Efficacy, Safety, and Tolerability of Centanafadine Sustained-Release Tablets in Adults With Attention-Deficit/Hyperactivity Disorder: Results of 2 Phase 3, Randomized, Double-blind, Multicenter, Placebo-Controlled Trials.

PURPOSE/BACKGROUND: Centanafadine is an inhibitor of norepinephrine, dopamine, and serotonin reuptake transporters under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS/PROCEDURES: Two phase 3 randomized, double-blind, placebo-controlled, parallel-group studies of 200 mg/d or 400 mg/d centanafadine sustained-release tablets versus placebo included adults (18-55 years of age) with a diagnosis of ADHD. The primary and key secondary efficacy endpoints were the change from baseline at day 42 in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score and the Clinical Global Impression-Severity of Illness Scale, respectively. FINDINGS/RESULTS: Subjects randomized in study 1 (centanafadine 200 mg/d, n = 149; centanafadine 400 mg/d, n = 149; placebo, n = 148) and study 2 (centanafadine 200 mg/d, n = 145; centanafadine 400 mg/d, n = 143; placebo, n = 142) had moderate to severe ADHD (mean AISRS total score, 38.7 [SD, 6.8] across both studies). At day 42, statistically significant least-squares mean differences in AISRS total score were observed in favor of centanafadine versus placebo in study 1 (200 mg/d: -3.16, P = 0.019; 400 mg/d: -2.74, P = 0.039) and study 2 (200 mg/d: -4.01, P = 0.002; 400 mg/d: -4.47, P = 0.001). Effect sizes versus placebo were -0.28 for 200 mg/d and -0.24 for 400 mg/d in study 1 and -0.37 for 200 mg/d and -0.40 for 400 mg/d in study 2. The overall rate of treatment-emergent adverse events (TEAEs) was low, but there was a small increase in TEAE occurrence with increasing dose. Incidences of serious TEAEs and abuse potential-related AEs were low. IMPLICATIONS/CONCLUSIONS: These are the first large-scale studies to demonstrate the efficacy and safety profiles of 200 mg/d and 400 mg/d centanafadine in adults with ADHD.

Screening for Adult ADHD.

PURPOSE OF REVIEW: This review paper aims to update readers on the importance of screening for attention-deficit/hyperactivity disorder (ADHD) in adults and to provide a primer on how best to screen and diagnose this condition in an efficient and reliable manner. RECENT FINDINGS: The ASRS Screening Scale was updated in 2017 to reflect the changes made to identify ADHD based on the DSM-5 criteria and to reflect our understanding that adult ADHD is characterized by executive functioning deficits that are not explicitly reflected in the DSM-5 criteria. The use of the ASRS Screening Scale improves the clinician's ability to rapidly identify adult patients who require a comprehensive evaluation to diagnose ADHD and/or other comorbid psychiatric conditions. The scale has been validated for use in both the general population and in the ADHD specialty treatment population, which supports its use by both general clinicians and mental health clinicians. Identification of adult ADHD is critical due to the profound personal, familial, and societal costs associated with this condition.

Establishing US norms for the Adult ADHD Self-Report Scale (ASRS-v1.1) and characterising symptom burden among adults with self-reported ADHD.

AIMS: To estimate Adult ADHD Self-Report Scale (ASRS-v1.1) Symptom Checklist normative total scores among the US adult general population and to evaluate overall attention-deficit hyperactivity disorder (ADHD) symptom burden among US adults with ADHD. METHODS: Prior 2012 and 2013 US National Health and Wellness Survey respondents were re-contacted. Demographics, comorbidities, and ASRS-v1.1 data were collected. ASRS-v1.1 scores were compared by sex, age, ADHD diagnosis, and ADHD medication use. Group differences were evaluated using chi-square tests and independent samples t-tests for categorical and continuous variables, respectively. RESULTS: Of 22 397 respondents, 465 self-reported being diagnosed with ADHD by a physician; of these, 174 self-reported using ADHD medication. The mean ASRS-v1.1 total score was 2.0 (SD = 3.2); scores differed by age and sex (all, P < 0.001). ADHD (vs no ADHD) was associated with depression (58.1% vs 18.0%), anxiety (53.1% vs 16.0%), and sleep difficulties (37.0% vs 14.0%) (all, P < 0.001). ADHD medication use (vs no use) was associated with depression (68.4% vs 51.9%), anxiety (67.2% vs 44.7%), panic disorder (25.9% vs 17.2%), and insomnia (27.6% vs 19.6%) (all, P < 0.05). ADHD (vs no ADHD) respondents scored higher on all 18 ASRS-v1.1 items (all, P < 0.05). Medication users (vs non-users) scored higher on six items (all, P < 0.05). DISCUSSION: Adult ADHD may be undertreated or sub-optimally treated, despite a high symptom burden. Normative data will allow comparisons with individuals' scores to support the assessment of ADHD symptom burden among adults. CONCLUSION: Findings highlight the importance of assessing ADHD symptom burden, especially among adults presenting with comorbidities.

Test-retest reliability of the adult ADHD Self-Report Scale (ASRS) v1.1 Screener in non-ADHD controls from a primary care physician practice.

Objectives: To examine the test-retest reliability of the DSM-IV Adult ADHD Self-Report Scale (ASRS) v1.1 Screener in adults without ADHD. Prior studies have not examined test-retest reliability of the Screener in non-ADHD controls. Methods: Subjects completed the Screener in a primary care physician (PCP) waiting room (T1); those who screened negative for ADHD (n = 104) (<4/6 significant Screener items) symptoms were further assessed on the phone (T2). T2 included phone administration of the full ASRS v1.1 Symptom Checklist (which contains the six items from the Screener). Spearman's correlations and intra-class correlation coefficients (ICCs) between T1 and T2 were calculated for the total Screener score and for each Screener item. McNemar-Bowker tests were conducted for the Screener total score and each item to check for significant changes from T1 to T2. Results: Screener T1 and T2 total scores were significantly correlated (Spearman's rho = 0.78, P < 0.0001), as were individual items. Correlations remained significant when controlling for a variety of demographic factors and psychiatric conditions. Confirming the significant Spearman correlations, ICCs for Screener total score and each item were also significant (ICC = 0.75, P < 0.0001). The McNemar-Bowker tests showed no significant differences for Screener total score and for the IA items; however, the H-I items were somewhat higher at T1 versus T2. Conclusions: The DSM-IV ASRS v1.1 Screener has high test-retest reliability in patients without ADHD.

Executive function in adults with attention-deficit/hyperactivity disorder during treatment with atomoxetine in a randomized, placebo-controlled, withdrawal study.

We assessed the executive function in adults with attention-deficit/hyperactivity disorder (ADHD) during atomoxetine treatment in a randomized withdrawal trial. Responders (Conners' ADHD Rating Scale-Investigator Rated: Screening Version [adult prompts] ≥30% reduction from baseline and Clinical Global Impression Scale-ADHD Severity score ≤3) to open-label atomoxetine (40-100 mg/d, 12 weeks) entered a 37-week double-blind maintenance period. Patients who maintained response (double-blind atomoxetine for 12 weeks) were randomized 1:1 to atomoxetine (80-100 mg/d, n = 266) or placebo (n = 258) for 25 weeks (total duration, 1 year). Patients and investigators were blinded to response criteria and randomization timing. Change in executive function was assessed with the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Self-Report and Informant T scores from the randomization to the last-observation-carried-forward postrandomization week 25 (after week 17). Of the enrolled patients (n = 2017; mean age, 33.2 years; male, 58.7%), 524 responders were randomized. During open-label atomoxetine, subscales and individual items on both BRIEF-A questionnaires showed significant improvement (P < 0.001). After randomization, the following T scores improved significantly (P ≤ 0.05) with patients in the atomoxetine group versus those in the placebo group: global executive composite, behavioral regulation, and metacognition indices; plan/organize, working memory, inhibit, task monitor and shift (both BRIEF-A questionnaires), emotional control and organization of materials (BRIEF-A Informant), and initiate (BRIEF-A Self-Report). Atomoxetine significantly improved the executive function compared with placebo, which was maintained for 25 weeks or more; the executive function of patients in the placebo group worsened but did not return to baseline levels after randomization.

Measuring Quality Care for Adult ADHD Patients: How Much Does Gender and Gender Identity Matter?

OBJECTIVE: Studies show adult ADHD presents differently in men and women, however few studies contrast ADHD in cisgender and gender diverse adults. We assessed care differences between these groups using previously identified quality measures (QMs). METHODS: Using EHR data, we matched a group of male ADHD patients to a female group. We followed the same procedure with a cisgender group and one identified as gender diverse through a gender dysphoria diagnosis. QM achievement was measured using logistic regression models. RESULTS: Most QMs exhibited increasing achievement over time for all groups. Variations in care quality between males and females persisted, with female patients achieving QMs more often. There were no appreciable differences between the cisgender and gender diverse groups. CONCLUSION: Though quality care for adult ADHD improved from 2010 to 2020, differences between male and female patients lingered. This effect was not observed in cisgender and gender diverse patients.

The Role of Age in Adult ADHD Quality Care: A Longitudinal Analysis of Electronic Health Record Data.

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.

A Single-Blind, Placebo Controlled Trial of Triple Beaded Mixed Amphetamine Salts in DSM-5 Adults With ADHD Assessing Effects Throughout the Day.

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.

Differences in Primary Care Management of Patients With Adult Attention Deficit Hyperactivity Disorder (ADHD) Based on Race and Ethnicity.

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.

Pilot Study of Prism EFP NeuroFeedback in Adult ADHD.

OBJECTIVE: A pilot study to preliminarily examine the effects of Prism EFP NeuroFeedback (NF) in adult ADHD. METHOD: Prism EFP NF is a form of NF specifically designed to target emotional dysregulation (ED) through down regulation of amygdala activity. Prism EFP NF has been shown to improve other disorders with significant ED. Nine participants with adult ADHD received an open trial of Prism EFP NF consisting of fifteen sessions over 8 weeks; all completed at least 5 weeks of treatment with seven completing all 8 weeks. Outcomes were assessed by change in ADHD symptoms from baseline to End of Treatment. RESULTS: About two-third reduction was seen in total DSM ADHD symptom scores (primary outcome measure) with improvement observed in all other clinical measures. No significant adverse events were seen. CONCLUSION: This preliminary trial found substantial effects of Prism EFP NF on ADHD/ED symptoms and global impairment.

Neurobiological basis of reinforcement-based decision making in adults with ADHD treated with lisdexamfetamine dimesylate: Preliminary findings and implications for mechanisms influencing clinical improvement.

BACKGROUND: ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation. METHODS: Twenty adults (M = 11, 55%, F = 9, 45%), ages 19-52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3-5 weeks of treatment with LDX and 3-5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels. RESULTS: Improvement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri). CONCLUSIONS: These findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD. Trial RegistrationClinicaltrials.gov Identifier: NCT01924429.

Amygdala-derived-EEG-fMRI-pattern neurofeedback for the treatment of chronic post-traumatic stress disorder. A prospective, multicenter, multinational study evaluating clinical efficacy.

We conducted a prospective, single arm, multisite, multinational, open label trial assessing the safety and efficacy of a novel amygdala derived neurofeedback treatment, designated Amygdala-Derived-EFP, for chronic PTSD. Participants, including veterans and civilians, underwent screening, training, 15 neurofeedback sessions over 8 weeks and; baseline, termination (8 weeks) and 3 month post treatment assessments with validated measures. The primary endpoint was more than 50 % of the participants demonstrating a Minimally Clinically Important Difference (MCID) defined as a 6-point reduction, on the Clinician Administered PTSD Scale (CAPS-5) total score at 3 months. Secondary measures included the PCL-5, ERQ, PHQ-9, and CGI. Statistical analyses were performed using SAS®V9.4. The primary endpoint was met, with a CAPS-5 MCID response rate of 66.7 %. The average reduction in CAPS-5 total scores at 3 month follow up was 13.5 points, more than twice the MCID. Changes from baseline in CAPS-5, PCL-5, PHQ-9 scores at 8 weeks and the 3 month follow-up demonstrated statistically significant improvements in response and; demonstrated effect sizes ranging from 0.46 to 1.07. Adverse events were mild and resolved after treatment. This study builds on prior research demonstrating similar outcomes using amygdala-derived neurofeedback. Positive attributes of this therapy include monitoring by non-physician personnel, affordability, accessibility, and tolerability.

Atomoxetine treatment of attention-deficit/hyperactivity disorder in young adults with assessment of functional outcomes: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with significant impairment in multiple functional domains. This trial evaluated efficacy in ADHD symptoms and functional outcomes in young adults treated with atomoxetine. METHODS: Young adults (18-30 years old) with ADHD were randomized to 12 weeks of double-blind treatment with atomoxetine (n = 220) or placebo (n = 225). The primary efficacy measure of ADHD symptom change was Conners' Adult ADHD Rating Scale (CAARS): Investigator-Rated: Screening Version Total ADHD Symptoms score with adult prompts. Secondary outcomes scales included the Adult ADHD Quality of Life-29, Clinical Global Impression-ADHD-Severity, Patient Global Impression-Improvement, CAARS Self-Report, Behavior Rating Inventory of Executive Function-Adult Version Self-Report, and assessments of depression, anxiety, sleepiness, driving behaviors, social adaptation, and substance use. RESULTS: Atomoxetine was superior to placebo on CAARS: Investigator-Rated: Screening Version (atomoxetine [least-squares mean ± SE, -13.6 ± 0.8] vs placebo [-9.3 ± 0.8], 95% confidence interval [-6.35 to -2.37], P < 0.001), Clinical Global Impression-ADHD-Severity (atomoxetine [-1.1 ± 0.1] vs placebo [-0.7 ± 0.1], 95% confidence interval [-0.63 to -0.24], P < 0.001), and CAARS Self-Report (atomoxetine [-11.9 ± 0.8] vs placebo [-7.8 ± 0.7], 95% confidence interval [-5.94 to -2.15], P < 0.001) but not on Patient Global Impression-Improvement. In addition, atomoxetine was superior to placebo on Adult ADHD Quality of Life-29 and Behavior Rating Inventory of Executive Function-Adult Version Self-Report. Additional assessments failed to detect significant differences (P ≥ 0.05) between atomoxetine and placebo. The adverse event profile was similar to that observed in other atomoxetine studies. Nausea, decreased appetite, insomnia, dry mouth, irritability, dizziness, and dyspepsia were reported significantly more often with atomoxetine than with placebo. CONCLUSIONS: Atomoxetine reduced ADHD symptoms and improved quality of life and executive functioning deficits in young adults compared with placebo. Atomoxetine was also generally well tolerated.

Self-Reported quality of life in adults with attention-deficit/hyperactivity disorder and executive function impairment treated with lisdexamfetamine dimesylate: a randomized, double-blind, multicenter, placebo-controlled, parallel-group study.

BACKGROUND: This study examined the effects of lisdexamfetamine dimesylate (LDX) on quality of life (QOL) in adults with attention-deficit/hyperactivity disorder (ADHD) and clinically significant executive function deficits (EFD). METHODS: This report highlights QOL findings from a 10-week randomized placebo-controlled trial of LDX (30-70 mg/d) in adults (18-55 years) with ADHD and EFD (Behavior Rating Inventory of EF-Adult, Global Executive Composite [BRIEF-A GEC] ≥65). The primary efficacy measure was the self-reported BRIEF-A; a key secondary measure was self-reported QOL on the Adult ADHD Impact Module (AIM-A). The clinician-completed ADHD Rating Scale version IV (ADHD-RS-IV) with adult prompts and Clinical Global Impressions-Severity (CGI-S) were also employed. The Adult ADHD QoL (AAQoL) was added while the study was in progress. A post hoc analysis examined the subgroup having evaluable results from both AIM-A and AAQoL. RESULTS: Of 161 randomized (placebo, 81; LDX, 80), 159 were included in the safety population. LDX improved AIM-A multi-item domain scores versus placebo; LS mean difference for Performance and Daily Functioning was 21.6 (ES, 0.93, P<.0001); Impact of Symptoms: Daily Interference was 14.9 (ES, 0.62, P<.0001); Impact of Symptoms: Bother/Concern was 13.5 (ES, 0.57, P=.0003); Relationships/Communication was 7.8 (ES, 0.31, P=.0302); Living With ADHD was 9.1 (ES, 0.79, P<.0001); and General Well-Being was 10.8 (ES, 0.70, P<.0001). AAQoL LS mean difference for total score was 21.0; for subscale: Life Productivity was 21.0; Psychological Health was 12.1; Life Outlook was 12.5; and Relationships was 7.3. In a post hoc analysis of participants with both AIM-A and AAQoL scores, AIM-A multi-item subgroup analysis scores numerically improved with LDX, with smaller difference for Impact of Symptoms: Daily Interference. The safety profile of LDX was consistent with amphetamine use in previous studies. CONCLUSIONS: Overall, adults with ADHD/EFD exhibited self-reported improvement on QOL, using the AIM-A and AAQoL scales in line with medium/large ES; these improvements were paralleled by improvements in EF and ADHD symptoms. The safety profile of LDX was similar to previous studies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01101022.

Progress and Pitfalls in the Provision of Quality Care for Adults With Attention Deficit Hyperactivity Disorder in Primary Care.

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.

Updates in Pharmacologic Strategies in Adult Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) significantly worsens quality of life and long-term functional outcomes in adults. Individual impairments in adults with ADHD can be further contextualized within considerable costs to society at large. Food and Drug Administration (FDA) approved stimulants and nonstimulant medications can significantly improve ADHD symptoms in adults. In the past 2 decades, the United States FDA has expanded approval of pharmacotherapeutic options for adult ADHD. However, limitations still persist in available psychotropics for certain patient populations such as those with comorbid substance use or cardiovascular illness. Clinicians therefore must appreciate several ongoing investigations into medications with unique mechanisms of action. This article reviews the current FDA approved and emerging medication options while providing guidelines for pharmacologic management of adult ADHD.

Economic burden of attention-deficit/hyperactivity disorder among children and adolescents in the United States: a societal perspective.

OBJECTIVE: To provide a comprehensive evaluation of the economic burden associated with attention-deficit/hyperactivity disorder (ADHD) among children and adolescents from a US societal perspective. MATERIALS AND METHODS: Direct healthcare costs of children (5-11 years) and adolescents (12-17 years) with ADHD were obtained using claims data from the IBM MarketScan Research Databases (01/01/2017-12/31/2018). Direct non-healthcare and indirect costs were estimated based on literature and government publications. Each cost component was estimated using a prevalence-based approach, with per-patient costs extrapolated to the national level. RESULTS: The total annual societal excess costs associated with ADHD were estimated at $19.4 billion among children ($6,799 per child) and $13.8 billion among adolescents ($8,349 per adolescent). Education costs contributed to approximately half of the total excess costs in both populations ($11.6 billion [59.9%] in children; $6.7 billion [48.8%] in adolescents). Other major contributors to the overall burden were direct healthcare costs ($5.0 billion [25.9%] in children; $4.0 billion [29.0%] in adolescents) and caregiving costs ($2.7 billion [14.1%] in children; $1.6 billion [11.5%] in adolescents). LIMITATIONS: Cost estimates were calculated based on available literature and/or governmental publications due to the absence of a single data source for all costs associated with ADHD. Thus, the quality of cost estimates is limited by the accuracy of available data as well as the study populations and methodologies used by different studies. CONCLUSION: ADHD in children and adolescents is associated with a substantial economic burden that is largely driven by education costs, followed by direct healthcare costs and caregiver costs. Improved intervention strategies and policies may reduce the clinical and economic burden of ADHD in these populations.

Economic burden of attention-deficit/hyperactivity disorder among adults in the United States: a societal perspective.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with substantial clinical burden as individuals transition to adulthood, including higher rates of comorbidities, mortality, incarceration, and psychiatric hospitalizations than in individuals without ADHD. These higher rates likely contribute to substantial economic burden as well. OBJECTIVE: To provide a comprehensive evaluation of the economic burden associated with ADHD in the US adult population. METHODS: Direct health care costs were obtained by using claims data from the IBM MarketScan Research Databases (January 1, 2017, through December 31, 2018). Direct non-health care costs and indirect costs were estimated on the basis of the literature and government publications. Excess costs incurred by adults with ADHD during 2018 were evaluated from a societal perspective; per-patient costs were extrapolated to the national level. RESULTS: An estimated 8.7 million adults live with ADHD in the United States, resulting in a total societal excess cost attributable to ADHD of $122.8 billion ($14,092 per adult). Excess costs of unemployment ($66.8 billion; 54.4%) comprised the largest proportion of the total, followed by productivity loss ($28.8 billion; 23.4%) and health care services ($14.3 billion; 11.6%). CONCLUSIONS: ADHD in adults is associated with substantial economic burden. DISCLOSURES: This study was funded by Otsuka Pharmaceutical Development & Commercialization, Inc. (Otsuka). The study sponsor contributed to and approved the study design, participated in the interpretation of data, and reviewed and approved the manuscript. Schein is an employee of Otsuka. Gagnon-Sanschagrin, Davidson, Kinkead, Cloutier, Guérin, and Lefebvre are employees of Analysis Group, Inc., a consulting company that provided paid consulting services to Otsuka to develop and conduct this study and write the manuscript. Adler has received research support from Shire/Takeda, Sunovion, and Otsuka; consulting fees from Bracket, Shire/Takeda, Sunovion, Otsuka, the State University of New York (SUNY), the National Football League (NFL), and Major League Baseball (MLB); and royalty payments (as inventor) from New York University (NYU) for license of adult ADHD scales and training materials. Childress has received research support from Allergan, Takeda/Shire, Emalex, Akili, Ironshore, Arbor, Aevi Genomic Medicine, Neos Therapeutics, Otsuka, Pfizer, Purdue, Rhodes, Sunovion, Tris, KemPharm, Supernus, and the US Food and Drug Administration; was on the advisory board of Takeda/Shire, Akili, Arbor, Cingulate, Ironshore, Neos Therapeutics, Otsuka, Pfizer, Purdue, Adlon, Rhodes, Sunovion, Tris, Supernus, and Corium; received consulting fees from Arbor, Ironshore, Neos Therapeutics, Purdue, Rhodes, Sunovion, Tris, KemPharm, Supernus, Corium, Jazz, and Tulex Pharma; received speaker fees from Takeda/Shire, Arbor, Ironshore, Neos Therapeutics, Pfizer, Tris, and Supernus; and received writing support from Takeda/Shire, Arbor, Ironshore, Neos Therapeutics, Pfizer, Purdue, Rhodes, Sunovion, and Tris. Part of the material in this study was presented as a poster at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 2021 Virtual Meeting; May 17-20, 2021.

Long-term safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: an open-label, dose-titration, 1-year study.

OBJECTIVE: To evaluate the long-term safety of OROS methylphenidate in the management of attention-deficit/hyperactivity disorder (ADHD) in adults. METHODS: This multicenter, open-label, dose-titration, flexible dose study enrolled adults with ADHD for 6 or 12 months of treatment with OROS methylphenidate. Dosing began at 36 mg/d, with titration in 18-mg increments every 7 days until a predefined outcome (efficacy threshold, maximum dosage of 108 mg/d, or limiting adverse event). Dose reduction occurred for prespecified reasons, and the subjects discontinued if unable to tolerate 36 mg/d. Assessments included ADHD symptoms, adverse events, vital signs, and laboratory results. RESULTS: A total of 550 subjects received treatment (52% were men; mean age, 39 years; range, 18-65 years), and 57% (146/258) and 44% (129/292) completed their 6 or 12 months of treatment with mean durations of 128 and 213 days, respectively. The final prescribed dosages were 36 mg/d (22.4%), 54 mg/d (25.1%), 72 mg/d (22.0%), 90 mg/d (17.1%), and 108 mg/d (13.5%). Modest increases from baseline to final visit were observed in mean systolic (2.6 mm Hg) and diastolic (1.9 mm Hg) blood pressure and pulse (4.1 beats per minute). The mean weight decreased by 2.3 kg. No clinically meaningful changes in laboratory values or electrocardiogram parameters were observed other than increased heart rate. Most common adverse events included decreased appetite (26.7%), headache (24.0%), and insomnia (20.7%). No serious adverse event was considered related to study medication. Several measures of efficacy indicated improvement during the study. CONCLUSIONS: OROS methylphenidate, in the flexible dosage range from 36 to 108 mg/d, was well tolerated for up to 1 year in adults with ADHD.

Divergence by ADHD subtype in smoking cessation response to OROS-methylphenidate.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition subclassified in DSM-IV according to its core symptoms domains as (a) predominantly inattentive (ADHD-IN), (b) predominantly hyperactive/impulsive (ADHD-H), and (c) combined inattentive and hyperactive/impulsive (ADHD-C). Whether these subtypes represent distinct clinical entities or points on a severity continuum is controversial. Divergence in treatment response is a potential indicator of qualitative heterogeneity. This study examined smoking cessation response by ADHD subtype to osmotic-release oral system methylphenidate (OROS-MPH). METHODS: Male and female adult smokers (ADHD-C = 167 and ADHD-IN = 87) were randomized to receive OROS-MPH or placebo as augmentation treatment to nicotine patch and counseling. Logistic regression was conducted to test the effect of OROS-MPH versus placebo on prolonged smoking abstinence by ADHD subtype. RESULTS: The subtypes were similar in baseline demographic, smoking, and psychiatric history but differed in smoking cessation response to OROS-MPH or placebo as a function of nicotine dependence level. The 3-way interaction was significant; χ(2)(1) = 8.22, p < .01. Among highly dependent smokers, the prolonged abstinence rates were greater with OROS-MPH than with placebo in the ADHD-C group (60% vs. 31.3%, respectively, p < .05) but higher with placebo than with OROS-MPH in the ADHD-IN group (60% vs. 11.8%, respectively, p < .01). Abstinence rates did not differ by subtype or treatment among smokers who were less nicotine dependent. CONCLUSION: Contrasting treatment response and divergence in the impact of nicotine dependence level support the hypothesis of ADHD subtypes as distinct clinical entities and may indicate the need and directions for personalized targeted treatments of smokers with ADHD.