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Objective: Quality care for attention deficit hyperactivity disorder (ADHD) in adults has lagged behind other psychiatric disorders. We sought to assess how the achievement of quality measures (QMs) for diagnosing and treating ADHD in adults has changed over time. Method: We assessed 10 QMs in electronic health records (EHRs) from primary care and behavioral health clinics from 2010 to 2020 for 71,310 patients diagnosed with ADHD. Results: The achievement of QMs increased over time ( p < .001). Some showed increases to high levels; others remained low throughout the observation period. No patients achieved more than six of 10 QMs in any year. Small but significant effects for sex, race, ethnicity, practice ownership, practice type, and age. Conclusion: Increase in quality care from 2010 to 2020 along with clear evidence that more efforts are needed to improve quality of care for adults with ADHD seen in primary care.

Early identification of bipolar disorder may provide appropriate support and treatment, however there is no current evidence for statistically predicting whether a child will develop bipolar disorder. Machine learning methods offer an opportunity for developing empirically-based predictors of bipolar disorder. This study examined whether bipolar disorder can be predicted using clinical data and machine learning algorithms. 492 children, ages 6-18 at baseline, were recruited from longitudinal case-control family studies. Participants were assessed at baseline, then followed-up after 10 years. In addition to sociodemographic data, children were assessed with psychometric scales, structured diagnostic interviews, and cognitive and social functioning assessments. Using the Balanced Random Forest algorithm, we examined whether the diagnostic outcome of full or subsyndromal bipolar disorder could be predicted from baseline data. 45 children (10%) developed bipolar disorder at follow-up. The model predicted subsequent bipolar disorder with 75% sensitivity, 76% specificity, and an Area Under the Receiver Operating Characteristics of 75%. Predictors best differentiating between children who did or did not develop bipolar disorder were the Child Behavioral Checklist Externalizing and Internalizing behaviors, the Child Behavioral Checklist Total t-score, problematic school functions indexed through the Child Behavioral Checklist School Competence scale, and the Child Behavioral Checklist Anxiety/Depression and Aggression scales. Our study provides the first quantitative model to predict bipolar disorder. Longitudinal prediction may help clinicians assess children with emergent psychopathology for future risk of bipolar disorder, an area of clinical and scientific importance. Machine learning algorithms could be implemented to alert clinicians to risk for bipolar disorder.

The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (FAs) and inositol alone and in combination for the treatment of pediatric bipolar (BP) spectrum disorder in young children.Participants were male and female children ages 5-12 meeting DSM-IV diagnostic criteria for a BP spectrum disorder and displaying mixed, manic, or hypomanic symptoms without psychotic features at the time of evaluation.Participants concomitantly taking psychotropic medication were excluded from efficacy analyses. There were significant reductions in YMRS and HDRS mean scores in the inositol and combination treatment groups (all p0.05) and in CDRS mean scores in the combination treatment group (p0.001), with the largest changes seen in the combination group. Those receiving the combination treatment had the highest rates of antimanic and antidepressant response. The odds ratios for the combination group compared to the omega-3 FAs and inositol groups were clinically meaningful (ORs ≥2) for 50% improvement on the YMRS, normalization of the YMRS (score12) (vs. inositol group only), 50% improvement on the HDRS, 50% improvement on CDRS (vs. omega-3 FAs group only), and CGI-I Mania, CGI-I MDD, and CGI-I Anxiety scores2.The antimanic and antidepressant effects of the combination treatment of omega-3 FAs and inositol were consistently superior to either treatment used alone. This combination may offer a safe and effective alternative or augmenting treatment for youth with BP spectrum disorder, but more work is needed to confirm the statistical significance of this finding.

Early identification of attention-deficit/hyperactivity disorder (ADHD) is critical for mitigating the many negative functional outcomes associated with its diagnosis. Because of the strong genetic basis of ADHD, the use of polygenic risk scores (PRS) could potentially aid in the early identification of ADHD and associated outcomes. Therefore, a systematic search of the literature on the association between ADHD and PRS in pediatric populations was conducted. All articles were screened for a priori inclusion and exclusion criteria, and, after careful review, 33 studies were included in our systematic review and 16 studies with extractable data were included in our meta-analysis. The results of the review were categorized into three common themes: the associations between ADHD-PRS with 1) the diagnosis of ADHD and ADHD symptoms 2) comorbid psychopathology and 3) cognitive and educational outcomes. Higher ADHD-PRS were associated with increased odds of having a diagnosis (OR = 1.37; p0.001) and more symptoms of ADHD (β = 0.06; p0.001). While ADHD-PRS were associated with a persistent diagnostic trajectory over time in the systematic review, the meta-analysis did not confirm these findings (OR = 1.09; p = 0.62). Findings showed that ADHD-PRS were associated with increased odds for comorbid psychopathology such as anxiety/depression (OR = 1.16; p0.001) and irritability/emotional dysregulation (OR = 1.14; p0.001). Finally, while the systematic review showed that ADHD-PRS were associated with a variety of negative cognitive outcomes, the meta-analysis showed no significant association (β = 0.08; p = 0.07). Our review of the available literature suggests that ADHD-PRS, together with risk factors, may contribute to the early identification of children with suspected ADHD and associated disorders.

Aim To conduct the first systematic review and meta-analysis assessing whether attention-deficit/hyperactivity disorder (ADHD) is associated with disorders of the eye, and/or altered measures of visual function. Method Based on a pre-registered protocol (PROSPERO: CRD42021256352), we searched PubMed, Web of Knowledge/Science, Ovid Medline, Embase and APA PsycINFO up to 16th November 2021, with no language/type of document restrictions. We included observational studies reporting at least one measure of vision in people of any age meeting DSM/ICD criteria for ADHD and in people without ADHD; or the prevalence of ADHD in people with and without vision disorders. Study quality was assessed with the Appraisal tool for Cross-Sectional Studies (AXIS). Random effects meta-analyses were used for data synthesis. Results We included 42 studies in the narrative synthesis and 35 studies in the meta-analyses (3,250,905 participants). We found meta-analytic evidence of increased risk of astigmatism (OR = 1.79 [CI: 1.50, 2.14]), hyperopia and hypermetropia (OR = 1.79 [CI: 1.66, 1.94]), strabismus (OR = 1.93 [CI: 1.75, 2.12]), unspecified vision problems (OR = 1.94 [CI: 1.38, 2.73]) and reduced near point of convergence (OR = 5.02 [CI: 1.78, 14.11]); increased lag (Hedge’s g = 0.63 [CI: 0.30, 0.96]) and variability (Hedge’s g = 0.40 [CI: 0.17, 0.64]) of the accommodative response; and increased self-reported vision problems (Hedge’s g = 0.63 [CI: 0.44, 0.82]) in people with ADHD compared to those without ADHD (with no significant heterogeneity). We also found meta-analytic evidence of no differences between people with and without ADHD on retinal nerve fiber layer thickness (Hedge’s g = −0.19 [CI: −0.41, 0.02]) and refractive error (Hedge’s g = 0.08 [CI: −0.26, 0.42]) (with no significant heterogeneity). Discussion ADHD is associated with some self-reported and objectively ascertained functional vision problems, but not with structural alterations of the eye. Further studies should clarify the causal relationship, if any, between ADHD and problems of vision. Trial registration PROSPERO registration: CRD42021256352.

Background: Pediatric bipolar disorder (BP) is frequently comorbid with conduct disorder (CD) and its presence adds to the morbidity of BP. While there are no known pharmacological treatments for CD, pediatric BP is responsive to treatment with medications initially indicated for the treatment of psychosis, several of which have Food and Drug Administration (FDA) approval for the treatment of pediatric mania. Aims: The main aim of this secondary analysis was to examine whether pediatric BP comorbid with CD responds similarly to treatment with such selected medications. Considering the well-documented morbidity of CD, this finding could have important clinical and public health significance. Methods: We conducted a secondary analysis of six prospective 8-week open-label trials of selected medications (risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) using identical methodology in youth with BP with and without comorbid CD. Results: Of 165 youths with BP, 54% ( N = 89) met criteria for comorbid CD. The antimanic effects observed did not significantly differ between BP youths with and without comorbid CD, as measured either by a reduction in Young Mania Rating Scale (YMRS) ⩾ 30% or Clinical Global Impression (CGI)-Improvement ⩽ 2 ( p = 0.23), or by the more stringent definition of a reduction in YMRS ⩾ 50% ( p = 0.61). Conclusion: Pediatric BP can be effectively treated with the abovementioned medications in the context of comorbid CD. Based on previous research showing that remission of BP is associated with remission of CD, if confirmed, these findings raise the possibility that antimanic treatment of youth with BP comorbid with CD could have secondary benefits in mitigating the morbidity associated with CD. This is a pilot scale finding, the results of which are promising and should be confirmed by larger and long-term follow-up studies.

To investigate long-term (12-month) safety and symptom control of extended-release methylphenidate (MPH-MLR) in children aged 4 to6 years after treatment optimization.A total of 90 children aged 4 to6 years with attention-deficit/hyperactivity disorder (ADHD) were enrolled from 2 MPH-MLR studies. Treatment-emergent adverse events (TEAEs) and ADHD symptom control were assessed in the safety population (n = 89) and modeled with mixed model analyses.Most TEAEs (89.9%) were rated by investigators as of mild or moderate severity. One serious AE was reported (unrelated to study drug). Ten children discontinued because of TEAEs. Two discontinued because of weight loss; no significant increase in the rate of underweight children from baseline to endpoint was observed. Overall, 18% lost weight and 18% reported decreased appetite. Weight and height z scores and obesity rates decreased significantly from baseline to endpoint. Insomnia was reported (9%); none of these children discontinued. Sleep quality did not change significantly. Hypertension was reported (6.7%); none of these children dropped out. Diastolic, but not systolic, blood pressure increased significantly during the follow-up. Control of ADHD symptoms was maintained throughout follow-up.These data contribute to the understanding of the long-term safety of an extended-release stimulant in children 4 to6 years of age. The observed risk of a TEAE-related discontinuation was ∼11%. TEAEs were not dose related, and most were of mild to moderate severity. Symptom control was maintained through the year-long study.A 12-Month Open Label Safety Study of Aptensio XR® in Children Ages 4-5 Years Diagnosed With ADHD (EF004); https://clinicaltrials.gov; NCT02677519.

Contains fulltext : 248384.pdf (Publisher’s version ) (Open Access) Several non-mental diseases seem to be associated with an increased risk of ADHD and ADHD seems to be associated with increased risk for non-mental diseases. The underlying trajectories leading to such brain-body co-occurrences are often unclear - are there direct causal relationships from one disorder to the other, or does the sharing of genetic and/or environmental risk factors lead to their occurring together more frequently or both? Our goal with this narrative review was to provide a conceptual synthesis of the associations between ADHD and non-mental disease across the lifespan. We discuss potential shared pathologic mechanisms, genetic background and treatments in co-occurring diseases. For those co-occurrences for which published studies with sufficient sample sizes exist, meta-analyses have been published by others and we discuss those in detail. We conclude that non-mental diseases are common in ADHD and vice versa and add to the disease burden of the patient across the lifespan. Insufficient attention to such co-occurring conditions may result in missed diagnoses and suboptimal treatment in the affected individuals.

Zusammenfassung. Hintergrund: Eine Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) im Kindesalter stellt einen Risikofaktor für Substanzmissbrauch und Störungen durch Substanzgebrauch (Substance Use Disorder, SUD) in der Pubertät und dem (frühen) Erwachsenenalter dar. ADHS und SUD treten auch häufig bei therapiesuchenden Jugendlichen auf, was die Diagnosestellung und Therapie erschwert sowie mit schlechten Behandlungsergebnissen verbunden ist. Forschungsergebnisse über die Wirkung der Behandlung von ADHS im Kindesalter auf die Prävention von SUD im Jugendalter sind nicht eindeutig und Studien über die Diagnose und Behandlung von Jugendlichen mit ADHS und SUD sind selten. Daher reicht die verfügbare Evidenz allgemein nicht aus, um starke Behandlungsempfehlungen zu rechtfertigen. Fragestellung: Ziel dieser Arbeit war es, eine Konsenserklärung auf der Grundlage von wissenschaftlichen Daten und klinischen Erfahrungen zu erhalten. Methodik: Es wurde eine modifizierte Delphi-Studie durchgeführt, um basierend auf der Kombination von wissenschaftlichen Daten und klinischer Erfahrung mit einer multidisziplinären Gruppe von 55 Expert_innen aus 17 Ländern einen Konsens zu erzielen. Die Expert_innen wurden gebeten, eine Reihe von Aussagen über die Wirkung der Behandlung von ADHS im Kindesalter auf die SUD bei Jugendlichen sowie über das Screening, die Diagnostik und die Behandlung von Jugendlichen mit komorbidem ADHS und SUD zu bewerten. Ergebnisse: Nach drei iterativen Bewertungsrunden und der Anpassung von 37 Aussagen wurde ein Konsens über 36 dieser Aussagen erzielt, die sechs Bereiche repräsentieren: allgemein ( n = 4), Risiko der Entwicklung einer SUD ( n = 3), Screening und Diagnostik ( n = 7), psychosoziale Behandlung ( n = 5), pharmakologische Behandlung ( n = 11) und komplementäre Behandlungen ( n = 7). Der Einsatz von Routinescreenings auf ADHS wird bei adoleszenten Patient_innen in einer Suchtbehandlung ebenso wie Routinescreenings auf SUD bei jugendlichen Patient_innen mit ADHS in allgemeinpsychiatrischen Therapiesettings empfohlen. Langwirksame Stimulanzien werden als Behandlung der ersten Wahl von ADHS bei Jugendlichen mit gleichzeitiger ADHS und SUD empfohlen. Die Pharmakotherapie sollte vorzugsweise in psychosoziale Behandlung eingebettet werden. Die einzige nichtkonsentierte Aussage betraf die Notwendigkeit von Abstinenz vor Beginn einer pharmakologischen Behandlung bei Jugendlichen mit ADHS und gleichzeitigem SUD. Im Gegensatz zur Mehrheit verlangten einige Expert_innen eine vollständige Abstinenz vor Beginn einer pharmakologischen Behandlung, einige waren gegen die Verwendung von Stimulanzien bei der Behandlung dieser Patient_innen (unabhängig von Abstinenz), während einige sich gegen die alternative Anwendung von Bupropion aussprachen. Schlussfolgerungen: Diese internationale Konsenserklärung kann von Kliniker_innen und Patient_innen zusammen in einem gemeinsamen Entscheidungsprozess genutzt werden, um die besten Interventionen auszuwählen und die bestmöglichen Ergebnisse bei adoleszenten Patient_innen mit gleichzeitiger ADHS und SUD zu erzielen.

The objective of this study is to quantify the impact of the COVID-19 pandemic on attention deficit hyperactivity disorder (ADHD) medication consumption globally and nationally using pharmaceutical sales data from 2014 to 2021 across 47 countries and regions. A seasonal autoregressive integrated moving average model (SARIMA) was applied to the time series until the end of 2019 at country level and used for the prediction of the ADHD medication consumption in 2020 and 2021. The deviations from the actual to the forecasted sales, which simulate the development without the emergence of COVID-19, yield estimates for the pandemic’s impact. In 36 of the 47 countries and regions, the actual sales in 2020 were lower than predicted, with an average relative drop of 6.23% in defined daily doses (DDD) per 1000 inhabitants per day at country-level. In 2021, most countries recorded actually higher ADHD medication use than predicted at the end of 2019. On average, the consumption increased per country by 1.60%. The findings suggest that the pandemic led to a substantially lower consumption of ADHD medication in 2020. However, in 2021 the pandemic had an accelerating effect as the increasing consumption trends are more pronounced than before the pandemic.

Contains fulltext : 293132.pdf (Publisher’s version ) (Open Access)

Objective To evaluate the frequency and correlates of needing to switch the initial treatment with a stimulant medication to the alternative family in newly referred, untreated adults with ADHD initiating treatment. Methods Subjects were consecutively referred unmedicated adults with DSM-5 ADHD who initiated stimulant treatment. Before assessment with an expert clinician, participants completed a battery of self-report measures to assess psychopathology, executive functioning, emotional dysregulation, and mind wandering. The rate of switching was examined using information from electronic medical records for up to three clinical follow-up visits. Those who did and did not need to switch were compared on baseline demographic and clinical characteristics. Results Twenty-four percent (N = 21/86) of ADHD patients needed to switch from their initially prescribed stimulant family within 60 days of initiating treatment due to poor tolerability. While the rate of switching was significantly higher in those initially prescribed MPH, the rate of patients requiring changes in formulation or additional antianxiety or antidepressant treatment was higher in those taking AMPH. There were some hints about predictive risk factors for switching by the presence of emotional dysregulation and depressive symptoms, depending on age and sex. Conclusions These findings call for improved efforts to help identify predictors of response to stimulant treatment in adults with ADHD to avoid unnecessary delays in identifying safe and effective treatments for these patients.

Improvement in attention-deficit/hyperactivity disorder (ADHD) symptoms vs. placebo was reported in a series of pediatric clinical trials of viloxazine extended-release capsules (viloxazine ER; Qelbree™). This post hoc analysis of those studies evaluated the effect of viloxazine ER on learning and school problems (LSPs). We used data from four Phase 3 placebo-controlled trials of 100–600 mg/day viloxazine ER (N = 1354; 6–17 years of age). LSPs were evaluated using the School domain of the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P-S) and the Learning Problems content scale of the Conners 3rd Edition-Parent Short Form (C3PS-LP) at baseline and end of study (≥ Week 6). ADHD symptoms were assessed weekly using the ADHD Rating Scale 5th Edition. The analyses were performed using the general linear mixed model with participant as a random effect. The responder analyses were performed using the Chi-square test. Viloxazine ER demonstrated significantly greater improvements in WFIRS-P-S (p p = 0.0113) scores vs. placebo. The response rate for the WFIRS-P-S was significantly greater for viloxazine ER vs. placebo (p = 0.001), and the number needed to treat (NNT) was 10.3 (effect size 0.7). Conversely, response rates for C3PS-LP did not differ between groups (p = 0.9069). In addition to ADHD symptoms improvement demonstrated in previous studies, viloxazine ER significantly reduced LSPs in pediatric subjects with ADHD. The responder analyses and NNT estimates indicate that a substantial number of children and adolescents with ADHD treated with viloxazine ER improved in clinically assessed LSPs.

Aim The aim of this study was to evaluate the effect of viloxazine extended-release capsules (viloxazine ER; Qelbree™) on executive function deficits (EFDs) in pediatric subjects (6–17 years of age) with attention-deficit/hyperactivity disorder (ADHD). Methods Data from four phase III placebo-controlled trials of 100–600 mg/day viloxazine ER (6–8 weeks of treatment) were used to evaluate the change from baseline (CFB) in the Conners 3rd Edition Parent Short Form—Executive Function (C3PS-EF) content scale T-score. Subjects were defined as EFD responders if they had C3PS-EF T-score > 70 at baseline and < 65 at end of study. ADHD symptoms were assessed with ADHD Rating Scale 5th Edition (ADHD-RS-5). Subjects were defined as ADHD symptom responders if they had a ≥ 50% reduction in CFB ADHD-RS-5 Total score at Week 6. The number needed to treat (NNT) and Cohen’s d effect sizes were estimated for EFD and ADHD symptoms. Results A total of 1154 subjects were included in the analysis. Statistically significant improvements in EFDs were observed with viloxazine ER versus placebo (p = 0.0002). There were 52.5% of EFD or ADHD symptom responders in the viloxazine ER treatment group and 35.4% in the placebo group (p

Despite a growing literature on the complex bidirectional relationship of ADHD and substance use, reviews specifically focusing on alcohol are scarce. ADHD and AUD show a significant genetic overlap, including genes involved in gluatamatergic and catecholaminergic neurotransmission. ADHD drives risky behavior and negative experiences throughout the lifespan that subsequently enhance a genetically increased risk for Alcohol Use Disorders (AUD). Impulsive decisions and a maladaptive reward system make individuals with ADHD vulnerable for alcohol use and up to 43 % develop an AUD; in adults with AUD, ADHD occurs in about 20 %, but is vastly under-recognized and under-treated. Thus, routine screening and treatment procedures need to be implemented in AUD treatment. Long-acting stimulants or non-stimulants can be used to treat ADHD in individuals with AUD. However, it is crucial to combine medical treatment for ADHD with pharmacotherapy and psychotherapy for AUD, and other comorbid disorders. Identification of individuals at risk for AUD, especially those with ADHD and conduct disorder or oppositional defiant disorder, is a key factor to prevent negative outcomes.

Objective: The Before School Functioning Questionnaire and Parent Rating of Evening and Morning Behavior–Revised assess early morning (BSFQ, PREMB-R AM subscale) and late afternoon/evening (PREMB-R PM subscale) functional impairment in children with ADHD. Clinically meaningful improvements were identified and applied to a trial of delayed-release and extended-release methylphenidate (DR/ER-MPH) in children with ADHD (NCT02520388) to determine if the statistically-determined improvements in functional impairment were also clinically meaningful. Method: Clinically meaningful improvements in BSFQ/PREMB-R were established post hoc by receiver operating characteristics curves, using anchors of Clinical Global Impression–Improvement (CGI-I) = 1 and CGI-I ≤ 2. Percentages of participants achieving these thresholds were calculated. Results: Thresholds for CGI-I = 1/CGI-I ≤ 2, respectively, were 27/20 (BSFQ), 5/3 (PREMB-R AM), and 9/5 (PREMB-R PM)-point decreases. More children achieved clinically meaningful improvements with DR/ER-MPH versus placebo (all p Conclusion: DR/ER-MPH increased proportions of children achieving clinically meaningful improvements in BSFQ and PREMB-R.

Objective To examine the utility of the Child Behavior Checklist (CBCL) to aid in the identification of comorbid psychopathological conditions affecting referred youth with suspected ADHD prior to the evaluation. The CBCL is an easy-to-use assessment tool that may provide invaluable information regarding the severity and characteristics of the presenting complaints. Methods The sample included 332 youths consecutively referred to an ADHD program for the assessment of suspected ADHD. Parents completed the CBCL, parent-rated ADHD Self-Report Scale (ASRS), Social Responsiveness Scale (SRS), and Behavior Rating Inventory of Executive Function (BRIEF). Because of the established association between the CBCL Attention Problems scale and a structured diagnostic interview of ADHD, all youths analyzed had abnormal Attention Problems T-scores (≥60). Results Seventy-six percent of youths with elevated Attention Problems T-scores had ≥3 additional abnormal CBCL scales, suggesting they were likely affected with multiple comorbid psychopathological conditions. Moreover, 44% had ≥1 CBCL clinical scale with a T-score more severe than their Attention Problems T-score, suggesting the putative comorbid condition was more severe than the ADHD symptoms. Additional CBCL scale elevations were associated with more severe functional impairments as assessed by the ASRS, SRS, BRIEF, and CBCL competence scales. Conclusion The CBCL obtained before the clinical assessment identified high rates of comorbid psychopathology in youths referred for the assessment of ADHD. It provided detailed information about the types and severity of suspected psychopathological conditions impacting a particular youth, which is critical to guide the assessing clinician on likely differing needs of the affected child.

Objectives: Clinical trials in psychiatry frequently report results from lengthy, comprehensive assessments to characterize a subject emotionally, cognitively, and behaviorally before and after treatment. However, the potential treatment implications of these results and how they translate into clinical practice remain unclear. Conversely, the Clinical Global Impressions (CGI) scales are quick, intuitive assessments used to assess the functional impact of a treatment in clinically relevant terms. The objectives of the present analyses are to translate scores from comprehensive assessments of symptom severity and functional impairment into clinically meaningful CGI levels. Methods: These post-hoc analyses use data integrated from four pivotal Phase 3 trials in attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated with the novel nonstimulant SPN-812 (Viloxazine Extended-Release). In this study, we evaluated the ADHD Rating Scale-5 (ADHD-RS-5) and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P), assessments of symptom severity and functional impairment, respectively, by linking these scales with the CGI scales at baseline and end of study. Results: For participants that improved, a one-level change on the CGI-Improvement (CGI-I) was associated with a 10–15-point change on the ADHD-RS-5, and a 0.2–0.5-point change on the WFIRS-P. On the CGI-I, ratings of much improved and very much improved were associated with a percent score decrease (i.e., improvement) of ∼55% and 80% on the ADHD-RS-5 and ∼40% and 70% on the WFIRS-P, respectively. Differences between children and adolescents were minor and are unlikely to be clinically meaningful. Conclusion: These post-hoc analyses provide clinically meaningful benchmarks for the interpretation of scores on the ADHD-RS-5 and WFIRS-P in terms of CGI evaluations in subjects with ADHD. These results may be useful for physicians seeking to understand a treatment's potential impact on their ADHD patients or for researchers looking to define their study results within a clinically relevant context. Data are from clinical trials NCT03247530, NCT03247543, NCT03247517, and NCT03247556.

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.

Adult attention-deficit/hyperactivity disorder (ADHD) is an early-onset disorder with many functional impairments and psychiatric comorbidities. Although no treatment fully mitigates impairments associated with ADHD, effective management is possible with pharmacologic and nonpharmacologic treatments. The etiology and pathophysiology of ADHD are remarkably complex and the disorder is continuously distributed in the population. While these findings have been well documented in studies with predominantly white samples, ADHD may affect racial and ethnic minorities differentially, given diagnostic and treatment disparities. This review provides an updated overview of the epidemiology, etiology, neurobiology, and neuropharmacology of ADHD, addressing racial and ethnic disparities whereby data are available.

BACKGROUND: Tourette syndrome (TS) is often found comorbid with other neurodevelopmental disorders across the impulsivity-compulsivity spectrum, with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) as most prevalent. This points to the possibility of a common etiological thread along an impulsivity-compulsivity continuum.METHODS: Investigating the shared genetic basis across TS, ADHD, ASD, and OCD, we undertook an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genome-wide association studies (93,294 individuals, 6,788,510 markers).RESULTS: As previously identified, a common unifying factor connects TS, ADHD, and ASD, while TS and OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and a targeted approach that is guided by genetic correlations, we were able to identify multiple novel hits and regions that seem to play a pleiotropic role for the specific disorders analyzed here and could not be identified through previous studies. In the TS-ADHD-ASD genome-wide association study single nucleotide polymorphism-based and gene-based meta-analysis, we uncovered 13 genome-wide significant regions that host single nucleotide polymorphisms with a high posterior probability for association with all three studied disorders (m-value > 0.9), 11 of which were not identified in previous cross-disorder analysis. In contrast, we also identified two additional pleiotropic regions in the TS-OCD meta-analysis. Through conditional analysis, we highlighted genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue specificity analysis implicated the hypothalamus-pituitary-adrenal gland axis in TS-ADHD-ASD.CONCLUSIONS: Our work underlines the value of redefining the framework for research across traditional diagnostic categories.

ADHD is a prevalent and morbid neurobiological disorder affecting up to 5% of adults. While stimulants have been documented to be safe and effective in adults with ADHD, uncertainties remain about adherence to these treatments. The main aim of this article was to evaluate contemporaneous rates and correlates of adherence to stimulants in adults with ADHD using data from electronic medical records from a large healthcare organization focusing on timely renewal of an initial prescription. Subjects were patients 18 to 44 years of age who had been prescribed a stimulant between January 1, 2015, and December 31, 2016. Prescription and sociodemographic data were extracted from the Partners HealthCare Research Patient Data Registry (RPDR). Our outcome metric was renewal of the index stimulant prescription defined as the first prescription recorded in the electronic record for the period under investigation. We identified 2689 patients with an index prescription for a stimulant medication. Results showed that only 42% of patients renewed their prescriptions in a timely enough fashion to be considered consistently medicated. Results indicate that adults with ADHD have a low rate of renewal of their initial stimulant prescription indicating poor patient engagement in their treatment for ADHD.

Variations in SLC9A9 gene expression and protein function are associated with multiple human diseases, which range from Attention-deficit/hyperactivity disorder (ADHD) to glioblastoma multiforme. In an effort to determine the full spectrum of human disease associations with SLC9A9, we performed a systematic review of the literature. We also review SLC9A9's biochemistry, protein structure, and function, as well as its interacting partners with the goal of identifying mechanisms of disease and druggable targets. We report gaps in the literature regarding the genes function along with consistent trends in disease associations that can be used to further research into treating the respective diseases. We report that SLC9A9 has strong associations with neuropsychiatric diseases and various cancers. Interestingly, we find strong overlap in SLC9A9 disease associations and propose a novel role for SLC9A9 in neuropsychiatric comorbidity. In conclusion, SLC9A9 is a multifunctional protein that, through both its endosome regulatory function and its protein-protein interaction network, has the ability to modulate signaling axes, such as the PI3K pathway, among others.

Background Children with attention‐deficit/hyperactivity disorder (ADHD) have a high risk for substance use disorders (SUDs). Early identification of at‐risk youth would help allocate scarce resources for prevention programs. Methods Psychiatric and somatic diagnoses, family history of these disorders, measures of socioeconomic distress, and information about birth complications were obtained from the national registers in Sweden for 19,787 children with ADHD born between 1989 and 1993. We trained (a) a cross‐sectional random forest (RF) model using data available by age 17 to predict SUD diagnosis between ages 18 and 19; and (b) a longitudinal recurrent neural network (RNN) model with the Long Short‐Term Memory (LSTM) architecture to predict new diagnoses at each age. Results The area under the receiver operating characteristic curve (AUC) was 0.73(95%CI 0.70–0.76) for the random forest model (RF). Removing prior diagnosis from the predictors, the RF model was still able to achieve significant AUCs when predicting all SUD diagnoses (0.69, 95%CI 0.66–0.72) or new diagnoses (0.67, 95%CI: 0.64, 0.71) during age 18–19. For the model predicting new diagnoses, model calibration was good with a low Brier score of 0.086. Longitudinal LSTM model was able to predict later SUD risks at as early as 2 years age, 10 years before the earliest diagnosis. The average AUC from longitudinal models predicting new diagnoses 1, 2, 5 and 10 years in the future was 0.63. Conclusions Population registry data can be used to predict at‐risk comorbid SUDs in individuals with ADHD. Such predictions can be made many years prior to age of the onset, and their SUD risks can be monitored using longitudinal models over years during child development. Nevertheless, more work is needed to create prediction models based on electronic health records or linked population registers that are sufficiently accurate for use in the clinic.

This study investigated the diagnostic utility of the Child Behavior Checklist (CBCL) Rule-Breaking Behavior scale to identify children of both sexes with conduct disorder (CD). Participants were derived from four independent datasets of children with and without attention deficit hyperactivity disorder and bipolar-I disorder of both sexes. Participants had structured diagnostic interviews with raters blinded to subject ascertainment status. Receiver operating characteristic (ROC) curves were used to examine the scale's ability to identify children with and without CD. The sample consisted of 674 participants (mean age of 11.7 ± 3.3 years, 57% male, 94% Caucasian). The interaction to test if CBCL Rule-Breaking Behavior scores identified males and females with CD differently was not significant, thus we performed ROC analysis in the combined group. The ROC analysis of the scale yielded an area under the curve of 0.9. A score of ≥ 60 on the scale correctly classified 82% of participants with CD with 85% sensitivity, 81% specificity, 48% positive predictive value, 96% negative predictive value. The CBCL Rule-Breaking Behavior scale was an efficient tool to identify children with CD.

Background Attention-deficit/hyperactivity disorder (ADHD) has substantial heritability, and a recent large-scale investigation has identified common genome-wide significant loci associated with increased risk for ADHD. Along the same lines, many studies using noninvasive neuroimaging have identified differences in brain functional connectivity in children with ADHD. We attempted to bridge these studies to identify differences in functional connectivity associated with common genetic risk for ADHD using polygenic risk score (PRS). Methods We computed ADHD PRSs for all participants in our sample (N = 315, children 7–13 years of age, 196 with ADHD and 119 unaffected comparison children) using ADHD data from the Psychiatric Genomics Consortium as a discovery set. Magnetic resonance imaging was used to evaluate resting-state functional connectivity of targeted subcortical structures. Results The functional connectivity between 2 region pairs demonstrated a significant correlation to PRS: right caudate–parietal cortex and nucleus accumbens–occipital cortex. Connectivity between these areas, in addition to being correlated with PRS, was correlated with ADHD status. The connection between the caudate and the parietal region acted as a statistical suppressor, such that when it was included in a path model, the association between PRS and ADHD status was enhanced. Conclusions Our results suggest that functional connectivity to certain subcortical brain regions is directly altered by genetic variants, and certain cortico–subcortical connections may modulate ADHD-related genetic effects.

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 40. Symptoms of mania and depression were assessed using the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Children’s Depression Rating Scale (CDRS), and Clinical Global Impression (CGI) Severity (CGI-S) and Improvement (CGI-I) scales for mania and depression. Results This study had a high drop-out rate with only 53% completing all 12 weeks. There was a significant reduction in YMRS, HDRS, and CDRS mean scores from baseline to endpoint. Of the 24 exposed participants, 54% had an anti-manic response measured by a reduction in YMRS ≥ 30% and 46% had a CGI-I mania score ≤ 2 at endpoint. Additionally, 62% of participants had an anti-depressive response measured by a reduction in HDRS ≥ 30%, 31% had an anti-depressive response measured by a reduction in CDRS ≥ 30%, and 38% had a CGI-I depression score ≤ 2 at endpoint. Conclusions These pilot open-label findings in a small sample provide preliminary data supporting the tolerability and safety of NAC in a pediatric population. The findings of this pilot scale study indicating improvement in mania and depression are promising, but require replication with a monotherapy randomized placebo controlled clinical trial and larger sample. Trial Registration ClinicalTrials.gov Identifier: NCT02357290. First Registration 06/02/2015.

Background: Aberrant reward behavior is known to associate with various forms of psychopathology. ‘Effort’, as one component of reward, is defined as the perception of the value of the prospective outcome as a function of its magnitude and the perceived costs of the physical or cognitive labor required to obtain it. This study sought to empirically validate the ‘effort’ construct via behavioral assessments and self-reports. Methods: Participants were 1536 children and 1270 of their parents. ‘Effort’ was assessed via the Effort Expenditure for Rewards Task (EEfRT). Child psychopathology was measured using the Child Behavior Checklist; adult psychopathology was measured using the Adult Self Report. Multitrait-multimethod matrices were used to demonstrate the divergent validity of ‘effort’ measures from other measures of reward behavior. We used linear regression models to assess familial transmission of ‘effort’, and zero-inflated negative binomial regression models to analyze the relationship between ‘effort’ and psychopathology and the moderating effects of sex. Results: For adults and their children, measures of ‘effort’ did not correlate with any other measures of reward constructs, suggesting divergent validity. Measures of ‘effort’ were positively correlated between siblings, while correlations between children and adults were not significant. In children, significant interactions were observed between sex and ‘effort’ valuation, in association with anxiety and thought problems, consistent with previous work. The moderating effects of sex had the greatest effect at low ‘effort’, with females having higher severity of psychopathology than males on average. Conclusions: This study identified the ‘effort’ component of reward behavior as a significant correlate of multiple psychopathologies, moderated by sex. These findings provide further evidence supporting ‘effort’ as a relevant construct for understanding psychopathology. The results consistently demonstrate aberrant ‘effort’ is associated with greater anxiety and thought problems. The presence of sibling-sibling correlations accompanied by the absence of parent-child correlations suggests a lack of continuity between child and parent measures and suggests that further evaluation and refinement of age-appropriate measures of effort is warranted.

Applications of machine learning (ML) in biomedical science are growing rapidly, spurred by interdisciplinary collaborations, aggregation of large datasets, accessibility of analytic routines, and availability of powerful computers. With this increased usage comes a responsibility for education, borne equally by data scientists plying their wares in medical research and biomedical scientists harnessing such methods to glean knowledge from data. This article provides a critical review of ML, covering common ML methods and historical trends of their use in psychiatry, and identifying areas of opportunity for future applications of ML in biological psychiatry. We also establish the ML in Psychiatry (MLPsych) Consortium, enumerate its objectives, and provide a set of standards (Guidelines for REporting ML Investigations in Neuropsychiatry [GREMLIN]) for designing and reporting studies that use ML. This review serves as a cautiously optimistic primer on ML for those on the precipice as they prepare to dive into the field, either as dedicated methodological practitioners or, at the very least, well-informed consumers.

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub ( https://covid19forecasthub.org/ ) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.

IntroductionThe Dextroamphetamine Transdermal System (d-ATS) was developed as an alternative to oral amphetamine (AMP) formulations for ADHD. In a pivotal study, d-ATS met primary and secondary efficacy endpoints for ADHD in children and adolescents. Study subjects wore d-ATS for 9 hours, and an improvement in Swanson, Kotkin, Agler, M-Flynn, and Pelham scale (SKAMP) total score was observed from 2 through 12 hours after application. Patients with ADHD may need varying durations of treatment for symptoms from day to day. This analysis describes the exposure-response (E-R) relationship for d-ATS and explores possible outcomes for wear times ≤9 hours under varying assumptions.MethodsA population pharmacokinetic (PK) model was developed to describe AMP disposition following d-ATS administration. This model was used to construct a population pharmacokinetic/pharmacodynamic (PK/PD) model from SKAMP total score data from two pediatric clinical studies to characterize onset and duration of effect after d-ATS administration. The integrated PK/PD model was used to describe the d-ATS E-R relationship and simulate the potential onset and duration of effect of d-ATS in response to various removal times (when ResultsData from 81 children and 41 adolescents, 6–17 years old, were included. The model provided a reasonable description of the SKAMP score over time, showing an initial decline ~2 hours after patch application. In approximately 50% of children and adolescents, the maximum decline in SKAMP scores was observed within the first 4 hours after patch application. Earlier simulated d-ATS removal times were associated with reduced systemic exposure and earlier return to near-baseline scores across the range of assumptions tested.Under different assumptions, the graphs changed modestly but not dramatically. For example, with moderate/conservative assumptions, following a 9-hour wear time, SKAMP scores returned to within 90% of baseline value in ~49% of subjects by 12 hours and ~80% of subjects by 16 hours. Following a 4-hour wear time, percentages were ~74% by 12 hours and ~95% by 16 hours.ConclusionsSimulation results suggest that the duration of d-ATS efficacy may be related to wear time, which can be adjusted according to treatment needs, consistent with published observations for another transdermal stimulant. The d-ATS patch provides the ability to control medication exposure by shortening wear time, allowing treatment duration to be individualized and optimized in ADHD patients who have varying schedules and needs.FundingNoven Pharmaceuticals, Inc.

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.

Background: Polygenic risk scores (PRSs), which sum the effects of SNPs throughout the genome to measure risk afforded by common genetic variants, have improved our ability to estimate disorder risk for Attention-Deficit/Hyperactivity Disorder (ADHD) but the accuracy of risk prediction is rarely investigated. Methods: With the goal of improving risk prediction, we performed gene set analysis of GWAS data to select gene sets associated with ADHD within a training subset. For each selected gene set, we generated gene set polygenic risk scores (gsPRSs), which sum the effects of SNPs for each selected gene set. We created gsPRS for ADHD and for phenotypes having a high genetic correlation with ADHD. These gsPRS were added to the standard PRS as input to machine learning models predicting ADHD. We used feature importance scores to select gsPRS for a final model and to generate a ranking of the most consistently predictive gsPRS. Results: For a test subset that had not been used for training or validation, a random forest (RF) model using PRSs from ADHD and genetically correlated phenotypes and an optimized group of 20 gsPRS had an area under the receiving operating characteristic curve (AUC) of 0.72 (95% CI: 0.70 to 0.74). This AUC was a statistically significant improvement over logistic regression models and RF models using only PRS from ADHD and genetically correlated phenotypes. Conclusions: Summing risk at the gene set level and incorporating genetic risk from disorders with high genetic correlations with ADHD improved the accuracy of predicting ADHD. Learning curves suggest that additional improvements would be expected with larger study sizes. Our study suggests that better accounting of genetic risk and the genetic context of allelic differences results in more predictive models.

BackgroundMany studies have been conducted with the goal of correctly predicting diagnostic status of a disorder using the combination of genetic data and machine learning. The methods of these studies often differ drastically. It is often hard to judge which components of a study led to better results and whether better reported results represent a true improvement or an uncorrected bias inflating performance.MethodsIn this systematic review, we extracted information about the methods used and other differentiating features in genomic machine learning models. We used the extracted features in mixed-effects linear regression models predicting model performance. We tested for univariate and multivariate associations as well as interactions between features.ResultsIn univariate models the number of hyperparameter optimizations reported and data leakage due to feature selection were significantly associated with an increase in reported model performance. In our multivariate model, the number of hyperparameter optimizations, data leakage due to feature selection, and training size were significantly associated with an increase in reported model performance. The interaction between number of hyperparameter optimizations and training size as well as the interaction between data leakage due to optimization and training size were significantly associated reported model performance.ConclusionsOur results suggest that methods susceptible to data leakage are prevalent among genomic machine learning research, which may result in inflated reported performance. The interactions of these features with training size suggest that if data leakage susceptible methods continue to be used, modelling efforts using larger data sets may result in unexpectedly lower results compared to smaller data sets. Best practice guidelines that promote the avoidance and recognition of data leakage may help the field advance and avoid biased results.

Contains fulltext : 287469.pdf (Publisher’s version ) (Open Access) Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.