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BackgroundMisconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base.MethodsWe reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder.ResultsWe generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents.ConclusionsMany findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.

Objective: Stability and developmental effects of electroencephalography (EEG) and event related potential (ERP) correlates of ADHD are understudied. This pilot study examined stability and developmental changes in ERP and EEG metrics of interest. Methods: Thirty-seven 7 to 11-year-old children with ADHD and 15 typically developing (TD) children completed EEG twice, 11 to 36 months apart. A series of mixed effects linear models were run to examine stability and developmental effects of EEG and ERP metrics. Results: Stability and developmental effects of EEG and ERP correlates of ADHD varied considerably across metrics. P3 amplitude was stable over time and showed diverging developmental trajectories across groups. Developmental differences were apparent in error related ERPs and resting aperiodic exponent. Theta-beta ratio was stable over time among all children. Conclusions: Developmental trajectories of EEG and ERP correlates of ADHD are candidate diagnostic markers. Replication with larger samples is needed. [ABSTRACT FROM AUTHOR]

Objective: ADHD is associated with suboptimal health behaviors including physical activity (PA). LEAP is a parent BMT group program enhanced to focus on health behaviors, integrated with mHealth technology. Little is known about implementing BMT via telemedicine "telegroups." Methods: Children ages 5 to 10 with ADHD and their caregiver wore activity trackers and participated in an 8 to 9 week parent BMT and social media group emphasizing PA, sleep, and screen use. A 7-day child accelerometer-wear and parent and teacher measures were completed pre- and post-group. Groups were in-person prior to the COVID-19 pandemic and in telegroup format during the pandemic. Results: Thirty-three families participated in person and 23 participated via virtual telegroup. Group attendance was superior for telegroup with equivalent satisfaction and skill use. Changes in health behavior and clinical outcomes were equivalent. Conclusions: LEAP is a feasible and novel BMT intervention that can be delivered in an accessible telegroup format with high participation and acceptability. [ABSTRACT FROM AUTHOR]

Background: Despite widespread use of stimulants to treat ADHD, individual responses vary considerably and few predictors of response have been identified. The identification of reliable and clinically feasible biomarkers would facilitate a precision medicine approach to pharmacological treatment of ADHD. We test the hypothesis that two electroencephalography (EEG) based neural signatures of ADHD, resting aperiodic slope exponent and novelty P3 amplitude, are markers of methylphenidate response in children. We hypothesize that positive response to methylphenidate treatment will be associated with greater abnormality of both neural markers. Methods: Twenty-nine 7-11 year-old children with ADHD and a history of methylphenidate treatment, and 30 controls completed resting EEG and visual oddball event related potential (ERP) paradigms. ADHD participants were characterized as methylphenidate responders (n = 16) or non-responders (n = 13) using the clinical global improvement (CGI-I) scale during blinded retrospective interview. All participants abstained from prescribed medications for at least 48 hours prior to the EEG. Results: As expected, methylphenidate responders (CGI-I rating < 3) demonstrated attenuated P3 amplitude relative to controls. Unexpectedly, methylphenidate non-responders showed atypically flat aperiodic spectral slope relative to controls, while responders did not differ on this measure. Conclusion: ADHD symptoms associated with atypical patterns of intrinsic neural activity may be less responsive to methylphenidate. In contrast, ADHD symptoms associated with abnormal frontal-striatal neural network excitation may be correctable with methylphenidate. Altogether, EEG is a feasible and promising candidate methodology for identifying biomarkers of stimulant response. [ABSTRACT FROM AUTHOR]

Objective: Quality measures (QMs; also known as Quality Indicators) quantify health care processes, outcomes, patient perceptions, and organizational structure and/or systems that are relevant to the provision of high-quality health care. We describe the first phase of a project that has as its ultimate goal the creation and validation of QMs for tracking the screening, diagnosis, treatment, and clinical follow-up of adults with ADHD. This will fill an important gap in the field of Adult ADHD because QMs for adult ADHD do not exist. Method: We followed the guidelines of the U.S. Agency for Healthcare Research and Quality (AHRQ) for the development of QMs. These guidelines call for two phases: (1) Identify Candidate QMs and (2) Assess Candidate QMs. This article describes the results of our Phase 1 activities. To generate QMs for adult ADHD, we took the following steps: (a) searched the clinical/research literature for adult ADHD QMs; (b) convened a multidisciplinary panel comprising clinical and research experts and had them brainstorm potential QMs in the areas of screening, diagnosis, treatment, follow-up, care coordination, and patient experience; (c) compared these QMs with existing guidelines for adult ADHD to see if any potential QMs had been missed, this led to a draft list of 46 QMs; (d) had 28 ADHD experts rate the importance, reliability, validity, feasibility, and usability of the QMs. Results: The literature review found several QMs for ADHD in youth but none for ADHD in adults. The brainstorming session generated 52 QMs. The survey showed that all of these QMs were highly rated but that there was sufficient variability in ratings to prioritize some QMs over others. Conclusion: Based on these results, we prioritized QMs to carry forward into the next phase of the project. This work fills an important gap for the clinical care of adult patients with ADHD and helps to set a precedent for mental health, which has lagged behind other areas of medicine in developing QMs. [ABSTRACT FROM AUTHOR]

Background: Attention-deficit/hyperactivity disorder (ADHD) treatment utilization among adolescents is highly variable. This article describes pharmacological and nonpharmacological treatment utilization in a community sample of primarily Latinx and/or Black adolescents with ADHD (N = 218), followed longitudinally for 4 years, from early adolescence until approximately age 17 (M = 16.80, standard deviation = 1.65). Methods: Electronic surveys administered between 2012 and 2019 queried parent and youth reports of medication initiation, persistence, diversion, and misuse, as well as reasons for desistence. Nonpharmacological treatment utilization (including complementary and alternative treatments) was also measured. Results: Results indicated that: (1) the majority of the sample sought treatment for ADHD in their community, (2) rates of psychosocial treatment utilization were higher than medication utilization, (3) approximately half of the medicated sample discontinued community-administered ADHD medication during the follow-up period, most frequently citing tolerability issues and concerns that they were "tired of taking" medication, and (4) medication misuse consisted of youth diversion and parent utilization of teen medication, but both were reported at low rates. Race/ethnicity did not predict treatment utilization patterns, but lower family adversity and psychiatric comorbidity predicted persistence of medication use over time. Conclusions: ADHD treatment engagement efforts for Latinx and/or Black adolescents might link treatment to goals valued by the youth, address concerns related to medication tolerability, and promote secure monitoring of medication. Nonpharmacological treatments for ADHD may be more palatable to Latinx and Black youth with ADHD, and efforts to engage youth with ADHD in treatment should consider offering medication and psychosocial treatment options. [ABSTRACT FROM AUTHOR]

We tested the interactive effect of feedback and reward on visuospatial working memory in children with ADHD. Seventeen boys with ADHD and 17 Normal Control (NC) boys underwent functional magnetic resonance imaging (fMRI) while performing four visuospatial 2-back tasks that required monitoring the spatial location of letters presented on a display. Tasks varied in reward size (large; small) and feedback availability (no-feedback; feedback). While the performance of NC boys was high in all conditions, boys with ADHD exhibited higher performance (similar to those of NC boys) only when they received feedback associated with large-reward. Performance pattern in both groups was mirrored by neural activity in an executive function neural network comprised of few distinct frontal brain regions. Specifically, neural activity in the left and right middle frontal gyri of boys with ADHD became normal-like only when feedback was available, mainly when feedback was associated with large-reward. When feedback was associated with small-reward, or when large-reward was expected but feedback was not available, boys with ADHD exhibited altered neural activity in the medial orbitofrontal cortex and anterior insula. This suggests that contextual support normalizes activity in executive brain regions in children with ADHD, which results in improved working memory. [ABSTRACT FROM AUTHOR]

Purpose: Children with attention-deficit/hyperactivity disorder (ADHD) often perform poorly during cognitive tests. We sought to evaluate cortisol as potential moderator of performance in mentally challenging tasks in children with ADHD. Materials and Methods: Ninety clinic-referred children with ADHD were studied. Cortisol contents in saliva were measured before and after administration of a continuous performance test (CPT). Results: Pre and post CPT cortisol levels were similar in 68 children. Children whose cortisol level increased after testing ( n = 22) displayed a significantly longer response time and increased response time variability scores as compared to children who did not display increase of cortisol after the CPT test. Even after controlling for the effects of response time and anxiety, the changes in cortisol levels were associated with effect on response time variability. Conclusion: The patients who showed an increased cortisol level after stress displayed a higher variability in response time than the patients who showed no change or a decreased cortisol level. The result of the current study suggests that stress- induced high norepinephrine (NE) release may accompany poorer attention performance in patients with ADHD. [ABSTRACT FROM AUTHOR]

Stimulant medications, such as methylphenidate (MPH), are the most commonly used, effective treatment for ADHD. MPH acts primarily by inhibiting the dopamine transporter (DAT), a protein responsible for the reuptake of dopamine from the synapse into presynaptic terminals. We sought to evaluate the relationship between DATI 3'-untranslated region (3'-UTR) variable number tandem repeats (VNTR) genotypes and dose response to MPH. Children with ADHD (n = 47), ages 5-16 years (mean = 9.07 years), underwent a 4-week, double-blinded, crossover trial with forced weekly dosage changes. Children were genotyped for the DATI VNTR and evaluated on placebo and three dosage levels of OROS® MPH. Parents and clinicians who were blind to genotype and medication status rated ADHD symptoms, impairment, and stimulant side effects each week. Children who were homozygous for the less common, 9repeat DATI 3'-UTR genotype displayed a distinct dose-response curve from that of the other genotype groups, with an absence of typical linear improvement when the dose was increased from 18 mg to 36 and 54 mg. Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype, and to determine if this group responds differentially to alternative treatments. [ABSTRACT FROM AUTHOR]

Objective: To identify patient- and treatment-level factors that predict intervention engagement and outcome for adolescents with attention-deficit/hyperactivity disorder (ADHD), guiding efforts to enhance care.Method: Integrative data analysis was used to pool data from 4 randomized controlled trials of adolescent ADHD treatment with participants (N = 854) receiving various evidence-based behavioral therapy packages in 5 treatment arms (standard [STANDARD], comprehensive [COMP], engagement-focused [ENGAGE]), community-based usual care (UC), or no treatment (NOTX). Participants also displayed varying medication use patterns (negligible, inconsistent, consistent) during the trial. Regression and latent growth curve analyses examined treatment- and patient-level predictors of engagement and outcome.Results: Compared with COMP, ENGAGE was associated with higher parent engagement in behavioral therapy (d = 1.35-1.73) when delivered in university, but not community, clinics. Under some conditions, ENGAGE also predicted youth engagement in behavioral therapy (d = 1.21) and lower likelihood of negligible medication use (odds ratio = 0.49 compared with NOTX). UC was associated with poorer parent engagement compared with COMP (d = -0.59) and negligible medication use (odds ratio = 2.29) compared with NOTX. Compared with COMP, ENGAGE (in university settings) was consistently associated with larger ADHD symptom improvements (d = 0.41-0.83) at 6-month follow-up and sometimes associated with larger grade point average (d = 0.68) and parent-teen conflict (d = 0.41) improvements. Consistent medication use during behavioral therapy was associated with larger improvements in ADHD symptoms (d = 0.28) and parent-teen conflict (d = 0.25-0.36). An ADHD+internalizing clinical profile predicted larger improvements in grade point average (d = 0.45). Family adversity predicted poorer parent and youth engagement (rate ratio = 0.90-0.95), negligible medication use (odds ratio = 1.22), and smaller improvements in grade point average (d = -0.23). African American race predicted smaller improvements in parent-teen conflict (d = -0.49).Conclusion: Engagement-focused behavioral therapy and consistent medication use most frequently predicted stronger clinical engagement and outcomes for adolescents with ADHD. Youths who are African American or who experience family adversity may demonstrate treatment-related disparities for certain outcomes; youths with ADHD+internalizing symptoms may demonstrate excellent academic outcomes following behavioral therapy.Data Sharing: The full ADHD TIDAL dataset is publicly available through the National Data Archive (https://nda.nih.gov), including a data dictionary. The study protocol is also publicly available: https://doi.org/10.1186/s12888-020-02734-6. [ABSTRACT FROM AUTHOR]

Reflecting on the accompanying article by Jans et al., we draw the following thoughts. Future research on multiplex ADHD families is needed to elucidate mechanisms, timing, and a sequencing of interventions, preferably in treatment naïve participants. Furthermore, in addition to symptom measures, it is likely that multi‐informant measures of functional impairments such as parenting and parent‐child observations may help elucidate the complex mechanisms linking maternal and child ADHD, and eventually lead to more targeted, efficient, and feasible prevention and intervention strategies. [ABSTRACT FROM AUTHOR]

Background: It has been posited that glutamate dysregulation contributes to the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Modulation of glutamate neurotransmission may provide alternative therapeutic options. The novel 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor positive allosteric modulator Org 26576 was investigated with a translational approach including preclinical and clinical testing. Methods: Neonatal rat 6-hydroxydopamine lesion-induced hyperactivity was used as preclinical model. Seventy-eight ADHD adults entered a multicenter, double-blind, placebo-controlled, two-period crossover trial. After 1 week placebo lead-in, 67 subjects were randomized into one of four treatment sequences: sequence A (n = 15) Org 26576 (100 mg b.i.d.) for 3 weeks, followed by a 2-week placebo crossover and 3 weeks placebo; sequence B (n = 16) 5 weeks placebo followed by 3 weeks Org 26576 (100 mg b.i.d.); sequence C (n = 18) Org 26576 flexible dose (100–300 mg b.i.d.) for 3 weeks, then 5 weeks placebo; sequence D (n = 18) 5 weeks placebo followed by 3 weeks Org 26576 (100–300 mg b.i.d.). The Adult ADHD Investigator Symptom Rating Scale was used to assess changes in ADHD symptomatology. Results: Org 26576 (1, 3, 10 mg/kg intraperitoneal) produced dose-dependent inhibition of locomotor hyperactivity in 6-hydroxydopamine-lesioned rats. Org 26576 (100 mg b.i.d.) was superior to placebo in treating symptoms of adult ADHD subjects. The primary Adult ADHD Investigator Symptom Rating Scale results were supported by some secondary analyses. However, Org 26576 (100–300 mg b.i.d.) did not confirm these results. Most frequently reported adverse events were nausea, dizziness, and headache. Conclusions: These preclinical and clinical findings suggest that Org 25676 may have utility in the treatment of ADHD. [ABSTRACT FROM AUTHOR]

Abstract: Central dopaminergic activity is critical to the functioning of both motor and cognitive systems. Based on the therapeutic action of dopaminergic agents in treating attention deficit hyperactivity disorder (ADHD), ADHD symptoms may be related to a reduction in central dopaminergic activity. We tested the hypothesis that dopaminergic activity, as reflected by plasma homovanillic acid (pHVA), may be related to dimensional aspects of ADHD in adults. Subjects were 30 healthy volunteer and 39 personality disordered subjects, in whom morning basal pHVA concentration and a dimensional measure of childhood ADHD symptoms (Wender Utah Rating Scale: WURS) were obtained. A significant inverse correlation was found between WURS Total score and pHVA concentration in the total sample. Among WURS factor scores, a significant inverse relationship was noted between pHVA and history of “childhood learning problems”. Consistent with the dopaminergic dysfunction hypothesis of ADHD and of cognitive function, pHVA concentrations were correlated with childhood history of ADHD symptoms in general and with history of “learning problems” in non-ADHD psychiatric patients and controls. Replication is needed in treated and untreated ADHD samples to confirm these initial results. [Copyright &y& Elsevier]

• ADHD occurs in 5.9 % of youth and 2.5 % of adults. • Most cases of ADHD are caused by the combined effects of many genetic and environmental risks. • There are small differences in the brain between people with and without ADHD. • Untreated ADHD can lead to many adverse outcomes. • ADHD costs society hundreds of billions of dollars each year, worldwide. Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma. [ABSTRACT FROM AUTHOR]

Objective: Parental attention-deficit/hyperactivity disorder (ADHD) is associated with suboptimal parenting and reduces the effectiveness of child ADHD treatments. We conducted a Pilot Sequential, Multiple Assignment, Randomized Trial (SMART Pilot) to evaluate the feasibility and acceptability of sequencing medication and behavioral treatments for mothers with ADHD to target outcomes, including maternal ADHD, parenting, and child ADHD symptoms/impairment in multiplex ADHD families. Methods: Thirty-five mothers with ADHD and their 5- to 8-year-old child with ADHD symptoms were enrolled. Mothers were randomized to 8 weeks of individually titrated stimulant medication (MSM) or behavioral parent training (BPT), followed by rerandomization to 8 weeks of continued first-line treatment (with as-needed modifications) or combined treatment, leading to four treatment sequences (MSM-MSM, MSM-BPT, BPT-MSM, and BPT-BPT). Results: Recruitment of multiplex ADHD families came primarily from child providers. Mothers were adherent to medication and had high therapy session attendance. Mothers and clinicians found both treatments to be acceptable and preferred combination treatment, especially receiving medication before BPT. Monotherapy treatment visits were viewed as more burdensome (MSM-MSM, BPT-BPT). Conclusions: Maternal stimulant medication and BPT are acceptable and feasible interventions for families in which both the mother and child have ADHD symptoms. Mothers with concerns about their children's ADHD symptoms are receptive to receiving treatment themselves as an initial strategy for improving their children's health and functioning. Fully powered SMART designs show promise in evaluating the sequencing of interventions and helping clinicians develop algorithms for treating multiplex families in real-world practice settings. [ABSTRACT FROM AUTHOR]

Objectives: Normal brain development is highly dependent on adequate levels of iodine and thyroid hormone. It has been suggested that Attention Deficit Hyperactivity Disorder (ADHD) is the consequence of prenatal thyroidal endocrine disruption. The hypothesis was examined using neonatal thyroxine levels as a bio-marker of prenatal thyroid status and comparing it to subsequent development of ADHD.Design and methods: In a matched case-control study, cases were defined as children diagnosed with ADHD, while children born in the same hospital and tested on the same day served as matched controls. Conditional logistic regression analysis with unequal numbers of controls was performed.Results: The neonatal thyroxine levels were within normal limits for each of the children who were subsequently diagnosed as having ADHD, and their distribution was no different from that of their controls.Conclusions: Children diagnosed with ADHD do not demonstrate prenatal thyroidal dysfunction as reflected in the newborn thyroxine levels, therefore neonatal thyroxine levels are not a bio-marker for the subsequent development of ADHD. [Copyright &y& Elsevier]

Objective: Methylphenidate has prominent effects in the dopamine-rich striatum that are absent for the selective norepinephrine transporter inhibitor atomoxetine. This study tested whether baseline striatal activation would predict differential response to the two medications in youth with attention-deficit/hyperactivity disorder (ADHD).Method: A total of 36 youth with ADHD performed a Go/No-Go test during functional magnetic resonance imaging at baseline and were treated with methylphenidate and atomoxetine using a randomized cross-over design. Whole-brain task-related activation was regressed on clinical response.Results: Task-related activation in right caudate nucleus was predicted by an interaction of clinical responses to methylphenidate and atomoxetine (F1,30 = 17.00; p < .001). Elevated caudate activation was associated with robust improvement for methylphenidate and little improvement for atomoxetine. The rate of robust response was higher for methylphenidate than for atomoxetine in youth with high (94.4% vs. 38.8%; p = .003; number needed to treat = 2, 95% CI = 1.31-3.73) but not low (33.3% vs. 50.0%; p = .375) caudate activation. Furthermore, response to atomoxetine predicted motor cortex activation (F1,30 = 14.99; p < .001).Conclusion: Enhanced caudate activation for response inhibition may be a candidate biomarker of superior response to methylphenidate over atomoxetine in youth with ADHD, purportedly reflecting the dopaminergic effects of methylphenidate but not atomoxetine in the striatum, whereas motor cortex activation may predict response to atomoxetine. These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach.Clinical Trial Registration Information: Stimulant Versus Nonstimulant Medication for Attention Deficit Hyperactivity Disorder in Children; https://clinicaltrials.gov/; NCT00183391. [ABSTRACT FROM AUTHOR]