Faculty Bibliography

BACKGROUND: Despite meta-analytic evidence for the association between attention-deficit/hyperactivity disorder (ADHD) and overweight/obesity, the mechanisms underlying the association are yet to be fully understood. METHODS: By linking multiple Swedish national and regional registers, we identified 472,735 index males born during 1973-1992, with information on body weight and height directly measured before they were conscripted for military service. We further identified 523,237 full siblings born during 1973-2002 for the index males. All individuals were followed up from their third birthday to December 31, 2009 for ADHD diagnosis. Logistic regression models were used to estimate the association between overweight/obesity in index males and ADHD in their full siblings. RESULTS: Siblings of index males with overweight/obesity had increased risk for ADHD (overweight: OR = 1.14, 95% CI = 1.05-1.24; obesity: OR = 1.42, 95% CI = 1.24-1.63), compared with siblings of index males with normal weight. The results were adjusted for birth year of the index male and sex of the sibling. After further adjustment for ADHD status of the index male, the familial coaggregation remained significant (overweight: OR = 1.13, 95% CI = 1.04-1.22; obesity: OR = 1.38, 95% CI = 1.21-1.57). The results were similar across sex of the siblings. CONCLUSIONS: Attention-deficit/hyperactivity disorder and overweight/obesity share familial risk factors, which are not limited to those causing overweight/obesity through the mediation of ADHD. Future research aiming at identifying family-wide environmental risk factors as well as common pleiotropic genetic variants contributing to both traits is warranted.

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.

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.

Attention-deficit/hyperactivity disorder (ADHD) is characterised by a persistent and impairing pattern of inattention and/or hyperactivity/impulsivity and it is one of the most common neuropsychiatric conditions. Evidence about interventions of adults with ADHD is growing rapidly and clinicians need a reliable summary of all the best available information in order to better inform their daily practice. We searched MEDLINE, PubMed, PsycINFO and Cochrane databases until 31 May 2016 for systematic reviews about pharmacological and non-pharmacological treatments in adults with ADHD and carried out a meta-review to address clinically relevant questions. We identified a total of 40 papers. Psychostimulants-such as methylphenidate, dexamphetamine, mixed amphetamine salts and lisdexamfetamine-and non-psychostimulants-such as atomoxetine-were the most studied agents. Overall, pharmacological treatments were significantly more efficacious than placebo (standardised mean difference (SMD) 0.45, 95% CI 0.37 to 0.52), albeit less well accepted (OR 1.18, 95% CI 1.02 to 1.36) and tolerated (OR 2.29, 95% CI 1.97 to 2.66). The effects of pharmacological treatment for individuals with co-occurring ADHD and substance use disorder are still uncertain. The evidence for the efficacy and effectiveness of non-pharmacological treatments of ADHD in adults, as well as the combination of pharmacological and non-pharmacological strategies, is only preliminary. In conclusion, while available evidence addressed mainly the efficacy and tolerability of psychostimulants and non-psychostimulants for ADHD core symptoms in the short term, we still need further empirical support for the non-pharmacological and multimodal treatments. A comprehensive evidence-informed hierarchy of ADHD drugs based on their efficacy and tolerability is not yet available but it should be the next research priority in the field.

Restless legs syndrome (RLS) is a relatively common neurological disorder in childhood, although it is usually overlooked due to the atypical presentation in children and associated comorbid conditions that may affect its clinical presentation. Here, we aimed to perform, for the first time, a systematic review of studies reporting the association between RLS in children and adolescents (<18 y) and somatic or neuropsychiatric conditions. We searched for peer-reviewed studies in PubMed, Ovid (including PsycINFO, Ovid MEDLINE(R), and Embase), Web of Knowledge (Web of Science, Biological abstracts, BIOSIS, FSTA) through November 2015, with no language restrictions. We found 42 pertinent studies. Based on the retrieved studies, we discuss the association between RLS and a number of conditions, including growing pains, kidney disease, migraine, diabetes, epilepsy, rheumatologic disorders, cardiovascular disease, liver and gastrointestinal disorders, and neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder (ADHD), depression, and conduct disorder). Our systematic review provides empirical evidence supporting the notion that RLS in children is comorbid with a number of somatic and neuropsychiatric conditions. We posit that the awareness on comorbid diseases/disorders is pivotal to improve the diagnosis and management of RLS and might suggest fruitful avenues to elucidate the pathophysiology of RLS in children.

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.

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.