HR and BP.

Background Measurement properties of the Weiss Functional Impairment Rating Scale-Parent Report Form (WFIRS-P), which assesses attention-deficit/hyperactivity disorder (ADHD)-related functional impairment in children/adolescents (6–17 years), were examined. Methods Data from seven randomized, controlled trials were pooled. Analyses were conducted in two random half-samples. WFIRS-P conceptual framework was evaluated using confirmatory factor analyses (CFA). Reliability was estimated using internal consistency (Cronbach’s alpha) and test–retest reliability methods. Convergent validity was assessed using correlations between WFIRS-P domain scores and the ADHD-RS-IV and Clinical Global Impression–Severity (CGI–S) scales. Responsiveness was tested by comparing mean changes in WFIRS-P domain scores between responders and non-responders based on clinical criteria. Results CFA adequately confirmed the item-to-scale relationships defined in the WFIRS-P conceptual framework. Cronbach’s alpha coefficient exceeded 0.7 for all domains and test–retest reliability exceeded 0.7 for all but Risky Activities. With few exceptions, WFIRS-P domains correlated significantly ( p <  0.05) with ADHD-RS-IV Total, Inattention and Hyperactivity-Impulsivity scores and CGI–S at baseline and follow-up in both random half-samples. Mean changes in WFIRS-P domain scores differed significantly between responder and non-responder groups in the expected direction ( p <  0.001). Conclusions Study results support the reliability, validity and responsiveness of the WFIRS-P. Findings were replicated between two random samples, further demonstrating the robustness of results.

Objectives: Medication nonadherence constitutes a major problem in adolescent psychiatry. Previous studies have identified various factors associated with nonadherent behavior. The aim of this study is to explore adolescents' health beliefs and subjective perceptions relating to psychotropic medication, and to statistically link these to reported medication adherence. Methods: The findings presented in this study are part of the multicenter SEMA study (Subjective Experience and Medication Adherence in Adolescents with Psychiatric Disorders). Patients 12–18 years of age were included, who had been treated with a psychotropic medication for at least 2 weeks. The validated MARS (Medication Adherence Rating Scale) and the QATT (Questionnaire on Attitudes Toward Treatment) were used to measure adherence, and a qualitative semi-structured interview was conducted to examine patients' subjective experiences and perceptions. A conventional content analysis was conducted, and Fisher's exact tests were performed to analyze group differences between completely adherent and not completely adherent patients. Results: A total of 64 patients were included in the study. 40.6% (n = 26) were classified as not completely adherent. Distribution patterns of answers to 7 out of 64 questions showed statistically significant group differences between completely and not completely adherent patients. Patients with lower adherence reported the following: feeling worse after taking medication; a lower sense of self-efficacy concerning the improvement of their symptoms; a less trustful physician–patient relationship; a worsened attitude toward medication after experiencing adverse events/“side effects”; less support from their relatives; and fewer individuals in their family who were fully informed about their condition. Conclusions: To our knowledge, this is the first interview-based study to investigate subjective experiences and health beliefs of adolescents with psychiatric disorders and to correlate these findings with rates of medication adherence. The study results will be useful for the development of tools and approaches to increase medication adherence, for example, psychoeducation programs and personalized treatment concepts.

Objectives The aim of this study was to compare the efficacy and safety of the prodrug psychostimulant lisdexamfetamine dimesylate (LDX) and the non-stimulant noradrenergic compound atomoxetine (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who had previously responded inadequately to methylphenidate (MPH). Methods This 9-week, head-to-head, randomized, double-blind, active-controlled study (SPD489-317; ClinicalTrials.gov NCT01106430) enrolled patients (aged 6–17 years) with at least moderately symptomatic ADHD and an inadequate response to previous MPH therapy. Patients were randomized (1:1) to an optimized daily dose of LDX (30, 50 or 70 mg) or ATX (patients <70 kg, 0.5–1.2 mg/kg with total daily dose not to exceed 1.4 mg/kg; patients ≥70 kg, 40, 80 or 100 mg). The primary efficacy outcome was time (days) to first clinical response. Clinical response was defined as a Clinical Global Impressions-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved). Secondary efficacy outcomes included the proportion of responders at each study visit and the change from baseline in ADHD Rating Scale (ADHD-RS-IV) and CGI-Severity scores. Tolerability and safety were assessed by monitoring treatment-emergent adverse events (TEAEs), height and weight, vital signs and electrocardiogram parameters. Endpoint was defined as the last post-baseline, on-treatment visit with a valid assessment. Results Of 267 patients randomized (LDX, n  = 133; ATX, n  = 134), 200 (74.9 %) completed the study. The median time to first clinical response [95 % confidence interval (CI)] was significantly shorter for patients receiving LDX [12.0 days (8.0–16.0)] than for those receiving ATX [21.0 days (15.0–23.0)] ( p  = 0.001). By week 9, 81.7 % (95 % CI 75.0–88.5) of patients receiving LDX had responded to treatment compared with 63.6 % (95 % CI 55.4–71.8) of those receiving ATX ( p  = 0.001). Also by week 9, the difference between LDX and ATX in least-squares mean change from baseline (95 % CI) was significant in favour of LDX for the ADHD-RS-IV total score [−6.5 (−9.3 to −3.6); p  < 0.001; effect size 0.56], inattentiveness subscale score [−3.4 (−4.9 to −1.8); p  < 0.001; effect size 0.53] and the hyperactivity/impulsivity subscale score [−3.2 (−4.6 to −1.7); p  < 0.001; effect size 0.53]. TEAEs were reported by 71.9 and 70.9 % of patients receiving LDX and ATX, respectively. At endpoint, both treatments were associated with mean (standard deviation) increases in systolic blood pressure [LDX, +0.7 mmHg (9.08); ATX, +0.6 mmHg (7.96)], diastolic blood pressure [LDX, +0.1 mmHg (8.33); ATX, +1.3 mmHg (8.24)] and pulse rate [LDX, +3.6 bpm (10.49); ATX, +3.7 bpm (10.75)], and decreases in weight [LDX, −1.30 kg (1.806); ATX, −0.15 kg (1.434)]. Conclusions LDX was associated with a faster and more robust treatment response than ATX in children and adolescents with at least moderately symptomatic ADHD who had previously responded inadequately to MPH. Both treatments displayed safety profiles consistent with findings from previous clinical trials.

Studies from different countries showed increasing use of antipsychotics in pediatric patients. However, these studies were methodologically limited and could not assess underlying diagnoses and off-label use sufficiently. This is the first study to examine antipsychotic prescriptions in a representative sample of minors over a long period, looking at changes regarding substances and drug classes, underlying diagnoses, and the rate of off-label use. Claims data of about two million pediatric subjects were used to calculate annual prevalences and incidence rates of antipsychotic prescriptions for the years 2004–2011. Analyses were stratified by sex, age, and drug type. Numbers of prescriptions, frequencies of diseases/disorders, the prescribing physicians’ specialties, and the share of off-label prescriptions were examined. During the study period, the prevalence of antipsychotic prescriptions ranged between 2.0 and 2.6 per 1000 minors. Antipsychotic prescriptions in children younger than 6 years decreased from 2.42 per 1000 subjects in 2004 to 0.48 in 2011. Among antipsychotic users, 47.0 % had only one prescription and hyperkinetic disorder was, by far, the most frequent diagnosis. The annual share of off-label prescriptions varied between 61.0 and 69.5 %. Antipsychotics were mainly prescribed to manage aggressive and impulsive behaviors in hyperkinetic disorder patients. This explains the high share of off-label prescriptions but raises concerns, since efficacy and safety of antipsychotics in this indication have not been sufficiently investigated. The decreasing antipsychotic use in younger children and the high proportion of antipsychotic users with one-time prescriptions are striking and should be further investigated in the future.

Many children with attention-deficit/hyperactivity disorder (ADHD) continue to experience this disorder as adults, which may, in part, be due to the discontinuity of health care that often occurs during the transition period between late adolescence and young adulthood. Although atomoxetine is reported to be efficacious in both adolescents and young adults, no longitudinal studies have been designed to assess directly the effects of atomoxetine treatment during this transition period. As a first step, we present the results of a post hoc, pooled analysis that compared the efficacy and safety profile of atomoxetine in these 2 patient populations. The aim of the present study was to assess the efficacy and safety profile of atomoxetine treatment in adolescents and young adults with ADHD. A post hoc, pooled analysis was conducted by combining data from 6 double-blind trials (6–9 weeks in duration) that studied adolescents (12–17 years of age; atomoxetine, n = 154; placebo, n = 88; mean final dose = 1.38 mg/kg) and 3 trials (10 weeks in duration) that studied young adults (18–30 years of age; atomoxetine, n = 117; placebo, n = 125; mean final dose = 1.21 mg/kg). Efficacy measures used in these analyses were ADHD Rating Scale (ADHDRS) for adolescents, Conners' Adult ADHD Rating Scale (CAARS) for young adults, and Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) for both age groups. Treatment response was defined as ≥30% reduction from baseline in total ADHD symptom score. In adolescents (mean age, 13.4 years), atomoxetine improved ADHD significantly compared with placebo (ADHDRS total score change, −12.9 vs −7.5; P < 0.001). In young adults (mean age, 24.7 years), atomoxetine improved ADHD significantly (CAARS total score change, −13.6 vs −7.7; P < 0.001; CGI-ADHD-S change, −1.1 vs −0.6; P < 0.001). No significant treatment-by-age subgroup interaction was observed. Tolerability was similar for both age subgroups, except for treatment-emergent nausea, which occurred significantly more frequently with atomoxetine than with placebo in young adults (13.7% vs 4.8%, respectively; P = 0.024); in adolescents no statistically significant differences were observed in frequency of nausea between atomoxetine and placebo treatment (4.5% vs 10.2%, respectively; P = 0.108). Results from this post hoc, pooled analysis suggest that acute treatment with atomoxetine was efficacious in both adolescent and young adult patients with ADHD. The safety profile findings from this study were consistent with the previously reported atomoxetine safety and tolerability profiles, suggesting that it may be continued during the transition from adolescence to young adulthood.

Objective: Only little is known about antipsychotic (AP) off-label use (OLU) in pediatric populations. It was the aim of this study to examine the frequency as well as the risks of off-label AP use in underaged patients. Methods: To calculate the frequency of off-label AP prescriptions for the years 2004–2011, we used claims data of more than two million minors aged 0–17 years. Off-label prescriptions were analyzed with regard to type of OLU, physician specialty, and underlying diagnoses. Incidence rates of selected adverse events were calculated for on-label as well as for OLU. The risk of poisoning associated with on- or OLU was assessed in a nested case-control study. Results: The annual share of pediatric AP users with off-label prescriptions varied between 52.3% and 71.1%. OLU by indication (42.8%–66.5%) was the most common type of OLU. Of the subjects with OLU by indication, 52.5% had a diagnosis of hyperkinetic disorder. Adverse events were scarce (incidence rates between 0.8 and 8.6 per 10,000 person-years), and no significant difference was observed between on- and OLU. Conclusion: Because of their frequent use in hyperkinetic disorder patients, APs are commonly prescribed off-label for minors. Since OLU by contraindication was rare and the risk of the adverse events under study was similarly small for on- and OLU, this is not necessarily an indication for inappropriate treatment. It rather indicates that further randomized studies are needed to examine efficacy and safety of pediatric AP use in this indication.