Explore the vast range of titles available.

Methylphenidate is a widely used first-line treatment for attention deficit/hyperactivity disorder (ADHD), but the underlying circuit mechanisms are poorly understood. Here we investigate whether a single dose of osmotic release oral system methylphenidate can remediate attention deficits and aberrancies in functional circuit dynamics in cognitive control networks, which have been implicated in ADHD. In a randomized placebo-controlled double-blind crossover design, 27 children with ADHD were scanned twice with resting-state functional MRI and sustained attention was examined using a continuous performance task under methylphenidate and placebo conditions; 49 matched typically-developing (TD) children were scanned once for comparison. Dynamic time-varying cross-network interactions between the salience (SN), frontoparietal (FPN), and default mode (DMN) networks were examined in children with ADHD under both administration conditions and compared with TD children. Methylphenidate improved sustained attention on a continuous performance task in children with ADHD, when compared to the placebo condition. Children with ADHD under placebo showed aberrancies in dynamic time-varying cross-network interactions between the SN, FPN and DMN, which were remediated by methylphenidate. Multivariate classification analysis confirmed that methylphenidate remediates aberrant dynamic brain network interactions. Furthermore, dynamic time-varying network interactions under placebo conditions predicted individual differences in methylphenidate-induced improvements in sustained attention in children with ADHD. These findings suggest that a single dose of methylphenidate can remediate deficits in sustained attention and aberrant brain circuit dynamics in cognitive control circuits in children with ADHD. Findings identify a novel brain circuit mechanism underlying a first-line pharmacological treatment for ADHD, and may inform clinically useful biomarkers for evaluating treatment outcomes.

The limitations of current US Food and Drug Administration (FDA)–approved medications for the treatment of attention-deficit/hyperactivity disorder (ADHD) set the need for the development of novel, effective, and tolerable medications to treat this disorder. The purpose of this study was to evaluate whether treatment with SPN-812 (viloxazine extended-release) significantly reduces symptoms of ADHD in children. This study was a randomized, double-blind, placebo-controlled 6-week trial to assess the efficacy and safety of once-daily 100- and 200-mg SPN-812 in the treatment of ADHD in male and female children 6–11 years of age. Inclusion criteria required subjects to have a confirmed Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, ADHD diagnosis, an ADHD-Rating Scale-5 (ADHD-RS-5) score ≥28, a Clinical Global Impression-Severity score ≥4, and for subjects to be free of ADHD medication ≥1 week before randomization. The primary efficacy endpoint was the change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 Total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) scores at EOS and CFB at EOS in the Conners 3–Parent Short Form (Conners 3–PS) Composite T-score and the Weiss Functional Impairment Rating Scale–Parent (WFIRS–P) Total average score. Safety assessments included adverse events (AEs), laboratory tests, vital signs, physical examinations, ECGs, and the Columbia-Suicide Severity Rating Scale. The primary efficacy endpoint was analyzed by using a mixed model for repeated measures; all secondary measures were analyzed by using an ANCOVA model. A total of 477 subjects were randomized to treatment (intent-to-treat population, n = 460). The majority of subjects were male (63%) and either White (51.3%) or African American (43.7%). The demographic and baseline characteristics between the groups were similar. Statistically significant improvements in ADHD-RS-5 Total score were observed in both the 100- and 200-mg/day SPN-812 treatment groups compared to placebo at week 1 of treatment (P = 0.0004 and P = 0.0244, respectively), which was maintained through EOS (P = 0.0004 and P < 0.0001). Significant improvements were also observed at EOS in the CGI-I scale (P = 0.0020 and P < 0.0001), Conners 3–PS Composite T-score (P = 0.0003 and P = 0.0002), and WFIRS–P Total average score (P = 0.0019 and P = 0.0002) versus placebo. Treatment-related AEs reported in ≥5% of subjects included somnolence, decreased appetite, and headache. The discontinuation rate due to AEs was <5%. SPN-812 significantly reduced ADHD symptoms in children and was well tolerated. SPN-812 may prove to be an effective treatment for children with ADHD. ClinicalTrials.gov identifier: NCT03247530. •SPN-812 improved ADHD symptoms in children (ADHD-RS-5 and CGI-I scores vs placebo).•Higher 50% respondent rate per ADHD-RS-5 in SPN-812 treatment groups vs placebo.•Greater proportion of patients who improved (categorical CGI-I) vs placebo.•Parent-rated Conners 3-PS and WFIRS-P scales also indicate improvement.•SPN-812 (100-mg/day and 200-mg/day) was well tolerated with low discontinuation rates.

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

In a prior report, we showed that extended-release guanfacine (GEXR) is safe and effective for children with autism spectrum disorder (ASD) accompanied by ADHD symptoms. Here, we examine the impact of GEXR on oppositional behavior, anxiety, repetitive behavior, and sleep disturbance. Sixty-two subjects with ASD (53 boys, 9 girls; ages 5–14 years) were randomly assigned to GEXR (n = 30) or placebo (n = 32) for 8 weeks. Outcomes include the Home Situation Questionnaire-Modified for ASD (HSQ-ASD), Anxiety scale of the Child and Adolescent Symptom Inventory (CASI), Children’s Yale-Brown Obsessive-Compulsive Scale-Modified for ASD (CYBOCS-ASD), and Children’s Sleep Habits Questionnaire (CSHQ). A repeated measures linear mixed model was used to determine the effects of treatment group and time on HSQ scores. For other measures, change from baseline was evaluated with Analysis of Covariance (ANCOVA).After 8 weeks of treatment, parent ratings of oppositional behavior on the HSQ declined by 44% (per item mean from 3.4 to 1.9) in the GEXR group compared to 12% (from 3.3 to 2.9) for placebo (p = 0.004). Repetitive behavior on the CYBOCS-ASD showed a significantly greater decline in GEXR-treated participants compared to placebo (24% vs. <1%, p = 0.01). No group differences were observed on CASI Anxiety or CSHQ (p = 0.64 and 0.75, respectively). GEXR was effective in reducing oppositional behavior and, more modestly, repetitive behavior. GEXR was not superior to placebo for anxiety, though baseline anxiety ratings were low. GEXR did not significantly improve sleep habits. Future studies could focus on repetitive behavior or anxiety, symptoms with limited treatment options.

Background and objective Attention-deficit/hyperactivity disorder is a neurodevelopmental disorder that typically begins in childhood and often persists into adulthood. Recent phase III trials have demonstrated the efficacy and safety of viloxazine extended-release capsules (viloxazine ER; Qelbree ® ) in pediatrics (6–17 years of age). The aim of this study was to evaluate the efficacy and safety of viloxazine ER in adults with attention-deficit/hyperactivity disorder. Methods This was a phase III, randomized, double-blind, placebo-controlled, two-arm trial in adults (18–65 years of age) with attention-deficit/hyperactivity disorder. Eligible subjects were randomized 1:1 to viloxazine ER (flexible dose of 200–600 mg/day) or matched placebo. The primary efficacy endpoint was the change from baseline at end of study (week 6) in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score. The key secondary endpoint was the change from baseline at end of study in the Clinical Global Impressions-Severity of Illness (CGI-S) score. Additional secondary outcome measures included the AISRS Inattention and Hyperactivity/Impulsivity subscales, the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A), the Generalized Anxiety Disorder-7 Item (GAD-7), and the Clinical Global Impressions-Improvement (CGI-I); each was analyzed at end of study. Responder rates on CGI scales and the AISRS were also assessed. Results A total of 374 subjects were randomized. At end of study, the mean viloxazine ER dose was 504 mg. The reduction in the change from baseline at end of study AISRS total score (least-square means ± standard error) was significantly greater in subjects treated with viloxazine ER (−15.5 ± 0.91) compared with placebo (−11.7 ± 0.90), p = 0.0040. The reduction in the CGI-S score was also significantly greater in subjects treated with viloxazine ER (−1.4 ± 0.10) compared with placebo (−1.0 ± 0.10), p = 0.0023. The viloxazine ER group demonstrated significantly greater improvements in the AISRS Inattention ( p = 0.0015) and Hyperactivity/Impulsivity ( p = 0.0380) subscales, the CGI-I ( p = 0.0076), and the BRIEF-A Global Executive Composite ( p = 0.0468) and Metacognition Index ( p = 0.0100). Analysis of categorical secondary endpoints revealed that the viloxazine ER group had a significantly higher AISRS 30% response rate compared with placebo ( p = 0.0395); all other comparisons were not significant. Many treatment effects (including the primary and key secondary endpoints) were significant by week 2. The most common treatment-related adverse events that occurred in ≥5% of subjects receiving viloxazine ER were insomnia (14.8%), fatigue (11.6%), nausea (10.1%), decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). Viloxazine ER was well tolerated, with a 9.0% discontinuation rate due to adverse events compared with 4.9% in the placebo group. Conclusions Treatment with viloxazine ER resulted in a statistically significant improvement in primary and key secondary endpoints, indicating improvements in attention-deficit/hyperactivity disorder symptomology, executive function, and overall clinical illness severity in adults. Viloxazine ER was well tolerated at the tested doses in adults with attention-deficit/hyperactivity disorder. Clinical Trial Registration Clinicaltrials.gov identifier: NCT04016779. Plain Language Summary Attention-deficit/hyperactivity disorder (ADHD) is a condition characterized by inattention (difficulty maintaining focus), and/or impulsiveness/hyperactivity. In 2021, a nonstimulant medication called viloxazine ER (brand name: Qelbree ® ) received US FDA-approval for ADHD in children and adolescents (aged 6 to 17 years), based on efficacy and safety demonstrated in clinical trials. Here we present results of a phase 3, randomized, double-blind, placebo-controlled, clinical trial that enrolled 374 adults with ADHD. In this trial, half the patients received viloxazine ER, and half received placebo (identical capsule without active ingredient). Medication doses ranged from 200–600 mg/day, based on symptom response and presence of side effects. To reduce bias, patients and investigators did not know which medication the patient was receiving. The primary measure of efficacy was the Adult ADHD Investigator Symptom Rating Scale (AISRS), a standardized questionnaire rating presence and severity of patient-reported ADHD symptoms. At the end of the 6-week trial, participants receiving viloxazine ER showed greater improvement in ADHD symptoms according to AISRS than those receiving placebo. Improvement was seen in both the Inattentive and Impulsive/Hyperactive components of ADHD and in other study measures, including a measure of behaviors called Executive Function. Viloxazine ER was generally safe and well-tolerated in the trial. The most common side effects were insomnia (14.8%), fatigue (11.6%), and nausea (10.1%). Overall, 9.0% of patients receiving viloxazine and 5% receiving placebo left the trial because of side effects. Due to these positive results, the US FDA recently approved viloxazine ER to treat adults with ADHD.

Background Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder often managed with medication. Improving cognitive functions alongside medication treatment is crucial for better outcomes. This study mainly aimed to investigate the therapeutic effects of combining digitally targeted cognitive training with medication compared to medication monotherapy on ADHD core symptoms. We hypothesized that targeted cognitive training could enhance treatment efficacy when combined with medication. Methods This was a randomized parallel-group controlled trial. A total of 124 children with ADHD were randomly allocated to two groups: 64 received medication treatment alone (M), including atomoxetine (ATX) and methylphenidate (MPH); 60 received targeted cognitive training combined with medication (TCT + M), including TCT + ATX and TCT + MPH. Both groups received 8 weeks of treatment. The primary outcome was the changes in ADHD core symptoms measured by the ADHD Rating Scale (ADHD-RS). The secondary outcomes were parent-reported ecological executive functions, social functions, and laboratory cognitive functions. Results Main results: When compared with M treatment, the TCT + M treatment did not show significant greater improvements in ADHD core symptoms, ecological executive functions, social functions, or laboratory cognitive functions. Post-hoc exploratory analysis results: (1) In patients who received ATX treatment, TCT + ATX led to greater improvement in ADHD-RS total, inattention, and hyperactivity/impulsivity symptoms. Similar between-group differences were observed in ecological executive functions, and the improvements were significantly correlated with changes of ADHD core symptoms. (2) In patients who received MPH treatment, no significant differences in the improvement of primary or secondary outcomes were observed between MPH monotherapy and TCT + MPH groups. Conclusions These findings demonstrated that, in comparison to medication monotherapy, the TCT + M treatment did not lead to more improvements in the core symptoms of ADHD, nor did it show superiority in other secondary outcomes. Specifically in children treated with atomoxetine, there’s a potential promoting effect of targeted cognitive training on medication treatment in terms of the alleviation of ADHD core symptoms. Trial registration This study was pre-registered with the Chinese Clinical Trial Registry under the identifier ChiCTR2100043525.

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.