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Background: Research examining the potential effects of stimulant exposure in childhood on subsequent development of substance use disorder (SUD) have focused on differences in the brain reward system as a function of risk., Methods: 18 drug naïve children ages 7 to 12 years (11 High Risk [ADHD + ODD/CD]; 7 Low Risk [ADHD only]), underwent fMRI scans before and after treatment with mixed amphetamine salts, extended release (MAS-XR). We examined correlations between clinical ratings and fMRI activation at baseline and following treatment as a function of risk status., Results: High Risk children had higher activation than Low Risk children at baseline during both the Reward and Surprising Non-Reward conditions. Treatment produced strong differential effects on brain activation pertinent to group and reward outcome., Conclusions: Findings support the hypothesized role of reward mechanisms in SUD risk, and suggest that stimulant treatment may have differential effects on reward processing in relation to SUD risk., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Iliyan Ivanov—no conflicts, Beth Krone—in the last 3 years was a consultant for Signant Health, Mind Tension, Hippo T&C, and Maxis Health, Kurt Schulz—no conflicts, Riaz Shaik—no conflicts, Muhammad Parvaz—no conflicts, Jeffrey Newcorn—in the last three years J.H.N. was a consultant/advisory board member for Adlon Therapeutics, Cingulate Therapeutics, Corium, Hippo T&C, Ironshore, Lumos, Medice, MindTension, Myriad, NLS, OnDosis, Otsuka, Rhodes, Shire/Takeda, Signant and Supernus; he received research support from Adlon, Otsuka, Shire, Supernus; honoraria for disease state lectures from Otsuka and Shire, and served as a consultant for the US National Football League.

Background: ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation., Methods: Twenty adults (M = 11, 55%, F = 9, 45%), ages 19-52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3-5 weeks of treatment with LDX and 3-5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels., Results: Improvement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri)., Conclusions: These findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD. Trial RegistrationClinicaltrials.gov Identifier: NCT01924429., Competing Interests: Declaration of competing interest The authors declare the following competing interests: Jeffrey Newcorn – in the last 3 years J.H.N. was a consultant/advisory board member for Adlon Therapeutics, Cingulate Therapeutics, Corium, Hippo T&C, Ironshore, Lumos, Lundbeck, Medice, Mind Tension, Myriad, NLS, OnDosis, Otsuka, Rhodes, Shire/Takeda, and Supernus; he received research support from Adlon, Otsuka, Shire, Supernus; honoraria for disease state lectures from Otsuka and Shire, and served as a consultant for the US National Football League; Iliyan Ivanov – no conflcits, Beth Krone – in the last 3 years was a consultant for Hippo T&C; Xioabo Li – no conflicts; Stephanie Duhoux – no conflict; Stuart White – no conflict; Kurt Schulz – no conflicts; AC Bedard-no conflicts; Juan Pedraza - Lenard Adler – in the last 3 years Dr Adler has received grant/research support from Shire/Takeda Pharmaceuticals, Otsuka; has served as a consultant to Bracket/Signant, Shire/Takeda Pharmaceuticals, Otsuka Pharmaceuticals, SUNY, the National Football League, and Major League Baseball; and has received royalty payments (as inventor) since 2004 from NYU for license of adult ADHD scales and training materials; James Blair – no conflicts., (Copyright © 2023. Published by Elsevier Ltd.)

Evidence of sensitization following stimulants administration in humans is just emerging, which prevents reaching more definitive conclusions in favor or against a purported protective role of stimulant treatments for ADHD for the development of substance use disorders. Existing evidence from both animal and human research suggest that stimulants produce neurophysiological changes in the brain reward system, some of which could be persistent. This could be relevant in choosing optimal treatments for young patients with ADHD who have additional clinical risk factors for substance abuse (e.g. conduct disorder (CD) and/or familial addictions). Here we stipulate that, while the majority of youth with ADHD greatly benefit from treatments with stimulants, there might be a subpopulation of individuals whose neurobiological profiles may confer risk for heightened vulnerability to the effects of stimulants on the responsiveness of the brain reward system. We propose that focused human research is needed to elucidate the unknown effects of prolonged stimulant exposure on the neurophysiology of the brain reward system in young patients with ADHD., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: Methylphenidate has prominent effects in the dopamine-rich striatum that are absent for the selective norepinephrine transporter inhibitor atomoxetine. This study tested whether baseline striatal activation would predict differential response to the two medications in youth with attention-deficit/hyperactivity disorder (ADHD)., Method: A total of 36 youth with ADHD performed a Go/No-Go test during functional magnetic resonance imaging at baseline and were treated with methylphenidate and atomoxetine using a randomized cross-over design. Whole-brain task-related activation was regressed on clinical response., Results: Task-related activation in right caudate nucleus was predicted by an interaction of clinical responses to methylphenidate and atomoxetine (F 1,30  = 17.00; p < .001). Elevated caudate activation was associated with robust improvement for methylphenidate and little improvement for atomoxetine. The rate of robust response was higher for methylphenidate than for atomoxetine in youth with high (94.4% vs. 38.8%; p = .003; number needed to treat = 2, 95% CI = 1.31-3.73) but not low (33.3% vs. 50.0%; p = .375) caudate activation. Furthermore, response to atomoxetine predicted motor cortex activation (F 1,30  = 14.99; p < .001)., Conclusion: Enhanced caudate activation for response inhibition may be a candidate biomarker of superior response to methylphenidate over atomoxetine in youth with ADHD, purportedly reflecting the dopaminergic effects of methylphenidate but not atomoxetine in the striatum, whereas motor cortex activation may predict response to atomoxetine. These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach., Clinical Trial Registration Information: Stimulant Versus Nonstimulant Medication for Attention Deficit Hyperactivity Disorder in Children; https://clinicaltrials.gov/; NCT00183391., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Aggression is a common, yet complex, behavioral complaint, and a frequent indication for referral to child and adolescent psychiatrist treatment. This article reviews the evidence supporting pharmacotherapy of aggression in youth, with a primary focus on impulsive aggression (the primary indication for this intervention). Relevant diagnostic considerations and consensus guidelines are discussed., Methods: Articles examining the role of medications in the treatment of aggression in youth with pathological aggression were identified using PubMed and MEDLINE® databases over the past 15 years (2000-2015); selected articles published prior to 2000 and deemed to be of high relevance were searched and also included. Search terms included: Aggression, aggressive, disruptive behavior, conduct, youth, children, and adolescents. Cited references were also searched for relevant articles., Results: There are a number of evidence-based medication treatments for aggression, which are generally best considered in the context of differential diagnosis and ongoing evidence-based psychosocial interventions. Impulsive aggression is generally considered the type of aggression most amenable to medication, but other aggression subtypes may also possibly respond to treatment. Medication classes with positive evidence include the psychostimulants and α-2 agonists (in the presence of attention-deficit/hyperactivity disorder [ADHD] and/or disruptive behavior disorders), mood stabilizing agents, and atypical antipsychotics. Published guidelines recommend systematic and adequate trials of medications in sequential order, to optimize response and minimize polypharmacy. Guidelines for safety monitoring are available for many of the medications used for aggression in youth, and are also discussed., Conclusions: Aggression in children carries a high risk of poor outcomes, and, therefore, a better understanding of treatment options is a high priority. The available literature points to the importance of identifying the underlying disorder, when possible, and using this information to guide treatment selection. Future studies are needed to better inform the treatment of aggression across disorders, and the treatment of different aggression subtypes.

Psychostimulants, such as methylphenidate, are thought to improve information processing in motivation-reward and attention-activation networks by enhancing the effects of more relevant signals and suppressing those of less relevant ones; however the nature of such reciprocal influences remains poorly understood. To explore this question, we tested the effect of methylphenidate on performance and associated brain activity in the Anticipation, Conflict, Reward (ACR) task. Sixteen healthy adult volunteers, ages 21-45, were scanned twice using functional magnetic resonance imaging (fMRI) as they performed the ACR task under placebo and methylphenidate conditions. A three-way repeated measures analysis of variance, with cue (reward vs. non-reward), target (congruent vs. incongruent) and medication condition (methylphenidate vs. placebo) as the factors, was used to analyze behaviors on the task. Blood oxygen level dependent (BOLD) signals, reflecting task-related neural activity, were evaluated using linear contrasts. Participants exhibited significantly greater accuracy in the methylphenidate condition than the placebo condition. Compared with placebo, the methylphenidate condition also was associated with lesser task-related activity in components of attention-activation systems irrespective of the reward cue, and less task-related activity in components of the reward-motivation system, particularly the insula, during reward trials irrespective of target difficulty. These results suggest that methylphenidate enhances task performance by improving efficiency of information processing in both reward-motivation and in attention-activation systems., (Published by Elsevier B.V.)

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing psychiatric disorder that affects both children and adults. There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD; however, little is known about the mechanisms by which these different treatments exert their therapeutic effects. OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylphenidate hydrochloride vs the nonstimulant atomoxetine hydrochloride. DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylphenidate (n = 18) or atomoxetine (n = 18) using a parallel-groups design. SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine, New York, New York. PARTICIPANTS Thirty-six youth with ADHD (mean [SD] age, 11.2 [2.7] years; 27 boys) recruited from randomized clinical trials. MAIN OUTCOME MEASURES Changes in brain activation during a go/no-go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version. RESULTS Treatment with methylphenidate vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean (SD) improvements in ratings of ADHD symptoms (55% [30%] vs 57% [25%]). Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments. Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylphenidate in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex. These findings were not attributable to baseline differences in activation. CONCLUSIONS Treatment with methylphenidate and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic actions in frontoparietal regions that have been implicated in the pathophysiology of ADHD. These results represent a first step in delineating the neurobiological basis of differential response to stimulant and nonstimulant medications for ADHD.

Objective: To examine late adolescent substance use outcomes in relation to childhood conduct disorder (CD) and psychostimulant treatment in urban youth found to have attention-deficit/hyperactivity disorder (ADHD) in childhood., Methods: Ninety-seven adolescents, evaluated during childhood, were seen for follow-up on average 9.30 (SD = 1.65) years later along with a well-matched never-ADHD control group. Stimulant treatment history was coded: Never (n = 28), up to 1 year (n = 19), 1 to 5 years (n = 28), and greater than 5 years (n = 22). Substance use at outcome was coded dimensionally for severity (frequency × intensity) and categorically for substance use disorders (SUDs)., Results: Individuals with ADHD+CD in childhood had significantly higher rates of SUD and substance use severity than those with childhood ADHD and controls. The ADHD and control groups did not differ significantly. Among those with childhood ADHD, there were no significant differences in SUD status or substance use severity as a function of medication history., Conclusions: Within an ethnically diverse urban sample, the increased rate of substance use associated with ADHD was fully accounted for by the presence of CD. These results extend previous findings indicating little impact of psychostimulant treatment on later substance use to an ethnically diverse urban sample and to individuals who received treatment for up to 12 years.

Objective: Disturbances in the basal ganglia portions of cortico-striato-thalamo-cortical circuits likely contribute to the symptoms of attention deficit hyperactivity disorder (ADHD). The authors examined the morphologic features of the basal ganglia nuclei (caudate, putamen, and globus pallidus) in children with ADHD., Method: A total of 104 individuals (combined-type ADHD patients: N=47; healthy comparison subjects: N=57), aged 7 to 18 years, were examined in a cross-sectional case-control study using anatomical magnetic resonance imaging. Conventional volumes and the surface morphology for the basal ganglia were measured., Results: Overall volumes were significantly smaller only in the putamen. Analysis of the morphological surfaces revealed significant inward deformations in each of the three nuclei, localized primarily in portions of these nuclei that are components of limbic, associative, and sensorimotor pathways in the cortico-striato-thalamo-cortical circuits in which these nuclei reside. The more prominent these inward deformations were in the patient group, the more severe the ADHD symptoms. Surface analyses also demonstrated significant outward deformations of all basal ganglia nuclei in the ADHD children treated with stimulants compared with those ADHD youth who were untreated. These stimulant-associated enlargements were in locations similar to the reduced volumes detected in the ADHD group relative to the comparison group. The outward deformations associated with stimulant medications attenuated the statistical effects of the primary group comparisons., Conclusions: These findings potentially represent evidence of anatomical dysregulation in the circuitry of the basal ganglia in children with ADHD and suggest that stimulants may normalize morphological features of the basal ganglia in children with the disorder.

Objective: The role of the thalamus in the genesis of attention deficit hyperactivity disorder (ADHD) remains poorly understood. The authors used anatomical MRI to examine the morphology of the thalamus in youths with ADHD and healthy comparison youths., Method: The authors examined 46 youths with ADHD and 59 comparison youths 8-18 years of age in a cross-sectional case-control study. Conventional volumes and measures of surface morphology of the thalamus served as the main outcome measures., Results: A mixed-effects model comparing whole thalamic volumes revealed no significant differences between groups. Maps of the thalamic surface revealed significantly smaller regional volumes bilaterally in the pulvinar in youths with ADHD relative to comparison subjects. Post hoc analyses showed that ADHD patients who received stimulants (N=31) had larger conventional thalamic volumes than untreated youths with ADHD, and maps of the thalamic surface showed enlargement over the pulvinar in those receiving stimulants. Smaller regional volumes in the right lateral and left posterior thalamic surfaces were associated with more severe hyperactivity symptoms, whereas larger regional volumes in the right medial thalamic surfaces were associated with more severe symptoms of inattention., Conclusion: These findings demonstrate reduced pulvinar volumes in youths with ADHD and indicate that this same area is relatively enlarged in patients treated with stimulants compared to those untreated. Associations of hyperactivity scores with smaller regional volumes on the lateral thalamic surface and inattention scores with larger regional volumes on the medial thalamic surface suggest the differential involvement of thalamic subcircuits in the pathogenesis of differing ADHD symptoms.

Objective: This study compared the methylphenidate (MPH) dose-response profiles of children with the Predominantly Inattentive (PI) and Combined (CB) subtypes of attention-deficit/hyperactivity disorder (ADHD). It is the first such study to enroll a sample comprised exclusively of children, all but one of whom had no prior exposure to ADHD medications., Method: The design was a double-blind crossover with 1-week exposures to placebo and low, medium, and high, fixed, three times daily (t.i.d.) dosage regimens of immediate-release MPH, administered in random order. Parents and teachers completed weekly behavioral questionnaires (Conners, Swanson, Kotkin, Agler, M-Flynn and Pelham Scale [SKAMP]) and a child psychiatrist provided weekly ratings of symptom severity (ADHD Rating Scale [ADHD-RS]), side effects (Side Effects Rating Scale), and a Clinical Global Impressions-Severity (CGI-S). In addition, laboratory measures of vigilance (Continuous Performance Test [CPT]) and resistance to cognitive interference (Stroop) were administered weekly., Results: Twenty-five children (15 CB, 10 PI), who met rigorous diagnostic criteria for their ADHD subtype, completed the study. Groups did not differ on demographic variables or severity at baseline. Behavioral questionnaires and clinical ratings indicated significant improvement on MPH for both subtypes but no differences in response profiles of the two groups. Drug effects were predominantly linear for both subtypes. Effects of MPH were significant for the CPT, but not the Stroop, instrument with no differences between ADHD subtypes., Conclusions: Results support the clinical utility of MPH in the treatment of the PI subtype and provide no evidence of differences in response between the subtypes.