Childhood adversities have been associated with long-lasting brain morphological differences and poor psychological outcomes over the lifespan. Evidence with regard to protective factors counteracting the detrimental effect of childhood adversity on neurobiology is scarce.

Therefore, we examined the interplay of childhood adversity with multiple protective factors in relation to brain morphology in a child and an adult cohort.

We analyzed data from two epidemiological longitudinal birth cohorts, the Generation R Study (N=3,008) and the Mannheim Study of Children at Risk (MARS) (N=179). Cumulative exposure to 12 adverse events (such as physical and sexual abuse), and the presence of protective factors, including child temperament, cognition, self-esteem, friendship quality and maternal sensitivity were assessed at different time points during childhood. Anatomical scans were acquired at the ages of 9-11 years in Generation R and at 25 years in MARS.

Childhood adversity was related to smaller global brain volumes in Generation R, with similar effect sizes observed for the cerebellar volume in MARS. While small interaction effects between adversity and protective factors were found on the medial orbitofrontal cortex, the cerebellum and the amygdala in either cohort study, no interactions were consistent across cohorts or survived correction for multiple comparisons.

We found no consistent or strong evidence for interaction effects between multiple protective factors and childhood adversities on brain structure in a child and an adult cohort study. Instead, small interaction effects were found in either children or adults warranting further investigation and more fine-grained analyses.

TB:consultancy for Actelion, Hexal Pharma, Lilly, Lundbeck, Medice, Novartis, Shire; conference support by Lilly, Medice, Novartis, Shire; clinical trials by Shire and Viforpharma; royalties by Hogrefe, Kohlhammer, CIP Medien, Oxford University Press

Patient-related factors and physicians’ attitudes leading to the decision which particular treatment is prescribed for attention-deficit/hyperactivity disorder (ADHD) have not been investigated in detail. We assessed the reasons for choice of medication and the socioeconomic status of treatment-naïve ADHD patients when initiated on ADHD medication.

Multicenter, prospective, 6-month observational study in children and adolescents with ADHD (ICD-10 or DSM-IV). Demographic, disease, and socioeconomic characteristics, and ADHD-related symptoms (ADHD-RS, CGI-S, GIPD) were captured at baseline, and compared between two medication groups (non-stimulant vs. stimulant). Physicians’ reasons for choice of medication were recorded. Correlations between those reasons were explored by Pearson"s correlation coefficient, Cohen"s Kappa, and cluster analyses.

Overall, 504 patients, mean age 9.6 years (range 6-17), 27.4% female, were included. Non-stimulant medication was prescribed in 50.0% and stimulant in 49.0% of patients (1% received both). In the non-stimulant group, patients were significantly older (0.6 years), had significantly more problems with regard to their psychosocial situation, and had more concomitant psychiatric disorders. There were no significant differences in questionnaire scores. Physicians’ reasons for prescribing medication differed for non-stimulant vs. stimulant treatment: duration of action (73.4%/28.7%), beneficial for compliance (60.3%/40.1%), and patient/parent decision (33.7%/26.3%) were reasons in favor of non-stimulant treatment; good efficacy (93.1%/73.0%), good tolerability (66.4%/44.1%), and well-priced (38.1%/2.8%) in favor of stimulant treatment.

Patients initiating stimulant or non-stimulant ADHD treatment differed significantly on some points according to their baseline characteristics. Physicians’ reasons for choice of medication clearly differed between the two medication groups.

Lisdexamfetamine dimesylate (LDX) is the first long-acting, prodrug stimulant, and is approved in the USA, Canada and Brazil for the treatment of attention-deficit/hyperactivity disorder (ADHD).

To evaluate the effect of LDX on functional impairment in patients with ADHD, using the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P).

A randomized, double-blind, placebo-controlled trial of an optimized daily dose of LDX was conducted in children and adolescents (6–17 years) with ADHD in Europe. A 4-week dose-optimization period was followed by 3-weeks of dose-maintenance. the WFIRS-P was completed at baseline, day 28 and endpoint. A decrease from baseline indicated an improvement in functional outcomes. Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference treatment arm.

of 336 randomized patients, 317 were included in the full analysis set and 196 completed the study. Baseline mean (SD) WFIRS-P total scores were similar across treatment groups: LDX, 1.01 (0.45); placebo, 1.10 (0.46); OROS-MPH, 1.07 (0.44). the least squares (LS) mean decrease (95% confidence intervals) in WFIRS-P total score from baseline to endpoint was statistically significantly greater with LDX than with placebo (difference of −0.3 [−0.4, −0.2], p < 0.001), with an effect size of 0.924 for LDX. the difference in LS mean change from baseline to endpoint between OROS-MPH and placebo was −0.2 (−0.3, −0.1; p < 0.001) in favour of OROS-MPH (effect size, 0.772).

LDX was more effective than placebo in improving functional impairments in children and adolescents with ADHD.

By funding from Shire Development Inc.

Lisdexamfetamine dimesylate (LDX) is a long-acting prodrug stimulant for treatment of attention-deficit/hyperactivity disorder (ADHD).

Review efficacy and safety data from two double-blind, randomized trials (SPD489-325 and SPD489-326) in patients with ADHD aged 6–17 years.

In SPD489-325, patients received placebo or optimized doses of LDX or the reference treatment, osmotic-release oral system methylphenidate (OROS-MPH) for ≤7 weeks. The primary efficacy measure was ADHD Rating Scale IV (ADHD-RS-IV) total score. Statistical comparison of LDX versus OROS-MPH was not pre-specified. In SPD489-326, a ≥26-week open-label LDX period preceded a 6-week, placebo-controlled, randomized-withdrawal period (RWP). The primary endpoint was treatment failure (50% increase in ADHD-RS-IV total score and ≥2-point increase in Clinical Global Impressions-Severity score from RWP baseline). Efficacy was assessed in the full analysis sets.

In SPD489-325 (N=317), placebo-adjusted least-squares-mean changes in ADHD-RS-IV total score from baseline to endpoint were: LDX, –18.6 (95% confidence interval [CI]: –21.5, –15.7; p<0.001; effect size 1.80) and OROS MPH, –13.0 (–15.9, –10.2; p<0.001; 1.26). In SPD489-326 (N=262, open-label period; N=153, RWP), 15.8% and 67.5% of patients receiving LDX and placebo, respectively, met treatment failure criteria at RWP endpoint (differen –51.7%; 95% CI: –65.0%, –38.5%; p<0.001). The most common treatment-emergent adverse events in LDX-treated patients were decreased appetite, headache and decreased weight.

Short-term LDX treatment improved symptoms of ADHD in children and adolescents. Continued LDX treatment was associated with maintenance of efficacy compared with placebo. The safety profile of LDX was generally consistent with that of stimulant therapy.

In a European, phase 3 study (SPD489-325), lisdexamfetamine dimesylate (LDX) and osmotic-release oral system methylphenidate (OROS-MPH) were more effective than placebo in improving core symptoms in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).

To compare post hoc the efficacy of LDX and OROS-MPH in study SPD489-325.

This 7-week, randomized, double-blind, parallel-group, dose-optimized, placebo-controlled trial enrolled patients aged 6-17 years with ADHD of at least moderate severity. Patients were randomized (1:1:1) to receive a once-daily dose of LDX (30, 50, 70 mg/day), OROS-MPH (18, 36, 54 mg/day) or placebo. Efficacy was assessed using the ADHD Rating Scale version IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Endpoint was defined as the last ontherapy treatment visit with a valid assessment.

The full analysis set comprised 317 patients (LDX, n=104; placebo, n=106; OROS-MPH, n=107). The difference between LDX and OROS-MPH in least squares mean change (95% confidence interval [CI]) in ADHD-RS-IV total score from baseline to endpoint was statistically significant in favour of LDX (-5.6 [-8.4, -2.7]; p < 0.001; effect size, 0.541). The difference (LDX minus OROS-MPH) in the percentage of patients (95% CI) with an improved CGI-I score at endpoint was also statistically significant in favour of LDX (17.4 [5.0, 29.8]; p < 0.05).

This post hoc analysis indicated that LDX is significantly more effective than OROS-MPH in improving core symptoms and global functioning in children and adolescents with ADHD.

Supported by: Funding from Shire Development LLC.

The Health Utilities Index-Mark 2 (HUI2), a generic instrument for assessing health status, is an important effectiveness input for pharmacoeconomic modelling. It has not previously been used in patients with attention deficit/hyperactivity disorder (ADHD).

To use HUI2 to assess health utility in patients aged 6–17 years with ADHD receiving the prodrug stimulant lisdexamfetamine dimesylate (LDX).

SPD489-325 was a 7-week, randomized, double-blind, placebo-controlled trial of LDX, with osmotic-release oral system methylphenidate (OROSMPH) as a reference treatment. Patients’ parents or guardians completed HUI2 questionnaires at baseline and weeks 4 and 7. Utilities were estimated for treatment responders and non-responders, with response defined as a Clinical Global Impressions-Improvement (CGI-I) score of 1 or 2, or a ≥25% or ≥30% reduction in ADHD Rating Scale IV (ADHD-RS-IV) total score.

Of 336 patients randomized, 317 were included in the full analysis set (LDX, n=104; OROS-MPH, n=107; placebo, n=106) and 196 completed the study. At endpoint, mean HUI2 utility scores across all treatment groups were higher for responders than non-responders when response was based on CGI-I score (responders: 0.896 [SD, 0.0990]; non-responders: 0.838 [0.1421]), on a ≥25% reduction in ADHD-RS-IV score from baseline (responders, 0.899 [0.0969]; non-responders, 0.809 [0.1474]), or on a ≥30% reduction in ADHD-RS-IV score from baseline (responders, 0.902 [0.0938]; non-responders 0.814 [0.1477]).

The HUI2 instrument is sensitive to treatment response in the child and adolescent ADHD patient population. Health utilities generated using HUI2 are therefore suitable for cost effectiveness evaluations of ADHD medications.

Supported by funding from Shire

The Weiss Functional Impairment Rating Scale–Parent Report (WFIRS-P) is an ADHD-specific instrument comprising 50 items, grouped into six domains. Parents score each item on a Likert scale (0–3 or not applicable).

To evaluate functional impairment using the WFIRS-P in two phase 3 studies (SPD489-325 and SPD489-326) of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD.

Patients’ parents or guardians completed WFIRS-P assessments at baseline, and weeks 4 and 7 of SPD489-325, a 7-week, randomized, placebo controlled trial incorporating a reference treatment (osmotic-release oral system methylphenidate; OROS-MPH). Statistical comparison of LDX versus OROS-MPH was not pre-specified. In SPD489-326, WFIRS-P assessments were performed in the ≥26-week open-label period and the subsequent 6-week randomized-withdrawal period.

In SPD489-325, statistically significant placebo-adjusted effects of LDX were observed in WFIRS-P total score (effect size, 0.924; p<0.001) and in Family, Learning and School, Social Activities and Risky Activities; OROS-MPH effects were significant in total score (effect size 0.772; p<0.001) and in all domains. In SPD489-326, scores were improved or stable in the open-label period. In the randomized-withdrawal period, total score and all domain scores were stable in the LDX group, but worsened in the placebo group. LDX was significantly more effective than placebo in Family, Learning and School, Risky Activities and in total score (effect size, 0.908; p<0.001).

Short-term treatment with LDX or OROS-MPH led to improved functional impairment scores. These benefits were maintained during long-term LDX treatment, and scores declined following treatment withdrawal.

Supported by funding from Shire.

Although neuroimaging studies suggest brain regional abnormalities in depressive disorders, it remains unclear whether abnormalities are present at illness onset or reflect disease progression.

We hypothesized that cerebral variations were present in adolescents with subthreshold depression known to be at high risk for later full-blown depression.

We examined brain structural and diffusion-weighted magnetic resonance images of adolescents with subthreshold depression.

The participants were extracted from the European IMAGEN study cohort of healthy adolescents recruited at age 14. Subthreshold depression was defined as a distinct period of abnormally depressed or irritable mood, or loss of interest, plus two or more depressive symptoms but without diagnosis of Major Depressive Episode. Comparisons were performed between adolescents meeting these criteria and control adolescents within the T1-weighted imaging modality (118 and 475 adolescents respectively) using voxel-based morphometry and the diffusion tensor imaging modality (89 ad 422 adolescents respectively) using tract-based spatial statistics. Whole brain analyses were performed with a statistical threshold set to p< 0.05 corrected for multiple comparisons.

Compared with controls, adolescents with subthreshold depression had smaller gray matter volume in caudate nuclei, medial frontal and cingulate cortices; smaller white matter volume in anterior limb of internal capsules, left forceps minor and right cingulum; and lower fractional anisotropy and higher radial diffusivity in the genu of corpus callosum.

The findings suggest that adolescents with subthreshold depression have volumetric and microstructural gray and white matter changes in the emotion regulation frontal-striatal-limbic network.

Sleep problems in children with common psychiatric disorders present a considerable challenge for clinicians in developing effective diagnosis and treatment strategies. Whilst sleep-disordered breathing (SDB) and periodic leg movements in sleep (PLMS) are very frequent in children with attention-deficit/hyperactivity disorder (ADHD) which can deviate sleep architecture, their co-existence in Tic disorder (TD) and ADHD/TD co-morbidity is less well understood.

To investigate the frequency of SDB and PLMS across children with ADHD, TD and ADHD/TD co-morbidity compared with healthy peers.

We asked whether and how the frequency of SDB and PLMS relates to sleep architecture.

Twenty-four children with ADHD, 21 with TD, 21 with ADHD/TD co-morbidity and 22 healthy controls underwent a two-night polysomnography supplemented by monitoring of apnea-hypopnea (AH) and PLMS events per hour of total sleep time.

Compared with controls, only ADHD children displayed a significantly higher AH and PLMS indices. Yet correlation analyses showed significant and negative association between AH and PLMS indices and rapid eye movement (REM) sleep amount in all, the ADHD, the TD (Fig. 1), the co-morbid, and the control (Fig. 2) groups. No such associations with the other sleep stages were found for all the groups.

[Figure 1]

Our preliminary results suggest that

1. (1) presence of co-existing sleep-related disorders may partially explain the contradicting sleep results found so far in children with ADHD,

2. (2) high frequency of SDB and PLMS could be associated with REM sleep reduction regardless of psychopathology.

In a European, phase 3 study (SPD489-325), lisdexamfetamine dimesylate (LDX) was more effective than placebo in improving symptoms and global functioning in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).

To evaluate the impact of age, sex and baseline disease severity on efficacy outcomes in SPD489- 325.

This 7-week, double-blind, parallel-group, dose-optimized study enrolled patients aged 6-17 years with ADHD. Patients were randomized (1:1:1) to once-daily LDX (30, 50 or 70mg/day), osmotic-release oral system methylphenidate (OROS-MPH; 18, 36 or 54mg/day) or placebo. Efficacy outcomes were analysed in patients dichotomized by age (6-12 years [n=229] or 13-17 years [n=88]), sex (male [n=255] or female [n=62]) and baseline ADHD Rating Scale version IV (ADHD-RSIV) total score (28-41 [n=161] or 42-54 [n=152]). Endpoint was the last on-treatment visit with a valid assessment.

At endpoint, differences (active-placebo) in least-squares mean changes from baseline in ADHD-RS-IV total scores were statistically significant in all age, sex and ADHD-RS-IV total score subgroups for LDX (p< 0.001; effect sizes, 1.68-2.26) and OROS-MPH (p< 0.01; effect sizes, 0.88-1.46). Proportions of patients with a Clinical Global Impressions-Improvement rating of 1 (very much improved) or 2 (much improved) were statistically significantly greater than placebo at endpoint in all subgroups receiving LDX (p< 0.01) and in all subgroups except females receiving OROS-MPH (p< 0.05).

LDX showed greater efficacy than placebo in children and adolescents with ADHD, regardless of their age, sex or baseline disease severity.

Supported by: Funding from Shire Development LLC.

The prodrug lisdexamfetamine dimesylate (LDX) is licensed in several European countries for treating attention-deficit/hyperactivity disorder (ADHD) in children and adolescents with an inadequate response to methylphenidate (MPH) treatment.

To evaluate post hoc the impact of ADHD medication history on the efficacy of LDX.

In this 7-week, dose-optimized, double-blind, study, patients (6–17 years) were randomized 1:1:1 to LDX, placebo or osmotic-release oral system methylphenidate (OROS-MPH). Efficacy assessments included ADHD Rating Scale IV (ADHD-RS-IV) and Clinical Global Impressions-Improvement (CGI-I) scores.

The full analysis set (FAS) comprised 317 patients. Baseline characteristics were similar across treatment groups and previous treatment subgroups. At endpoint, the mean change from baseline in ADHD-RS-IV total score and proportions of responders based on a CGI-I of 1 or 2 for LDX, OROS-MPH and placebo are presented below.

LDX and OROS-MPH were associated with clinically relevant improvements in ADHD symptoms irrespective of ADHD medication history.

Study funded by Shire

Individuals with attention-deficit/hyperactivity disorder (ADHD) may require long-term medication.

To measure growth and sexual maturation of children and adolescents with ADHD receiving lisdexamfetamine dimesylate (LDX) in a 2-year trial (SPD489-404).

To investigate the impact of long-term LDX treatment on growth and maturation.

Participants (6–17 years) received dose-optimized, open-label LDX (30–70 mg/day) for 104 weeks. Weight, height and BMI z-scores were derived using the Centers for Disease Control and Prevention norms [1]. Sexual maturation was assessed using the Tanner scale (participant-rated as closest to their stage of development based on standardized drawings).

Of 314 enrolled participants, 191 (60.8%) completed the study. Mean z-scores at baseline and last on-treatment assessment (LOTA) were 0.53 (standard deviation, 0.963) and 0.02 (1.032) for weight, 0.61 (1.124) and 0.37 (1.131) for height, and 0.32 (0.935) and–0.27 (1.052) for BMI. In general, z-scores shifted lower over the first 36 weeks and then stabilized. At LOTA, most participants remained at their baseline Tanner stage or shifted higher, based on development of hair (males, 95.5%; females, 92.1%) or genitalia/breasts (males, 94.7%; females, 98.4%).

Consistent with previous studies of stimulants used to treat ADHD [2], z-scores for weight, height and BMI decreased, mostly in the first year, then stabilized. No clinically concerning trends of LDX treatment on sexual maturation or the onset of puberty were observed.

Study funded by Shire Development LLC.

Dr Isabel Hernández Otero (Alicia Koplowitz Foundation, Eli Lilly, Forest, Janssen-Cilag, Junta de Andalucia, Roche, Shire, Shire Pharmaceuticals Iberica S.L., and Sunovion).

To document patient characteristics and treatment patterns in a real-world population diagnosed with attention-deficit/hyperactivity disorder (ADHD).

This was a retrospective chart review of children/adolescents (6–17 years) diagnosed with ADHD in the UK, Germany and Netherlands who initiated stimulant monotherapy (SM), non-stimulant (atomoxetine) monotherapy (NSM) or polypharmacy (SM/NSM ± SM/NSM or other psychotropics) on/after 1-1-2012. To facilitate descriptive comparisons, cohort quotas were imposed: ∼50% SM; ∼25% NSM; ∼25% polypharmacy. Index date was first SM, NSM or polypharmacy treatment on/after 1-1-2012. Patients were required to have ≥ 6 months’ pre-index (baseline) history and ≥ 12 months’ post-index follow-up. Analyses were descriptive.

In total, 497 patients were included (mean [SD] age: 10.8 [2.9] years; 77% male); 65% (SM), 63% (NSM) and 83% (polypharmacy) had at least marked baseline ADHD severity based on Clinical Global Impressions scale (P < 0.05 SM/NSM vs polypharmacy). Ninety percent (SM), 75% (NSM) and 73% (polypharmacy) were pharmacotherapy naïve at index (all P < 0.10); 61% (SM), 65% (NSM) and 72% (polypharmacy) received previous behavioural therapy. In SM patients, methylphenidate was predominant (most frequent brands: Concerta® [29%], Medikinet® [28%]); in polypharmacy patients, methylphenidate plus atomoxetine (22%) or other psychotropic (19%) was most common. Index therapy switch was common, particularly in polypharmacy patients (25%) (P < 0.05 vs SM [14%] and NSM [13%]). Switches were precipitated by poor response in 75% of cases overall.

Polypharmacy patients generally presented a more complicated history (including higher ADHD severity) and treatment pathway versus monotherapy patients. Index therapy switches were commonplace and more frequent in polypharmacy patients, often due to poor response.

The authors have not supplied their declaration of competing interest.

The long-term safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention deficit/hyperactivity disorder (ADHD) was evaluated in a European 2-year, open-label study (SPD489-404).

To evaluate the time-course of treatment-emergent adverse events (TEAEs) in SPD489-404.

Participants aged 6–17 years received open-label LDX (30, 50 or 70 mg/day) for 104 weeks (4 weeks dose-optimization; 100 weeks dose-maintenance).

All enrolled participants (n = 314) were included in the safety population and 191 (60.8%) completed the study. TEAEs occurred in 282 (89.8%) participants; most were mild or moderate. TEAEs considered by the investigators as related to LDX were reported by 232 (73.9%) participants with the following reported for ≥ 10% of participants: decreased appetite (49.4%), weight decreased (18.2%), insomnia (13.1%). TEAEs leading to discontinuation and serious TEAEs occurred in 39 (12.4%) and 28 (8.9%) participants, respectively. The median (range) time to first onset and duration, respectively, of TEAEs identified by the sponsor as being of special interest were: insomnia (insomnia, initial insomnia, middle insomnia, terminal insomnia), 17.0 (1–729) and 42.8 (1–739) days; weight decreased, 29.0 (1–677) and 225.0 (26–724) days; decreased appetite, 13.5 (1–653) and 169.0 (1–749) days; headache, 22.0 (1–718) and 2.0 (1–729) days. Reports of insomnia, weight decreased, decreased appetite and headache were highest in the first 4–12 weeks.

TEAEs associated with long-term LDX treatment were characteristic of stimulant medications, with the greatest incidence observed during the first 4–12 weeks.

The authors have not supplied their declaration of competing interest.

Whilst preterm-born individuals have an increased risk of developing attention-deficit/hyperactivity disorder (ADHD), and are reported to have ADHD-like attention and arousal impairments, direct group comparisons are scarce.

We directly compared preterm-born adolescents (n = 186) to term-born adolescents with ADHD (n = 69), and term-born controls (n = 135), aged 11–23, on cognitive-performance, event-related potential and skin conductance level (SCL) measures associated with attention and arousal. The measures are from baseline and fast-incentive conditions of a four-choice reaction time task, previously shown to discriminate between the individuals with ADHD and controls. We aimed to establish whether preterm-born adolescents show: (a) identical cognitive-neurophysiological impairments to term-born adolescents with ADHD (b) possible additional impairments, and whether (c) the observed impairments correlate with ADHD symptom scores.

The preterm group, like the term-born ADHD group, showed increased mean reaction time (MRT) and reaction time variability (RTV) in the baseline condition, and attenuated contingent negative variation (CNV) amplitude (response preparation) in the fast-incentive condition. The preterm group, only, did not show significant within-group adjustments in P3 amplitude (attention allocation) and SCL (peripheral arousal). Dimensional analyses showed that ADHD symptoms scores correlated significantly with MRT, RTV and CNV amplitude only.

We find impairments in cognition and brain function in preterm-born adolescents that are linked to increased ADHD symptoms, as well as further impairments, in lack of malleability in neurophysiological processes. Our findings indicate that such impairments extend at least to adolescence. Future studies should extend these investigations into adulthood.