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Abstract Although the efficacy of pharmacy in the treatment of attention deficit/hyperactivity disorder (ADHD) has been well established, the lack of predictors of treatment response poses great challenges for personalized treatment. The current study employed a comprehensive approach, combining genome-wide association analyses (GWAS) and deep learning (DL) methods, to elucidate the genetic underpinnings of pharmacological treatment response in ADHD. Based on genotype data of medication-naïve patients with ADHD who received pharmacological treatments for 12 weeks, the current study performed GWAS using the percentage changes in ADHD-RS score as phenotype. Then, DL models were constructed to predict percentage changes in symptom scores using genetic variants selected based on four different genome-wide P thresholds (E-02, E-03, E-04, E-05) as inputs. The current GWAS results identified two significant loci (rs10880574, P = 2.39E-09; rs2000900, P = 3.31E-09) which implicated two genes, TMEM117 and MYO5B, that were primarily associated with both brain- and gut-related disorders. The convolutional neural network (CNN) model, using variants with genome-wide P values less than E-02 (5516 SNPs), demonstrated the best performance with mean squared error (MSE) equals 0.012 (Accuracy = 0.83; Sensitivity = 0.90; Specificity = 0.75) in the validation dataset, 0.081 in an independent test dataset (Acc = 0.61, Sensitivity = 0.81; Specificity = 0.26). Notably, the variant that contributed most to the CNN model was NKAIN2, an ADHD-related gene, which is also associated with metabolic processes. To conclude, the integration of GWAS and DL methods revealed new genes contribute to ADHD pharmacological treatment responses, and underscored the interplay between neural systems and metabolic processes, potentially providing critical insights into precision treatment. Furthermore, our CNN model exhibited good performance in an independent dataset, encouraged future studies and implied potential clinical applications.

Objective: To examine the effects of triple beaded mixed amphetamine salts (TB MAS) on ADHD and executive dysfunction symptoms throughout the day in adults with DSM-5 ADHD. Method: This was a 6 week, single-blind, placebo-lead in trial of TB MAS (12.5-37.5 mg/day); all participants received 2 weeks of single-blind placebo); one individual was a placebo responder and was discontinued. One of these 18 dropped after 1 week on 12.5 mg/day, while all others completed the trial and received 37.5 mg/day TB MAS. Results: There were significant effects of TB MAS on all clinical measures, including investigator overall symptoms (AISRS); self-report overall (ASRS), time-sensitive ADHD (TASS) scores throughout the day, impairment (CGI) and executive function scores (BRIEF-A). TB MAS was generally well tolerated. Conclusions: This study extends prior findings of TB MAS to adults with DSM-5 ADHD; it further re-validates findings of efficacy of TB MAS throughout the day.

Objective: To explore outcomes of stimulant treatment for ADHD in pediatric populations with particular attention to bipolar disorder (BPD). Method: We conducted a literature search of PubMed articles published prior to August 25, 2022 that focused on BPD, mania, and psychosis prior to, or as result of, stimulant treatment. We excluded studies: (1) unrelated to stimulants, (2) general stimulant research, (3) articles older than 40 years, (4) study protocols, or (5) case reports. Results: A total of 11 articles met all inclusion/exclusion criteria. Some reports found stimulant treatment safe and well-tolerated in children with comorbid BPD and ADHD. Others found evidence of treatment-emergent mania (TEM), discontinuation, and other adverse events with stimulant treatment. Conclusion: Poor outcomes associated with stimulant treatment in pediatric populations with BPD necessitate work to identify patients at risk of serious stimulant-related adverse events. Our results were limited by automated search filters and a pediatric, primarily male sample. "(J. of Att. Dis. 2024; 28(5) 740-750)"

Objective: Examine differences in care patterns around adult ADHD between race (White/Non-White) and ethnic (Hispanic/Non-Hispanic) groups utilizing existing quality measures (QMs), concerning diagnosis, treatment, and medication prescribing. Methods: The AAFP National Research Network in partnership with SUNY Upstate Medical used an EHR dataset to evaluate achievement of 10 ADHD QMs. The dataset was obtained from DARTNet Institute and includes 4 million patients of 873 behavioral and primary care practices with at least 100 patients from 2010 to 2020. Patients 18-years or older with adult ADHD were included in this analysis. Results: White patients and Non-Hispanic/Latinx patients were more likely to achieve these QMs than Non-White patients and Hispanic/Latinx patients, respectively. Differences between groups concerning medication and monitoring demonstrate a disparity for Non-White and Hispanic/ Latinx populations. Conclusions: Using QMs in EHR data can help identify gaps in ADHD research. There is a need to continue investigating disparities of quality adult ADHD care. "(J. of Att. Dis. 2024; 28(5) 923-934)"

Objective: There is growing evidence of involvement of inflammatory mechanisms in ADHD. Previous studies found significantly higher rates of ADHD among children with FMF. The present study examined the rate of exposure to FMF in children with a later (within a 5-year period) diagnosis of ADHD compared to non-ADHD children. Methods: A population-based case-control study of all children (<18 years) registered in Leumit Health Services during 01.01.2006 to 06.30.2021. All cases met ICD-9/10 criteria for ADHD. They were matched by age, sex, and socioeconomic status on a 1:2 rate to randomly selected non-ADHD controls. Results: Fifty-six (0.30%) children with ADHD (N = 18,756) were previously diagnosed with FMF compared to 65 of 37,512 controls (0.17%). A significant, independent association existed between a preceding FMF diagnosis and a later ADHD diagnosis [OR = 1.72 (95% CI 1.18-2.51); p = 0.003]. Conclusions: The mechanisms underlying the association w between FMF and later ADHD diagnosis merit further elucidation.

Objective: Several studies have shown that Adult ADHD presents differently in younger and older adults. We sought to assess the difference in care between these two groups using previously identified quality measures (QMs). Methods: Using electronic health record data, we matched a younger group of ADHD patients to an older group. We then assessed the achievement of the QMs using probit models with and without interaction terms. Results: The majority of QMs shown an increase in achievement for both groups over time. However, significant differences in quality of care between younger and older adult ADHD patients persisted. By the end of the study period, with the exception of three QMs, younger patients achieved the QMs more. Conclusion: While, in general, the quality of care for adult ADHD increased from 2010 to 2020, there were still differences in care between younger and older adult ADHD patients.

Objective: We examined the association between the number, magnitude, and frequency of febrile episodes during the 0 to 4 years of life and subsequent diagnosis of ADHD. Methods: This population-based case-control study in an Israeli HMO, Leumit Health Services (LHS), uses a database for all LHS members aged 5 to 18 years between 1/1/2002 and 1/30/2022. The number and magnitude of measured fever episodes during the 0 to 4 years were recorded in individuals with ADHD (N = 18,558) and individually matched non-ADHD controls in a 1:2 ratio (N = 37,116). Results: A significant, independent association was found between the number and magnitude of febrile episodes during the 0 to 4 years and the probability of a later diagnosis of ADHD. Children who never had a measured temperature >37.5°C had a significantly lower rate of ADHD (OR = 0.834, 95% CI [0.802, 0.866], p < 0.0001). Conclusions: Febrile episodes during 0 to 4 years are associated with a significantly increased rate of a later diagnosis of ADHD in a dose-response relationship.

Objective: To provide additional information about clinical features associated with adult ADHD in patients diagnosed in childhood compared to those first diagnosed in adulthood. Method: We stratified a sample of adults with ADHD into patients diagnosed in childhood versus adulthood and compared demographic and clinical characteristics. Results: We found similar clinical features in adults diagnosed in childhood and adults diagnosed in adulthood. Among those diagnosed in adulthood, 95% reported symptom onset in youth. Our results do not support the hypothesis that ADHD diagnosed in adulthood is due to misinterpreting symptoms of other disorders as ADHD. They also suggest incorporating behavioral signs of executive dysfunction into diagnostic criteria for ADHD in adults may increase diagnostic sensitivity. Conclusion: These results support the validity of ADHD diagnoses in adulthood, as these adults show similar clinical profiles to those diagnosed in youth. Our results also suggest that if adult-onset ADHD exists, it is rare.

Objective: To investigate the associations of symptoms of attention deficit hyperactivity disorder (ADHD) with binge eating spectrum conditions (BESC) (binge eating disorder [BED], bulimia nervosa [BN], and recurrent binge eating [RBE]), psychiatric and somatic comorbidity, and healthcare utilization in a representative sample of a Brazilian city. Methods: A household survey of 2,297 adult residents of the city of Rio de Janeiro was conducted. The Adult Self-Rating Scale Screener (ASRS-6) was used to assess ADHD symptoms. BESC was assessed using the Questionnaire on Eating and Weight Patterns-5 (QEWP-5) and confirmed by telephone interview. Standardized questionnaires were used to assess psychiatric comorbidity. Closed-ended questions investigated somatic comorbidity and healthcare utilization. Results: ADHD symptoms were highly associated with BESC (BED: OR = 13.2, 95%CI 4.3-40.6; BN: OR = 27.5, 95%CI 5.9-128.7; RBE: OR = 5.8, 95%CI 2.9-11.4). However, with further adjustment for psychiatric comorbidity (depression, anxiety, alcohol use, and impulsivity), the ORs were no longer significant. Healthcare resource utilization was significantly higher in participants with ADHD and BESC but lost significance after controlling for psychiatric comorbidity. Conclusion: ADHD was associated with an increased prevalence of BESC and greater healthcare utilization. Nonetheless, there was an essential interplay among psychiatric comorbidity in the associations of ADHD and BESC.

Abstract Background Although the COVID-19 pandemic and its implications have been associated with mental health services utilization and medication consumption, there is no longitudinal study on the long-term impact on ADHD medication use trends. Methods This study examines the European ADHD medication consumption in 2020 to 2022 compared to the predicted consumption assuming the persistence of pre-pandemic trends. Predictions are calculated using Seasonal Autoregressive Integrated Moving Average (SARIMA) models. Results While European ADHD medication sales recorded a drop in 2020, they returned to the predicted level in 2021, even slightly exceeding it. In 2022, we found a clear exceedance of the predicted level by 16.4% on average at country level. Furthermore, the increase in consumption growth in the post-pandemic period (2021–2022) compared to the pre-pandemic period (2014–2019) was significant in 26 of the 28 European countries under consideration. Conclusion There is strong evidence of a trend change in the ADHD medicine consumption growth throughout Europe after the COVID-19 pandemic.

Background: Pediatric pain significantly affects children’s lives, leading to school absenteeism, impaired social interactions, and psychological distress. The perception of sensory signals as pain is influenced by the brain’s noradrenergic system, and recent evidence suggests that chronic pain may impact cognitive functioning and emotional regulation. Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with alterations in the dopaminergic/noradrenergic systems, which could affect pain perception. Pain-associated conditions and frequent analgesic use in childhood may be linked to ADHD development and could serve as early indicators, yet data on this potential association remain limited. Study Aim: This population-based case-control study in Israel aimed to assess the prevalence of pain-related diagnoses prior to ADHD diagnosis in children aged 5 to 18. The study included children registered with Leumit Health Services (LHS) between 1 January 2006, and 30 June 2021. Children diagnosed with ADHD were compared to matched controls, selected based on age, gender, socioeconomic status, and other sociodemographic factors, who were never diagnosed with ADHD during the study period. Results: Children with ADHD (N = 18,756) and controls (N = 37,512) were precisely matched for sociodemographic characteristics. Individuals with ADHD exhibited significantly higher frequencies of diverse pain conditions, including those associated with illness [headache, earaches, and throat pain (odds ratios [OR] = 1.156 [95%CI 1.085, 1.232], 1.295 [95%CI 1.217, 1.377], and 1.080 [95%CI 1.019, 1.145], respectively; p < 0.01)] and injury [sprains and strains (OR = 1.233 [95% CI 1.104,1.376)]. Analgesics were more frequently purchased by individuals with ADHD, particularly paracetamol (OR = 1.194 [95%CI 1.152, 1.237], p < 0.001) and ibuprofen (OR = 1.366 [95%CI 1.318, 1.416], p = 0.001). Conclusions: This study highlights a potential connection between ADHD and pediatric pain. The elevated rates of pain diagnoses and analgesic usage among children with ADHD underscore the need for further research.

Abstract In vivo experimental analysis of human brain tissue poses substantial challenges and ethical concerns. To address this problem, we developed a computational method called the Brain Gene Expression and Network-Imputation Engine (BrainGENIE) that leverages peripheral-blood transcriptomes to predict brain tissue-specific gene-expression levels. Paired blood–brain transcriptomic data collected by the Genotype-Tissue Expression (GTEx) Project was used to train BrainGENIE models to predict gene-expression levels in ten distinct brain regions using whole-blood gene-expression profiles. The performance of BrainGENIE was compared to PrediXcan, a popular method for imputing gene expression levels from genotypes. BrainGENIE significantly predicted brain tissue-specific expression levels for 2947–11,816 genes (false-discovery rate-adjusted p

IntroductionSluggish Cognitive Tempo (SCT) is a syndrome characterized by cognitive hypo-arousal that often appears as daytime sleepiness or drowsiness, mental fogginess, being easily confused, having difficulty with holding and manipulating information in working memory, and being forgetful. Although it frequently co-travels with attention-deficit/hyperactivity disorder (ADHD) or other conditions and confers significantly greater impairment, there are few studies examining SCT among adults with ADHD. Understanding what features SCT confers in association with ADHD, distinct from other conditions associating with ADHD, is critically important to confirm if SCT is a distinct syndrome that requires special assessment methods and special, distinct treatment efforts to reduce its impact. This study describes the clinical and neuropsychological features of SCT in a sample of adults with well-defined ADHD, and examines the relationship of SCT with other measures of ADHD, neurocognition, executive function (EF), and impairment.MethodsA sample of n = 106 adults with ADHD, ages 18-57 years, was assessed for SCT using the Barkley SCT scale. Adults with (SCT+) and without (SCT-) SCT received a comprehensive clinical assessment battery, and neuropsychological testing. Clinical and neuropsychological variables were examined for their associations with SCT. The variables were treated with Principal Axis Factoring with Promax with Kaiser Normalization to elucidate latent constructs and determine performance profiles associated with SCT among people with ADHD.ResultsEF Deficits and emotional dyscontrol (ED) symptoms significantly differentiated adults with ADHD and SCT whether measured via self or clinician report. Additionally, significantly greater impairment via both clinician and participant report was seen in the SCT + versus SCT - cohorts. SCT was also associated with a significantly distinct profile on the neuropsychological battery, characterized by a pattern of slower latencies and cognitive strategy choices across CANTAB and WAIS subtests, that reveals difficulty with increased cognitive load, which primarily accounted for the higher level of impairment in the SCT group.DiscussionThe convergence of clinical ratings and neurocognitive measures of EF deficits is consistent with the conclusion that SCT represents a distinct subgroup of adults with ADHD.

Abstract Background attention‐deficit/hyperactivity disorder (ADHD) is associated with both polygenic liability and environmental exposures, both intrinsic to the family, such as family conflict, and extrinsic, such as air pollution. However, much less is known about the interplay between environmental and genetic risks relevant to ADHD—a better understanding of which could inform both mechanistic models and clinical prediction algorithms. Methods Two independent data sets, the population‐based Adolescent Brain Cognitive Development Study (ABCD) (N = 11,876) and the case‐control Oregon‐ADHD‐1000 (N = 1449), were used to examine additive (G + E) and interactive (GxE) effects of selected polygenic risk scores (PRS) and environmental factors in a cross‐sectional design. Genetic risk was measured using PRS for nine mental health disorders/traits. Exposures included family income, family conflict/negative sentiment, and geocoded measures of area deprivation, lead exposure risk, and air pollution exposure (nitrogen dioxide and fine particulate matter). Results ADHD PRS and family conflict jointly predicted concurrent ADHD symptoms in both cohorts. Additive‐effects models, including both genetic and environmental factors, explained significantly more variation in symptoms than any individual factor alone (joint R2 = .091 for total symptoms in ABCD; joint R2 = .173 in Oregon‐ADHD‐1000; all delta‐R2 p‐values

Background: The relationship between attention-deficit/hyperactivity disorder (ADHD) symptoms and type 2 diabetes mellitus (T2D) and its cardiovascular outcomes have not been sufficiently studied. Methods: 2,986 adults with T2D from the Joslin Diabetes Center at Upstate Medical University were assessed for ADHD-like symptoms, executive dysfunction, and emotional control using the Adult Self-Report Scale V1.1 (ASRS) expanded version. Surveys were sent electronically, and clinical data were obtained from the electronic medical record. Pearson chi-square test was used for categorical variables association. When ASRS scores were the dependent variable, negative binomial regression correcting for demographic variables that were associated with the ASRS scores was used. Results: 155 (49.2%) of respondents met DSM-5 criteria for ADHD using the ASRS scores; Only ten (3.6%) of respondents had an ICD10 diagnosis of ADHD in their medical record; Forty-three (13.7%) had either a diagnosis of ADHD in the medical history or were taking medications used by people with ADHD. Higher levels of ADHD-like symptoms were found in patients with T2D compared with population norms. There was a modest association of the ASRS executive dysfunction subscale with overall cardiovascular comorbidities (p = 0.03). However, the p-value did not survive the multiple testing correction. Both ADHD-like symptoms and symptoms associated with emotional control, however, were not associated with specific cardiovascular diseases, hypertension, or with HbA1c, LDL-cholesterol, triglycerides, ALT, creatinine, or eGFR. Conclusion: Our results suggest that adults with T2D attending a tertiary care diabetes clinic are at risk for having ADHD-like symptoms, highlighting the importance of screening for ADHD symptoms in this specialty setting and referring undiagnosed adult patients for further assessment and treatment of ADHD. Larger studies are needed to clarify the relationship between ADHD-like symptoms, executive dysfunction, and emotional control with diabetic control and comorbidities.

Abstract Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast “resilient” unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.

Abstract Background Pediatric bipolar disorder is a highly prevalent and morbid disorder and is considered a prevalent public health concern. Currently approved treatments often pose the risk of serious side effects. Therefore, this study assessed the efficacy and tolerability of N-acetylcysteine (NAC), in children and adolescents with bipolar spectrum disorder. Methods We conducted a 12-week open-label trial of NAC for treatment of mania and hypomania in children and adolescents ages 5–17 with bipolar spectrum disorder including participants with full and subthreshold manic symptoms, accepting those with and without mixed states with co-occurring depression, and Young Mania Rating Scale scores ≥ 20 and

Abstract Introduction Attention‐deficit/hyperactivity disorder (ADHD) is associated with impairments related to peer relations (PR) and social activities (SA). The objective of this post hoc analysis was to assess the degree to which viloxazine extended‐release (viloxazine ER; viloxazine extended‐release capsules; Qelbree®) improves clinical assessments of PR and SA in children and adolescents with ADHD. Methods Data were used from four Phase III placebo‐controlled trials of 100 to 600 mg/day of viloxazine ER (N = 1354; 6–17 years of age). PR and SA were measured with the Peer Relations content scale of the Conners 3rd Edition Parent Short Form's Peer Relation content scale (C3PS‐PR) and the Social Activities domain of the Weiss Functional Impairment Rating Scale‐Parent Report's (WFIRS‐P‐SA) at baseline and end of study. ADHD symptoms were assessed weekly with the ADHD Rating Scale, 5th Edition. The analyses relied on the general linear mixed model with the subject as a random effect. Results Improvement in C3PS‐PR (p = .0035) and WFIRS‐P‐SA (p = .0029) scores were significantly greater in subjects treated with viloxazine ER compared with placebo. When using measures of clinically meaningful response, the C3PS‐PR responder rate was significantly higher for viloxazine ER (19.2%) compared with placebo (14.1%) and the difference was statistically significant (p = .0311); the Number Needed to Treat (NNT) was 19.6. The WFIRS‐P‐SA responder rate was significantly higher for viloxazine ER (43.2%) compared with placebo (28.5%) and the difference was statistically significant (p

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, and around two-thirds of affected children report persisting problems in adulthood. This negative trajectory is associated with high comorbidity with disorders like obesity, depression, or substance use disorder (SUD). Decreases in cortical volume and thickness have also been reported in depression, SUD, and obesity, but it is unclear whether structural brain alterations represent unique disorder-specific profiles. A transdiagnostic exploration of ADHD and typical comorbid disorders could help to understand whether specific morphometric brain changes are due to ADHD or, alternatively, to the comorbid disorders. In the current study, we studied the brain morphometry of 136 subjects with ADHD with and without comorbid depression, SUD, and obesity to test whether there are unique or common brain alterations. We employed a machine-learning-algorithm trained to classify subjects with ADHD in the large ENIGMA-ADHD dataset and used it to predict the diagnostic status of subjects with ADHD and/or comorbidities. The parcellation analysis demonstrated decreased cortical thickness in medial prefrontal areas that was associated with presence of any comorbidity. However, these results did not survive correction for multiple comparisons. Similarly, the machine learning analysis indicated that the predictive algorithm grouped most of our ADHD participants as belonging to the ADHD-group, but no systematic differences between comorbidity status came up. In sum, neither a classical comparison of segmented structural brain metrics nor an ML model based on the ADHD ENIGMA data differentiate between ADHD with and without comorbidities. As the ML model is based in part on adolescent brains, this might indicate that comorbid disorders and their brain changes are not captured by the ML model because it represents a different developmental brain trajectory.

BackgroundMindfulness can improve overall well-being by training individuals to focus on the present moment without judging their thoughts. However, it is unknown how much mindfulness practice and training are necessary to improve well-being. ObjectiveThe primary aim of this study was to determine whether a standard 8-session web-based mindfulness-based cognitive therapy (MBCT) program, compared with a brief 3-session mindfulness intervention, improved overall participant well-being. In addition, we sought to explore whether the treatment effects differed based on the baseline characteristics of the participants (ie, moderators). MethodsParticipants were recruited from 17 patient-powered research networks, web-based communities of stakeholders interested in a common research area. Participants were randomized to either a standard 8-session MBCT or a brief 3-session mindfulness training intervention accessed on the web. The participants were followed for 12 weeks. The primary outcome of the study was well-being, as measured by the World Health Organization—Five Well-Being Index. We hypothesized that MBCT would be superior to a brief mindfulness training. ResultsWe randomized 4411 participants, 3873 (87.80%) of whom were White and 3547 (80.41%) of female sex assigned at birth. The mean baseline World Health Organization—Five Well-Being Index score was 50.3 (SD 20.7). The average self-reported well-being in each group increased over the intervention period (baseline to 8 weeks; model-based slope for the MBCT group: 0.78, 95% CI 0.63-0.93, and brief mindfulness group: 0.76, 95% CI 0.60-0.91) as well as the full study period (ie, intervention plus follow-up; baseline to 20 weeks; model-based slope for MBCT group: 0.41, 95% CI 0.34-0.48; and brief mindfulness group: 0.33, 95% CI 0.26-0.40). Changes in self-reported well-being were not significantly different between MBCT and brief mindfulness during the intervention period (model-based difference in slopes: −0.02, 95% CI −0.24 to 0.19; P=.80) or during the intervention period plus 12-week follow-up (−0.08, 95% CI −0.18 to 0.02; P=.10). During the intervention period, younger participants (P=.05) and participants who completed a higher percentage of intervention sessions (P=.005) experienced greater improvements in well-being across both interventions, with effects that were stronger for participants in the MBCT condition. Attrition was high (ie, 2142/4411, 48.56%), which is an important limitation of this study. ConclusionsStandard MBCT improved well-being but was not superior to a brief mindfulness intervention. This finding suggests that shorter mindfulness programs could yield important benefits across the general population of individuals with various medical conditions. Younger people and participants who completed more intervention sessions reported greater improvements in well-being, an effect that was more pronounced for participants in the MBCT condition. This finding suggests that standard MBCT may be a better choice for younger people as well as treatment-adherent individuals. Trial RegistrationClinicalTrials.gov NCT03844321; https://clinicaltrials.gov/ct2/show/NCT03844321

Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Many of the non-pharmacological treatments, which are preferred to drug-treatment by some patients, either lack efficacy for core symptoms or are associated with small effect sizes. No evidence-based decision tools are currently available to allocate pharmacological or psychosocial treatments based on the patient's clinical, environmental, cognitive, genetic, or biological characteristics. We systematically reviewed potential biomarkers that may help in diagnosing ADHD and/or stratifying ADHD into more homogeneous subgroups and/or predict clinical course, treatment response, and long-term outcome across the lifespan. Most work involved exploratory studies with cognitive, actigraphic and EEG diagnostic markers to predict ADHD, along with relatively few studies exploring markers to subtype ADHD and predict response to treatment. There is a critical need for multisite prospective carefully designed experimentally controlled or observational studies to identify biomarkers that index inter-individual variability and/or predict treatment response.

Abstract Attention-deficit/hyperactivity disorder (ADHD) affects 5% of children world-wide. Of these, two-thirds continue to have impairing symptoms of ADHD into adulthood. Although a large literature implicates structural brain differences of the disorder, it is not clear if adults with ADHD have similar neuroanatomical differences as those seen in children with recent reports from the large ENIGMA-ADHD consortium finding structural differences for children but not for adults. This paper uses deep learning neural network classification models to determine if there are neuroanatomical changes in the brains of children with ADHD that are also observed for adult ADHD, and vice versa. We found that structural MRI data can significantly separate ADHD from control participants for both children and adults. Consistent with the prior reports from ENIGMA-ADHD, prediction performance and effect sizes were better for the child than the adult samples. The model trained on adult samples significantly predicted ADHD in the child sample, suggesting that our model learned anatomical features that are common to ADHD in childhood and adulthood. These results support the continuity of ADHD’s brain differences from childhood to adulthood. In addition, our work demonstrates a novel use of neural network classification models to test hypotheses about developmental continuity.

ADHD is often found to be comorbid with disruptive behavior disorders, but the genetic loci underlying this comorbidity are unknown. Here, the authors have performed a GWAS meta-analysis of ADHD with disruptive behavior disorders, finding three genome-wide significant loci in Europeans, and replicating one in a Chinese cohort.

Objective: Increased prescription stimulant nonmedical use (NMU) is part of a growing polysubstance use landscape. The purpose of the present study was to characterize prescription stimulant NMU among adults reporting past 5-year non-oral prescription stimulant NMU. Methods: Adults who reported non-oral prescription stimulant NMU within the last 5 years were recruited by banner ads placed on the Reddit website between February and September 2019. Types of prescription stimulants used, routes of administration, preferred routes of administration, motivations for prescription stimulant NMU, concurrent substances used simultaneously during prescription stimulant NMU, illicit substances used and factors impacting prescription stimulant NMU were queried. Results: Respondents (n = 225) were male (86.2%), non-Hispanic (92.4%), white (78.2%), between 18 and 24 (48.0%) or 25–34 (43.1%) years with some amount of college education (81.3%). Most reported lifetime intranasal (93.8%) or oral use (85.2%). Prescription stimulants were diverted: 64.5% reported the prescription stimulants were given to them by a family or a friend and 10.5% reported that they had stolen these medications from a family or friend. Preferred route of administration was oral use (70.2%). Motivations to use were stratified by route of administration: intranasal (55.6%) or oral (63.0%) use was primarily endorsed as an attempt to enhance performance at work or at school; use by injection (57.1%) or smoking (62.5%) was primarily endorsed to get high. Most of the sample reported concurrent drug use (79.1%) including tobacco (57.3%), marijuana (52.0%), caffeine (47.6%) or alcohol (41.8%), among others. When excluding licit substances, 30.7% reported using 1 illicit substance concurrently with prescription stimulants and 25.3% reported using 2 or more illicit substances concurrently with prescription stimulants. Whether participants would undertake prescription stimulant NMU was determined by their work/school schedules or the location of the NMU (48.9%) whereas the route of administration employed was primarily influenced by the desired feeling or effect (56.9%). Conclusions: Adults reporting lifetime non-oral prescription stimulant NMU engage in substantial risky behaviors that in addition to alternate routes of administration include polysubstance use, diversion and concurrent substance use.

Abstract Background Autism spectrum disorder (ASD) is characterized by a spectrum of social and communication impairments and rigid and stereotyped behaviors that have a neurodevelopmental origin. Although many imaging studies have reported structural and functional alterations in multiple brain regions, clinically useful diagnostic imaging biomarkers for ASD remain unavailable. Methods In this study, we applied machine learning (ML) models to regional volumetric and cortical thickness data from the largest structural magnetic resonance imaging (sMRI) dataset available from the Enhancing Neuro Imaging Genetics Through Meta‐Analysis (ENIGMA) consortium (1833 subjects with ASD and 1838 without ASD; age range: 1.5–64; average age: 15.6; male/female ratio: 4.2:1). Results The highest classification accuracy on a hold‐out test set was achieved using a stacked Extra Tree Classifier. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.62 (95% confidence interval [CI]: 0.57, 0.68) and the area under the precision‐recall curve was 0.58. Learning curve analysis showed the good fit of the model and suggests that more training examples will not likely benefit model performance. Conclusions Our results suggest that sMRI volumetric and cortical thickness data alone may not provide clinically sufficient useful diagnostic biomarkers for ASD. Developing clinically useful imaging classifiers for ASD will benefit from combining other data modalities or feature types, such as functional MRI data and raw images that can leverage other machine learning (ML) techniques such as convolutional neural networks.

Introduction: Non-medical use (NMU) of prescription stimulant medications is a continuing public health concern. Stimulant medications prescribed for attention-deficit/hyperactivity disorder (ADHD) are widely available on college campuses, and, as a consequence, college students may have multiple opportunities to engage in prescription stimulant NMU. This online self-report survey examined prescription stimulant NMU among college students, including: (1) patterns of non-oral route of administration (ROA); (2) motivations for non-oral ROAs; and (3) retrospectively recalled pathways of initiation.Method: The survey sample was created from a pool of 3,379 respondents, who were matched to a sampling frame constructed from the 18–26-year-old, college student sample of the 2016 American Community Survey (ACS). About 14% (n = 486) from the overall pool were identified as college students with self-reported prescription stimulant NMU, all of whom completed the survey. The survey covered user characteristics, prescription and illicit substance use, age of first NMU, motivations for NMU, sources of procurement, and ROAs used.Results: Among 486 students reporting prescription stimulant NMU, 43% had a lifetime diagnosis of ADHD. More than 90% reported polysubstance use, with 55% using illicit substances other than marijuana. Slightly more than 2 in 5 (43.3%) reported using illicit substances prior to prescription stimulant NMU, 24.6% used both at the same age, and 32.0% engaged in NMU of prescription stimulants prior to using illicit substances. Prescription stimulant NMU preceded prescription opioid NMU 45% of the time. More than a quarter of those engaged in prescription stimulant NMU (27.9%) initiated prescription stimulants alone or at the same age as other drugs. Most prescription stimulant NMU was oral, however 23.0% reported any non-oral use: snorting (20.4%), smoking (6.0%)and/or injection (3.5%). Non-oral use was associated with being male, obtaining medication from a dealer, use to get high, and/or a substance use disorder diagnosis.Conclusions: Prescription stimulant NMU often occurs in the larger context of other substance use among college students. Injection, an under-researched route for prescription stimulants, was associated with male gender, history of substance use and higher likelihood of illicit substance use. Nearly a quarter of college student survey respondents reported use with non-oral routes, which is associated with other high-risk behaviors. Efforts to reduce non-oral prescription stimulant NMU in college students are warranted.

Objective: Prescription stimulant non-medical use (NMU) is a national predicament. While the risks of prescription stimulant NMU have been considered, less is known about non-oral use. To focus on this gap, a sample of adults with non-oral prescription stimulant NMU within the last 5-years was recruited. The purpose of the present study was to characterize the pathways and substance transitions associated with prescription stimulant NMU and non-oral prescription stimulant NMU in this unique sample of adults.Methods: Adults (n = 225) reporting non-oral prescription stimulant NMU within the last 5 years were recruited to complete an online survey by banner ads placed on the Reddit website between February and September 2019. After completion of the survey, a second study consisting of an in-depth telephone interview was conducted with 23 participants: interviews took place between July and September 2019. Data reported here include substance, route of administration and class transitions, as well as qualitative data from the interviews.Results: Approximately 1 in 5 began their substance use trajectory with prescription stimulants (19.1%). Other than marijuana, most exposures to illicit substances occurred after both initial prescription stimulant NMU and initial non-oral prescription stimulant NMU. The most frequently reported route of administration transition was from oral use to snorting (n = 158, 70.2%), however, other route of administration transitions included oral use to injection drug use (n = 14, 6%). In-depth interviews elaborated upon these transitions and indicated that prescription stimulant NMU was consequential to substance use pathways.Conclusions: Oral prescription stimulant NMU was a precursor to non-oral prescription stimulant NMU. Non-oral prescription stimulant NMU was a precursor to illicit substance use, suggesting that prescription stimulant NMU impacts substance use pathways and revealing opportunities for intervention.

BackgroundSuicide is a major public health concern globally. Accurately predicting suicidal behavior remains challenging. This study aimed to use machine learning approaches to examine the potential of the Swedish national registry data for prediction of suicidal behavior.Methods and findingsThe study sample consisted of 541,300 inpatient and outpatient visits by 126,205 Sweden-born patients (54% female and 46% male) aged 18 to 39 (mean age at the visit: 27.3) years to psychiatric specialty care in Sweden between January 1, 2011 and December 31, 2012. The most common psychiatric diagnoses at the visit were anxiety disorders (20.0%), major depressive disorder (16.9%), and substance use disorders (13.6%). A total of 425 candidate predictors covering demographic characteristics, socioeconomic status (SES), electronic medical records, criminality, as well as family history of disease and crime were extracted from the Swedish registry data. The sample was randomly split into an 80% training set containing 433,024 visits and a 20% test set containing 108,276 visits. Models were trained separately for suicide attempt/death within 90 and 30 days following a visit using multiple machine learning algorithms. Model discrimination and calibration were both evaluated. Among all eligible visits, 3.5% (18,682) were followed by a suicide attempt/death within 90 days and 1.7% (9,099) within 30 days. The final models were based on ensemble learning that combined predictions from elastic net penalized logistic regression, random forest, gradient boosting, and a neural network. The area under the receiver operating characteristic (ROC) curves (AUCs) on the test set were 0.88 (95% confidence interval [CI] = 0.87-0.89) and 0.89 (95% CI = 0.88-0.90) for the outcome within 90 days and 30 days, respectively, both being significantly better than chance (i.e., AUC = 0.50) (p < 0.01). Sensitivity, specificity, and predictive values were reported at different risk thresholds. A limitation of our study is that our models have not yet been externally validated, and thus, the generalizability of the models to other populations remains unknown.ConclusionsBy combining the ensemble method of multiple machine learning algorithms and high-quality data solely from the Swedish registers, we developed prognostic models to predict short-term suicide attempt/death with good discrimination and calibration. Whether novel predictors can improve predictive performance requires further investigation.

Background: Recently, RBFOX1, a gene encoding an RNA binding protein, has consistently been associated with aggressive and antisocial behavior. Several loci in the gene have been nominally associated with aggression in genome-wide association studies, the risk alleles being more frequent in the general population. We have hence examined the association of four RBFOX1 single nucleotide polymorphisms, previously found related to aggressive traits, with aggressiveness, personality, and alcohol use disorder in birth cohort representative samples.Methods: We used both birth cohorts of the Estonian Children Personality Behavior and Health Study (ECPBHS; original n = 1,238). Aggressiveness was assessed using the Buss–Perry Aggression Questionnaire and the Lifetime History of Aggressiveness structured interview at age 25 (younger cohort) or 33 (older cohort). Big Five personality at age 25 was measured with self-reports and the lifetime occurrence of alcohol use disorder assessed with the MINI interview. RBFOX1 polymorphisms rs809682, rs8062784, rs12921846, and rs6500744 were genotyped in all participants. Given the restricted size of the sample, correction for multiple comparisons was not applied.Results: Aggressiveness was not significantly associated with the RBFOX1 genotype. RBFOX1 rs8062784 was associated with neuroticism and rs809682 with extraversion. Two out of four analyzed RBFOX1 variants, rs8062784 and rs12921846, were associated with the occurrence of alcohol use disorder.Conclusions: In the birth cohort representative sample of the ECPBHS, no association of RBFOX1 with aggressiveness was found, but RBFOX1 variants affected basic personality traits and the prevalence of alcohol use disorder. Future studies on RBFOX1 should consider the moderating role of personality and alcohol use patterns in aggressiveness.

BackgroundNeonatal abstinence syndrome (NAS) is common, expensive, and hurts opioid addicted women and their families. Current treatments do not sufficiently address comorbid addictions, especially tobacco use, among pregnant buprenorphine-maintained women.Methods25 consecutive admissions of pregnant, opioid addicted women were treated with buprenorphine maintenance and a novel intervention for pregnant opioid addicted patients, Drug Use Targeted Therapy (DUST). DUST entails a combination of informing women about the impact of various drugs on their fetus, discussing the woman’s thinking about these consequences of drug use, and varying the frequency of psychotherapy; increasing if addictive drugs are used and decreasing if the woman wishes when drug use is stopped.Results20/25 remained in treatment until delivery. All 20 women were using addictive drugs at admission. None were planned pregnancies. There was a high prevalence of emotional, physical or sexual abuse, criminal behavior, comorbid psychiatric disorders, and chronic pain. Nineteen stopped all addictive drugs. NAS was present for 5 out of 19 newborns with a duration of hospitalization from 4 to 6 days.ConclusionsThis preliminary open-label case series found that pregnant buprenorphine maintained women can stop tobacco. What has sometimes been termed “neonatal opioid abstinence syndrome” may most accurately be termed, “neonatal opioid/tobacco abstinence syndrome.” If the treatment effectively addresses tobacco use, other addictive drugs are rarely used. DUST resulted in a 95% quit rate for addictive drugs. Pilot data on this new intervention is limited; a case series that does not have a corresponding control group.

Summary: Background: Attention-deficit hyperactivity disorder (ADHD) is a common paediatric neurodevelopmental disorder with substantial effect on families and society. Alternatives to traditional care, including novel digital therapeutics, have shown promise to remediate cognitive deficits associated with this disorder and may address barriers to standard therapies, such as pharmacological interventions and behavioural therapy. AKL-T01 is an investigational digital therapeutic designed to target attention and cognitive control delivered through a video game-like interface via at-home play for 25 min per day, 5 days per week for 4 weeks. This study aimed to assess whether AKL-T01 improved attentional performance in paediatric patients with ADHD. Methods: The Software Treatment for Actively Reducing Severity of ADHD (STARS-ADHD) was a randomised, double-blind, parallel-group, controlled trial of paediatric patients (aged 8–12 years, without disorder-related medications) with confirmed ADHD and Test of Variables of Attention (TOVA) Attention Performance Index (API) scores of −1·8 and below done by 20 research institutions in the USA. Patients were randomly assigned 1:1 to AKL-T01 or a digital control intervention. The primary outcome was mean change in TOVA API from pre-intervention to post-intervention. Safety, tolerability, and compliance were also assessed. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02674633 and is completed. Findings: Between July 15, 2016, and Nov 30, 2017, 857 patients were evaluated and 348 were randomly assigned to receive AKL-T01 or control. Among patients who received AKL-T01 (n=180 [52%]; mean [SD] age, 9·7 [1·3] years) or control (n=168 [48%]; mean [SD] age, 9·6 [1·3] years), the non-parametric estimate of the population median change from baseline TOVA API was 0·88 (95% CI 0·24–1·49; p=0·0060). The mean (SD) change from baseline on the TOVA API was 0·93 (3·15) in the AKL-T01 group and 0·03 (3·16) in the control group. There were no serious adverse events or discontinuations. Treatment-related adverse events were mild and included frustration (5 [3%] of 180) and headache (3 [2%] of 180). Patient compliance was a mean of 83 (83%) of 100 expected sessions played (SD, 29·2 sessions). Interpretation: Although future research is needed for this digital intervention, this study provides evidence that AKL-T01 might be used to improve objectively measured inattention in paediatric patients with ADHD, while presenting minimal adverse events. Funding: Sponsored by Akili Interactive Labs.

Abstract Background Attention-deficit/hyperactivity disorder (ADHD) is associated with substance use disorders (SUD; alcohol and/or drug dependence) and nicotine dependence. This study aims to advance our knowledge about the association between SUD, nicotine dependence, and the course of ADHD (persistent versus remittent ADHD and late-onset ADHD). Methods ADHD, SUD, and nicotine dependence were longitudinally assessed (mean age at study entry 11.3 years, mean age at follow-up 21.1 years) using structured psychiatric interviews and multi-informant questionnaires in a subsample of the Dutch part of the International Multicenter ADHD Genetics study. Individuals with persistent ADHD (n = 62), remittent ADHD (n = 12), late-onset ADHD (n = 18; age of onset after 12 years), unaffected siblings (n = 50), and healthy controls (n = 47) were assessed. Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated by Cox regression and adjusted for clustered family data, gender, follow-up length, and current age. Results Individuals with persistent ADHD were at significantly higher risk of development of SUD relative to healthy controls (HR = 4.56, CI 1.17–17.81). In contrast, levels of SUD in those with remittent ADHD were not different from healthy controls (HR = 1.00, CI .07–13.02). ADHD persisters had also higher prevalence rates of nicotine dependence (24.2%) than ADHD remitters (16.7%) and healthy controls (4.3%). A similar pattern was found in initially unaffected siblings who met ADHD criteria at follow-up (“late-onset” ADHD); they had also a higher prevalence of SUD (33%) compared to stable unaffected siblings (20%) and were at significantly increased risk of development of nicotine dependence compared to healthy controls (HR = 13.04, CI 2.08–81.83). Conclusions SUD and nicotine dependence are associated with a negative ADHD outcome. Results further emphasize the need for clinicians to comprehensively assess substance use when diagnosing ADHD in adolescents and adults.

Objective: To examine the association between gestational age (GA) at birth across the normal GA spectrum (37–41 weeks) and the temperament and health of 3-month old infants. Methods: The sample comprised 242 “low-risk” mothers and infants without chronic illnesses or severe pregnancy complications. Infant temperament was defined by three constructs: Negative Affectivity (NA), Extraversion, and Regulation, assessed by parents’ reports on the Infant Behavior Questionnaire. Infants’ health was defined as the number of nonroutine doctors’ visits attended by the infants since their release from the hospital after birth. Analyses employed a continuous measure of GA to assess outcomes across GAs and a categorical measure (37, 38, 39–41 weeks GA) to examine contrasts. Results: Extraversion was positively related to GA primarily due to the lower scores of infants born at 37 weeks compared to infants born at 39–41 weeks GA. NA showed a similar effect. The odds of infants born at 37 weeks attending a nonroutine medical visit were 2.8 times that of infants born full-term. Discussion: Infants born at 37 weeks GA express less affect and use more nonroutine medical services than do infants born at 39–41 weeks GA. The findings underscore the importance of considering the risks of pregnancy prolongation with the developmental risk associated with early-term delivery.