Faculty Bibliography

OBJECTIVE:Sleep problems are common in adults with attention-deficit/hyperactivity disorder (ADHD). The presence of sleep problems at the time of presentation for ADHD treatment could impact the level of improvement in ADHD symptoms or executive function occurring with ADHD pharmacotherapy. Therefore, we examined the influence of baseline sleep quality on the effects of SHP465 mixed amphetamine salts (MAS) extended-release. METHODS:Adults (18-55 years) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-defined ADHD and baseline ADHD Rating Scale IV (ADHD-RS-IV) total scores ≥ 24 were randomized to once-daily SHP465 MAS (12.5-75 mg) or placebo in a 7-week, double-blind, dose-optimization study. Post-hoc analyses evaluated SHP465 MAS treatment effects on ADHD symptoms, using the ADHD-RS-IV, and executive function, using the Brown Attention-Deficit Disorder Scale (BADDS), based on baseline sleep quality as defined by Pittsburgh Sleep Quality Index (PSQI) scores [sleep quality impaired (PSQI total score > 5; PSQI component scores 2 or 3) versus not impaired (PSQI total score ≤ 5; PSQI component scores 0 or 1)]. Analyses were conducted in the intent-to-treat population. RESULTS:Of 280 enrolled participants, 272 were randomized (placebo, n = 135; SHP465 MAS, n = 137). The intent-to-treat population consisted of 268 participants (placebo, n = 132; SHP465 MAS, n = 136), and 170 participants (placebo, n = 76; SHP465 MAS, n = 94) completed the study. Treatment differences nominally favored SHP465 MAS over placebo in both sleep impairment groups regarding ADHD-RS-IV total score changes (all nominal p < 0.05), except for those with impairment defined by sleep efficiency (p = 0.2696), and regarding BADDS total score changes (all nominal p < 0.05), except for those with impairment defined by sleep duration (p = 0.1332) and sleep efficiency (p = 0.8226). There were no statistically significant differences in SHP465 MAS treatment effects between sleep impairment groups. CONCLUSIONS:Improvements in ADHD symptoms and executive function occurred with dose-optimized SHP465 MAS, regardless of baseline impairment in some aspects of sleep in adults with ADHD, with no significant differences observed as a function of sleep impairment. CLINICAL TRIALS REGISTRATION/BACKGROUND:ClinicalTrials.gov identifier-NCT00150579.

Introduction Despite stimulants being highly efficacious in short-term randomised controlled trials (RCTs), not all patients respond or can successfully tolerate them. A number of novel non-stimulant options are currently in the pipeline for the treatment of ADHD. Areas covered The authors conducted a systematic review of RCTs registered in ClinicalTrials.gov in the past five years (January 2014 and February 2019), supplemented by searches in PubMed, Web of Science, and drug manufacturers websites to find recent RCTs on novel non-stimulant ADHD medications. Expert opinion The authors found 28 pertinent RCTs of compounds acting on a variety of biological targets, including Dasotraline, Viloxazine (SPN-812), Centanafadine SR (CTN SR), OPC-64005, Fasoracetam (NFC-1, AEVI-001), Metadoxine (MDX), Vortioxetine, Tipepidine Hibenzate, Oxytocin, Sativex (delta-9-tetrahydrocannabinol (THC) plus cannabidiol), Mazindol, and Molindone hydrochloride (SPN-810). Given the high effect size found in RCTs of stimulants in terms of efficacy on ADHD core symptoms, it is unlikely that these novel agents will show better efficacy than stimulants, at the group level. However, they may offer comparable or better tolerability. Additionally, agents acting on etiopathophysiological targets disrupted in specific subgroups of patients with ADHD will move forward the pharmacotherapy of ADHD from a "one size fits all" to a "precision medicine" approach.

It is unclear if impairments in social functioning and peer relationships significantly differ across common developmental conditions such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), conduct disorder (CD), and associated callous-unemotional traits (CU traits). The current study explored sex differences and symptoms of parent- and teacher-reported psychopathology on peer relationships and prosocial behaviour in a sample of 147 referred children and adolescents (aged 5-17 years; 120 m). The results showed that increases in parent-reported ADHD Inattentive symptoms and teacher-reported ADHD Hyperactive-Impulsive symptoms, CD, ODD, and CU traits were significantly associated with peer relationship problems across sex. At the same time, teacher-reported symptoms of ODD and both parent- and teacher-reported CU traits were related to difficulties with prosocial behaviour, for both boys and girls, with sex explaining additional variance. Overall, our findings show a differential association of the most common disruptive behaviours to deficits in peer relationships and prosocial behaviour. Moreover, they highlight that different perspectives of behaviour from parents and teachers should be taken into account when assessing social outcomes in disruptive behaviours. Given the questionable separation of conduct problem-related constructs, our findings not only point out the different contribution of those aspects in explaining peer relationships and prosocial behaviour, but furthermore the variance from different informants about those aspects of conduct problems.

Although pharmacological therapies are recommended as a key component in the treatment of attention-deficit hyperactivity disorder, their use continues to prompt intense debate. Despite considerable research efforts, several gaps in the knowledge base and several questions over the quality of evidence exist. Particular issues surrounding pharmacological treatments include uncertainties about long-term effectiveness and safety, safety profiles in adults, and the comparative effectiveness of different medications. In this Review, we focus on four key methodological issues for future research: (1) the use of appropriate trial designs; the need for (2) outcome measures targeting effectiveness beyond symptom control and (3) safety outcome measures; and (4) the application of clinical and administrative research databases to assess real-world outcomes. Potential solutions include increased use of randomised placebo-controlled withdrawal trials and large pharmacoepidemiological studies that use electronic health-care records on the long-term effectiveness and safety of medications. Pragmatic head-to-head randomised trials would also provide direct evidence on comparative effectiveness and safety profiles.

OBJECTIVE:Meta-analytic evidence shows alterations of peripheral inflammatory cytokines in adults with depressive disorders. By contrast, no evidence synthesis on alterations of peripheral inflammatory cytokines in children/adolescents with depressive disorders is available to date. To fill this gap, we conducted a systematic review and meta-analysis of case-control studies comparing serum cytokine levels in children/adolescents with depressive disorders and healthy controls. METHODS:Based on a preregistered protocol (PROSPERO-CRD42018095418), we searched PubMed, Ovid, and Web of Knowledge from inception through July 21, 2018, with no language restrictions, and contacted study authors for unpublished data/information. Random-effects model was used to compute effect size for each cytokine. The Newcastle-Ottawa Scale was used to asses study bias. RESULTS:From a pool of 4231 nonduplicate, potentially relevant references, 8 studies were retained for the qualitative synthesis and 5 for the meta-analysis. TNF-α was higher in participants with depressive disorders versus controls, falling short of statistical significance. CONCLUSIONS:Overall, due to the small number of studies, in contrast to the literature in adults, further evidence is needed to confirm possible inflammatory alterations associated with depression in youth.

The relationship between ADHD and suicidal spectrum behaviors (SSBs) remains uncertain. We conducted the first meta-analysis on the association between ADHD and SSBs taking possible confounders into account. Based on a pre-registered protocol (PROSPERO-CRD42018093003), we searched Pubmed, Ovid and Web of Knowledge databases through April 6^th, 2018, with no language/publication type restrictions, and contacted study authors for unpublished data/information. From a pool of 2,798 references, we retained 57 studies. Random-effects models were performed. Study quality was rated using the Newcastle-Ottawa Scale. After pooling crude ORs, we found a significant association between ADHD and suicidal attempts (2.37, 95% CI = 1.64 to 3.43; I² = 98.21), suicidal ideations (3.53, 2.94 to 4.25; I²â€‰= 73.73), suicidal plans (4.54, 2.46 to 8.37; I² = 0), and completed suicide (6.69, 3.24 to 17.39; I² = 87.53). Results did not substantially change when pooling adjusted ORs. Findings were also in general robust to sensitivity analyses to assess possible moderators. Awareness of the association between ADHD and SSBs should contribute to more effectively prevent SSBs.

Whilst the association between Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity is supported by meta-analytic evidence, the mechanisms underpinning this link need to be further elucidated. Inflammatory processes may increase the risk of ADHD symptoms in individuals with obesity. This pilot study set out to start testing this hypothesis by assessing the correlation between serum levels of inflammatory cytokines and ADHD symptoms severity in a sample of children and adolescents with obesity. We measured ADHD symptoms severity in 52 children/adolescents with obesity (BMI > 95th centile) with the Conners questionnaire, revised, short version, parent (CPRS-R:S) and teacher (CTRS-R:S) versions. Additionally, a categorical diagnosis of ADHD was established using the Kiddie-SADS-PL. Serum levels of IL-6, Il-10, and TNF-alpha were also obtained. The prevalence of ADHD was 9.6%. We found a significant correlation between IL-6, as well as TNF-alpha, and hyperactivity/impulsivity subscores of the CPRS-R:S and CTRS-R:S, that held even after controlling for BMI and oppositional symptoms. This study provides a rationale for larger, longitudinal studies to gain insight into inflammatory processes underpinning the link between obesity and ADHD. This line of research has the potential to lead to novel, pathophysiologically-based management strategies for individuals with obesity and ADHD.

BACKGROUND:Prior follow-up studies of attention-deficit/hyperactivity disorder (ADHD) have mostly been from North America. They have provided a good deal of information about ADHD, but whether these results generalize to population samples and to other countries is not certain. Most prior studies have also not assessed predictors of possible new onsets of ADHD in non-ADHD youth or the validity of subthreshold forms of the disorder. METHODS:1,012 families were recruited at baseline, when a telephone interview assessed a child in the 6-12 years age range. The interview covered symptoms of ADHD, conduct disorder, and oppositional defiant disorder as well as family living situation, school performance, sleep disturbance, eating habits, use of supplemental iron, and history of ADHD treatment. Nine years later, the persistence of ADHD and its impairments and the emergence of new conditions were assessed. DSM-5 diagnostic criteria were used to diagnose ADHD. RESULTS:492 of the 1,012 participants seen at baseline were followed up 9 years later, at a mean age of 18 years. At follow-up, 16.7% of the children diagnosed with ADHD at baseline met full criteria for ADHD and 11.1% met criteria for subthreshold ADHD, yielding a persistence rate of 27.8%. Among children not diagnosed with ADHD at baseline, 1.1% met criteria for ADHD at follow-up. The persistence of ADHD and new onsets of ADHD were predicted by several baseline clinical features and by a family history of ADHD. CONCLUSIONS:We replicated predictors of the persistence of ADHD found in prior studies and provide new data about predictors of new ADHD onsets in the population. Our findings about subthreshold ADHD support a dimensional conceptualization of the disorder, highlighting the potential clinical utility of a subthreshold diagnostic category. This study also contributes to the ongoing debate regarding adult-onset ADHD.

OBJECTIVE:Sleep disturbances are a feature of attention-deficit/hyperactivity disorder (ADHD) and an adverse event (AE) of methylphenidate treatment. The authors sought to clarify methylphenidate-associated sleep problems and how studies are affected by confounding factors. DATA SOURCES/METHODS:Published studies in English collected via online databases and unpublished data from www.clinicaltrials.gov and US Food and Drug Administration websites. Sources were searched from inception to August 2017. STUDY SELECTION/METHODS:Included were blinded placebo-controlled studies of youth with ADHD conducted in naturalistic settings, leading to 35 studies yielding 75 observations of sleep-related AEs. These studies comprised 3,079 drug-exposed and 2,606 placebo-treated patients. DATA EXTRACTION/METHODS:Two PhD-level reviewers reviewed each study for inclusion. Four PhD/PharmD-level reviewers extracted data in duplicate. Discrepancies were resolved by discussion or, if needed, by the senior author. RESULTS:Increased pooled relative risks (RRs) were found for methylphenidate-associated sleep-related AEs for insomnia (general), initial insomnia, middle insomnia, combined insomnia, and sleep disorder. Several sample or study design features were significantly associated with the RR for sleep-related AEs and the methylphenidate formulation studied (P < .05). After correction for confounding variables, significant differences among drugs were found for initial insomnia, insomnia (general), and sleep disorder (P < .0001) as the other categories could not be tested due to insufficient studies. The findings also show that the RR and its interpretation are constrained by the placebo AE rate. CONCLUSIONS:Several types of insomnia and sleep problems are associated with methylphenidate treatment. Study design and sample features influence the RR statistic. By showing that the rate of placebo AEs impacts the RR, this study provides the field with a useful covariate for adjusting RR statistics.