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Background and Objective Although there are several treatments for narcolepsy type 2 and idiopathic hypersomnia, studies that assess amphetamines, symptoms beyond sleepiness, and comparative effectiveness are needed. We performed a randomized, fully blinded, noninferiority trial of modafinil versus amphetamine–dextroamphetamine in these disorders. Methods Forty-four adults were randomized to modafinil or amphetamine–dextroamphetamine, individually titrated to a maximum of modafinil 200 mg twice daily or amphetamine–dextroamphetamine 20 mg twice daily, for 12 weeks. Primary outcome was change in Epworth from baseline to week 12, with a noninferiority threshold of 2 points. Secondary outcomes were (1) patient global impression of change measures of disease severity, sleepiness, sleep inertia, and cognition; (2) change from baseline in Hypersomnia Severity Index; and (3) change from baseline in Sleep Inertia Questionnaire. Adverse events were compared between groups. Results Epworth improved 5.0 [± standard deviation (SD) 2.7] points with modafinil and 4.4 (± SD 4.7) with amphetamine–dextroamphetamine; noninferiority of amphetamine–dextroamphetamine was not demonstrated ( P = 0.11). Noninferiority of amphetamine-dextroamphetamine was demonstrated for change scores of severity, sleepiness, sleep inertia, Hypersomnia Severity Index, and Sleep Inertia Questionnaire. Dropouts due to adverse events were 31.8% for modafinil (including two severe events) and 9.1% for amphetamine–dextroamphetamine, P = 0.13. Anxiety was more common with modafinil and appetite suppression with amphetamine-dextroamphetamine. Conclusion Noninferiority of amphetamine–dextroamphetamine to modafinil was not demonstrated for the primary outcome. However, amphetamine–dextroamphetamine was noninferior on multiple secondary measures of disease severity and symptomatology. These data may inform shared decision-making regarding treatment for idiopathic hypersomnia and narcolepsy type 2. Registration Clinicaltrials.gov Registration (NCT03772314) 12/10/18. .

Methylphenidate is a widely used and effective treatment for attention-deficit/hyperactivity disorder (ADHD), yet the underlying neural mechanisms and their relationship to changes in behavior are not fully understood. Specifically, it remains unclear how methylphenidate affects brain and behavioral dynamics, and the interplay between these dynamics, in individuals with ADHD. To address this gap, we used a novel Bayesian dynamical system model to investigate the effects of methylphenidate on latent brain states in 27 children with ADHD and 49 typically developing children using a double-blind, placebo-controlled crossover design. Methylphenidate remediated greater behavioral variability on a continuous performance task in children with ADHD. Children with ADHD exhibited aberrant latent brain state dynamics compared to typically developing children, with a single latent state showing particularly abnormal dynamics, which was remediated by methylphenidate. Additionally, children with ADHD showed brain state-dependent hyper-connectivity in the default mode network, which was also remediated by methylphenidate. Finally, we found that methylphenidate-induced changes in latent brain state dynamics, as well as brain state-related functional connectivity between salience and default mode networks, were correlated with improvements in behavioral variability. Taken together, our findings reveal a novel latent brain state dynamical process and circuit mechanism underlying the therapeutic effects of methylphenidate in childhood ADHD. We suggest that Bayesian dynamical system models may be particularly useful for capturing complex nonlinear changes in neural activity and behavioral variability associated with ADHD. Our approach may be of value to clinicians and researchers investigating the neural mechanisms underlying pharmacological treatment of psychiatric disorders.

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.

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.

RationaleDisorders of compulsivity such as stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD) are characterised by deficits in behavioural flexibility, some of which have been captured using probabilistic reversal learning (PRL) paradigms.ObjectivesThis study used computational modelling to characterise the reinforcement learning processes underlying patterns of PRL behaviour observed in SUD and OCD and to show how the dopamine D2/3 receptor agonist pramipexole and the D2/3 antagonist amisulpride affected these responses.MethodsWe applied a hierarchical Bayesian method to PRL data across three groups: individuals with SUD, OCD, and healthy controls. Participants completed three sessions where they received placebo, pramipexole, and amisulpride, in a double-blind placebo-controlled, randomised design. We compared seven models using a bridge sampling estimate of the marginal likelihood.ResultsStimulus-bound perseveration, a measure of the degree to which participants responded to the same stimulus as before irrespective of outcome, was significantly increased in SUD, but decreased in OCD, compared to controls (on placebo). Individuals with SUD also exhibited reduced reward-driven learning, whilst both the SUD and OCD groups showed increased learning from punishment (nonreward). Pramipexole and amisulpride had similar effects on the control and OCD groups; both increased punishment-driven learning. These D2/3-modulating drugs affected the SUD group differently, remediating reward-driven learning and reducing aspects of perseverative behaviour, amongst other effects.ConclusionsWe provide a parsimonious computational account of how perseverative tendencies and reward- and punishment-driven learning differentially contribute to PRL in SUD and OCD. D2/3 agents modulated these processes and remediated deficits in SUD in particular, which may inform therapeutic effects.

In infants with very low birth weight who have apnea of prematurity, caffeine therapy reduced the risk of bronchopulmonary dysplasia assessed at 36 weeks of postmenstrual age. Caffeine temporarily reduced weight gain; it did not affect the rates of death, ultrasonographic signs of brain injury, or necrotizing enterocolitis. These short-term data demonstrate an important benefit of caffeine therapy in this population, but a definitive assessment of its benefits and risks awaits results of long-term follow-up of this cohort. In infants with very low birth weight who have apnea of prematurity, caffeine therapy reduced the risk of bronchopulmonary dysplasia. Caffeine temporarily reduced weight gain; it did not affect the rates of death. Apnea of prematurity — defined as cessation of breathing that lasts for more than 15 seconds and is accompanied by hypoxia or bradycardia — occurs in at least 85 percent of infants who are born at less than 34 weeks of gestation. 1 Widely used treatments include the application of continuous positive airway pressure and the prescription of a methylxanthine. 2 The methylxanthines — aminophylline, theophylline, and caffeine — reduce the frequency of apnea and the need for mechanical ventilation during the first seven days of therapy. 3 However, it has remained uncertain whether methylxanthines have any additional short- and long-term benefits or . . .

A previous report showed that the use of caffeine to treat apnea of prematurity reduces the risk of bronchopulmonary dysplasia, but whether it has long-term effects on neurodevelopment and growth is unknown. In this placebo-controlled, randomized trial, treatment with caffeine significantly improved the rate of survival without neurodevelopmental disability at 18 to 21 months. Treatment with caffeine significantly improved the rate of survival without neurodevelopmental disability at 18 to 21 months. Apnea of prematurity is one of the most common reasons for the initiation of drug therapy in neonatal medicine. 1 The methylxanthines — aminophylline, theophylline, and caffeine — have been administered to preterm infants as respiratory stimulants for more than 30 years. 2 Caffeine is presently one of the 10 most frequently prescribed medications in neonatal intensive care. 1 Despite their widespread use, caffeine and the other methylxanthines have been evaluated in only a few small, short-term studies. 3 – 5 It has been uncertain whether these drugs might adversely affect the development of the preterm brain and of other organs. Methylxanthines are inhibitors of . . .

Research has shown that 20-30% of prisoners meet the diagnostic criteria for attention-deficit hyperactivity disorder (ADHD). Methylphenidate reduces ADHD symptoms, but effects in prisoners are uncertain because of comorbid mental health and substance use disorders. To estimate the efficacy of an osmotic-release oral system methylphenidate (OROS-methylphenidate) in reducing ADHD symptoms in young adult prisoners with ADHD. We conducted an 8-week parallel-arm, double-blind, randomised placebo-controlled trial of OROS-methylphenidate versus placebo in male prisoners (aged 16-25 years) meeting the DSM-5 criteria for ADHD. Primary outcome was ADHD symptoms at 8 weeks, using the investigator-rated Connors Adult ADHD Rating Scale (CAARS-O). Thirteen secondary outcomes were measured, including emotional dysregulation, mind wandering, violent attitudes, mental health symptoms, and prison officer and educational staff ratings of behaviour and aggression. In the OROS-methylphenidate arm, mean CAARS-O score at 8 weeks was estimated to be reduced by 0.57 points relative to the placebo arm (95% CI -2.41 to 3.56), and non-significant. The responder rate, defined as a 20% reduction in CAARS-O score, was 48.3% for the OROS-methylphenidate arm and 47.9% for the placebo arm. No statistically significant trial arm differences were detected for any of the secondary outcomes. Mean final titrated dose was 53.8 mg in the OROS-methylphenidate arm. ADHD symptoms did not respond to OROS-methylphenidate in young adult prisoners. The findings do not support routine treatment with OROS-methylphenidate in this population. Further research is needed to evaluate effects of higher average dosing and adherence to treatment, multi-modal treatments and preventative interventions in the community.

Stimulants, such as methylphenidate (MPH), are beneficial for attention-deficit/hyperactivity disorder (ADHD), but individual response varies. A deeper understanding of the mechanisms underpinning response is needed. Previous studies suggest that a single MPH dose modulates resting-state functional connectivity (rs-fc). We investigated whether single-dose induced rs-fc changes were associated with post-dose optimization clinical response. Fifty-six adults with ADHD underwent rs-functional magnetic resonance imaging (rs-fMRI) under placebo and a single MPH dose, before starting MPH treatment. Clinical response was measured at two months. We tested if a single MPH dose (vs. placebo) shifted rs-fc; how these shifts were associated with treatment response (categorical approach); and whether these associations were driven by improvement on either ADHD symptom domain. A single MPH dose (vs. placebo) increased rs-fc in three subcortical-cortical and cerebellar-cortical clusters. Enhanced rs-fc between the cerebellar vermis (lobule 6) and the left precentral gyrus was associated with a greater probability of responding to treatment (χ 2 (7) = 22.740, p  = .002) and with an improvement on both inattentive and hyperactive/impulsive symptoms (both p  ≤ .001). We provide proof-of-concept that the brain functional response to a single MPH dose, administered before starting routine treatment, is indicative of two-month clinical response in adult ADHD. This may encourage future replication using clinically applicable measures.

The current study aimed to explore the possible effect of stimulants on oxytocin (OT), a neuropeptide which regulates social behavior, as a mediator of the pro-social effect of methylphenidate (MPH) in children with attention deficit hyperactivity disorder (ADHD) compared to healthy controls (HCs). Utilizing a double-blind placebo-controlled design, we compared the performance of 50 children with ADHD and 40 HCs in “theory of mind” (ToM) tasks and examined the effect of a single dose of MPH/placebo on ToM and salivary OT levels in children with ADHD at baseline and following an interpersonal interaction. Children with ADHD displayed significantly poorer ToM performance; however, following MPH administration, their performance normalized and differences between children with ADHD and HC were no longer found. Salivary OT levels at baseline did not differ between children with ADHD and HCs. However, after a parent–child interaction, OT levels were significantly higher in the HC group compared to children with ADHD. Administration of MPH attenuated this difference such that after parent–child interaction differences in OT levels between children with ADHD and HC were no longer found. In the ADHD group, OT levels decreased from administration of placebo to the parent–child interaction. However, the administration of MPH to children with ADHD was associated with an increase in OT levels after the parent–child interaction. We conclude that OT might play a role as a mediator of social deficits in children with ADHD and that the reactivity of the OT system to social interaction in children with ADHD might be impaired. Stimulants may improve ToM and social functions in children with ADHD via its impact on the OT system. PRS: OT and Social Cognition in Children with ADHD: Impact of MPH.