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.

ADHD and Exposure to Maltreatment in Children and Youth: a Systematic Review of the Past 10 Years.

PURPOSE OF THE REVIEW: The purpose of the current paper was to review and summarize the literature on ADHD and maltreatment over the past 10 years. RECENT FINDINGS: The majority of research on ADHD and exposure to maltreatment focuses on the high rates of comorbidity, including international studies from Asia, South America, North America, and Europe. Longitudinal studies showed that early exposure to maltreatment is a risk factor for ADHD symptoms later in development; however, this finding was not consistent. There were some preliminary studies on the neurological and genetic mechanisms underlying the link between ADHD and exposure to maltreatment. Finally, ADHD and exposure to maltreatment were found to have an additive effect on clinically salient outcomes (e.g., aggression, suicide attempts). Results from the review have direct clinical and future implications, including the need to understand the effect of comorbid ADHD and exposure to maltreatment in treatment studies.

Descriptive and psychometric properties of the Persian version of the Weiss functional impairment rating scale: parent report form in Iranian children.

BACKGROUND: This study evaluates the descriptive and psychometric properties of the Persian version of the Weiss Functional Impairment Rating Scale-Parent Report Form (WFIRS-P) in a normal sample of Iranian children. METHOD: Parents of 282 students (grades 1-6) completed the WFIRS-P. Means and standard deviations were computed for the total scale, each domain, and each item of the WFIRS-P. Internal consistency, interdomain correlations, and test-retest reliability were used to assess the reliability of the scale. RESULTS: Among the WFIRS-P domains, life skills had the highest rated impairment (M = 0.50, SD = 0.37) and risky activities had the lowest. Internal consistency (α = .88) and test-retest reliability (r = 0.77) were strong for the WFIRS-P total scale. The correlation between the WFIRS-P domains and the total scale ranged from 0.52 to 0.81. CONCLUSIONS: Results suggest that the Persian version of the WFIRS-P is a useful and psychometrically reliable measure for assessing functional skills in children.

Parent and Child ADHD Symptoms in Relation to Parental Attitudes and Parenting: Testing the Similarity-Fit Hypothesis.

OBJECTIVE: We tested the similarity-fit hypothesis that predicts more positive parenting when both parent and child have high levels of ADHD symptoms compared to when only one does. METHOD: Mothers and fathers of 156, 5 to 13 year old sons participated (110 boys with ADHD, 46 without). Parent inattentive and hyperactive-impulsive symptoms were examined, in interaction with child ADHD, as predictors of parental tolerance, empathy, encouragement of child autonomy, and positive parenting. RESULTS: Several interactions of parent ADHD symptoms and child ADHD were detected which suggested that for parents with low levels of symptoms, the presence of child ADHD was associated with less positive parenting attitudes and behavior, but this negative relation between positive parenting and child ADHD was dampened among parents with more ADHD symptoms. CONCLUSIONS: Considered alongside the well documented parenting difficulties associated with parental ADHD, our findings suggest that parental ADHD symptoms also may help to mitigate some of the challenges facing families of children with ADHD.

Estimating minimal important differences for several scales assessing function and quality of life in patients with attention-deficit/hyperactivity disorder.

OBJECTIVE: Defining minimal important difference (MID) is critical to interpreting patient-reported outcomes data and treatment efficacy in clinical trials. This study estimates the MID for the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) and the Child Health and Illness Profile-Parent Report (CHIP-CE-PRF76) among parents of young people with attention-deficit/hyperactivity disorder (ADHD) in the UK. METHODS: Parents of children (6-12 years; n=100) and adolescents (13-17 years; n=117) with ADHD completed a socio-demographic form, the CHIP-CE-PRF76, the WFIRS-P, and the Pediatric Quality of Life scale at baseline and 4 weeks later. At follow-up, a subset of parents completed anchor questions measuring change in the child/adolescent from baseline. MIDs were estimated using anchor-based and distribution-based methods, and separately for children and adolescents. RESULTS: The MID estimates for overall change in the WFIRS-P total score ranged from 11.31 (standard error of measurement) to 13.47 (anchor) for the total sample. The range of MID estimates for the CHIP-CE-PRF76 varied by domain: 6.80-7.41 (satisfaction), 6.18-7.34 (comfort), 5.60-6.72 (resilience), 6.06-7.57 (risk avoidance), and 4.00-5.63 (achievement) for the total sample. Overall, MID estimates for WFIRS-P MID and CHIP-CE-PRF76 were slightly higher for adolescents than for children. CONCLUSION: This study estimated MIDs for these instruments using several methods. The observed convergence of the MID estimates increases confidence in their reliability and could assist clinicians and decision makers in deriving meaningful interpretations of observed changes in the WFIRS-P and CHIP-CE in clinical trials and practice.

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.

Sleep, executive functions, and functional impairment in children with specific learning disorder: An investigation of the mediating pathways.

OBJECTIVE: Sleep problems and executive dysfunction are associated with functional impairment in children with neurodevelopmental disorders. In this study, we aimed to investigate these aspects in children with Specific Learning Disorders (SLD) and SLD with comorbid Attention-Deficit Hyperactivity Disorder (ADHD), while also evaluating differences with typically developing (TD) children. Our study hypothesizes that children with SLD, especially those with comorbid ADHD, face greater sleep disturbances and executive function challenges compared to TD peers. We also propose that sleep disturbances aggravate functional impairment and that executive functions mediate this relationship. METHOD: The data obtained from psychiatric evaluations, semi-structured interviews and questionnaires filled out by parents were analyzed. RESULTS: SLD + ADHD group had worse scores in all scales, followed by SLD and TD groups. Mediator analysis demonstrated that executive functions had a mediator role in the relationship between sleep problems and functional impairment. CONCLUSION: Our findings suggest that children with SLD experience more significant difficulties in daily living than their typically developing peers and having ADHD comorbidity, poor executive functions, and additional sleep problems can further exacerbate impairment. Notably, our mediation analysis suggests that executive functions mediate the relationship between sleep disturbances and the severity of functional impairments.

Editorial: Longitudinal Associations Between Sleep and ADHD Symptoms: ADHD Is a 24-Hour Disorder.

There is a robust literature of predominantly cross-sectional studies demonstrating an association between attention-deficit/hyperactivity disorder (ADHD) and sleep quality in childhood and adolescence, measured by subjective as well as objective measures, dimensional and categorical variables, and controlling for a wide range of confounders such as other disorders.1 Moreover, ADHD symptoms and sleep problems are independently associated with adverse functional outcome and quality of life.2 As a result, these are viewed as common and mutually exacerbating conditions, likely mediated by common neuropathways.3-5.

Receiver operating characteristic curve analysis of the Weiss Functional Impairment Rating Scale-Parent Report for screening children with ADHD: Looking beyond symptoms in ADHD diagnosis.

AIM: The current study aimed at examining the ability of the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) to discriminate between children with ADHD and controls in functional impairment and identifying optimal cutoff scores for the WFIRS-P subscales and total scale. METHODS: Parents of 51 children with ADHD (90.2% male; grades 1-6) and 51 gender/grade matched controls (90.2% male; grades 1-6) completed the WFIRS-P. Receiver operating characteristic (ROC) curve analysis was used to examine the ability of the WFIRS-P to differentiate children with ADHD from controls and to determine optimal cutoff scores of the WFIRS-P. RESULTS: Area under the curve (AUC) was 0.98 for the WFIRS-P total scale, indicating excellent ability to differentiate children with ADHD from controls. The score of 0.45 with 0.88 for sensitivity and 0.96 for specificity was determined as the optimal cutoff score for the total scale of the WFIRS-P. AUC was 0.73 to 0.97 for the WFIRS-P subscales, suggesting good to excellent ability for discriminating between children with ADHD and controls. Among the subscales, the family subscale score of 0.42 with 0.92 for sensitivity and 0.96 for specificity showed the highest discriminating power. The self-concept and life skills subscales had low sensitivity, suggesting Iranian mothers do not identify problems with self-concept or difficulty with life skills as particularly problematic in ADHD. CONCLUSIONS: The WFIRS-P is a sensitive and specific measure of the functional impairment associated with ADHD in Iranian children. Our sample was predominantly male, limiting the generalizability of results to females.

Catatonia with Psychosis in an 8-Year-Old Child: A Case Report and a Literature Review.

Objective: We present a narrative review of pediatric catatonia and a case report illustrating the complexity of management of psychosis in a child with catatonia. Method: The literature search used the text terms pediatric, catatonia, and antipsychotics and the search engines PubMed and EBSCO. All references from peer-reviewed journals were reviewed for treatment strategies specific to management in children who are also psychotic. Findings. This 8-year-old girl presented with psychotic symptoms which were initially treated with antipsychotics and evolved into life-threatening catatonia that was eventually stabilized with a total daily dose of 46 mg of lorazepam. Lower doses led to recurrence. Once catatonia improved, she tolerated combined benzodiazepine and antipsychotic treatment. Long-term maintenance over 5 years required maintenance treatment with both benzodiazepines and antipsychotics to prevent relapse. Conclusions: The extraordinary doses of benzodiazepines found to be optimal for management of catatonia in this child led to improved alertness and orientation, without evident sedation. Catatonia did not recur with later management of psychosis using neuroleptics when added to lorazepam. The current literature on pediatric catatonia does not provide guidance on dose maintenance or when and if to rechallenge with antipsychotics.

The Association between ADHD and the Severity of COVID-19 Infection.

OBJECTIVE: Patients with ADHD are at increased risk of acquiring COVID-19. The present study assessed the possibility that ADHD also increases the risk of severe COVID-19 infection. METHOD: We assessed 1,870 COVID-19 positive patients, aged 5 to 60 years, registered in the database of Leumit Health Services (LHS, Israel), February to -June 2020, of whom 231 with ADHD. Logistic regression analysis models evaluated the association between ADHD and the dependent variables of being symptomatic/referral to hospitalization, controlling for demographic and medical variables. RESULTS: Age, male sex, and BMI were confirmed to be significant risk factors for increased COVID-19 severity. ADHD was found to be associated with increased severity of COVID-19 symptoms (OR = 1.81, 95% CI [1.29, 2.52], p < .05) and referral to hospitalization (OR =1.93, 95% CI [1.06, 3.51], p = .03). CONCLUSION: ADHD is associated with poorer outcomes in COVID-19 infection.

Study of Functional Impairment in Students of Elementary and Secondary Public Schools in Iran.

OBJECTIVE: The current study aimed to investigate the frequency of impairment in different functional domains of life and the relationship between sex and age and functional impairment in school-based samples of Iranian children and adolescents. METHOD: A sample of 270 children (ages 6-11) enrolled in two public elementary schools and a sample of 386 adolescents (ages 12-17) enrolled in four public secondary schools were selected by multistage sampling. The Persian version of the parent report form and self-report form of the Weiss Functional Impairment Rating Scale (WFIRS-P and WFIRS-S) were used for evaluating functional impairment in children and adolescents, respectively. Two-way analyses of variance (two-way ANOVAs) were conducted to explore the main effects and the interaction effect of sex and age on functional impairment. RESULTS: 11.9% of children and 29.5% of adolescents showed impairment in at least two functional domains of life. The most frequent impaired domain was life skills (22.6% of children and 30.3% of adolescents). While no significant sex and age effect was found during childhood, male adolescents showed more impairment in externalizing domains and female adolescents showed more internalizing difficulties. In addition, older adolescents showed more functional impairment relative to younger adolescents. CONCLUSIONS: Detailed knowledge of the relationship between sex and age and functional impairment could be a starting point to target the major psychosocial elements of these challenges.

OBJECTIF: La présente étude visait à investiguer la fréquence de la déficience dans différents domaines fonctionnels de la vie et la relation entre le sexe et l'âge et la déficience fonctionnelle dans des échantillons recrutés en milieu scolaire d'enfants et adolescents iraniens. MÉTHODE: Un échantillon de 270 enfants (de 6 à 11 ans) inscrits dans deux écoles primaires publiques et un échantillon de 386 adolescents (de 12 à 17 ans) inscrits dans 4 écoles secondaires publiques ont été choisis par un échantillonnage à plusieurs degrés. La version persane du formulaire du rapport des parents et du formulaire d'auto-déclaration de la Weiss Functional Impairment Rating Scale (WFIRS-P et WFIRS-S) a servi à évaluer la déficience fonctionnelle chez les enfants et les adolescents, respectivement. L'analyse de la variance à deux facteurs (ANOVA à deux facteurs) a été menée pour explorer les principaux effets et l'effet d'interaction du sexe et de l'âge sur la déficience fonctionnelle. RÉSULTATS: 11,9 % des enfants et 29,5 % des adolescents révélaient une déficience dans au moins deux domaines fonctionnels de la vie. Le domaine le plus fréquemment déficient était celui des compétences essentielles (22,6 % des enfants et 30,3 % des adolescents). Bien qu'aucun effet significatif du sexe et de l'âge n'ait été constaté durant l'enfance, les adolescents de sexe masculin affichaient plus de déficience dans les domaines externalisants et les adolescentes de sexe féminin montraient plus de difficultés d'internalisation. En outre, les adolescents plus âgés affichaient plus de déficience fonctionnelle relativement aux adolescents plus jeunes. CONCLUSIONS: Une connaissance détaillée de la relation entre le sexe et l'âge et la déficience fonctionnelle pourrait constituer un point de départ pour cibler les éléments psychosociaux majeurs de ces difficultés.

Efficacy and Safety of PRC-063, Extended-Release Multilayer Methylphenidate in Adults with ADHD Including 6-Month Open-Label Extension.

Objective: To evaluate the efficacy and safety of a 16-hr multilayer-release methylphenidate (PRC-063) in a community-based adult ADHD population. Method: In a double-blind study, 375 participants were randomized to one of four fixed doses of PRC-063 or placebo. The primary outcome was the ADHD-Rating Scale-5 (RS). The first 50% of double-blind completers were invited to participate in a 6-month dose-optimized open-label study to assess response and safety. Results: In total, 333 participants completed the double-blind trial; 184 entered the open-label study. PRC-063 produced greater symptom reduction in ADHD-RS-5 total score from baseline compared with placebo in the double-blind study (least-square [LS] mean = -4.7 [-7.7, -1.6], p = .003). The most frequent adverse events were headache, insomnia, and decreased appetite. No significant sleep quality impact was observed (p = .123). Significant improvements in ADHD-RS-5 scores from baseline continued through the open-label study (p < .0001), coincident with dose optimization. Conclusion: PRC-063 was well tolerated and significantly improved ADHD symptomatology in adults.

Efficacy and Safety of a Long-Acting Multilayer-Release Methylphenidate Formulation (PRC-063) in the Treatment of Adolescent Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Clinical Trial with a 6-Month Open-Label Extension.

Objectives: To study the safety and efficacy of the long-acting methylphenidate formulation PRC-063 in adolescents with attention-deficit/hyperactivity disorder (ADHD). Methods: Adolescents 12 to ≤17 years who met Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for ADHD and had a baseline ADHD Rating Scale DSM-5 (ADHD-5-RS) score ≥24 participated in a randomized, double-blind, placebo-controlled, fixed-dose, parallel-group study. Participants were randomized 1:1:1:1:1 to receive placebo or one of four doses of PRC-063 once daily for 4 weeks. The primary endpoint was change from baseline in least-squares mean clinician-rated ADHD-5-RS total score for PRC-063 (all doses combined) versus placebo. Other efficacy assessments included Conners third Edition: Self-Report (C3SR) and Clinical Global Impression-Improvement (CGI-I). A subset of double-blind study participants entered a subsequent open-label, dose-optimized study. Safety outcomes in both studies included treatment-emergent adverse events (TEAEs). Results: Three hundred fifty-four participants were included in the primary analysis. The least-squares mean change from baseline in ADHD-5-RS total score was -15.17 for PRC-063 versus -10.98 for placebo (least-squares mean difference -4.2, p = 0.0067). For individual PRC-063 doses, improvements in ADHD-5-RS total score versus placebo were significant for 45 mg (p = 0.0155) and 70 mg (p = 0.0401), but not for 25 or 85 mg. A significant improvement for PRC-063 versus placebo was recorded for C3SR Inattention (p = 0.0168), but not for the other C3SR subscales. About 52.7% of participants randomized to PRC-063 were responders based on CGI-I versus 32.4% of those randomized to placebo (p = 0.0004). Further improvements in ADHD symptoms based on ADHD-5-RS were observed from 1 month through 6 months of open-label treatment (p < 0.0001). There were two serious adverse events (both during the open-label study), one of which (aggressive behavior) was assessed as related to study drug. The only TEAEs that occurred in >10% of participants during double-blind treatment were decreased appetite (20.1%) and headache (15.0%). Most TEAEs were of mild or moderate severity. Conclusion: PRC-063 significantly improved ADHD symptomatology in adolescents. It was generally well tolerated, with an AE profile consistent with other long-acting stimulants. NCT02139111 and NCT02168127.

Attention-deficit/hyperactivity disorder and the explore/exploit trade-off.

The ability to maximize rewards and minimize the costs of obtaining them is vital to making advantageous explore/exploit decisions. Exploratory decisions are theorized to be greater among individuals with attention-deficit/hyperactivity disorder (ADHD), potentially due to deficient catecholamine transmission. Here, we examined the effects of ADHD status and methylphenidate, a common ADHD medication, on explore/exploit decisions using a 6-armed bandit task. We hypothesized that ADHD participants would make more exploratory decisions than controls, and that MPH would reduce group differences. On separate study days, adults with (n = 26) and without (n = 23) ADHD completed the bandit task at baseline, and after methylphenidate or placebo in counter-balanced order. Explore/exploit decisions were modeled using reinforcement learning algorithms. ADHD participants made more exploratory decisions (i.e., chose options without the highest expected reward value) and earned fewer points than controls in all three study days, and methylphenidate did not affect these outcomes. Baseline exploratory choices were positively associated with hyperactive ADHD symptoms across all participants. These results support several theoretical models of increased exploratory choices in ADHD and suggest the unexplained variance in ADHD decisions may be due to less value tracking. The inability to suppress actions with little to no reward value may be a key feature of hyperactive ADHD symptoms.

The Functional Impact of Sleep Disorders in Children With ADHD.

Objective: Children with ADHD display higher rates of sleep problems, and both sleep disorders and ADHD have been shown to affect functioning in childhood. The current study examines the frequency and relationship between sleep problems and ADHD, and their impact on quality of life (QoL) and functional impairment. Method: Parents of 192 children with ADHD (M = 10.23 years) completed measures regarding their child's ADHD symptoms (Swanson, Nolan and Pelham [SNAP]), sleep disorders (Pediatric Sleep Questionnaire [PSQ]), QoL (Child Health Illness Profile [CHIP-PE]), and functioning (Weiss Functional Impairment Rating Scale-Parent Report [WFIRS-P]). Results: Common sleep complaints in participants were insomnia, excessive daytime sleepiness (EDS), and variability in sleep schedule. Regression analysis indicated that sleep problems and ADHD symptoms independently predicted lower levels of QoL (ΔR2 = .12, p < .001) and social functioning (ΔR2 = .12, p < .001). Conclusion: The results suggest that ADHD may coexist with somnolence and that both conditions have a significant impact on a child's functioning and QoL.

Psychometric Properties of the Persian Version of the Weiss Functional Impairment Rating Scale-Self-Report Form in Iranian Adolescents.

OBJECTIVE: The Weiss Functional Impairment Rating Scale-Self-Report Form (WFIRS-S) was developed as a measure of functional impairment in adolescents and adults with ADHD. This study reports the psychometric properties of the Persian version of the WFIRS-S in a sample of normal Iranian adolescents. METHOD: Internal consistency and factor structure of the WFIRS-S were tested on a sample of 386 students (Grades 7-12). The test-retest reliability and the convergent validity of the WFIRS-S were evaluated by using two different subsamples including 50 and 100 students, respectively. RESULTS: The Cronbach's alpha values were between .72 and .94 for the WFIRS-S subdomains and total scale. The test-retest reliability was .80 for the total scale. The WFIRS-S subdomains had moderate to high significant correlations with the Pediatric Quality of Life total scale. CONCLUSION: The Persian version of the WFIRS-S has acceptable psychometric properties and could be used as a functional impairment assessment for adolescents.

Symptom Profiles Specific to Trauma in a Child Inpatient Unit.

Adverse childhood experiences (ACE) score showing 4 or more types of trauma have been shown to be a strong predictor of deleterious outcomes.1 We report here on the relationship between ACE or number of trauma types, and symptom profile as measured by the Child Behavior Checklist (CBCL) of children on an inpatient unit. Previous work has been limited to samples preselected for trauma, thus limiting the ability to identify whether the clinical presentation of trauma has unique attributes when compared to a clinical sample of comparable severity.

Methylphenidate increases willingness to perform effort in adults with ADHD.

BACKGROUND: A reduced willingness to perform effort based on the magnitude and probability of potential rewards has been associated with diminished dopamine function and may be relevant to attention-deficit/hyperactivity disorder (ADHD). Here, we investigated the influence of ADHD status and methylphenidate on effort-based decisions. We hypothesized that ADHD participants would make fewer high-effort selections than non-ADHD subjects, and that methylphenidate would increase the number of high-effort selections. Furthermore, we hypothesized there would be associations among ADHD severity and methylphenidate-related changes in effort-based and attentional performance across all participants. METHODS AND PARTICIPANTS: ADHD (n = 23) and non-ADHD (n = 23) adults completed the Effort Expenditure for Rewards Task in which participants select between low-effort and high-effort options to receive monetary rewards at varying levels of reward magnitude and probability. A test of attentional performance was also completed. RESULTS: Overall, participants made more high-effort selections as potential reward magnitude and probability increased. ADHD participants did not make fewer high-effort selections than non-ADHD participants, but ADHD participants showed greater methylphenidate-related increases in high-effort selections. ADHD participants had worse attentional performance than non-ADHD participants. ADHD severity was associated with methylphenidate-related changes in high-effort selections, but not changes in attentional performance. CONCLUSIONS: These results indicate that methylphenidate increases the willingness to perform effort in individuals with ADHD, possibly due to disorder-related motivational deficits. This provides support for theories of insufficient effort allocation among individuals with ADHD. TRIAL REGISTRATION: Clinicaltrials.gov Identifier, NCT02630017.

Atomoxetine treatment of adults with ADHD and comorbid alcohol use disorders.

OBJECTIVE: Adults with attention-deficit/hyperactivity disorder (ADHD) have higher rates of alcohol and drug use disorders than adults without ADHD. The study aim was to determine if atomoxetine was superior to placebo in improving ADHD and alcohol use in recently abstinent adults with ADHD and comorbid alcohol use disorder. METHODS: Adults with DSM-IV diagnoses of ADHD and alcohol abuse and/or dependence were abstinent from alcohol at least 4 days (maximum 30 days) before study randomization. Participants received atomoxetine (25-100mg daily) or placebo for 12 weeks. ADHD symptoms were assessed using ADHD Investigator Symptom Rating Scale (AISRS) total score. Time-to-relapse to heavy alcohol use was analyzed using a 2-sided log-rank test based on Kaplan-Meier estimates and cumulative heavy drinking events over time were evaluated post hoc with recurrent-event analysis. RESULTS: Subjects received atomoxetine (n=72) or placebo (n=75) and 80 subjects completed the 12-week double-blind period (n=32 and 48, respectively). ADHD symptoms were significantly improved in the atomoxetine cohort compared to placebo (AISRS total score mean [S.D.], atomoxetine: -13.63 [11.35], P<.001; placebo: -8.31 [11.44], P<.001, difference: P=.007; effect size=0.48). No significant differences between treatment groups occurred in time-to-relapse of heavy drinking (P=.93). However, cumulative heavy drinking days were reduced 26% in atomoxetine-treated subjects versus placebo (event ratio=0.74, P=.023). There were no serious adverse events or specific drug-drug reactions related to current alcohol use. CONCLUSIONS: This 3-month, double-blind, placebo-controlled study of atomoxetine in adults with ADHD and comorbid alcohol use disorder demonstrates clinically significant ADHD improvement, and inconsistent effects on drinking behavior.