Risk factors associated with newly diagnosed attention-deficit/hyperactivity disorder in adults: a retrospective case-control study.

BACKGROUND: Knowledge of risk factors for attention-deficit/hyperactivity disorder (ADHD) may facilitate early diagnosis; however, studies examining a broad range of potential risk factors for ADHD in adults are limited. This study aimed to identify risk factors associated with newly diagnosed ADHD among adults in the United States (US). METHODS: Eligible adults from the IQVIA PharMetrics® Plus database (10/01/2015-09/30/2021) were classified into the ADHD cohort if they had ≥ 2 ADHD diagnoses (index date: first ADHD diagnosis) and into the non-ADHD cohort if they had no observed ADHD diagnosis (index date: random date) with a 1:3 case-to-control ratio. Risk factors for newly diagnosed ADHD were assessed during the 12-month baseline period; logistic regression with stepwise variable selection was used to assess statistically significant association. The combined impact of selected risk factors was explored using common patient profiles. RESULTS: A total of 337,034 patients were included in the ADHD cohort (mean age 35.2 years; 54.5% female) and 1,011,102 in the non-ADHD cohort (mean age 44.0 years; 52.4% female). During the baseline period, the most frequent mental health comorbidities in the ADHD and non-ADHD cohorts were anxiety disorders (34.4% and 11.1%) and depressive disorders (27.9% and 7.8%). Accordingly, a higher proportion of patients in the ADHD cohort received antianxiety agents (20.6% and 8.3%) and antidepressants (40.9% and 15.8%). Key risk factors associated with a significantly increased probability of ADHD included the number of mental health comorbidities (odds ratio [OR] for 1 comorbidity: 1.41; ≥2 comorbidities: 1.45), along with certain mental health comorbidities (e.g., feeding and eating disorders [OR: 1.88], bipolar disorders [OR: 1.50], depressive disorders [OR: 1.37], trauma- and stressor-related disorders [OR: 1.27], anxiety disorders [OR: 1.24]), use of antidepressants (OR: 1.87) and antianxiety agents (OR: 1.40), and having ≥ 1 psychotherapy visit (OR: 1.70), ≥ 1 specialist visit (OR: 1.30), and ≥ 10 outpatient visits (OR: 1.51) (all p < 0.05). The predicted risk of ADHD for patients with treated anxiety and depressive disorders was 81.9%. CONCLUSIONS: Mental health comorbidities and related treatments are significantly associated with newly diagnosed ADHD in US adults. Screening for patients with risk factors for ADHD may allow early diagnosis and appropriate management.

Reasons for treatment changes in adults with attention-deficit/hyperactivity disorder: a chart review study.

BACKGROUND: Adults with attention-deficit hyperactivity disorder (ADHD) often cycle through multiple treatments for reasons that are not well documented. This study analyzed the reasons underlying treatment changes among adults treated for ADHD in a real-world setting. METHODS: Data were collected via an online reporting form completed by eligible physicians between October and November 2020. Data for adult patients in the United States who were diagnosed with ADHD and initiated a treatment regimen within 1 to 5 years of chart abstraction were obtained. Reason for a treatment change was described for a randomly selected regimen episode, which spanned from treatment initiation until the earliest among treatment add-on/switch or discontinuation, death, or date of chart abstraction. The overall rate of ADHD/treatment-related complications were also described. Physician satisfaction with current treatment options for adult ADHD and opinions on areas for improvement were assessed. RESULTS: Data on 320 patients were reported by 152 physicians specializing in psychiatry (40.1%), pediatrics (25.0%), family medicine (21.7%), and internal medicine (13.2%). Patients had a mean age of 29.3 years; most were diagnosed with ADHD as adults (57.5%) and within the previous 5 years (56.5%). Selected treatment regimens included stimulants (79.1%), nonstimulants (14.7%), and combination therapy (5.6%) for an average duration of 1.9 years. Among patients with treatment discontinuation (N = 59), the most common reasons for discontinuation were suboptimal symptom management (55.9%), occurrence of ADHD/treatment-related complications (25.4%), and patient attitude/dislike of medication (25.4%). The main reasons for other key treatment changes were inadequate/suboptimal management of symptoms and cost considerations. Over 40% of patients had ≥ 1 documented ADHD/treatment-related complication, irrespective of whether they led to a treatment change. One in 5 physicians (19.8%) were very dissatisfied, moderately dissatisfied, or neither satisfied nor dissatisfied with current treatment options for ADHD in adults; the top 3 suggested improvements were lower risk of abuse (71.7%), longer effect duration (65.1%), and fewer ADHD/treatment-related complications (61.2%). CONCLUSIONS: The top reasons for treatment changes among adults with ADHD are lack of efficacy and ADHD/treatment-related complications, highlighting the importance of developing more effective and safer treatments to alleviate the burden of ADHD.

Treatment patterns among children and adolescents with attention-deficit/hyperactivity disorder in the United States - a retrospective claims analysis.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder affecting approximately 10.0% of children and 6.5% of adolescents in the United States (US). A comprehensive assessment of the current treatment landscape is warranted to highlight potential unmet needs of children and adolescents with ADHD. Therefore, this study described treatment patterns and healthcare costs among commercially insured children and adolescents with ADHD in the US. METHODS: Children and adolescents with ADHD initiating pharmacological treatment indicated for ADHD were identified from IBM MarketScan Commercial Database (2014-2018). A treatment sequence algorithm was used to examine treatment patterns, including discontinuation (≥ 180 days following the last day of supply of any ADHD treatment), switch, add-on, and drop (discontinuation of an agent in combination therapy), during the 12-month study period following the index date (i.e., first observed ADHD treatment). Total adjusted annual healthcare costs were compared between patients with and without treatment changes. RESULTS: Among 49,756 children and 29,093 adolescents included, mean age was 9 and 15 years, respectively, and 31% and 38% were female. As the first treatment regimen observed, 92% of both children and adolescents initiated a stimulant and 11% initiated combination therapy. Over half of the population had a treatment change over 12 months-59% of children and 68% of adolescents. Treatment discontinuation over 12 months was common in both populations-21% of children and 36% of adolescents discontinued treatment. Healthcare costs increased with the number of treatment changes observed; children and adolescents with treatment changes (i.e., 1, 2, or ≥ 3) incurred an incremental annual cost of up to $1,443 and $2,705, respectively, compared to those without a treatment change (p < 0.001). Costs were largely driven by outpatient visits. CONCLUSIONS: Over a 12-month period, treatment changes were commonly observed and were associated with excess costs, highlighting the unmet treatment needs of children and adolescents with ADHD in the US.

Reviewing the role of emerging therapies in the ADHD armamentarium.

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder that can be treated with both pharmacologic and nonpharmacologic modalities. Effective drug treatments for ADHD have been available for more than six decades. However, initial treatments had limitations in duration of effect, need for multiple daily doses, requirement for patients to swallow intact tablets, adverse effects and risk for abuse and diversion. During the past 20 years, more than two dozen stimulant and nonstimulant drugs have been developed. Nonetheless, there remain unmet needs in the treatment of ADHD.Areas covered: New stimulant and nonstimulant formulations in development are reviewed with emphasis on drugs in phase II and III trials. Efficacy, mechanism of action and adverse effect data are described where available. Abuse liability studies are described for abuse-deterrent formulations in development.Expert opinion: The review found a robust pipeline of stimulants and nonstimulants. Medications in development are formulated to optimize onset and duration of effect, alter the time of administration, obviate the need to swallow whole capsules or tablets and to deter abuse. While each of these formulations may fill a unique niche, these incremental improvements based on new drug delivery technologies may lead to very significant clinical effects.

Practitioner Review: Emotional dysregulation in attention-deficit/hyperactivity disorder - implications for clinical recognition and intervention.

BACKGROUND: Because emotional symptoms are common in attention-deficit/hyperactivity disorder (ADHD) patients and associate with much morbidity, some consider it to be a core feature rather than an associated trait. Others argue that emotional symptoms are too nonspecific for use as diagnostic criteria. This debate has been difficult to resolve due, in part, to the many terms used to describe emotional symptoms in ADHD and to concerns about overlap with mood disorders. METHODS: We sought to clarify the nature of emotional symptoms in ADHD by reviewing conceptual and measurement issues and by examining the evidence base regarding specificity of such symptoms for ADHD. We reviewed the various terms used to define emotional symptoms in ADHD, clarify how these symptoms are demarcated from mood disorders, and assess the possibility that symptoms of emotional impulsivity and deficient emotional self-regulation should be considered as core symptoms. We addressed psychiatric comorbidities, the effects of ADHD treatments on associated emotional dysregulation, and the utility of current rating scales to assess emotional symptoms associated with ADHD. RESULTS: Emotional symptoms are common and persistent in youth and adults with ADHD. Although emotional symptoms are common in other psychiatric disorders, emotional impulsivity (EI), and deficient emotional self-regulation (DESR) may be sufficiently specific for ADHD to function as diagnostic criteria. CONCLUSIONS: Emotional symptoms in ADHD cause clinically significant impairments. Although there is a solid theoretical rationale for considering EI and DESR to be core symptoms of ADHD, there is no consensus about how to define these constructs sin a manner that would be specific to the disorder. An instrument to measure EI and DESR which demarcates them from irritability and other emotional symptoms could improve the accuracy of diagnostic criteria for ADHD.

Recent advances in pharmacological management of attention-deficit/hyperactivity disorder: moving beyond stimulants.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder characterized by impairing inattention and/or hyperactivity and impulsivity in children and adults. Although medications have been available to treat ADHD symptoms for decades, many are stimulant formulations. Stimulants, such as amphetamine and methylphenidate, are available in more than two dozen formulations, but all have similar adverse effects and carry a risk of misuse and dependence. AREAS COVERED: In the United States (US), several nonstimulants are available to treat ADHD. Two, including atomoxetine and viloxazine extended-release (ER), are approved by the Food and Drug Administration for the treatment of ADHD in children and adults. Two others, clonidine ER and guanfacine ER, are only approved for children and adolescents in the US. Several other compounds are under investigation. Drugs in Phase 3 trials include centanafadine, solriamfetol, and L-threonic acid magnesium salt. Efficacy and safety data for nonstimulants is presented. EXPERT OPINION: Although many effective formulations for the treatment of ADHD are available, more than 33% of children and 50% of adults discontinue treatment during the first year. The lack of individual drug response and tolerability are reasons many stop treatment. The development of new nonstimulants may offer hope for patients who need medication alternatives.

A critical review of the dextroamphetamine transdermal system for the treatment of ADHD in adults and pediatric patients.

INTRODUCTION: The dextroamphetamine transdermal system (d-ATS) is a stimulant patch recently approved by the United States (U.S.) Food and Drug Administration for the treatment of attention-deficit/hyperactivity disorder (ADHD). AREAS COVERED: The composition of the d-ATS, pharmacokinetics, and metabolism are presented along with data from dermal trials evaluating the tolerability of patch application at various skin sites. Efficacy and safety data from a laboratory classroom study in children and adolescents including effect sizes are assessed. Pharmacokinetic-pharmacodynamic modeling of variable wear times is also discussed. EXPERT OPINION: Although stimulants are recommended as first-line treatment for ADHD in the U.S. some patients may have difficulty swallowing intact tablets and capsules, or dislike the taste or texture of chewable, oral disintegrating, or liquid formulations. The d-ATS fills an unmet need for those with ADHD who are unable or prefer not to take medication orally. Varying wear time of the d-ATS also gives flexibility in length of stimulant effect which may be useful for patients with changing schedules. However, dermal discomfort must be considered in addition to the usual amphetamine side effects when prescribing the d-ATS. Patient and provider experience will determine how frequent the use of d-ATS becomes.

Costs associated with adverse events during treatment episodes for adult attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) medication is frequently associated with adverse events (AEs), but limited real-world data exist regarding their costs from a payer's perspective. Therefore, this study evaluated the healthcare costs associated with common AEs among adult patients treated for ADHD in the US. METHODS: Eligible adults treated for ADHD were identified from a large US claims database (1 October 2015-30 September 2021). A retrospective cohort study design was used to assess excess healthcare costs and costs directly related to AE-specific claims per-patient-per-month (PPPM) associated with 10 selected AEs during ADHD treatment. To account for all costs associated with the AE, treatment episodes with a given AE were compared to similar treatment episodes without this AE. Entropy balancing was used to create cohorts with similar characteristics. Studied AEs were selected based on their prevalence in clinical trials for common ADHD medications and were identified from ICD-10-CM diagnosis codes recorded in claims. RESULTS: Among the 461,464 patients included (mean age: 34.2 years; 45.5% males), 49.4% had ≥1 AE during their treatment episode. Treatment episodes with AEs were associated with statistically significant AE-specific medical costs (erectile dysfunction: $57; fatigue: $82; dry mouth: $90; diarrhea: $162; insomnia: $147; anxiety: $281; nausea: $299; constipation: $356; urinary hesitation: $491; feeling jittery: $723) and excess healthcare costs PPPM (erectile dysfunction: $120, fatigue: $248, insomnia: $265, anxiety: $380, diarrhea: $441, dry mouth: $485, nausea: $709, constipation: $802, urinary hesitation: $1,105, feeling jittery: $1,160; p < .05). LIMITATIONS: AEs were identified based on recorded diagnosis on medical claims and likely represent more severe AEs. Therefore, costs may not be representative of milder AEs. CONCLUSIONS: This study found that AEs occurring during ADHD treatment episodes are associated with significant healthcare costs. This highlights the potential of treatments with favorable safety profiles to alleviate the burden experienced by patients and the healthcare system.

Assessment of centanafadine in adults with attention-deficit/hyperactivity disorder: A matching-adjusted indirect comparison vs lisdexamfetamine dimesylate, atomoxetine hydrochloride, and viloxazine extended-release.

BACKGROUND: Head-to-head trials comparing centanafadine, an investigational therapy for adults with attention-deficit/hyperactivity disorder (ADHD), with other treatment options are lacking. OBJECTIVE: To compare safety and efficacy outcomes of centanafadine sustained-release vs lisdexamfetamine dimesylate (lisdexamfetamine), atomoxetine hydrochloride (atomoxetine), and viloxazine extended-release (viloxazine ER), respectively, using matching-adjusted indirect comparison (MAIC). METHODS: This MAIC included patient-level data pooled from 2 centanafadine trials (NCT03605680 and NCT03605836) and published aggregate data from comparable trials of 3 comparators-lisdexamfetamine (NCT00334880), atomoxetine (NCT00190736), and viloxazine ER (NCT04016779)-in adult patients with ADHD. Propensity score weighting was used to match characteristics of individual patients from the centanafadine trials to aggregate baseline characteristics from the respective comparator trials. Safety outcomes were rates of adverse events for which information was available in the centanafadine and respective comparator trials. Efficacy outcome was mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) score (ADHD Rating Scale [ADHD-RS] was used as proxy in the comparison with lisdexamfetamine). Anchored indirect comparisons were conducted across matched populations of the centanafadine and respective comparator trials. RESULTS: After matching, baseline characteristics in the centanafadine trials were the same as those in the respective comparator trials. Compared with lisdexamfetamine, centanafadine was associated with a significantly lower risk of lack of appetite (risk difference [RD] in percentage points: 23.42), dry mouth (19.27), insomnia (15.35), anxiety (5.21), nausea (4.90), feeling jittery (3.70), and diarrhea (3.47) (all P < 0.05) but a smaller reduction in the AISRS/ADHD-RS score (6.58-point difference; P < 0.05). Compared with atomoxetine, centanafadine was associated with a significantly lower risk of nausea (RD in percentage points: 18.64), dry mouth (17.44), fatigue (9.21), erectile dysfunction (6.76), lack of appetite (6.71), and urinary hesitation (5.84) (all P < 0.05) and no statistically significant difference in the change in AISRS score. Compared with viloxazine ER, centanafadine was associated with a significantly lower risk of fatigue (RD in percentage points: 11.07), insomnia (10.67), nausea (7.57), and constipation (4.63) (all P < 0.05) and no statistically significant difference in the change in AISRS score. CONCLUSIONS: In an anchored MAIC, centanafadine showed a significantly better short-term safety profile than lisdexamfetamine, atomoxetine, and viloxazine ER; efficacy was lower than with lisdexamfetamine and comparable (ie, nondifferent) with atomoxetine and viloxazine ER. This MAIC provides important insights on the relative safety and efficacy of common treatment options to help inform treatment decisions in adults with ADHD. Safety assessment was limited to rates of adverse events reported in both trials of a given comparison. STUDY REGISTRATION NUMBERS: NCT03605680, NCT03605836, NCT00334880, NCT00190736, and NCT04016779.

Health care resource utilization and costs associated with psychiatric comorbidities in adult patients with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous condition with extensive psychiatric comorbidities. ADHD has been associated with substantial clinical and economic burden; however, little is known about the incremental burden specifically attributable to psychiatric comorbidities of ADHD in adults. OBJECTIVE: To assess the impact of psychiatric comorbidities, specifically anxiety and depression, on health care resource utilization (HRU) and costs in treated adults with ADHD in the United States. METHODS: A retrospective case-cohort study was conducted. Adults with ADHD were identified in the IQVIA PharMetrics Plus database (10/01/2015-09/30/2021). The index date was defined as the date of initiation of a randomly selected ADHD treatment. The baseline period was defined as the 6 months prior to the index date, and the study period as the 12 months following the index date. Patients with at least 1 diagnosis for anxiety and/or depression during both the baseline and study periods were classified in the ADHD+anxiety/depression cohort, whereas those without diagnoses for anxiety or depression at any time were classified in the ADHD-only cohort. Entropy balancing was used to create reweighted cohorts with similar baseline characteristics. All-cause HRU and health care costs were assessed during the study period and compared between cohorts using regression analyses. Cost analyses were also conducted in subgroups stratified by comorbid conditions. RESULTS: After reweighting, patients in the ADHD-only cohort (N = 276,906) and ADHD+anxiety/depression cohort (N = 217,944) had similar characteristics (mean age 34.1 years; 54.8% male). All-cause HRU was higher in the ADHD+anxiety/depression cohort than the ADHD-only cohort (incidence rate ratios for inpatient admissions: 4.5, emergency department visits: 1.8, outpatient visits: 2.0, and psychotherapy visits: 6.4; all P < 0.01). All-cause health care costs were more than 2 times higher in the ADHD+anxiety/depression cohort than the ADHD-only cohort (mean per-patient per-year [PPPY] costs in ADHD-only vs ADHD+anxiety/depression cohort: $5,335 vs $11,315; P < 0.01). Among the ADHD+anxiety/depression cohort, average all-cause health care costs were $9,233, $10,651, and $15,610 PPPY among subgroup of patients with ADHD and only anxiety, only depression, and both anxiety and depression, respectively. CONCLUSIONS: Comorbid anxiety and depression is associated with additional HRU and costs burden in patients with ADHD. Comanagement of these conditions is important and has the potential to alleviate the burden experienced by patients and the health care system.

Assessment of centanafadine in adults with ADHD: a matching adjusted indirect comparison versus methylphenidate hydrochloride extended release (Concerta).

OBJECTIVE: To compare safety and efficacy of centanafadine versus methylphenidate hydrochloride extended release (ER; Concerta) in adults with ADHD. METHODS: Without head-to-head trials, anchored matching-adjusted indirect comparisons (MAIC) of adverse event rates reported across trials and mean change from baseline in Adult ADHD Investigator Symptom Rating Scale (AISRS) score between centanafadine and methylphenidate hydrochloride ER were conducted. Pooled patient-level data from two centanafadine trials (NCT03605680/NCT03605836) and aggregate data from one published methylphenidate hydrochloride ER trial (NCT00937040) were used. Characteristics of individual patients from the centanafadine trials were matched to aggregate baseline characteristics from the methylphenidate hydrochloride ER trial using propensity score weighting. A sensitivity analysis assessed the robustness of the results to the capping of extreme weights (i.e. >99th percentile). RESULTS: Compared with methylphenidate hydrochloride ER, centanafadine was associated with significantly lower risk of dry mouth (risk difference [RD] in percentage points: -11.95), initial insomnia (-11.10), decreased appetite (-8.05), anxiety (-5.39), palpitations (-5.25), and feeling jittery (-4.73) though a significantly smaller reduction in AISRS score (4.16-point). In the sensitivity analysis, the safety results were consistent with the primary analysis but there was no significant difference in efficacy between centanafadine and methylphenidate hydrochloride ER. CONCLUSION: In this MAIC, centanafadine had better safety and possibly lower efficacy than methylphenidate hydrochloride ER. While safety results were robust across analyses, there was no efficacy difference between centanafadine and methylphenidate hydrochloride ER in the sensitivity analysis. Considering its favorable safety profile, centanafadine may be preferred among patients for whom treatment-related adverse events are a concern.

Healthcare resource utilization and costs associated with psychiatric comorbidities in pediatric patients with attention-deficit/hyperactivity disorder: a claims-based case-cohort study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has been shown to pose considerable clinical and economic burden; however, research quantifying the excess burden attributable to common psychiatric comorbidities of ADHD among pediatric patients is scarce. This study assessed the impact of anxiety and depression on healthcare resource utilization (HRU) and healthcare costs in pediatric patients with ADHD in the United States. METHODS: Patients with ADHD aged 6-17 years were identified in the IQVIA PharMetrics Plus database (10/01/2015-09/30/2021). The index date was the date of initiation of a randomly selected ADHD treatment. Patients with ≥ 1 diagnosis for anxiety and/or depression during both the baseline (6 months pre-index) and study period (12 months post-index) were classified in the ADHD+anxiety/depression cohort; those without diagnoses for anxiety nor depression during both periods were classified in the ADHD-only cohort. Entropy balancing was used to create reweighted cohorts. All-cause HRU and healthcare costs during the study period were compared using regression analyses. Cost analyses were also performed in subgroups by comorbid conditions. RESULTS: The reweighted ADHD-only cohort (N = 204,723) and ADHD+anxiety/depression cohort (N = 66,231) had similar characteristics (mean age: 11.9 years; 72.8% male; 56.2% had combined inattentive and hyperactive ADHD type). The ADHD+anxiety/depression cohort had higher HRU than the ADHD-only cohort (incidence rate ratios for inpatient admissions: 10.3; emergency room visits: 1.6; outpatient visits: 2.3; specialist visits: 5.3; and psychotherapy visits: 6.1; all p < 0.001). The higher HRU translated to greater all-cause healthcare costs; the mean per-patient-per-year (PPPY) costs in the ADHD-only cohort vs. ADHD+anxiety/depression cohort was $3,988 vs. $8,682 (p < 0.001). All-cause healthcare costs were highest when both comorbidities were present; among patients with ADHD who had only anxiety, only depression, and both anxiety and depression, the mean all-cause healthcare costs were $7,309, $9,901, and $13,785 PPPY, respectively (all p < 0.001). CONCLUSIONS: Comorbid anxiety and depression was associated with significantly increased risk of HRU and higher healthcare costs among pediatric patients with ADHD; the presence of both comorbid conditions resulted in 3.5 times higher costs relative to ADHD alone. These findings underscore the need to co-manage ADHD and psychiatric comorbidities to help mitigate the substantial burden borne by patients and the healthcare system.

Two single arm trials of AKL-T01, a digital therapeutic for adolescents and adults with ADHD.

Inattention symptoms represent a key driver of functional impairment in ADHD and often persist into adolescence and adulthood, underscoring a need for novel treatments targeting attentional control. We evaluated AKL-T01-a digital therapeutic that is FDA-cleared for children 8-12 y with ADHD-in adolescents and adults with ADHD in two independent single-arm trials: STARS-ADHD-Adolescent, a 4-week trial in adolescents 13-17 y (n = 162 enrolled), and STARS-ADHD-Adult, a 6-week trial in adults 18 and older (n = 221 enrolled). AKL-T01 was linked with improvements on the Test of Variables of Attention (TOVA®) Attention Comparison Score (ACS) of 2.6 (95% CI: 2.02, 3.26; p < 0.0001) in adolescents and 6.5 in adults (95% CI: 5.35, 7.57; p < 0.0001), along with improvements in secondary endpoints. 15 participants reported adverse device effects, all mild or moderate. Though limited by a single-arm design, results provide preliminary support for the safety and efficacy of AKL-T01 for adolescents and adults with ADHD.

From Consensus Statement to Pills to Pixels: New Innovations in Attention-Deficit/Hyperactivity Disorder Care.

Objectives: This review aims to present recent innovations and advancements in attention-deficit/hyperactivity disorder (ADHD) care, encompassing international consensus statement, new medication formulations, digital therapeutics, and neurostimulation devices. Methods: A comprehensive literature search of relevant articles published in the past five years was conducted, emphasizing the evidence base, efficacy, safety, and practical implications of these advancements. Results: The World Federation of ADHD Consensus Statement offers an updated diagnostic and treatment framework rooted in global scientific evidence. There are several newer ADHD medication formulations, including a nonstimulant (Viloxazine extended release) and the first transdermal amphetamine patch approved to treat ADHD. These options offer some unique benefits to personalize treatment based on symptom profile, lifestyle, preferences, and response. Digital tools offer additional means to restructure environments for individuals with ADHD, reducing impairment and reliance on others. In addition, digital therapeutics enhance access, affordability, personalization, and feasibility of ADHD care, complementing or augmenting existing interventions. Trigeminal nerve stimulation emerges as a well-tolerated nonpharmacological, device-based treatment for pediatric ADHD, with initial trials indicating effect sizes comparable to nonstimulant medications. Conclusions: These innovations in ADHD care represent clinically significant new treatment options and opportunities for personalized care. Health care professionals should integrate these developments into clinical practice, mindful of individual patient and family needs and preferences. Future research should assess long-term outcomes, cost-effectiveness, and acceptability of these innovations.

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

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

A Post-Hoc Analysis of Emotional Lability With Delayed-Release/Extended-Release Methylphenidate in Children Aged 6 to 12 Years of Age Participating in Two Phase 3 Clinical Trials.

OBJECTIVE: DR/ER-MPH (formerly HLD200) is an evening-dosed delayed-release and extended-release methylphenidate approved for the treatment of ADHD in patients ≥6 years. Post hoc analyses of two pivotal Phase 3 trials: HLD200-107 (NCT02493777) and HLD200-108 (NCT02520388) evaluated emotional lability (EL) with DR/ER-MPH treatment. METHODS: Differences in Conners Global Index-Parent (CGI-P) EL subscale scores and age- and gender-adjusted T-scores over an open-label titration phase (HLD200-107) and between treatment and placebo groups at endpoint (HLD200-108) were evaluated. RESULTS: In HLD200-107 (N = 117) mean CGI-P EL subscale scores improved from 5.3 to 1.3 (p < .0001) after 6 weeks; in HLD200-108 significant improvements were observed in the treatment group (n = 81) versus placebo (n = 80; 3.11 vs. 4.08; p = .0053). T-scores showed an improvement with DR/ER-MPH treatment in both trials. Few emotional adverse events (AEs) were reported. CONCLUSION: DR/ER-MPH treatment resulted in statistically significant improvements in EL to the level of non-ADHD peers as contextualized by T-scores.

An updated safety review of the current drugs for managing ADHD in children.

INTRODUCTION: Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent condition that causes persistent problems with attention and/or hyperactivity-impulsivity and often results in significant impairment when left untreated. Medications for this disorder continue to evolve and provide new treatment options. Ongoing review of related medication safety and tolerability remains an important task for prescribers. AREAS COVERED: This manuscript provides an updated safety review of medications used to treat ADHD in children and adolescents. PubMed and OneSearch online databases were utilized to search for literature relevant to the topic of ADHD medications and safety. Clinical trials of medications used to treat ADHD, systematic reviews and meta-analyses, and articles covering specific safety issues (adverse or unfavorable events) such as cardiovascular effects, seizures, impact on growth, depression, suicidal ideation, substance use disorders, psychosis, and tics are described. EXPERT OPINION: Available pharmacologic treatments for ADHD have favorable efficacy, safety and tolerability and allow many patients to achieve significant improvement of their symptoms. Despite the availability of multiple stimulant and non-stimulant formulations, some individuals with ADHD may not tolerate available medications or attain satisfactory improvement. To satisfy unmet clinical needs, ADHD pharmaceutical research with stimulant and nonstimulant formulations targeting dopamine, norepinephrine, and novel receptors is ongoing.

Viloxazine extended-release capsules for the treatment of attention-deficit/ hyperactivity disorder in adult patients.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder with symptoms that may persist in up to 90% of adults diagnosed during childhood and continue to cause significant impairment throughout the lifespan. In the United States (US), amphetamine and methylphenidate formulations have been available to treat ADHD for several decades. Only one nonstimulant, atomoxetine, was available for the treatment of ADHD in adults until recently. In April 2022, a second nonstimulant, viloxazine extended-release (VLX-ER), became available in the US for the treatment of adult ADHD. Efficacy was previously established in placebo-controlled trials in children and adolescents. AREAS COVERED: VLX-ER is a norepinephrine reuptake inhibitor with serotonin activity. The efficacy in adults, adverse event profile, pharmacokinetics, drug-drug interactions, and metabolism of VLX-ER are reviewed. EXPERT OPINION: Despite the availability of effective pharmacological treatments for ADHD, many patients discontinue treatment in less than 1 year. Stimulants are effective in more than 80% of patients; however, some may have difficulty tolerating them. Although there were no head-to-head studies, the effect size of VLX-ER in an adult efficacy trial was lower than has been shown for stimulants. Nevertheless, the approval of VLX-ER adds another effective ADHD treatment option for adults.

Early Morning ADHD Symptoms and Functional Impairment: Impact on Patients and Caregivers, and Pharmacological Approaches to Management.

Attention-deficit/hyperactivity disorder (ADHD) is a common and impairing mental disorder. Individuals with ADHD typically experience symptoms from awakening throughout the entire day, contributing to impaired function at home, at school, and in the workplace. Treatment is available to address the symptoms of ADHD; however, the extent to which treatments afford improved function remains less clear. Impaired function in children and adolescents, particularly in the early morning where multiple tasks must be completed, from getting out of bed, and having breakfast to leaving for school on time, is common even among stimulant-treated children, and can increase stress upon caregivers and family members. Herein, we present a narrative review on early morning functioning impairment in children and adolescents with ADHD, its impact on caregivers, the rating scales available for clinicians to identify the degree of early morning functioning impairment, and the efficacy of currently available treatments in providing functional improvements to patients with ADHD during the early morning, identifying that only treatments that are available upon awakening have been shown to statistically separate from placebo for early morning functioning improvement.

Analysis of Growth Velocity in Children with Attention-Deficit/Hyperactivity Disorder Treated for up to 12 Months with Serdexmethylphenidate/Dexmethylphenidate.

Objective: Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A 12-month, open-label safety study with SDX/d-MPH in children with ADHD showed that SDX/d-MPH was well tolerated and comparable with other methylphenidate products. In this post hoc analysis of the 12-month study, the objective was to characterize the effect of SDX/d-MPH on growth in children with ADHD over 12 months. Methods: This was a post hoc analysis of a dose-optimized, open-label, phase 3 safety study of SDX/d-MPH in children aged 6-12 years with ADHD (NCT03460652). Weight and height Z-score analyses were conducted. Z-score change from baseline was calculated based on the baseline values for the subjects remaining in the study at the observation time point. Results: Subjects (N = 238) from the treatment-phase safety population included all enrolled subjects who received ≥1 dose of study drug and had ≥1 postdose safety assessment. During treatment, the mean weight and height Z-scores decreased over time from their respective baselines. At the 12-month time point, mean (standard deviation [SD]) Z-score changes from baseline for weight and height for the subjects remaining in the study were -0.20 (0.50) and -0.21 (0.39), respectively; however, these mean changes in Z-scores were not clinically significant (change <0.5 SD). Long-term treatment with SDX/d-MPH was associated with modest reductions in expected weight and lower-than-expected increases in height: effects that plateaued or diminished later in treatment. Conclusion: The overall effects of SDX/d-MPH on growth velocity (the change in weight and height from one time point to the next) were minimal, and the range of changes was not considered clinically significant. ClinicalTrials.gov identifier: NCT03460652.