Serdexmethylphenidate/dexmethylphenidate for children with attention-deficit/hyperactivity disorder: dose optimization from a laboratory classroom study.

Objective: To evaluate treatment responder rate using the Attention-Deficit/Hyperactivity Disorder Rating Scale-5 (ADHD-RS-5) score based on optimized dose level of serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) and changes in ADHD severity in children (aged 6-12 years) with ADHD. Methods: During a 21-day dose-optimization phase, 155 patients initiated treatment with 39.2/7.8 mg SDX/d-MPH in the first week and then were titrated to an optimum dose; 5 patients were downtitrated to 26.1/5.2 mg, 76 were uptitrated to 52.3/10.4 mg, and 69 remained at 39.2/7.8 mg during the following 2 weeks. Responder threshold values were 30% and 50% based on the percent change from baseline (day 0) to days 7, 14, and 21 in the ADHD-RS-5 score. The Conners 3rd Edition-Parent score was used to assess weekly changes in ADHD severity during the dose-optimization and treatment phases. Results: Of the 5 subjects whose dose was optimized at 26.1/5.2 mg, ≥80% across all days had ≥50% responder rate. Of the 69 subjects whose dose was optimized at 39.2/7.8 mg, 81.2% had ≥50% responder rate by day 21. Of the 76 subjects whose dose was optimized to 52.3/10.4 mg, 72.4% had ≥50% responder rate by day 21. Changes in ADHD severity, based on mean Conners 3rd Edition-Parent scores, improved from baseline at each visit during dose optimization for each subscale. At the dose-optimization phase, Conners 3rd Edition-Parent scores improved from baseline for SDX/d-MPH in all subscales. Conclusion: A high percentage of subjects were responders upon reaching their final optimized dose. SDX/d-MPH demonstrated significant reductions in ADHD severity in children based on the Conners 3rd Edition-Parent scores. Determining the optimal dosage of SDX/d-MPH and its effect on ADHD severity could enable the development of a more clinically relevant treatment regimen in children with ADHD.

Secondary analyses of sex differences in attention improvements across three clinical trials of a digital therapeutic in children, adolescents, and adults with ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) remains underdiagnosed and undertreated in girls. Inattentive symptoms, often predominant in girls with ADHD, represent a key driver of impairment and often persist into adulthood. AKL-T01 is a regulated digital therapeutic targeting inattention. We examined potential sex differences in the efficacy of AKL-T01 in three separate trials for 1) children, 2) adolescents, and 3) adults. METHODS: We conducted secondary analyses of clinical outcomes by sex in three AKL-T01 randomized clinical trials in ADHD (n1 = 180 children 30.6% female, M(SD) age = 9.71 (1.32); n2 = 146 adolescents; 41.1% female, M(SD) age = 14.34 (1.26); n3 = 153 adults; 69.9% female, M(SD) age = 39.86 (12.84)). Active treatment participants used AKL-T01 for 25 min/day over 4-6 weeks. Primary outcomes included change in attention on the Test of Variables of Attention (TOVA) and symptom change on the clinician-rated ADHD Rating Scale (ADHD-RS). To evaluate study hypotheses, we conducted a series of robust linear regressions of TOVA and ADHD-RS change scores by sex, adjusting for baseline scores. RESULTS: In children, girls demonstrated greater improvement in objective attention relative to boys following AKL-T01 (TOVA Attentional Composite Score; Cohen's d = .36 and Reaction Time Mean Half; Cohen's d = .54), but no significant sex differences in ADHD rating scale change. We did not observe significant sex differences in outcomes in the adolescent or adult trials. Limitations include binary sex categorization and slight study design variation across the three samples. CONCLUSION: AKL-T01 might notably improve attentional functioning in girls with ADHD relative to boys. Objective attention measures may be particularly important in the assessment of attentional improvement in childhood, given known gender biases in ADHD symptom reporting. We emphasize the importance of considering sex and gender-specific factors in ADHD treatment evaluation. TRIAL REGISTRATIONS: STARS ADHD CHILD: ClinicalTrials.gov ID NCT03649074; STARS ADHD ADOLESCENT: ClinicalTrials.gov ID NCT04897074; STARS ADHD ADULT: ClinicalTrials.gov ID NCT05183919.

Sleep Physiology and Neurocognition Among Adolescents With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Few studies have characterized the nature of sleep problems among adolescents with attention-deficit/hyperactivity disorder (ADHD) using polysomnography (PSG). Additionally, although adolescents with ADHD and adolescents with sleep disturbances display similar neurocognitive deficits, the role of sleep in contributing to neurocognitive impairment in adolescent ADHD is unknown. This study investigated differences in PSG-measured sleep among adolescents with ADHD compared with non-psychiatric controls and associations with neurocognition. METHOD: Medication-free adolescents aged 13 to 17 (N = 62, n = 31 with ADHD; mean age = 15.3 years; 50% female) completed a diagnostic evaluation, 3 nights of ambulatory PSG, the Cambridge Neuropsychological Test Automated Battery, and subjective reports of sleep and executive functioning. Linear regressions covarying for age, sex, and pubertal status examined group differences in sleep indices, and partial Pearson correlations assessed relations between sleep and neurocognition. RESULTS: Although adolescents with ADHD did not exhibit differences in PSG-measured sleep duration, awakenings, or latency (ps > .05) compared with non-psychiatric controls, they displayed lower slow wave sleep percentage (ß = -.40) and non-rapid eye movement (NREM) electroencephalogram (EEG) delta power (ß = -.29). They also exhibited greater stage 2 percentage (ß = .41), NREM EEG sigma power (ß = .41), and elevated self-reported sleep disturbances (ps < .05). Lower NREM EEG delta power, increased high-frequency power, and slower decline in NREM EEG delta power overnight were associated with poorer neurocognition among adolescents with ADHD. CONCLUSIONS: Adolescents with ADHD reported more sleep disturbances than non-psychiatric controls and exhibited differences in sleep stage distribution and NREM sleep EEG frequency. Sleep-EEG spectral indices were associated with impaired neurocognition, suggesting that physiological sleep processes may underlie neurocognitive deficits in ADHD. Future studies may clarify whether sleep plays a causal role in neurocognitive impairments in adolescent ADHD and whether interventions normalizing sleep improve neurocognition. CLINICAL TRIAL REGISTRATION INFORMATION: Sleep Dysfunction and Neurocognitive Outcomes in Adolescent ADHD; https://clinicaltrials.gov/; NCT02897362. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list.

Associations of comorbid substance use disorders with clinical outcomes in schizophrenia using electronic health record data.

BACKGROUND AND HYPOTHESIS: Schizophrenia and comorbid substance use disorders (SUDs) are associated with poor treatment outcomes but differences between the associations of different SUDs with clinical outcomes are poorly characterized. This study examines the associations of comorbid SUDs with clinical outcomes in schizophrenia using a largescale electronic health record (EHR) database. DESIGN: Real-world data (RWD) analysis using the NeuroBlu database; de-identified EHR data were analysed. Multivariable logistic regression, Poisson and CoxPH models were used to compare the associations of specific comorbid SUDs with outcome variables. RESULTS: Comorbid SUD was significantly different on all outcome measures compared to no SUD (U = 1.44e7-1.81e7, all ps < .001), except number of unique antipsychotics (U = 1.61e7, p = .43). Cannabis (OR = 1.58, p < .001) and polysubstance (OR = 1.22, p = .007) use disorders were associated with greater CGI-S. Cannabis (IRR = 1.13, p = .003) and polysubstance (IRR = 1.08, p = .003) use disorders were associated with greater number of unique antipsychotics prescribed, while cocaine (HR = 1.87, p < .001), stimulants (HR = 1.64, p = .024), and polysubstance (HR = 1.46, p < .001) use disorders were associated with a shorter time to antipsychotic discontinuation. Conversely, alcohol use (IRR = 0.83, p < .001), cocaine use (IRR = 0.61, p < .001), opioid use (IRR = 0.61, p < .001), stimulant use (IRR = 0.57, p < .001) and polysubstance use (IRR = 0.87, p < .001) disorders were associated fewer inpatient days. CONCLUSION: Comorbid SUDs were generally associated with greater CGI-S and poorer clinical outcomes in patients with schizophrenia. Treatment strategies should target not only schizophrenia symptoms but also comorbid SUD to improve management of both conditions.

"Click and mortar" opportunities for digitization and consumerism in trials.

BACKGROUND: Digitization (using novel digital tools and strategies) and consumerism (taking a consumer-oriented approach) are increasingly commonplace in clinical trials, but the implications of these changes are not well described. METHODS: We assembled a group of trial experts from academia, industry, non-profit, and government to discuss implications of this changing trial landscape and provide guidance. RESULTS: Digitization and consumerism can increase the volume and diversity of trial participants and expedite recruitment. However, downstream bottlenecks, challenges with retention, and serious issues with equity, ethics, and security can result. A "click and mortar" approach, combining approaches from novel and traditional trials with the thoughtful use of technology, may optimally balance opportunities and challenges facing many trials. CONCLUSION: We offer expert guidance and three "click and mortar" approaches to digital, consumer-oriented trials. More guidance and research are needed to navigate the associated opportunities and challenges.

Early trajectory of clinical global impression as a transdiagnostic predictor of psychiatric hospitalisation: a retrospective cohort study.

BACKGROUND: Identifying patients most at risk of psychiatric hospitalisation is crucial to improving service provision and patient outcomes. Existing predictors focus on specific clinical scenarios and are not validated with real-world data, limiting their translational potential. This study aimed to determine whether early trajectories of Clinical Global Impression Severity are predictors of 6 month risk of hospitalisation. METHODS: This retrospective cohort study used data from the NeuroBlu database, an electronic health records network from 25 US mental health-care providers. Patients with an ICD-9 or ICD-10 code of major depressive disorder, bipolar disorder, generalised anxiety disorder, post-traumatic stress disorder, schizophrenia or schizoaffective disorder, ADHD, or personality disorder were included. Using this cohort, we assessed whether clinical severity and instability (operationalised using Clinical Global Impression Severity measurements) during a 2-month period were predictors of psychiatric hospitalisation within the next 6 months. FINDINGS: 36 914 patients were included (mean age 29·7 years [SD 17·5]; 21 156 [57·3%] female, 15 748 [42·7%] male; 20 559 [55·7%] White, 4842 [13·1%] Black or African American, 286 [0·8%] Native Hawaiian or other Pacific Islander, 300 [0·8%] Asian, 139 [0·4%] American Indian or Alaska Native, 524 (1·4%) other or mixed race, and 10 264 [27·8%] of unknown race). Clinical severity and instability were independent predictors of risk of hospitalisation (adjusted hazard ratio [HR] 1·09, 95% CI 1·07-1·10 for every SD increase in instability; 1·11, 1·09-1·12 for every SD increase in severity; p<0·0001 for both). These associations were consistent across all diagnoses, age groups, and in both males and females, as well as in several robustness analyses, including when clinical severity and clinical instability were based on the Patient Health Questionnaire-9 rather than Clinical Global Impression Severity measurements. Patients in the top half of the cohort for both clinical severity and instability were at an increased risk of hospitalisation compared with those in the bottom half along both dimensions (HR 1·45, 95% CI 1·39-1·52; p<0·0001). INTERPRETATION: Clinical instability and severity are independent predictors of future risk of hospitalisation, across diagnoses, age groups, and in both males and females. These findings could help clinicians make prognoses and screen patients who are most likely to benefit from intensive interventions, as well as help health-care providers plan service provisions by adding additional detail to risk prediction tools that incorporate other risk factors. FUNDING: National Institute for Health and Care Research, National Institute for Health and Care Research Oxford Health Biomedical Research Centre, Medical Research Council, Academy of Medical Sciences, and Holmusk.

Predictive Value of Early Autism Detection Models Based on Electronic Health Record Data Collected Before Age 1 Year.

Importance: Autism detection early in childhood is critical to ensure that autistic children and their families have access to early behavioral support. Early correlates of autism documented in electronic health records (EHRs) during routine care could allow passive, predictive model-based monitoring to improve the accuracy of early detection. Objective: To quantify the predictive value of early autism detection models based on EHR data collected before age 1 year. Design, Setting, and Participants: This retrospective diagnostic study used EHR data from children seen within the Duke University Health System before age 30 days between January 2006 and December 2020. These data were used to train and evaluate L2-regularized Cox proportional hazards models predicting later autism diagnosis based on data collected from birth up to the time of prediction (ages 30-360 days). Statistical analyses were performed between August 1, 2020, and April 1, 2022. Main Outcomes and Measures: Prediction performance was quantified in terms of sensitivity, specificity, and positive predictive value (PPV) at clinically relevant model operating thresholds. Results: Data from 45 080 children, including 924 (1.5%) meeting autism criteria, were included in this study. Model-based autism detection at age 30 days achieved 45.5% sensitivity and 23.0% PPV at 90.0% specificity. Detection by age 360 days achieved 59.8% sensitivity and 17.6% PPV at 81.5% specificity and 38.8% sensitivity and 31.0% PPV at 94.3% specificity. Conclusions and Relevance: In this diagnostic study of an autism screening test, EHR-based autism detection achieved clinically meaningful accuracy by age 30 days, improving by age 1 year. This automated approach could be integrated with caregiver surveys to improve the accuracy of early autism screening.

Intranasal Use of Prescription Stimulants Among Adults Aged 18 to 30: Results From A Crowdsourcing Platform.

OBJECTIVE: Few studies of prescription stimulant non-oral, non-medical use (NMU) (defined by use not as prescribed) have been conducted in adults beyond the college population. The purpose of this study was to characterize prescription stimulant non-oral use, specifically intranasal (IN) use (snorting) in young adults. METHOD: Amazon's MTurk platform was used to recruit participants for an online survey. Data were collected from March to April 2020. RESULTS: Thirty-two percent (n = 157) of survey respondents (N = 975), aged 18 to 30, reported IN prescription stimulant use (average of 32.1 episodes of lifetime IN use). Adderall was the most-reported prescription stimulant used intranasally (89.2%). Most IN users (82%; n = 68) reported spending no more than 5 minutes tampering with prescription stimulants. Intranasal users said they would take the medication orally if unable to tamper or manipulate medication for IN use. CONCLUSION: These data help quantify a complex public health issue of ongoing IN use of prescription stimulants and suggest a potential role for manipulation-deterrent medications.

Adaptive Behavior in Young Autistic Children: Associations with Irritability and ADHD Symptoms.

Attention-deficit/hyperactivity disorder (ADHD) symptoms affect 40-60% of autistic children and have been linked to differences in adaptive behavior. It is unclear whether adaptive behavior in autistic youth is directly impacted by co-occurring ADHD symptoms or by another associated feature of both autism and ADHD, such as increased irritability. The current study examined relationships between irritability, ADHD symptoms, and adaptive behavior in 3- to 7-year-old autistic children. Results suggest that, after adjusting for co-occurring ADHD symptoms, higher levels of irritability are associated with differences in social adaptive behavior specifically. Understanding relationships between irritability, ADHD, and adaptive behavior in autistic children is critical because measures of adaptive behavior, such as the Vineland Scales of Adaptive Functioning, are often used as a proxy for global functioning, as well as for developing intervention plans and measuring outcomes as primary endpoints in clinical trials.

NeuroBlu, an electronic health record (EHR) trusted research environment (TRE) to support mental healthcare analytics with real-world data.

PURPOSE: NeuroBlu is a real-world data (RWD) repository that contains deidentified electronic health record (EHR) data from US mental healthcare providers operating the MindLinc EHR system. NeuroBlu enables users to perform statistical analysis through a secure web-based interface. Structured data are available for sociodemographic characteristics, mental health service contacts, hospital admissions, International Classification of Diseases ICD-9/ICD-10 diagnosis, prescribed medications, family history of mental disorders, Clinical Global Impression-Severity and Improvement (CGI-S/CGI-I) and Global Assessment of Functioning (GAF). To further enhance the data set, natural language processing (NLP) tools have been applied to obtain mental state examination (MSE) and social/environmental data. This paper describes the development and implementation of NeuroBlu, the procedures to safeguard data integrity and security and how the data set supports the generation of real-world evidence (RWE) in mental health. PARTICIPANTS: As of 31 July 2021, 562 940 individuals (48.9% men) were present in the data set with a mean age of 33.4 years (SD: 18.4 years). The most frequently recorded diagnoses were substance use disorders (1 52 790 patients), major depressive disorder (1 29 120 patients) and anxiety disorders (1 03 923 patients). The median duration of follow-up was 7 months (IQR: 1.3 to 24.4 months). FINDINGS TO DATE: The data set has supported epidemiological studies demonstrating increased risk of psychiatric hospitalisation and reduced antidepressant treatment effectiveness among people with comorbid substance use disorders. It has also been used to develop data visualisation tools to support clinical decision-making, evaluate comparative effectiveness of medications, derive models to predict treatment response and develop NLP applications to obtain clinical information from unstructured EHR data. FUTURE PLANS: The NeuroBlu data set will be further analysed to better understand factors related to poor clinical outcome, treatment responsiveness and the development of predictive analytic tools that may be incorporated into the source EHR system to support real-time clinical decision-making in the delivery of mental healthcare services.

Shuffle the Decks: Children Are Sensitive to Incidental Nonrandom Structure in a Sequential-Choice Task.

As children age, they can learn increasingly complex features of environmental structure-a key prerequisite for adaptive decision-making. Yet when we tested children (N = 304, 4-13 years old) in the Children's Gambling Task, an age-appropriate variant of the Iowa Gambling Task, we found that age was negatively associated with performance. However, this paradoxical effect of age was found only in children who exhibited a maladaptive deplete-replenish bias, a tendency to shift choices after positive outcomes and repeat choices after negative outcomes. We found that this bias results from sensitivity to incidental nonrandom structure in the canonical, deterministic forms of these tasks-and that it would actually lead to optimal outcomes if the tasks were not deterministic. Our results illustrate that changes in decision-making across early childhood reflect, in part, increasing sensitivity to environmental structure.

Pragmatic adaptations of telehealth-delivered caregiver coaching for children with autism in the context of COVID-19: Perspectives from the United States and South Africa.

LAY ABSTRACT: COVID-19 caused many autism spectrum disorder caregiver-coaching studies to move to telehealth. Telehealth can increase the diversity of people who take part in research. This matters because most autism spectrum disorder studies have included people who have resources, are White, and live in North America and Europe. When study participants are similar, it is hard to understand which interventions can help different types of people who live in different parts of the world. While telehealth may allow more people to take part in research, it needs to "fit" the local context and consider the "digital divide" because many people around the world have no access to computers and the Internet. This short report describes changes to two research studies that include caregiver coaching based on the Early Start Denver Model in the United States and South Africa. We describe how the local context, including technology and Internet access, guided the telehealth approach. By doing so, we highlight ways to make telehealth available to more people around the world. The pandemic can help us understand how telehealth can "fit" diverse places and support high-quality research. It is important that study changes are tracked and we assess how well the changes work. COVID-19 telehealth changes to caregiver coaching can result in new ways to reach more people around the world.

Impact of daily caffeine intake and timing on electroencephalogram-measured sleep in adolescents.

STUDY OBJECTIVES: Caffeine use is ubiquitous among adolescents and may be harmful to sleep, with downstream implications for health and development. Research has been limited by self-reported and/or aggregated measures of sleep and caffeine collected at a single time point. This study examines bidirectional associations between daily caffeine consumption and electroencephalogram-measured sleep among adolescents and explores whether these relationships depend on timing of caffeine use. METHODS: Ninety-eight adolescents aged 11-17 (mean =14.38, standard deviation = 1.77; 50% female) participated in 7 consecutive nights of at-home sleep electroencephalography and completed a daily diary querying morning, afternoon, and evening caffeine use. Linear mixed-effects regressions examined relationships between caffeine consumption and total sleep time, sleep-onset latency, sleep efficiency, wake after sleep onset, and time spent in sleep stages. Impact of sleep indices on next-day caffeine use was also examined. RESULTS: Increased total caffeine consumption was associated was increased sleep-onset latency (ß = .13; 95% CI = .06, .21; P < .001) and reduced total sleep time (ß = -.17; 95% confidence interval [CI] = -.31, -.02; P = .02), sleep efficiency (ß = -1.59; 95% CI = -2.51, -.67; P < .001), and rapid eye movement sleep (ß = -.12; 95% CI = -.19, -.05; P < .001). Findings were driven by afternoon and evening caffeine consumption. Reduced sleep efficiency was associated with increased afternoon caffeine intake the following day (ß = -.006; 95% CI = -.012, -.001; P = .01). CONCLUSIONS: Caffeine consumption, especially afternoon and evening use, impacts several aspects of adolescent sleep health. In contrast, most sleep indicators did not affect next-day caffeine use, suggesting multiple drivers of adolescent caffeine consumption. Federal mandates requiring caffeine content labeling and behavioral interventions focused on reducing caffeine intake may support adolescent sleep health. CITATION: Lunsford-Avery JR, Kollins SH, Kansagra S, Wang KW, Engelhard MM. Impact of daily caffeine intake and timing on electroencephalogram-measured sleep in adolescents. J Clin Sleep Med. 2022;18(3):877-884.

Regularity and Timing of Sleep Patterns and Behavioral Health Among Adolescents.

OBJECTIVE: Sleep is vital to supporting adolescent behavioral health and functioning; however, sleep disturbances remain under-recognized and undertreated in many health care settings. One barrier is the complexity of sleep, which makes it difficult for providers to determine which aspects-beyond sleep duration-may be most important to assess and treat to support adolescent health. This study examined associations between 2 sleep indices (regularity and timing) and adolescent behavioral health and functioning over and above the impact of shortened/fragmented sleep. METHOD: Eighty-nine adolescents recruited from the community (mean age = 14.04, 45% female participants) completed 7 days/nights of actigraphy and, along with a parent/guardian, reported on behavioral health (internalizing and externalizing symptoms) and psychosocial functioning. Stepwise linear regressions examined associations between sleep timing and regularity and behavioral/functional outcomes after accounting for shortened/fragmented sleep. RESULTS: Delayed sleep timing was associated with greater self-reported internalizing (F[6,82] = 11.57, p = 0.001) and externalizing (F[6,82] = 11.12, p = 0.001) symptoms after accounting for shortened/fragmented sleep. Irregular sleep was associated with greater self-reported and parent-reported externalizing symptoms (self: F[7,81] = 6.55, p = 0.01; parent: F[7,80] = 6.20, p = 0.01) and lower psychosocial functioning (self: F[7,81] = 6.03, p = 0.02; parent: F[7,78] = 3.99, p < 0.05) after accounting for both shortened/fragmented sleep and delayed sleep timing. CONCLUSION: Sleep regularity and timing may be critical for understanding the risk of poor behavioral health and functional deficits among adolescents and as prevention and intervention targets. Future work should focus on developing and evaluating convenient, low-cost, and effective methods for addressing delayed and/or irregular adolescent sleep patterns in real-world health care settings.

Parenting Stress, Child Weight-Related Behaviors, and Child Weight Status.

Background: There has been limited examination of the association between parenting stress and child weight-related behaviors. We aimed to determine whether parenting stress is associated with child weight-related behaviors, including physical activity, screen time, diet, sedentary time, and eating in the absence of hunger (EAH). Secondarily, we assessed association between parenting stress and child weight status. Methods: Mother-child dyads (N = 291) enrolled in the Newborn Epigenetic STudy (NEST), a longitudinal cohort study, completed surveys to describe parenting stress, and child diet. Children participated in the EAH task and wore accelerometers to assess sedentary time and physical activity. Child weight status was assessed using measured height and weight. Outcomes and exposures were examined using generalized linear models and restricted cubic splines as appropriate based on linear lack-of-fit test. Results: Child sedentary time and vegetable consumption were inversely associated with parenting stress (Total Stress B = -0.78; 95% confidence interval [CI]: -1.35 to -0.20; p = 0.017; and Total Stress adjusted odds ratio [aOR] = 0.98; 95% CI: 0.99 to 1.00; p = 0.022, respectively). Child screen time was directly associated with parenting stress (Total Stress = aOR 1.01; 95% CI: 1.00-1.02; p = 0.032). Fast-food intake was nonlinearly associated with parenting stress. There was no evidence of association between parenting stress and child EAH, physical activity, or weight status. Associations between parenting stress and child weight-related behaviors were not moderated by race or family structure. Conclusions: Parenting stress was associated with important child weight-related behaviors but not weight status. Management of parenting stress may represent a reasonable adjunct to family-based behavioral interventions.

ADHD, Religiosity, and Psychiatric Comorbidity in Adolescence and Adulthood.

OBJECTIVE: Religiosity has been repeatedly proposed as protective in the development of depression, sociopathy and addictions. ADHD frequently co-occurs with these same conditions. Although ADHD symptoms may affect religious practice, religiosity in ADHD remains unexplored. METHOD: Analyses examined data from >8000 subjects aged 12 to 34 in four waves of the Add Health Study. Relationships of religious variables with childhood ADHD symptoms were statistically evaluated. Observed correlations of ADHD symptoms to depression, delinquency, and substance use were tested for mediation and moderation by religiosity. RESULTS: ADHD symptoms correlated with lower levels of all religious variables at nearly all waves. In some analyses at Wave IV, prayer and attendance interacted with ADHD to predict worsened psychopathology. CONCLUSION: ADHD symptoms predicted lower engagement in religious life. In adulthood, some aspects of religiosity interacted with ADHD symptoms to predict worse outcomes. Further research should explore whether lower religiosity partially explains prevalent comorbidities in ADHD.

Large-scale genetic investigation reveals genetic liability to multiple complex traits influencing a higher risk of ADHD.

Attention Deficit-Hyperactivity Disorder (ADHD) is a complex psychiatric and neurodevelopmental disorder that develops during childhood and spans into adulthood. ADHD's aetiology is complex, and evidence about its cause and risk factors is limited. We leveraged genetic data from genome-wide association studies (GWAS) and performed latent causal variable analyses using a hypothesis-free approach to infer causal associations between 1387 complex traits and ADHD. We identified 37 inferred potential causal associations with ADHD risk. Our results reveal that genetic variants associated with iron deficiency anemia (ICD10), obesity, type 2 diabetes, synovitis and tenosynovitis (ICD10), polyarthritis (ICD10), neck or shoulder pain, and substance use in adults display partial genetic causality on ADHD risk in children. Genetic variants associated with ADHD have a partial genetic causality increasing the risk for chronic obstructive pulmonary disease and carpal tunnel syndrome. Protective factors for ADHD risk included genetic variants associated with the likelihood of participating in socially supportive and interactive activities. Our results show that genetic liability to multiple complex traits influences a higher risk for ADHD, highlighting the potential role of cardiometabolic phenotypes and physical pain in ADHD's aetiology. These findings have the potential to inform future clinical studies and development of interventions.

Efficacy and Safety of a Long-Acting Multilayer-Release Methylphenidate Formulation (PRC-063) in the Treatment of Adolescent Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Clinical Trial with a 6-Month Open-Label Extension.

Objectives: To study the safety and efficacy of the long-acting methylphenidate formulation PRC-063 in adolescents with attention-deficit/hyperactivity disorder (ADHD). Methods: Adolescents 12 to ≤17 years who met Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for ADHD and had a baseline ADHD Rating Scale DSM-5 (ADHD-5-RS) score ≥24 participated in a randomized, double-blind, placebo-controlled, fixed-dose, parallel-group study. Participants were randomized 1:1:1:1:1 to receive placebo or one of four doses of PRC-063 once daily for 4 weeks. The primary endpoint was change from baseline in least-squares mean clinician-rated ADHD-5-RS total score for PRC-063 (all doses combined) versus placebo. Other efficacy assessments included Conners third Edition: Self-Report (C3SR) and Clinical Global Impression-Improvement (CGI-I). A subset of double-blind study participants entered a subsequent open-label, dose-optimized study. Safety outcomes in both studies included treatment-emergent adverse events (TEAEs). Results: Three hundred fifty-four participants were included in the primary analysis. The least-squares mean change from baseline in ADHD-5-RS total score was -15.17 for PRC-063 versus -10.98 for placebo (least-squares mean difference -4.2, p = 0.0067). For individual PRC-063 doses, improvements in ADHD-5-RS total score versus placebo were significant for 45 mg (p = 0.0155) and 70 mg (p = 0.0401), but not for 25 or 85 mg. A significant improvement for PRC-063 versus placebo was recorded for C3SR Inattention (p = 0.0168), but not for the other C3SR subscales. About 52.7% of participants randomized to PRC-063 were responders based on CGI-I versus 32.4% of those randomized to placebo (p = 0.0004). Further improvements in ADHD symptoms based on ADHD-5-RS were observed from 1 month through 6 months of open-label treatment (p < 0.0001). There were two serious adverse events (both during the open-label study), one of which (aggressive behavior) was assessed as related to study drug. The only TEAEs that occurred in >10% of participants during double-blind treatment were decreased appetite (20.1%) and headache (15.0%). Most TEAEs were of mild or moderate severity. Conclusion: PRC-063 significantly improved ADHD symptomatology in adolescents. It was generally well tolerated, with an AE profile consistent with other long-acting stimulants. NCT02139111 and NCT02168127.