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Contains fulltext : 290864.pdf (Publisher’s version ) (Open Access) The science of attention-deficit/hyperactivity disorder (ADHD) is motivated by a translational goal - the discovery and exploitation of knowledge about the nature of ADHD to the benefit of those individuals whose lives it affects. Over the past fifty years, scientific research has made enormous strides in characterizing the ADHD condition and in understanding its correlates and causes. However, the translation of these scientific insights into clinical benefits has been limited. In this review, we provide a selective and focused survey of the scientific field of ADHD, providing our personal perspectives on what constitutes the scientific consensus, important new leads to be highlighted, and the key outstanding questions to be addressed going forward. We cover two broad domains - clinical characterization and, risk factors, causal processes and neuro-biological pathways. Part one focuses on the developmental course of ADHD, co-occurring characteristics and conditions, and the functional impact of living with ADHD - including impairment, quality of life, and stigma. In part two, we explore genetic and environmental influences and putative mediating brain processes. In the final section, we reflect on the future of the ADHD construct in the light of cross-cutting scientific themes and recent conceptual reformulations that cast ADHD traits as part of a broader spectrum of neurodivergence. 01 april 2023

Nonstimulants have an important role when response or tolerability to psychostimulants is poor, when certain comorbid disorders are present, or if patients prefer nonstimulants. Here, we discuss monotherapy and combined treatment of ADHD and review mechanism of action, pharmacokinetics, efficacy, tolerability, and safety of approved, off-label, and pipeline nonstimulants. We present detailed information regarding the 4 FDA-approved nonstimulant medications-the norepinephrine reuptake inhibitors, atomoxetine and viloxazine extended release, and the α-2 adrenergic agonists, clonidine XR and guanfacine XR. We additionally review evidence regarding the off-label use of a variety of other medications. Variability across and within drug classes in nature of response, approach to titration, and temporal characteristics of treatment allow a nuanced treatment approach for individuals with comorbid disorders and complicated clinical presentations. Availability of nonstimulant medications enhances our opportunity to offer personalized treatment of ADHD across the lifespan.

OBJECTIVE: It is estimated that childhood ADHD remits by adulthood in approximately 50% of cases; however, this conclusion is typically based on single endpoints, failing to consider longitudinal patterns of ADHD expression. We investigated the extent to which children with ADHD experience recovery and variable patterns of remission by adulthood. METHOD: Children with ADHD (N=558) in the Multimodal Treatment Study of ADHD (MTA) were administered eight assessments from 2-year (M age=10.44) to 16-year follow-up (M age=25.12). We identified participants with fully remitted, partially remitted, and persistent ADHD at each timepoint based on parent, teacher, and self-reports of ADHD symptoms and impairment, treatment utilization, and substance use and mental disorders. Longitudinal patterns of remission and persistence were identified that considered context and timing. RESULTS: Approximately 30% of children with ADHD experienced full remission at some point during the 14-year follow-up period; however, a majority (60% of these) experienced recurrence of ADHD after the initial period of remission. Only 9.1% of the sample demonstrated recovery (sustained remission) by study endpoint and only 10.8% demonstrated stable ADHD persistence across study timepoints. Instead, most participants with ADHD (63.8%) had fluctuating periods of remission and recurrence over time. CONCLUSIONS: The MTA findings challenge the notion that approximately 50% of children with ADHD outgrow the disorder by adulthood. Most cases demonstrated fluctuating symptoms between childhood and young adulthood. Although intermittent periods of remission can be expected in most cases, 90% of children with ADHD continued to struggle with residual ADHD through young adulthood. Clinical Trial Number: NCT00000388, Multimodal Treatment Study of Children with Attention Deficit and Hyperactivity Disorder (MTA). https://clinicaltrials.gov/ct2/show/NCT00000388

To investigate long-term (12-month) safety and symptom control of extended-release methylphenidate (MPH-MLR) in children aged 4 to6 years after treatment optimization.A total of 90 children aged 4 to6 years with attention-deficit/hyperactivity disorder (ADHD) were enrolled from 2 MPH-MLR studies. Treatment-emergent adverse events (TEAEs) and ADHD symptom control were assessed in the safety population (n = 89) and modeled with mixed model analyses.Most TEAEs (89.9%) were rated by investigators as of mild or moderate severity. One serious AE was reported (unrelated to study drug). Ten children discontinued because of TEAEs. Two discontinued because of weight loss; no significant increase in the rate of underweight children from baseline to endpoint was observed. Overall, 18% lost weight and 18% reported decreased appetite. Weight and height z scores and obesity rates decreased significantly from baseline to endpoint. Insomnia was reported (9%); none of these children discontinued. Sleep quality did not change significantly. Hypertension was reported (6.7%); none of these children dropped out. Diastolic, but not systolic, blood pressure increased significantly during the follow-up. Control of ADHD symptoms was maintained throughout follow-up.These data contribute to the understanding of the long-term safety of an extended-release stimulant in children 4 to6 years of age. The observed risk of a TEAE-related discontinuation was ∼11%. TEAEs were not dose related, and most were of mild to moderate severity. Symptom control was maintained through the year-long study.A 12-Month Open Label Safety Study of Aptensio XR® in Children Ages 4-5 Years Diagnosed With ADHD (EF004); https://clinicaltrials.gov; NCT02677519.

The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood.

Objective: The Before School Functioning Questionnaire and Parent Rating of Evening and Morning Behavior–Revised assess early morning (BSFQ, PREMB-R AM subscale) and late afternoon/evening (PREMB-R PM subscale) functional impairment in children with ADHD. Clinically meaningful improvements were identified and applied to a trial of delayed-release and extended-release methylphenidate (DR/ER-MPH) in children with ADHD (NCT02520388) to determine if the statistically-determined improvements in functional impairment were also clinically meaningful. Method: Clinically meaningful improvements in BSFQ/PREMB-R were established post hoc by receiver operating characteristics curves, using anchors of Clinical Global Impression–Improvement (CGI-I) = 1 and CGI-I ≤ 2. Percentages of participants achieving these thresholds were calculated. Results: Thresholds for CGI-I = 1/CGI-I ≤ 2, respectively, were 27/20 (BSFQ), 5/3 (PREMB-R AM), and 9/5 (PREMB-R PM)-point decreases. More children achieved clinically meaningful improvements with DR/ER-MPH versus placebo (all p Conclusion: DR/ER-MPH increased proportions of children achieving clinically meaningful improvements in BSFQ and PREMB-R.

Viloxazine has a long history of clinical use in Europe as an antidepressant, and has recently been repurposed into an extended-release form for the treatment of attention-deficit/hyperactivity disorder in the USA. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In contrast to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine was associated with a relatively low risk for cardiotoxicity. Gastrointestinal symptoms were the most commonly reported side effects. The therapeutic effects of viloxazine are thought to be primarily the result of its action as a norepinephrine reuptake inhibitor, although in vitro and preclinical in vivo animal data suggest that viloxazine may also impact the serotoninergic system. This review summarizes the evolving knowledge of viloxazine based on information from previously published preclinical and clinical investigations, and acquired unpublished historical study reports from both open-label and blinded controlled clinical trials. We review the chemical properties, mechanism of action, safety, and tolerability across these studies, and discuss the contemporary rationale for the development of this agent as an extended-release oral formulation for the treatment of attention-deficit/hyperactivity disorder.

Growing evidence shows an association between in utero exposure to natural disasters and child behavioral problems, but we still know little about the development of specific psychopathology in preschool-aged children.Preschool children (n = 163, mean age = 3.19, 85.5% racial and ethnic minorities) and their parents (n = 151) were evaluated annually at ages 2-5 to assess the emergence of psychopathology using the Preschool Age Psychopathological Assessment (PAPA), a parent-report structured diagnostic interview developed for preschool-age children. Sixty-six (40.5%) children were exposed to Sandy Storm (SS) in utero and 97 (59.5%) were not. Survival analysis evaluated patterns of onset and estimated cumulative risks of psychopathology among exposed and unexposed children, in total and by sex. Analyses were controlled for the severity of objective and subjective SS-related stress, concurrent family stress, and demographic and psychosocial confounders, such as maternal age, race, SES, maternal substance use, and normative prenatal stress.Exposure to SS in utero was associated with a substantial increase in depressive disorders (Hazard Ratio (HR) = 16.9, p = .030), anxiety disorders (HR = 5.1, p .0001), and attention-deficit/disruptive behavioral disorders (HR = 3.4, p = .02). Diagnostic rates were elevated for generalized anxiety disorder (GAD; HR = 8.5, p = .004), attention-deficit/hyperactivity disorder (ADHD; HR = 5.5, p = .01), oppositional-defiant disorder (ODD; HR = 3.8, p = .05), and separation-anxiety disorder (SAD; HR = 3.5, p = .001). Males had distinctively elevated risks for attention-deficit/disruptive behavioral disorders (HR = 7.8, p = .02), including ADHD, CD, and ODD, whereas females had elevated risks for anxiety disorders (HR = 10.0, p .0001), phobia (HR = 2.8, p = .02) and depressive disorders (HR = 30.0, p = .03), including SAD, GAD, and dysthymia.The findings demonstrate that in utero exposure to a major weather-related disaster (SS) was associated with increased risk for psychopathology in children and provided evidence of distinct psychopathological outcomes as a function of sex. More attention is needed to understand specific parent, child, and environmental factors which account for this increased risk, and to develop mitigation strategies.

Different drugs of abuse impact the morphology of fronto-striatal dopaminergic targets in both common and unique ways. While dorsal striatal volume tracks with addiction severity across drug classes, opiates impact ventromedial prefrontal cortex (vmPFC) and nucleus accumbens (NAcc) neuroplasticity in preclinical models, and psychostimulants alter inhibitory control, rooted in cortical regions such as the inferior frontal gyrus (IFG). We hypothesized parallel grey matter volume changes associated with human heroin or cocaine use disorder: lower grey matter volume of vmPFC/NAcc in heroin use disorder and IFG in cocaine use disorder, and putamen grey matter volume to be associated with addiction severity measures (including craving) across both. In this cross-sectional study, we quantified grey matter volume (P < 0.05-corrected) in age/sex/IQ-matched individuals with heroin use disorder (n = 32, seven females), cocaine use disorder (n = 32, six females) and healthy controls (n = 32, six females) and compared fronto-striatal volume between groups using voxel-wise general linear models and non-parametric permutation-based tests. Overall, individuals with heroin use disorder had smaller vmPFC and NAcc/putamen volumes than healthy controls. Bilateral lower IFG grey matter volume patterns were specifically evident in cocaine versus heroin use disorders. Correlations between addiction severity measures and putamen grey matter volume did not reach nominal significance level in this sample. These results indicate alterations in dopamine-innervated regions (in the vmPFC and NAcc) in heroin addiction. For the first time we demonstrate lower IFG grey matter volume specifically in cocaine compared with heroin use disorder, suggesting a signature of reduced inhibitory control, which remains to be tested directly using select behavioural measures. Overall, results suggest substance-specific volumetric changes in human psychostimulant or opiate addiction, with implications for fine-tuning biomarker and treatment identification by primary drug of abuse.

Objectives: Inadequately controlled symptoms and associated impaired functioning have a significant negative impact on caregivers of children with attention-deficit/hyperactivity disorder (ADHD). This study aimed to assess the impact of evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) treatment on caregiver strain, measured by the Caregiver Strain Questionnaire (CGSQ), and present post hoc psychometric analyses assessing the reliability and validity of the CGSQ, its ability to detect change (responsiveness), and to derive responder definitions. Methods: The CGSQ was an exploratory efficacy endpoint in a phase 3, 3-week, randomized, double-blind, multicenter, placebo-controlled, forced-dose titration trial of DR/ER-MPH in children aged 6–12 years with ADHD (NCT02520388). Psychometric properties of the CGSQ evaluated post hoc included internal consistency using Cronbach's alpha; test/retest reliability using intraclass correlation coefficients (ICCs); construct validity (known groups and convergent/divergent validity); responsiveness to changes in assessments of ADHD severity (ADHD Rating Scale-IV [ADHD-RS-IV], Conners' Global Index–Parent [CGI-P], and Clinical Global Impression—Severity [CGI-S]/CGI—Improvement [CGI-I]); and meaningful change threshold (MCT) using receiver operating characteristic curves, which were used to compare response between DR/ER-MPH and placebo groups. Results: Randomized DR/ER-MPH (54.5) and placebo (54.9) groups had similar mean CGSQ scores at screening. Caregivers of children on DR/ER-MPH reported significant reductions in CGSQ scores after 3 weeks of DR/ER-MPH treatment versus placebo (least-squares mean: 41.2 vs. 49.1; p

Attention deficit hyperactive disorder (ADHD) is a highly heritable neurodevelopmental disorder, and excessive daytime sleepiness is frequently observed in ADHD patients. Excessive daytime sleepiness is also a core symptom of narcolepsy and essential hypersomnia (EHS), which are also heritable conditions. Psychostimulants are effective for the symptomatic control of ADHD (primary recommended intervention) and the two sleep disorders (frequent off-label use). However, the common biological mechanism for these disorders has not been well understood. Using a previously collected genome-wide association study of narcolepsy and EHS, we calculated polygenic risk scores (PRS) for each individual. We investigated a possible genetic association between ADHD and narcolepsy traits in the Hamamatsu Birth Cohort for mothers and children (HBC study) (n = 876). Gene-set enrichment analyses were used to identify common pathways underlying these disorders. Narcolepsy PRS were significantly associated with ADHD traits both in the hyperactivity domain (e.g., P-value threshold P = 0.002) and inattention domain (e.g., P-value threshold P = 0.004). However, EHS PRS was not significantly associated with either domain of ADHD traits. Gene-set enrichment analyses revealed that pathways related to dopaminergic signaling, immune systems, iron metabolism, and glial cell function involved in both ADHD and narcolepsy. Findings indicate that ADHD and narcolepsy are genetically related, and there are possible common underlying biological mechanisms for this relationship. Future studies replicating these findings would be warranted to elucidate the genetic vulnerability for daytime sleepiness in individuals with ADHD.

OBJECTIVE To assess the efficacy of the non-stimulant guanfacine extended release (GXR) on attention-deficit/hyperactivity disorder (ADHD) symptoms in children and adolescents, with and without comorbid oppositional defiant disorder (ODD). METHODS Data were derived from 4 phase 3, randomized, placebo-controlled trials of dose-optimized GXR monotherapy, in which at least 10% of participants had a diagnosis of comorbid ODD. SPD503-312 and SPD503-316 were 10- to 13-week studies of GXR (1-7 mg/d). SPD503-314 and SPD503-307 were 8-week studies of GXR (1-4 mg/d). Efficacy was assessed using the ADHD Rating Scale IV (ADHD-RS-IV) total scores. RESULTS In total, 1,084 participants were included (SPD503-312 and SPD503-316, n = 537; SPD503-314, n = 333; and SPD503-307, n = 214). GXR was associated with significant improvements in ADHD core symptoms at endpoint in participants with and without ODD (p < 0.01 in all studies). Placebo-adjusted least-squares mean (95% confidence interval) changes from baseline to endpoint in the ADHD-RS-IV total scores in participants with and without ODD were -8.6 (-14.4, -2.8) and -7.3 (-9.5, -5.0) in the pooled data from SPD503-312 and SPD503-316, -12.6 (-19.6, -5.7) and -8.7 (-11.8, -5.5) in SPD503-314, and -12.7 (-17.3, -8.1) and -11.8 (-19.3, -4.4) in SPD503-307, respectively. The corresponding effect sizes were 0.688 and 0.598 in SPD503-312 and SPD503-316, 0.876 and 0.729 in SPD503-314, and 0.962 and 0.842 in SPD503-307. CONCLUSION The findings demonstrate the efficacy of GXR for treating ADHD in children and adolescents with comorbid ODD.

Objectives: To assess the efficacy and safety of a methylphenidate hydrochloride extended-release capsule (MPH-MLR) formulation in treating attention-deficit/hyperactivity disorder (ADHD) in preschool children. Methods: Children aged 4 to

Objective: We compared the placebo response (PR) as measured by the Test of Variables of Attention (TOVA) and the Conners’ Adult ADHD Rating Scale (CAARS) scores. Method: A retrospective data analysis from a double-blind placebo-controlled study of metadoxine-ER in adults with ADHD. An additional database was used for comparison to TOVA response after methylphenidate challenge (TOVA-MPH-R). Results: PR was highest when calculated from the TOVA-Attention Composite Score (ACS). The PR showed significantly fewer variables improving concomitantly compared with MPH-R. The most prominent correlation between the CAARS-PR and the TOVA-PR was in the Omissions score ( p = .032), which was age-dependent ( b = .0007, p

Objective To review all literature on the nonmedical use (NMU) and diversion of prescription stimulants to better understand the characteristics, risk factors, and outcomes of NMU and to review risk-reduction strategies. Method We systematically searched PubMed, PsycINFO, and SCOPUS from inception to May 2018 for studies containing empirical data about NMU and diversion of prescription stimulants. Additional references identified by the authors were also assessed for inclusion. Results A total of 111 studies met inclusion criteria. NMU and diversion of stimulants are highly prevalent; self-reported rates among population samples range from 2.1% to 58.7% and from 0.7% to 80.0%, respectively. A variety of terms are used to describe NMU, and most studies have examined college students. Although most NMU is oral, non-oral NMU also occurs. The majority of NMU is associated with no, or minor, medical effects; however, adverse medical outcomes, including death, occur in some individuals, particularly when administered by non-oral routes. Although academic and occupational performance enhancement are the most commonly cited motivations, there is little evidence that academic performance is improved by NMU in individuals without attention-deficit/hyperactivity disorder. Conclusion NMU of stimulants is a significant public health problem, especially in college students, but variations in the terms used to describe NMU and inconsistencies in the available data limit a better understanding of this problem. Further research is needed to develop methods to detect NMU, identify individuals at greatest risk, study routes of administration, and devise educational and other interventions to help reduce occurrence of NMU. Colleges should consider including NMU in academic integrity policies.

Background: The nature and magnitude of placebo and nocebo responses to ADHD medications is unclear. The extent to which response to active medications and placebo are inter-correlated has not been explored. Methods: We searched scientific literature until June 26, 2019 for published/unpublished double-blind, randomised placebo-controlled trials (RCTs) of ADHD medications in children, adolescents and adults. Authors and drug manufacturers were contacted for additional information. We assessed placebo effects on efficacy and nocebo effects on tolerability outcomes using aggregate data from trials and random-effects meta-analysis. We assessed the association of study design and patient features with placebo/nocebo response. Findings: We analysed 128 RCTs and found significant and heterogenous placebo effects for all efficacy outcomes, with no publication bias. We found nocebo effects on some tolerability outcomes. Apart from self-ratings, efficacy outcomes from other raters showed significant positive correlations between the baseline to endpoint placebo effects and the baseline to endpoint drug effects, suggesting that response to placebo and ADHD medications are influenced by similar non-specific factors. Baseline severity and type of rating scale influenced the magnitude of placebo response. Interpretation: Placebo effects are highly significant and response to placebo and ADHD medications are correlated, suggesting that shared non-specific factors influence response to both placebo and active medication. Although ADHD medications are superior to placebo, and placebo treatment in clinical practice is not feasible, clinicians should attempt to incorporate factors associated with placebo effects into clinical care, and future studies should explore how such effects influence response to medication treatment. Funding Statement: This was not a funded study. Declaration of Interests: In the past year, Dr. Faraone received income, potential income, travel expenses continuing education support and/or research support from Takeda, OnDosis, Tris, Otsuka, Arbor, Ironshore, Rhodes, Akili Interactive Labs, Enzymotec, Sunovion, Supernus and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is Program Director of www.adhdinadults.com. In the past year, Dr. Newcorn is/has been an advisor and/or consultant for Adlon Therapeutics, Arbor, Eisai, NLS, OnDosis, Rhodes, Shire/Takeda, and Supernus. He was a DSMB member for Pfizer and Sunovion, and received research funds from Otsuka, Shire and Supernus. He also has received speaker fees from Shire/Takeda for disease-state presentations and served as a consultant for the US National Football League. Dr. Cipriani has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation and Angelini Pharma. Dr. Brandeis serves as an unpaid scientific consultant for an EUfunded neurofeedback trial. Anna Kaiser reports has no financial disclosures. Sarah Hohmann has no financial disclosures. Dr. Hage received conference support, speaker´s fee and/or served in an advisory role for Shire/Takeda and Lily. He was involved as investigator in clinical trials by Shire, Janssen-Cilag, Otsuka, Sunovion, Servier, Lundbeck, Takeda,Nuvelution, Gedeon Richter, and Emalex. The present work is unrelated to the above relationships. Dr. Cortese declares reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH) in relation to lectures delivered for ACAMH, Canadian ADHD Resource Alliance (CADDRA), British Association of Psychopharmacology (BAP), and from Healthcare Convention for educational activity on ADHD.

The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood.In vitro studies using cryopreserved, plated human hepatocytes (cPHHs) and pooled human liver microsomes (HLMs) were performed to more thoroughly characterise the metabolism of several ADHD medications.The use of enzyme-specific chemical inhibitors indicated a role for CYP2D6 in atomoxetine (ATX) metabolism, and roles for CYP3A4/5 in guanfacine (GUA) metabolism.The 4-hydroxy-atomoxetine and N-desmethyl-atomoxetine pathways represented 98.4% and 1.5% of ATX metabolism in cPHHs, respectively. The 3-OH-guanfacine pathway represented at least 2.6% of GUA metabolism in cPHHs, and 71% in HLMs.The major metabolising enzyme for methylphenidate (MPH) and dexmethylphenidate (dMPH) could not be identified using these methods because these compounds were too unstable. Hydrolysis of these medications was spontaneous and did not require the presence of protein to occur.Clonidine (CLD), amphetamine (AMPH), and dextroamphetamine (dAMPH) did not deplete substantially in cPHHs nor HLMs, suggesting that these compounds may not undergo considerable hepatic metabolism. The major circulating metabolites of AMPH and dAMPH (benzoic acid and hippuric acid) were not observed in either system, and therefore could not be characterised. Additionally, inhibition experiments suggested a very minimal role for CYP2D6 in CLD and AMPH metabolism. The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood. In vitro studies using cryopreserved, plated human hepatocytes (cPHHs) and pooled human liver microsomes (HLMs) were performed to more thoroughly characterise the metabolism of several ADHD medications. The use of enzyme-specific chemical inhibitors indicated a role for CYP2D6 in atomoxetine (ATX) metabolism, and roles for CYP3A4/5 in guanfacine (GUA) metabolism. The 4-hydroxy-atomoxetine and N-desmethyl-atomoxetine pathways represented 98.4% and 1.5% of ATX metabolism in cPHHs, respectively. The 3-OH-guanfacine pathway represented at least 2.6% of GUA metabolism in cPHHs, and 71% in HLMs. The major metabolising enzyme for methylphenidate (MPH) and dexmethylphenidate (dMPH) could not be identified using these methods because these compounds were too unstable. Hydrolysis of these medications was spontaneous and did not require the presence of protein to occur. Clonidine (CLD), amphetamine (AMPH), and dextroamphetamine (dAMPH) did not deplete substantially in cPHHs nor HLMs, suggesting that these compounds may not undergo considerable hepatic metabolism. The major circulating metabolites of AMPH and dAMPH (benzoic acid and hippuric acid) were not observed in either system, and therefore could not be characterised. Additionally, inhibition experiments suggested a very minimal role for CYP2D6 in CLD and AMPH metabolism.

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.

Stimulants (methylphenidate or amphetamines) are the recommended first-line option for the pharmacological treatment of individuals with attention deficit hyperactivity disorder (ADHD). However, some patients with ADHD will not respond optimally to stimulants. Here, we discuss strategies to manage stimulant-refractory ADHD, based on the recommendations advanced in clinical guidelines, knowledge of expert practice in the field, and our own clinical recommendations, informed by a comprehensive literature search in PubMed, PsycInfo, EMBASE + EMBASE classic, OVID Medline, and Web of Science (up to 30 March 2021). We first highlight the importance of stimulant optimization as an effective strategy to increase response. We then discuss a series of factors that should be considered before using alternative pharmacological strategies for ADHD, including poor adherence, time action properties of stimulants (and wearing-off of effects), poor tolerability (that prevents the use of higher, more effective doses), excessive focus on or confounding from presence of comorbid non-ADHD symptoms, and tolerance. Finally, we consider the role of non-stimulants and combined pharmacological approaches. While the choice of medication for ADHD is still to a large extent based on a trial-and-error process, there are reasonably accepted data and guidelines to aid in clinical decision-making. It is hoped that advances in precision psychiatry in the years ahead will further guide prescribers to tailor medication choice to the specific characteristics of the patient.

Objective: To examine the efficacy of lisdexamfetamine (LDX) versus placebo on behavioral attributes of sluggish cognitive tempo (SCT) in adults with attention-deficit/hyperactivity disorder (ADHD) and SCT. Methods: In a randomized crossover trial conducted January 2016-April 2018, 38 adults with DSM-5 ADHD (via the Adult ADHD Clinical Diagnostic Scale v1.2) and SCT were recruited at 2 academic medical centers and assessed for symptoms of ADHD, SCT, executive function deficits, and functional impairment at baseline and weekly during treatment. Participants received 4 weeks of treatment with either LDX (30-70 mg/d; mean = 59.1 ± 14.8 mg/d) or matching placebo (mean = 66.6 ± 9.1 mg/d) with a 2-week washout before switching to the other arm. The ADHD Rating Scale and Barkley Adult ADHD Rating Scale-IV SCT subscale were coprimary outcome measures. Results: There were moderately large treatment effects of LDX vs placebo on SCT ratings in both treatment periods (block 1 effect size = 0.68; block 2 effect size = 0.61), which reached significance only in block 1 owing to carryover effects of the first treatment epoch into the second. Significant effects were also seen for LDX over placebo in ADHD, executive function deficit, and functional impairment ratings, without order effects; no site differences were seen except on the Global Executive Complex score of the Behavior Rating Inventory of Executive Function-Adult Version. No moderating effects of sex, age, race, and ethnicity were seen. Conclusions: Adults with ADHD and comorbid SCT had significant improvement after LDX vs placebo in ratings of SCT, ADHD, executive function deficits, and functional impairment. This is the first study to show improvement in SCT after stimulant therapy in adults with ADHD. Trial Registration: ClinicalTrials.gov identifier: NCT02635035.

The objective of this study was to identify the relationship between sluggish cognitive tempo (SCT) symptoms and symptoms of attention-deficit/hyperactivity disorder (ADHD), executive function (EF), and emotional dyscontrol. A referred sample of adults (N = 87, age 18–57 years) was assessed for symptoms of ADHD using the Adult ADHD Investigator Symptom Rating Scale (AISRS), Barkley SCT scale, and Behavior Rating Inventory of Executive Function - Adult version (BRIEF-A), and for symptoms of impairment using the Clinical Global Impressions scale and Barkley Functional Impairment Scale. Adults with SCT and ADHD had greater inattention and impairment than adults with ADHD only. Also, the group with both SCT and ADHD had higher self-reported ratings of EF on the BRIEF-A, which was not evident on the clinician ratings of EF on the AISRS. The results show that adults with comorbid SCT and ADHD have greater symptoms of inattention and higher levels of impairment in this preliminary analysis. [ Psychiatr Ann. 2019;49(10)457–465.]

Background: It has been hypothesized that attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) share common neurobiological features. When abnormalities in the mesolimbic reward system are characteristic of children with ADHD, it is unclear whether youth at particularly elevated risk for SUD may exhibit any further disturbances. The objective of this pilot study is to examine possible neurobiological differences among youth with different levels of SUD risk before exposure to any abusable substances. Methods: We recruited 47 drug-naive children aged 8–13 divided into (1) Low Risk (LR)—ADHD only (n = 16); (2) High Risk (HR)—ADHD+familial SUD (n = 17); and (3) healthy controls (HC, n = 14) who underwent one functional magnetic resonance imaging scan while performing a hybrid task. We used the omnibus analysis of covariance model to assess for group differences in brain activation in regions linked to the brain reward and behavioral control systems. Results: Behavioral analysis showed significant Cue and Flanker main effects, but no significant main effect for Group. Whole-brain analysis showed significant differences in widely distributed networks related to both reward processing and behavioral control. Region of interest (ROI) activations showed that the HR group had the highest activation in the right putamen during both expected rewards and unexpected nonreward outcomes and in the anterior cingulate cortex (ACC) during unexpected nonreward outcomes, while LR and HC youth showed similarly low activation during these contrasts. Furthermore, the LR and HR groups showed lower activation than HC in the right ACC and the right caudate during flanker contrasts. Conclusions: These are the first preliminary results to demonstrate that the magnitude of activation during reward notification differs as a function of reward outcome in youth at high versus LR for SUD, such that youth at LR for SUD exhibit the highest activation for positive rewards, whereas those at HR for SUD exhibit the highest activation during negative rewards.

The present study investigated whether symptom reduction in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with guanfacine extended release (GXR) can be explained by sedative effects of the medication. Data from four double-blind, randomized, placebo-controlled, phase 3 trials of GXR monotherapy (1-7 mg/day; morning administration) in children (aged 6-12 years) and adolescents (aged 13-17 years) with ADHD were analyzed post hoc. Two studies used forced-dose titration and two used flexible-dose titration. Efficacy was determined using ADHD Rating Scale IV (ADHD-RS-IV) scores. Sedative treatment-emergent adverse events (TEAEs) included somnolence, sedation and hypersomnia. The proportion of responders (≥ 30% reduction in ADHD-RS-IV total score) increased from weeks 1 to 4 and remained stable to study endpoint. Sedative TEAEs generally peaked at the first week in which the target dose was achieved and then declined. In subgroup analyses, significant placebo-adjusted improvements in ADHD-RS-IV total scores were observed in participants without any sedative TEAEs in the forced-dose and flexible-dose studies (nominal p 0.001). In addition, GXR was associated with significant improvements in both inattentive and hyperactive-impulsive symptoms, as assessed by the ADHD-RS-IV subscale scores (nominal p 0.001) and by the ADHD-RS-IV total score in participants with different ADHD subtypes (nominal p 0.05). Thus, the efficacy of GXR in children and adolescents with ADHD is not primarily due to sedation, although some contribution to symptom reduction cannot be excluded, especially early in treatment when rates of sedative TEAEs are at their highest.

Background: The objective of this study was to examine changes in the activation of the brain reward system following treatment with lisdexamfetamine (LDX) vs. placebo (PL) as a function of clinical improvement in attention deficit/hyperactivity disorder (ADHD) symptoms. Methods: Twenty adults with ADHD were included in a randomized cross-over study. Participants underwent two functional magnetic resonance imaging (fMRI) scans, after receiving 3 to 5 weeks of treatment with both LDX and PL. During scanning, participants performed the passive-avoidance learning task to assess reward-related learning using computational variables (e.g., estimated value and prediction error). Pre-treatment to post-treatment symptom change was assessed via the ADHD Rating Scale (ADHD-RS). The imaging contrasts were Object Choose or Object Refuse during the object choice component of the task, modulated by expected value (reward vs. nonreward cue), and Reward vs. Punishment during feedback, modulated by prediction error (expected vs. actual outcome). To address the primary objective, we performed group-level mass univariate analyses between pre-treatment to post-treatment percent change of the ADHD-RS total scores and the four contrast images under the choice and feedback conditions, with significance set at a whole-brain voxel-wise threshold of p < .05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels. Results: Improvement in ADHD symptoms was accompanied by significant increases of brain activation during the Object Refuse, Reward and Punishment contrasts in a widespread network including left caudate and putamen, and right orbitofrontal cortex (i.e., reward-related signaling) and left middle frontal, superior frontal, and precentral gyri (i.e., executive control). Conclusions: These findings are the first to show that the increase in responsiveness of systems engaged in reward processing with LDX treatment is positively related to symptom improvement. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD.

The nature and magnitude of placebo and nocebo responses to ADHD medications and the extent to which response to active medications and placebo are inter-correlated is unclear. To assess the magnitude of placebo and nocebo responses to ADHD and their association with active treatment response. We searched literature until June 26, 2019, for published/unpublished double-blind, randomised placebo-controlled trials (RCTs) of ADHD medication. Authors were contacted for additional data. We assessed placebo effects on efficacy and nocebo effects on tolerability using random effects meta-analysis. We assessed the association of study design and patient features with placebo/nocebo response. We analysed 128 RCTs (10,578 children/adolescents and 9175 adults) and found significant and heterogenous placebo effects for all efficacy outcomes, with no publication bias. The placebo effect was greatest for clinician compared with other raters. We found nocebo effects on tolerability outcomes. Efficacy outcomes from most raters showed significant positive correlations between the baseline to endpoint placebo effects and the baseline to endpoint drug effects. Placebo and nocebo effects did not differ among drugs. Baseline severity and type of rating scale influenced the findings. Shared non-specific factors influence response to both placebo and active medication. Although ADHD medications are superior to placebo, and placebo treatment in clinical practice is not feasible, clinicians should attempt to incorporate factors associated with placebo effects into clinical care. Future studies should explore how such effects influence response to medication treatment. Upon publication, data will be available in Mendeley Data: PROSPERO (CRD42019130292).

Objective: The purpose of the present study was to characterize prescription stimulant non-medical use (NMU) in adolescents between the ages of 13 and 18 years seeking treatment for substance use disorder (SUD) with the Comprehensive Health Assessment Tool for Teens (CHAT™). Method: Adolescents being evaluated for SUD treatment between Q1 2010 and Q3 2017 ( n = 20,189) completed the CHAT™. Results: About 4.3% of the sample ( N = 867) of adolescents in SUD treatment reported past 30-day prescription stimulant NMU. Compared to those without past 30-day prescription stimulant NMU, more reported a lifetime diagnosis of learning disorder or ADHD, more took medication for emotional, behavioral, or learning disorders, received past-month inpatient treatment, or were currently not enrolled in school. Prescription stimulants were most often taken orally for NMU, however, approximately half reported using alternate routes of administration, the most prominent of which was intranasal use. Conclusion: About 4.3% of adolescents in SUD treatment evaluation reported past 30-day prescription stimulant NMU. Greater percentages of lifetime learning disorder, medication use, past-month inpatient treatment, school unenrollment, and overall substance misuse were associated with prescription stimulant NMU, as were alternate routes of administration. These data reveal an ongoing, persistent level of past-30-day NMU of prescription stimulants among adolescents being evaluated for SUD treatment.

Impulsive aggressive (IA, or impulsive aggression) behavior describes an aggregate set of maladaptive, aggressive behaviors occurring across multiple neuropsychiatric disorders. IA is reactive, eruptive, sudden, and unplanned; it provides information about the severity, but not the nature, of its associated primary disorder. IA in children and adolescents is of serious clinical concern for patients, families, and physicians, given the detrimental impact pediatric IA can have on development. Currently, the ability to properly identify, monitor, and treat IA behavior across clinical populations is hindered by two major roadblocks: (1) the lack of an assessment tool designed for and sensitive to the set of behaviors comprising IA, and (2) the absence of a treatment indicated for IA symptomatology. In this review, we discuss the clinical gaps in the approach to monitoring and treating IA behavior, and highlight emerging solutions that may improve clinical outcomes in patients with IA.

Background Prefrontal-limbic circuits that form the neural architecture for emotion to influence behavior have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and represent a potentially important target of medication treatment that has not been substantively evaluated. This study tested the effect of the psychostimulant prodrug lisdexamfetamine dimesylate on amygdala activation and connectivity during the emotional bias of response execution and inhibition. Methods Twenty-five adults with ADHD were scanned twice with event-related functional magnetic resonance imaging while performing an emotional go/no-go task after 3 to 4 weeks of lisdexamfetamine treatment and 3 weeks off medication in a randomized, counterbalanced, hybrid crossover design. Drug, trial type, and face emotion (happy, sad, or neutral) were included as within-subjects factors in repeated measures analyses of activation and connectivity. Results Lisdexamfetamine was associated with increased right amygdala activation and reduced psychophysiological interactions with the orbital aspect of the left inferior frontal gyrus specifically for responses to sad faces compared with placebo, but there was no effect on the accuracy of response execution or inhibition. The relative gain in right amygdala activation in response to sad faces for lisdexamfetamine was correlated with a reduction in symptoms of ADHD. Conclusions Treatment with lisdexamfetamine potentiates affective encoding in amygdala, purportedly via catecholaminergic mechanisms, but functionally disconnects the amygdala from inferior frontal regions that encode behavioral significance—resulting in reduced emotional bias of cognitive control. Pinpointing the neurophysiologic underpinnings of therapeutic improvement with lisdexamfetamine represents a first step in developing targeted approaches to treatment of ADHD.

Objective: Several ADHD pharmacological trials reported high placebo response (PR) rates. This study aims to characterize the PR in adult ADHD. Method: A retrospective cohort analysis of the placebo arm (140 adults with ADHD, 18-55 yrs, M:F 46.4%-53.6%) of a 6-week randomized, multicenter, double-blind metadoxine study, using Conners’ Adult ADHD Rating Scale (CAARS) and the Adult ADHD Self-Report Scale (ASRS), was conducted. Results: Pre–post changes in placebo-treated adults were significant for both the CAARS and ASRS, F(2.9, 404.5) = 61.2, p < .00001, F(2.8, 383.0) = 43.1, p < .00001, respectively. Less than half of the participants had a PR which began early in treatment and persisted; almost 50% had a variable, inconsistent PR. Conclusion: In the current sample, PR in adult ADHD was prominent on both symptom scales and the investigator–rater instrument. Therefore, using investigator ratings as a primary endpoint does not necessarily attenuate PR. Of note, about half of the PR is variable, suggesting unreliable determination of efficacy.

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.

Data are reported from SPD503-318, a phase 3, open-label, safety study of guanfacine extended release (GXR) in European children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Participants received dose-optimized GXR (1–7 mg/day) for up to 2 years. Of 215 enrolled participants, 214 were included in the safety population and 133 completed the study. Participants’ mean age was 11.7 years and 73.8% were male. Overall, 177 participants (82.7%) experienced a treatment-emergent adverse event (TEAE). TEAEs reported in at least 10% of participants were somnolence (36.0%), headache (28.5%), fatigue (20.1%), and nasopharyngitis (11.7%). Serious TEAEs were reported in 4.7% of participants and TEAEs leading to discontinuation were reported in 3.3% of participants. There were no deaths. Mean z-scores for BMI were stable throughout the study. The incidence of sedative TEAEs (somnolence, sedation, and hypersomnia) peaked during week 3 and decreased thereafter. Small changes from baseline to the final assessment in mean supine pulse [− 5.5 bpm (standard deviation, 12.98)] and blood pressure [systolic, 0.6 mmHg (9.32); diastolic, 0.2 mmHg (9.17)] were reported. ADHD symptoms initially decreased and remained significantly lower than baseline at study endpoint. At the final assessment, the mean change in ADHD-RS-IV total score from baseline was − 19.8 (standard error of mean, 0.84; nominal p

Background Psychostimulants are considered first-line pharmacotherapy for youth with attention-deficit/hyperactivity disorder (ADHD), but questions remain regarding the comparative efficacy of amphetamine- and methylphenidate-based agents. Objective Our objective was to describe two acute randomized, double-blind, placebo-controlled, head-to-head studies of lisdexamfetamine dimesylate (LDX) and osmotic-release oral system methylphenidate (OROS-MPH) in adolescents with ADHD. Methods Adolescents (13–17 years) diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria were enrolled in an 8-week flexible-dose study [LDX 30–70 mg/day (n = 186 randomized); OROS-MPH 18–72 mg/day (n = 185 randomized); placebo (n = 93 randomized)] or a 6-week forced-dose study [LDX 70 mg/day (n = 219 randomized); OROS-MPH 72 mg/day (n = 220 randomized); placebo (n = 110 randomized)]. Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) total score changes from baseline (primary endpoint) at week 8 (flexible-dose study) or week 6 (forced-dose study) were assessed with mixed-effects models for repeated measures. Secondary endpoints included improvement on the dichotomized Clinical Global Impressions–Improvement scale (CGI-I; key secondary endpoint) and changes from baseline on the ADHD-RS-IV subscales. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. Results Least squares (LS) mean ± standard error of the mean (SEM) ADHD-RS-IV total score changes from baseline to end of treatment were −17.0 ± 1.03 with placebo, −25.4 ± 0.74 with LDX, and −22.1 ± 0.73 with OROS-MPH in the forced-dose study and −13.4 ± 1.19 with placebo, −25.6 ± 0.82 with LDX, and −23.5 ± 0.80 with OROS-MPH in the flexible-dose study. LS mean ± SEM treatment difference for the change from baseline significantly favored LDX over OROS-MPH in the forced-dose [−3.4 ± 1.04, p = 0.0013, effect size (ES) −0.33] but not the flexible-dose (−2.1 ± 1.15, p = 0.0717, ES −0.20) study. The percentage of improved participants on the dichotomized CGI-I at end of treatment was significantly greater with LDX than with OROS-MPH in the forced-dose study (81.4 vs. 71.3%, p = 0.0188) but not the flexible-dose study (LDX 83.1%, OROS-MPH 81.0%, p = 0.6165). The LS mean ± SEM treatment differences for change from baseline on the ADHD-RS-IV hyperactivity/impulsivity and inattentiveness subscales nominally favored LDX in the forced-dose study (hyperactivity/impulsivity subscale −1.3 ± 0.49, nominal p = 0.0081, ES −0.27; inattentiveness subscale −2.0 ± 0.63, nominal p = 0.0013, ES −0.33), but there were no significant differences between active treatments in the flexible-dose study. In both studies, LDX and OROS-MPH were superior to placebo for all efficacy-related endpoints (all nominal p