Faculty Bibliography

BACKGROUND/OBJECTIVE/OBJECTIVE:Sleep problems are commonly reported by individuals with Autism Spectrum Disorder (ASD). However, to date, no quantitative evidence synthesis of available studies has been performed to quantify sleep alterations in adults with ASD. We performed a systematic review and meta-analysis of objective (ie, based on actigraphy or polysomnography [PSG]) and subjective (ie, based on sleep diaries/questionnaires) studies comparing sleep parameters in adults with ASD and in a typically developing (TD) control group. METHODS:PubMed, OVID databases and Web of Knowledge were systematically searched up to February 2019 with no language restrictions. Original studies including adults with a diagnosis of ASD according to DSM, ICD, or based on standard diagnostic tools (eg, ADOS), and a TD control group were included. Random-effects models were used. Study quality was evaluated with the Newcastle Ottawa Scale (NOS). Analyses were conducted using Comprehensive Meta-Analysis. RESULTS:From initial pool of 1948 references, 14 publications including 8 datasets, (194 ASD and 277 controls) met the inclusion criteria. Compared to controls, individuals with ASD were significantly more impaired in six out of 11 subjective parameters, including lower sleep efficiency (SE, SMD = -0.87, CI = -1.14 - 0.60) and in 10 out of 17 objective outcomes, including longer sleep onset latency (PSG) (SMD = 0.86, CI = 0.29-1.07) and wake after sleep onset (WASO, actigraphy) (SMD = 0.57, CI = 0.28-0.87). The mean NOS score was 4.88/6. CONCLUSIONS:Individuals with ASD demonstrated impaired sleep compared to controls in most subjective and objective measures.

INTRODUCTION/BACKGROUND:Increasing numbers of children and young people (CYP) are receiving prescriptions for antidepressants. This is the protocol of a study aiming to describe the trends and variation in antidepressant prescriptions in CYP in England, and to examine the indications for the prescriptions recorded and whether there was contact with secondary care specialists on or around the time of the first antidepressant prescription. METHODS AND ANALYSIS/UNASSIGNED:All eligible CYP aged between 5 and 17 years in 1998-2017 from the QResearch primary care database will be included. Incidence and prevalence rates of any antidepressant prescription in each year will be calculated. We will examine four different antidepressant classes: selective serotonin reuptake inhibitors, tricyclic and related antidepressants, serotonin and norepinephrine reuptake inhibitors and other antidepressants, as well as for individual drugs. Linked primary and secondary care data (hospital episode statistics) in the year before and up to 6 months after the first antidepressant prescription will be examined for CYP whose first antidepressant prescription was in 2006-2017. Whether there were records of indications and being seen by psychiatric or paediatric specialists will be identified. Trends over time and differences by region, deprivation and ethnicity will be examined using Poisson regression. DISCUSSION/CONCLUSIONS:This large, population-based study will give an up-to-date picture of antidepressant prescribing in CYP and identify any variation. Understanding what indications are recorded when CYP are being prescribed antidepressants, and whether this was done in partnership with secondary care specialists, will provide evidence of whether appropriate guidelines are being followed.

BACKGROUND:The cortisol awakening response (CAR) is characterised by an increase in cortisol in the 30 to 60 min after waking. Research has found significant associations between an atypical CAR and symptoms of stress and anxiety in typically developing (TD) children and adolescents. A number of studies have explored the CAR in autism spectrum disorder (ASD), but no evidence synthesis is available to date. OBJECTIVE AND METHODS/OBJECTIVE:Based on a preregistered protocol (PROSPERO: CRD42017051187), we carried out a systematic review (SR) and meta-analysis (MA) of CAR studies to explore potential significant differences between children and adolescents with ASD and TD controls. Web of Science, PubMed and PsychInfo were searched until January 2019. A random-effects model was used to pool studies and we used the Newcastle-Ottawa scale (NOS) to assess study quality and risk of bias. FINDINGS/RESULTS:DISCUSSION AND CLINICAL IMPLICATIONS: Given the relatively few studies and lack of appropriately matched TD controls, additional research is needed to further understand and recommend the utility of the CAR as a reliable marker to differentiate ASD and TD.

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.