Faculty Bibliography

Emotional dysregulation (ED) is a dysfunction in modifying an emotional state in an adaptive and goal oriented way, with excitability, ease anger, and mood lability. It is present in up to 70% of adults with ADHD, regardless of other comorbidities, and substantially worsens the psychosocial outcomes of the disorder. Besides fronto-parietal circuits mediating top-down control, brain regions involved in bottom-up processes (e.g., amygdala, orbitofrontal cortex, and ventral striatum) are implicated in ED. We performed a systematic review/meta-analysis of double-blind randomized controlled trials of ADHD medications to assess their effects on ED in adults with ADHD. We searched an extensive set of databases, international trials registries, and contacted study authors/drug companies for unpublished data. We retained 21 trials. We found small-to-moderate effects (methylphenidate: SMD=0.34, 95% CI=0.23-0.45; atomoxetine: SMD=0.24, 95% CI=0.15-0.34; lisdexamfetamine: SMD=0.50, 95% CI=0.21-0.8). We suggest that, whilst ADHD medications are effective on ADHD core symptoms, they may be less effective on bottom-up mechanisms underlying ED. Further research on novel pharmacological and non-pharmacological strategies for ED in adults with ADHD is warranted.

A systematic review with meta-analyses was performed to: 1) quantify the association between ADHD and risk of unintentional physical injuries in children/adolescents ("risk analysis"); 2) assess the effect of ADHD medications on this risk ("medication analysis"). We searched 114 databases through June 2017. For the risk analysis, studies reporting sex-controlled odds ratios (ORs) or hazard ratios (HRs) estimating the association between ADHD and injuries were combined. Pooled ORs (28 studies, 4,055,620 individuals without and 350,938 with ADHD) and HRs (4 studies, 901,891 individuals without and 20,363 with ADHD) were 1.53 (95% CI=1.40,1.67) and 1.39 (95% CI=1.06,1.83), respectively. For the medication analysis, we meta-analysed studies that avoided the confounding-by-indication bias [four studies with a self-controlled methodology and another comparing risk over time and groups (a "difference in differences" methodology)]. The pooled effect size was 0.879 (95% CI=0.838,0.922) (13,254 individuals with ADHD). ADHD is significantly associated with an increased risk of unintentional injuries and ADHD medications have a protective effect, at least in the short term, as indicated by self-controlled studies.

BACKGROUND: Behavioural interventions are recommended for use with children and young people with attention deficit hyperactivity disorder (ADHD); however, specific guidance for their implementation based on the best available evidence is currently lacking. METHODS: This review used an explicit question and answer format to address issues of clinical concern, based on expert interpretation of the evidence with precedence given to meta-analyses of randomised controlled trials. RESULTS: On the basis of current evidence that takes into account whether outcomes are blinded, behavioural intervention cannot be supported as a front-line treatment for core ADHD symptoms. There is, however, evidence from measures that are probably blinded that these interventions benefit parenting practices and improve conduct problems which commonly co-occur with ADHD, and are often the main reason for referral. Initial positive results have also been found in relation to parental knowledge, children's emotional, social and academic functioning - although most studies have not used blinded outcomes. Generic and specialised ADHD parent training approaches - delivered either individually or in groups - have reported beneficial effects. High-quality training, supervision of therapists and practice with the child, may improve outcomes but further evidence is required. Evidence for who benefits the most from behavioural interventions is scant. There is no evidence to limit behavioural treatments to parents with parenting difficulties or children with conduct problems. There are positive effects of additive school-based intervention for the inattentive subtype. Targeting parental depression may enhance the effects of behavioural interventions. CONCLUSIONS: Parent training is an important part of the multimodal treatment of children with ADHD, which improves parenting, reduces levels of oppositional and noncompliant behaviours and may improve other aspects of functioning. However, blinded evidence does not support it as a specific treatment for core ADHD symptoms. More research is required to understand how to optimise treatment effectiveness either in general or for individual patients and explore potential barriers to treatment uptake and engagement. In terms of selecting which intervention formats to use, it seems important to acknowledge and respond to parental treatment preferences.

BACKGROUND: Diffusion tensor imaging studies have shown atypical fractional anisotropy (FA) in individuals with attention-deficit/hyperactivity disorder (ADHD), albeit with conflicting results. We performed meta-analyses of whole-brain voxel-based analyses (WBVBA) and tract-based spatial statistics (TBSS) studies in ADHD, along with a qualitative review of TBSS studies addressing the issue of head motion, which may bias results. METHODS: We conducted a systematic literature search (last search on April 1st, 2016) to identify studies comparing FA values between individuals with ADHD and typically developing (TD) participants. Signed differential mapping was used to compute effect sizes and integrate WBVBA and TBSS studies, respectively. TBSS datasets reporting no between-group motion differences were identified. RESULTS: We identified 14 WBVBA (ADHDn = 314, TDn = 278) and 13 TBSS datasets (ADHDn = 557, TDn = 568). WBVBA meta-analysis showed both significantly lower and higher FA values in individuals with ADHD; TBSS meta-analysis showed significantly lower FA in ADHD compared with TD in four clusters: two in the corpus callosum (isthmus and posterior midbody), one in right inferior fronto-occipital fasciculus, and one in left inferior longitudinal fasciculus. However, four of six datasets confirming no group-differences in motion showed no significant between-group FA differences. CONCLUSIONS: A growing diffusion tensor imaging (DTI) literature (total N = 1,717) and a plethora of apparent findings suggest atypical interhemispheric connection in ADHD. However, FA results in ADHD should be considered with caution, since many studies did not examine potential group differences in head motion, and most of the studies reporting no difference in motion showed no significant results. Future studies should address head motion as a priority and assure that groups do not differ in head motion.

INTRODUCTION: Attention-deficit hyperactivity disorder (ADHD) has been related to increased rates of unintentional injuries. However, the magnitude of the effect and to which extent variables such as sex, age or comorbidity can influence this relationship is unknown. Additionally, and importantly, it is unclear if, and to which degree, ADHD medications can decrease the number of unintentional injuries. Due to the amount of economic and social resources invested in the treatment of injuries, filling these gaps in the literature is highly relevant from a public health standpoint. Here, we present a protocol for a systematic review and meta-analysis to estimate the relationship between ADHD and unintentional injuries and assess the impact of pharmacological treatment for ADHD METHODS AND ANALYSIS: We will combine results from 114 bibliographic databases for studies relating ADHD and risk of injuries. Bibliographic searches and data extraction will be carried out independently by two researchers. The studies' risk of bias will be assessed using the Newcastle-Ottawa Scale. Articles reporting ORs or HRs of suffering an injury in ADHD compared with controls (or enough data to calculate them) will be combined using Robust Variance Estimation, a method that permits to include multiple non-independent outcomes in the analysis. All analyses will be carried out in Stata. Age, sex and comorbid conduct disorders will be considered as potential causes of variance and their effect analysed through meta-regression and subgroup analysis. Sensitivity analyses will exclude articles with longer follow-ups, non-stringent definitions of ADHD or controls and statistically uncontrolled/controlled outcomes. Studies implementing a self-controlled case series methodology to investigate if ADHD drugs reduce the risk of injuries will be combined with a generalised linear mixed model using the Poisson distribution and a log link function. REGISTRATION DETAILS: PROSPERO-Prospective Register of Systematic Reviews (CRD42017064967).

PURPOSE OF REVIEW: To systematically review the literature on the prevalence and pharmacological treatment of ADHD in looked-after children (LAC). RECENT FINDINGS: LAC are a very challenging population from a clinical and psychosocial standpoint, with higher mental health needs compared to non LAC. To date, no systematic review on the prevalence of ADHD, and its treatment, in LAC is available. SUMMARY: We searched Pubmed, PsycInfo EMBASE + EMBASE CLASSIC, OVID Medline and Web of Science up to November 9 th, 2016. We found 24 papers meeting our criteria. The vast majority of the retained studies are from the USA and show rates of ADHD and of its pharmacological treatment substantially higher in LAC than those reported in national estimates. Future studies from countries other than the USA, aiming to understand the most cost-effective strategies, in the short as well as long term, to manage symptoms of ADHD in LAC are needed.

OBJECTIVE: A large proportion of paediatric patients with attention-deficit/hyperactivity disorder (ADHD) have associated sleep problems which not only affect the child's wellbeing but also impact family functioning. Management of sleep problems is consequently an important aspect of overall ADHD management in paediatric patients. Although some drugs are being used off-label for the management of paediatric insomnia, there is scant clinical evidence supporting their use. Our aim was to identify and assess the quality of published studies reporting the safety, tolerability and efficacy of drugs used for treating behavioural insomnia in children with ADHD. METHODS: After an initial screen to determine which drugs were most commonly used, we conducted a systematic review of English-language publications from searches of PubMed, EMBASE, PsycINFO and two trial register databases to February 2017, using keywords 'clonidine', 'melatonin', 'zolpidem', 'eszopiclone', 'L-theanine', 'guanfacine', 'ADHD', 'sleep disorder' and 'children'. For quality assessment of included studies, we used the CONSORT checklist for randomised control trials (RCTs) and the Downs and Black checklist for non-RCTs. RESULTS: Twelve studies were included. Two case series for clonidine, two RCTs and four observational studies for melatonin and one RCT each for zolpidem, eszopiclone, L-theanine and guanfacine. Of the 12 included studies, only one on eszopiclone scored excellent for quality. The quality of the rest of the studies varied from moderate to low. For clonidine, melatonin and L-theanine, improvements in sleep-onset latency and total sleep duration were reported; however, zolpidem, eszopiclone and guanfacine failed to show any improvement when compared with placebo. Clonidine, melatonin, L-theanine, eszopiclone and guanfacine were well tolerated with mild to moderate adverse events; zolpidem was associated with neuropsychiatric adverse effects. CONCLUSION: There is generally poor evidence for prescribing drugs for behavioural insomnia in children with ADHD. Further controlled studies are warranted.

Psychostimulants are the recommended first-line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD). Methylphenidate is one of the most commonly used psychostimulants worldwide. Given that immediate-release and/or tablet/capsule formulations may decrease adherence to methylphenidate treatment, several drug companies have been developing novel long-acting and/or liquid/chewable formulations that may improve adherence as well as (for long-acting formulations) reduce abuse potential, decrease stigma associated with multiple administrations per day, and decrease the potential for adverse effects related to dosage peak. Here, we review the pharmacokinetics, efficacy, and tolerability of novel formulations of methylphenidate that are in development or have been approved by the US FDA or European Medicines Agency (EMA) in the last 5 years. We searched the websites of the FDA, EMA, ClinicalTrials.gov, and the pertinent drug companies. We also searched PubMed, Ovid databases (MEDLINE, PsycINFO, Embase + Embase classic), and ISI Web of Knowledge (Web of Science [Science Citation Index Expanded], Biological Abstracts, Biosis, Food Science and Technology Abstracts) to retrieve any additional pertinent information. We found data from trials for the following compounds: (1) methylphenidate extended-release oral suspension (MEROS; NWP06, Quillivant); (2) methylphenidate extended-release chewable capsules (NWP09, QuilliChew ER); (3) methylphenidate hydrochloride extended-release capsules (Aptensio XR); (4) methylphenidate extended-release orally disintegrating tablets (XR-ODT; NT-0102, Cotempla); (5) ORADUR technology (once-daily tamper-resistant formulation) methylphenidate sustained release (SR); and (6) methylphenidate modified-release (HLD-200; Bejorna). Overall, available evidence based on trials suggests these compounds have good efficacy and tolerability. Future research should further explore the effectiveness and tolerability of these new formulations as well as their potential to improve adherence to treatment in the 'real world' via pragmatic trials.