Faculty Bibliography

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.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD. Currently, there is a lack of up-to-date and comprehensive evidence on how available ADHD drugs compare and rank in terms of efficacy and tolerability, in children or adolescents as well as in adults. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs), to rank pharmacological treatments for ADHD according to their efficacy and tolerability profiles. METHODS AND ANALYSIS: We will search a broad range of electronic databases, including PubMed, MEDLINE, EMBASE, PsycINFO, ERIC and Web of Science, with no date or language restrictions. We will also search for unpublished studies using international clinical trial registries and contacting relevant drug companies. We will identify and include available parallel-group, cross-over and cluster randomised trials that compare methylphenidate, dexmethylphenidate, amphetamine derivatives (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion or modafinil (as oral therapy) either with each other or to placebo, in children, adolescents or adults with ADHD. Primary outcomes will be efficacy (indicated by reduction in severity of ADHD core symptoms measured on a standardised scale) and tolerability (the proportion of patients who left a study early due to side effects). Secondary outcomes will be global functioning, acceptability (proportion of patients who left the study early by any cause) and changes in blood pressure and body weight. NMA will be conducted in STATA within a frequentist framework. The quality of RCTs will be evaluated using the Cochrane risk of bias tool, and the quality of the evidence will be assessed using the GRADE approach. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. ETHICS AND DISSEMINATION: No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and possibly presented at relevant national and international conferences. TRIAL REGISTRATION NUMBER: CRD42014008976.

OBJECTIVE: To evaluate the long-term effects of methylphenidate imediate-release (MPH-IR), and to confirm the efficacy established in previous meta-analyses of short-term studies. METHOD: Published and unpublished studies in which participants were treated with MPH-IR for 12 weeks or more were searched. Pooled effect sizes from these studies were computed with the DerSimonian and Laird random-effect model. Meta-regression analysis was conducted to estimate covariates associated with treatment effects. RESULTS: Seven studies were included. Pooled parents ratings for inattention and hyperactivity/impulsivity resulted in standardized mean difference (SMD) = 0.96 (95% confidence interval [CI] = [0.60, 1.32]) and SMD = 1.12 (95% CI = [0.85, 1.39]), respectively; pooled teachers ratings showed SMD = 0.98 (95% CI = [0.09, 1.86]) for inattention and SMD = 1.25 (95% CI = [0.7, 1.81]) for hyperactivity/impulsivity. No evidence of association of any covariates with treatment effect was detected in the meta-regression. CONCLUSION: MPH-IR is efficacious for childhood ADHD for periods longer than 12 weeks.

While psychiatric comorbidities of attention-deficit/hyperactivity disorder (ADHD) have been extensively explored, less attention has been paid to somatic conditions possibly associated with this disorder. However, mounting evidence in the last decade pointed to a possible significant association between ADHD and certain somatic conditions, including obesity. This papers provides an update of a previous systematic review on the relationship between obesity and ADHD (Cortese and Vincenzi, Curr Top Behav Neurosci 9:199-218, 2012), focusing on pertinent peer-reviewed empirical papers published since 2012. We conducted a systematic search in PubMed, Ovid, and Web of Knowledge databases (search dates: from January 1st, 2012, to July 16th, 2016). We retained a total of 41 studies, providing information on the prevalence of obesity in individuals with ADHD, focusing on the rates of ADHD in individuals with obesity, or reporting data useful to gain insight into possible mechanisms underlying the putative association between ADHD and obesity. Overall, over the past 4 years, an increasing number of studies have assessed the prevalence of obesity in individuals with ADHD or the rates of ADHD in patients with obesity. Although findings are mixed across individual studies, meta-analytic evidence shows a significant association between ADHD and obesity, regardless of possible confounding factors such as psychiatric comorbidities. An increasing number of studies have also addressed possible mechanisms underlying the link between ADHD and obesity, highlighting the role, among others, of abnormal eating patterns, sedentary lifestyle, and possible common genetic alterations. Importantly, recent longitudinal studies support a causal role of ADHD in contributing to weight gain. The next generation of studies in the field should explore if and to which extent the treatment of comorbid ADHD in individuals with obesity may lead to long-term weight loss, ultimately improving their overall well-being and quality of life.

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.

BACKGROUND: Task-based functional magnetic resonance imaging (fMRI) studies of adult attention-deficit/hyperactivity disorder (ADHD) have revealed various ADHD-related dysfunctional brain regions, with heterogeneous findings across studies. Here, we used novel meta-analytic data-driven approaches to characterize the function and connectivity profile of ADHD-related dysfunctional regions consistently detected across studies. METHODS: We first conducted an activation likelihood estimation meta-analysis of 24 task-based fMRI studies in adults with ADHD. Each ADHD-related dysfunctional region resulting from the activation likelihood estimation meta-analysis was then analyzed using functional decoding based on ~7500 fMRI experiments in the BrainMap database. This approach allows mapping brain regions to functions not necessarily tested in individual studies, thus suggesting possible novel functions for those regions. Additionally, ADHD-related dysfunctional regions were clustered based on their functional coactivation profiles across all the experiments stored in BrainMap (meta-analytic connectivity modeling). RESULTS: ADHD-related hypoactivation was found in the left putamen, left inferior frontal gyrus (pars opercularis), left temporal pole, and right caudate. Functional decoding mapped the left putamen to cognitive aspects of music perception/reproduction and the left temporal lobe to language semantics; both these regions clustered together on the basis of their meta-analytic functional connectivity. Left inferior gyrus mapped to executive function tasks; right caudate mapped to both executive function tasks and music-related processes. CONCLUSIONS: Our study provides meta-analytic support to the hypothesis that, in addition to well-known deficits in typical executive functions, impairment in processes related to music perception/reproduction and language semantics may be involved in the pathophysiology of adult ADHD.

A recent Cochrane review assessed the efficacy of methylphenidate for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. Notwithstanding the moderate-to-large effect sizes for ADHD symptom reduction found in the meta-analysis, the authors concluded that the quality of the evidence is low and therefore the true magnitude of these effects remains uncertain. We identified a number of major concerns with the review, in the domains of study inclusion, approaches to quality assessment and interpretation of data relating to serious adverse events as well as of the clinical implications of the reported effects. We also found errors in the extraction of data used to estimate the effect size of the primary outcome. Considering all the shortcomings, the conclusion in the Cochrane review that the status of the evidence is uncertain is misplaced. Professionals, parents and patients should refer to previous reviews and existing guidelines, which include methylphenidate as one of the safe and efficacious treatment strategies for ADHD.

Until recently, no comprehensive guidance specifically on the conduction of systematic reviews and meta-analyses of pharmacoepidemiological studies of safety outcomes was available. In December 2015, the European Network of Centres for Pharmacoepidemiology and Pharamacovigilance (ENCePP), a network coordinated by the European Medicines Agency, published their 'Guidance on conducting systematic reviews and meta-analyses of completed comparative pharmacoepidemiological studies of safety outcomes', filling an important gap in the field. This paper highlights the ENCePP recommendations in terms of study identification, data extraction, study quality appraisal and analytical plan. Although the ENCePP document should not be considered as definitive, since it will likely be refined following researchers' feedback, it is expected that it will be highly influential and useful for the field, with the ultimate goal to improve and standardise the conduction and reporting of systematic reviews/meta-analyses of pharmacoepidemiological studies of safety outcomes.