Faculty Bibliography

In this clinical review we summarise what in our view have been some the most important advances in the past two decades, in terms of diagnostic definition, epidemiology, genetics and environmental causes, neuroimaging/cognition and treatment of attention-deficit/hyperactivity disorder (ADHD), including: (1) the most recent changes to the diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders and International Classification of Diseases; (2) meta-analytic evidence showing that, after accounting for diagnostic methods, the rates of ADHD are fairly consistent across Western countries; (3) the recent finding of the first genome-wide significant risk loci for ADHD; (4) the paradigm shift in the pathophysiological conceptualisation of ADHD from alterations in individual brain regions to a complex dysfunction in brain networks; (5) evidence supporting the short-term efficacy of ADHD pharmacological treatments, with a different profile of efficacy and tolerability in children/adolescents versus adults; (6) a series of meta-analyses showing that, while non-pharmacological treatment may not be effective to target ADHD core symptoms, some of them effectively address ADHD-related impairments (such as oppositional behaviours for parent training and working memory deficits for cognitive training). We also discuss key priorities for future research in each of these areas of investigation. Overall, while many research questions have been answered, many others need to be addressed. Strengthening multidisciplinary collaborations, relying on large data sets in the spirit of Open Science and supporting research in less advantaged countries will be key to face the challenges ahead.

INTRODUCTION/BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) is developmental disorder characterized by inattention and/or hyperactivity/impulsivity. Psychostimulants, including methylphenidate (MPH), are recommended as a first-line pharmacological intervention, whereas neurofeedback (NF) has been proposed as a nonpharmacological option. The comparative effects of MPH and NF need further exploration. We will conduct a systematic review and meta-analysis of head-to-head randomized controlled trials (RCTs) comparing the efficacy and/or tolerability of MPH and NF in children/adolescents and adults with ADHD. METHOD AND ANALYSIS/UNASSIGNED:We will include published as well as unpublished data. Two investigators will independently search PubMed, OVID, ERIC, Web of Science, ClinialTrials.gov, and a set of Chinese databases, including CNKI, CQVIP, and WanFang for head-to-head RCTs comparing MPH and NF. Experts will be contacted for unpublished data. The primary outcome will be the efficacy on ADHD core symptoms, measured by the change in the severity of ADHD symptoms, from baseline to endpoint and, if available, at follow-up (at any available time point). Secondary outcomes will be: dropouts for any reasons; efficacy on neuropsychological measures (working memory, inattention, and inhibition). We will conduct subgroup analyses to assess the impact of the following variables: age; type of NF; language of publication; comorbidities. Additionally, we will carry out meta-regression analyses to investigate the effect of sponsorship, year of publication, duration of intervention, and age of participants. Sensitivity analyses will be conducted to test the robustness of the findings. Risk of bias of individual studies will be assessed using the Cochrane risk of bias tool. Analyses will be performed using Comprehensive Meta-Analysis Software. ETHICS AND DISSEMINATION/UNASSIGNED:No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and presented at relevant national and international conferences. TRIALS REGISTRATION NUMBER/UNASSIGNED:PROSPERO CRD42018090256.

BACKGROUND:Weight gain is a potentially concerning side effect of second-generation antipsychotics (SGAs). Metformin, a biguanide with antihyperglycemic effects, is used to manage weight gain in adults treated with SGAs. OBJECTIVE:The objective of this study was to perform the first systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effects of metformin on weight gain in children and adolescents treated with SGAs. METHODS:Based on a pre-registered protocol (PROSPERO-CRD42017074839), we searched the PubMed, EMBASE, PsychoINFO, BIOSIS, Science Direct, Cochrane Central, and ClinicalTrials.gov electronic databases through March 2018 (with no restrictions on language, date, or type of publication) for RCTs that assessed the effect of metformin or placebo on body weight in children or adolescents (< 18 years of age) treated with selected SGAs (risperidone, aripiprazole, olanzapine, and clozapine) for any psychiatric disorder. We also contacted relevant drug manufacturers for possible additional pertinent studies/data. A random effects model was used and the quality of the included RCTs was assessed using the Cochrane Risk of Bias tool. RESULTS:Five RCTs (205 participants in total) were included in the meta-analysis. We found a significant weight decrease in the metformin group compared with placebo after 4, 12, and 16 weeks of treatment {mean difference - 0.98 kg (95% confidence interval [CI] - 1.26, - 0.69); - 1.83 kg (95% CI - 2.47, - 1.18); and - 3.23 kg (95% CI - 5.59, - 0.86), respectively}. A weight decrease at weeks 2 and 8 did not reach statistical significance. The decrease in body mass index (BMI) paralleled that of weight, with a significant effect at weeks 4, 12, and 16. Overall, four studies were rated as unclear, and one study was rated as high, risk of bias. CONCLUSION/CONCLUSIONS:Meta-analytical evidence shows that metformin might decrease weight in children/adolescents treated with SGAs but additional high-quality evidence is needed. Clinicians need to be aware that this use of metformin is currently off-label.

OBJECTIVES/OBJECTIVE:A recent systematic review and meta-analysis of randomised controlled trials of methylphenidate (MPH) in children and adolescents by a Cochrane group, led by Storebø, raised concern around the level of evidence supporting the use of this medication for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This led to several critical responses from a number of ADHD experts. METHODS:This paper reviews the conclusions reached from the Storebø meta-analysis by a critical analysis of methodologies used along with drawing on extant literature. RESULTS:The controversy raised by the Cochrane meta-analysis should lead to a balanced reflection on the research priorities and needs for the field. CONCLUSIONS:It is hoped the controversy will ultimately lead to improve the quality of the research on the efficacy, effectiveness and tolerability of MPH for ADHD.

BACKGROUND:The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. METHODS:We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. FINDINGS/RESULTS:133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD -1·02, 95% CI -1·19 to -0·85 for amphetamines, -0·78, -0·93 to -0·62 for methylphenidate, -0·56, -0·66 to -0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD -0·82, 95% CI -1·16 to -0·48) and modafinil (-0·76, -1·15 to -0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD -0·79, 95% CI -0·99 to -0·58), methylphenidate (-0·49, -0·64 to -0·35), bupropion (-0·46, -0·85 to -0·07), and atomoxetine (-0·45, -0·58 to -0·32), but not modafinil (0·16, -0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36-3·89) and adults (3·26, 1·54-6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20-5·81); and atomoxetine (2·33, 1·28-4·25), methylphenidate (2·39, 1·40-4·08), and modafinil (4·01, 1·42-11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs -0·46 to -0·24) and adults (-0·94 to -0·29). We did not find sufficient data for the 26-week and 52-week timepoints. INTERPRETATION/CONCLUSIONS:Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs. FUNDING/BACKGROUND:Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.

BACKGROUND:Several studies have assessed the possible association between attention deficit hyperactivity disorder (ADHD) and asthma. However, existing evidence is inconclusive as to whether this association remains after controlling for possible important confounders. To fill this knowledge gap, we did a systematic review and meta-analysis, followed by a population-based study. METHODS:statistics. A random-effects model was used to calculate pooled ORs. The systematic review is registered with PROSPERO (CRD42017073368). To address the fact that the ORs obtained in the meta-analysis were adjusted for confounders that inevitably varied across studies, we did a population-based study of individuals in multiple national registers in Sweden. We calculated an unadjusted OR and an OR that was simultaneously adjusted for all confounders identified in a directed acyclic graph based on the studies of asthma and ADHD identified in our systematic review. FINDINGS/RESULTS:=50·76), indicating a significant association between asthma and ADHD. Possible lack of representativeness of the study population was detected with the Newcastle-Ottawa Scale in 42 of 49 datasets. In the population-based study, we included 1 575 377 individuals born between Jan 1, 1992, and Dec 31, 2006, of whom 259 253 (16·5%) had asthma and 57 957 (3·7%) had ADHD. Asthma was significantly associated with ADHD (OR 1·60, 95% CI 1·57-1·63) in the crude model adjusting for sex and year of birth, and this association remained significant after simultaneous adjustment for all covariates (1·45, 1·41-1·48). INTERPRETATION/CONCLUSIONS:The combined results of the meta-analysis and the population-based study support a significant association between asthma and ADHD, which remained even after simultaneously controlling for several possible confounders in the population-based study. Awareness of this association might help to reduce delay in the diagnosis of both ADHD and asthma. FUNDING/BACKGROUND:Swedish Research Council and Shire International GmbH.

BACKGROUND:The efficacy of meditation-based therapies for attention deficit/hyperactivity disorder (ADHD) across the lifespan remains uncertain. OBJECTIVE:To conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) assessing the efficacy of meditation-based therapies for ADHD core symptoms and associated neuropsychological dysfunctions in children/adolescents or adults with ADHD. METHODS:statistics. Publication (small studies) bias was assessed with funnel plots and the Egger's test. Studies were evaluated with the Cochrane risk of bias (RoB) tool. Analyses were conducted using Comprehensive Meta-Analysis. FINDINGS/RESULTS:81.81%). No significant effects were found on neuropsychological measures of inattention and inhibition in children/adolescents. In adults, significant effects were detected on working memory and inhibition, although these results were based on a small number of studies (n=3). 57% and 43% of the studies in children/adolescents were rated at overall unclear and high risk of bias, respectively. In adults, 33% and 67% of the studies were deemed at overall unclear and high risk of bias, respectively. No evidence of publication bias was found. CONCLUSIONS:Despite statistically significant effects on ADHD combined core symptoms, due to paucity of RCTs, heterogeneity across studies and lack of studies at low risk of bias, there is insufficient methodologically sound evidence to support meditation-based therapies for ADHD. TRIAL REGISTRATION NUMBER/BACKGROUND:PROSPERO 2018 [CRD42018096156].

OBJECTIVE:To perform a systematic review of studies of lurasidone in children and/or adolescents and to present a case report aimed to add further insights into its use in clinical practice with youth. METHODS:We searched the following databases for empirical studies, of any design, focusing on the pharmacokinetics, efficacy, or safety of lurasidone in children and/or adolescents: Pubmed (Medline), OVID (PsycInfo, EMBASE+EMBASE classic, OVID Medline), Web of Knowledge, and ClinicalTrials.gov (last search January 23, 2018). RESULTS:From a pool of 301 potentially relevant references, we retained 12 pertinent studies (reported in 28 references), including 1 pharmacokinetics study, 1 double blind randomized controlled trial (RCT) for bipolar depression (BD) with 1 related interim analysis study of its extension phase and 1 related external posterior predictive check study, 1 double blind RCT for schizophrenia with 3 related interim analyses of its extension phase, 1 RCT and 1 case report for autism spectrum disorder, and 2 open-label studies focusing on a variety of disorders. Overall, these studies show that lurasidone is significantly more efficacious than placebo, with moderate effect sizes, and is well tolerated for BD and schizophrenia in youth. Published studies in youth have in general used doses up to 80 mg/day. Our case report suggests that high doses of lurasidone (148 mg/day) were well tolerated and might have contributed to substantial functional improvement in a 14-year old girl with psychosis and a previous history of anorexia nervosa, who had not responded to previous antipsychotics (olanzapine, risperidone, aripiprazole). CONCLUSIONS:There is increasing evidence that lurasidone may be moderately effective and well tolerated for the treatment of BD and psychosis in youth and may have procognitive effects. Our case report suggests that future RCTs should assess the efficacy and tolerability of high doses (>80 mg/day) of lurasidone in youth.

INTRODUCTION/BACKGROUND:Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder, characterized by age inappropriate and impairing levels of inattention and/or hyperactivity/impulsivity. Pharmacotherapy is an important part of the ADHD multimodal treatment. The extent to which ADHD is pharmacologically over or under treated worldwide is controversial. We aimed to estimate the pooled worldwide rate of ADHD pharmacological treatment in individuals with and without the disorder. METHOD AND ANALYSIS/UNASSIGNED:We will include published or unpublished studies reporting the rates of ADHD pharmacological treatment in participants with and without ADHD of any age group. Population-based, cohort, or follow-up studies, as well as data from insurance health system and third-party reimbursements will be eligible. Searches will be performed in a large number of electronic databases, including Medline, Embase, CINAHL, Cochrane, PsycINFO, Web of Science, and Scopus. The primary outcome will be the prevalence of ADHD pharmacological treatment in individuals with ADHD and without ADHD. Two independent reviewers will perform the screening, and data extraction process. Study quality/bias will be assessed with the Newcastle-Ottawa scale by 2 independent reviewers. To test the robustness of the findings, we will perform a series of sensitivity and meta-regression analysis. Analyses will be performed with R and STATA software. ETHICS AND DISSEMINATION/UNASSIGNED:No IRB approval will be necessary. The results of this systematic review and meta-analysis will be presented at international conferences and published in peer-reviewed journals. REGISTRATION AND STATUS/UNASSIGNED:PROSPERO 2018 CRD42018085233.

OBJECTIVE:Impulsive choices can lead to suboptimal decision making, a tendency which is especially marked in individuals with ADHD. We compared two different paradigms assessing impulsive choice: the simple choice paradigm (SCP) and the temporal discounting paradigm (TDP). METHOD/METHODS:Random effects meta-analyses on 37 group comparisons (22 SCP; 15 TDP) consisting of 3.763 participants (53% ADHD). RESULTS:Small-to-medium effect sizes emerged for both paradigms, confirming that participants with ADHD choose small immediate over large delayed rewards more frequently than controls. Moderation analyses show that offering real rewards in the SCP almost doubled the odds ratio for participants with ADHD. CONCLUSION/CONCLUSIONS:We suggest that a stronger than normal aversion toward delay interacts with a demotivating effect of hypothetical rewards, both factors promoting impulsive choice in participants with ADHD. Furthermore, we suggest the SCP as the paradigm of choice due to its larger ecological validity, contextual sensitivity, and reliability.