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Many youths with attention-deficit/hyperactivity disorder (ADHD) experience significant long-term impairment and may develop concurrent mental and somatic health difficulties as adults. This is associated with burden and costs for the individual and society which could be prevented through continued support in youth. Yet, only few young people transition to adult mental health services for ongoing care in different countries worldwide. We provide an overview on current transition practices, highlighting the gaps in knowledge and the barriers to effective service transitioning, while considering the large geographical variation in available guidelines and service provision. For ease of use, this review is organized in a question-and-answer format covering different aspects of the transition process and considering both service users' and clinicians' perspectives. Consensus is needed to identify those that require continued care, the optimal timing to arrange transition, and the most suitable services. Finally, we discuss cost-effectiveness of transition practices, consider examples of best practice, and propose recommendations on how to improve transitional care, including the importance of service users' input into transition planning., (© 2024 The Author(s). Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

We appreciate the comments of Gilman et al. (2023) on our paper and their acknowledgement of its importance in highlighting the significance of this area of research. Further, their acknowledgment that the primary results of our study are in a range that is similar to those from other published studies of children exposed to highly stressful environmental events emphasizes the validity of our findings and the important extension of our results to children experiencing these events in utero. They, however, raised concerns about some of the results regarding specific types of psychiatric disorders and sex-specific results related to the prenatal Superstorm Sandy hurricane exposure. We comment on the various issues related to the paper below but will not respond to comments regarding the press coverage of this article, which we think are beyond the scope of this commentary., (© 2023 Association for Child and Adolescent Mental Health.)

Importance: The use of evidence-based standardized outcome measures is increasingly recognized as key to guiding clinical decision-making in mental health. Implementation of these measures into clinical practice has been hampered by lack of clarity on what to measure and how to do this in a reliable and standardized way., Objective: To develop a core set of outcome measures for specific neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder (ADHD), communication disorders, specific learning disorders, and motor disorders, that may be used across a range of geographic and cultural settings., Evidence Review: An international working group composed of clinical and research experts and service users (n = 27) was convened to develop a standard core set of accessible, valid, and reliable outcome measures for children and adolescents with NDDs. The working group participated in 9 video conference calls and 8 surveys between March 1, 2021, and June 30, 2022. A modified Delphi approach defined the scope, outcomes, included measures, case-mix variables, and measurement time points. After development, the NDD set was distributed to professionals and service users for open review, feedback, and external validation., Findings: The final set recommends measuring 12 outcomes across 3 key domains: (1) core symptoms related to the diagnosis; (2) impact, functioning, and quality of life; and (3) common coexisting problems. The following 14 measures should be administered at least every 6 months to monitor these outcomes: ADHD Rating Scale 5, Vanderbilt ADHD Diagnostic Rating Scale, or Swanson, Nolan, and Pelham Rating Scale IV; Affective Reactivity Index; Children's Communication Checklist 2; Colorado Learning Disabilities Questionnaire; Children's Sleep Habits Questionnaire; Developmental-Disability Children's Global Assessment Scale; Developmental Coordination Disorder Questionnaire; Family Strain Index; Intelligibility in Context Scale; Vineland Adaptive Behavior Scale or Repetitive Behavior Scale-Revised and Social Responsiveness Scale; Revised Child Anxiety and Depression Scales; and Yale Global Tic Severity Scale. The external review survey was completed by 32 professionals and 40 service users. The NDD set items were endorsed by more than 70% of professionals and service users in the open review survey., Conclusions and Relevance: The NDD set covers outcomes of most concern to patients and caregivers. Use of the NDD set has the potential to improve clinical practice and research.

Objective: To provide an overview of Joe Biederman's contributions to child and adolescent psychiatry., Method: Nine colleagues described his contributions to: psychopharmacology, comorbidity and genetics, pediatric bipolar disorder, autism spectrum disorders, Tourette's and tic disorders, clinical and neuro biomarkers for pediatric mood disorders, executive functioning, and adult ADHD., Results: Joe Biederman left us with many concrete indicators of his contributions to child and adolescent psychiatry. He set up the world's first pediatric psychopharmacology clinic and clinical research program in child adolescent psychiatry. As a young faculty member he began a research program that led to many awards and eventual promotion to full professor at Harvard Medical School. He was for many years the most highly cited researcher in ADHD. He achieved this while maintaining a full clinical load and was widely respected for his clinical acumen., Conclusion: The world is a better place because Joe Biederman was here., 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: Stephen V. Faraone: Over the past 3 years, Dr. Faraone received income, potential income, travel expenses, and/or research support from Aardvark, Aardwolf, AIMH, Akili, Arbor, Atentiv, Axsome, Genomind, Ironshore, Johnson & Johnson/Kenvue, Kanjo, KemPharm/Corium, Medice, Noven, Ondosis, Otsuka, Rhodes, Shire/Takeda, Sky Therapeutics, Supernus, Tris, and Vallon. 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. In addition, he is the program director of www.adhdinadults.com. Dr. Faraone is supported by the European Union’s Horizon 2020 research and innovation program under grant agreement No 965381; NIMH grants U01AR076092-01A1, 1R21MH1264940, R01MH116037; 1R01NS128535-01; Oregon Health and Science University, Otsuka Pharmaceuticals, Noven Pharmaceuticals Incorporated, and Supernus Pharmaceutical Company. Jeffrey Newcorn over the past 3 years, has received financial compensation as a consultant, advisory board member, and lecturer from Shire Pharmaceuticals (the study sponsor and manufacturer of the study drug Vyvanse (Lisdexamfetamine)). Dr. Newcorn also receives financial compensation from other companies which either develop or assess medicines used for the treatment of ADHD. Janet Wozniak, MD receives research support from PCORI, Demarest Lloyd, Jr. Foundation, and the Baszucki Brain Research Fund. In the past, Dr. Wozniak has received research support, consultation fees or speaker’s fees from Eli Lilly, Janssen, Johnson and Johnson, McNeil, Merck/Schering-Plough, the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH), Pfizer, and Shire. She is the author of the book, “Is Your Child Bipolar” published May 2008, Bantam Books. Her spouse receives royalties from UpToDate; consultation fees from Indorsia, Cozen O’Connor, Noctrix, FoxRothschild, Sterne Kessler Goldstein & Fox, Teladoc Health, Inc., and The International Law Firm of Winston & Strawn LLP; and research support from Merck, NeuroMetrix, American Regent, NIH, NIMH, the RLS Foundation, and the Baszucki Brain Research Fund. In the past, he has received honoraria, royalties, research support, consultation fees or speaker’s fees from: Emalex, Disc Medicine, Avadel, HALEO, OrbiMed, CVS, Otsuka, Cambridge University Press, Advance Medical, Arbor Pharmaceuticals, Axon Labs, Boehringer-Ingelheim, Cantor Colburn, Covance, Cephalon, Eli Lilly, FlexPharma, GlaxoSmithKline, Impax, Jazz Pharmaceuticals, King, Luitpold, Novartis, Neurogen, Novadel Pharma, Pfizer, Sanofi-Aventis, Sepracor, Sunovion, Takeda, UCB (Schwarz) Pharma, Wyeth, Xenoport, and Zeo. Gagan Joshi is supported by the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) under Award Number K23MH100450. In 2023, he receives research support from the Demarest Lloyd, Jr. Foundation as a primary investigator (PI) for investigator-initiated studies. Additionally, he receives research support from Genentech as a site PI for multi-site trials. Dr. Joshi is also a consultant for EuMentis Theraputics. In the past 3 years, he has received speaker’s honorariums from the American Academy of Child and Adolescent Psychiatry, American Physician Institute, Asian College of Neuro-psychopharmacology, Hackensack Meridian Health, University of Colorado-Colorado Springs, and Kennedy Krieger Institute; he received research support from F. Hoffmann-La Roche Ltd. s a site PI for multi-site trial. Through Mass General Brigham Innovation, Dr. Joshi receives royalties from a licensed method for treating autism spectrum disorder. Barbara Coffey receives income, research support, or honoraria payments from: American Academy of Child and Adolescent Psychiatry, Emalex, Florida Department of Health, Galen Mental Health, Harvard Medical School /Psychiatry Academy, New Venture Fund, NIMH/NINDS, Partners Healthcare, Skyland Trail, Tourette Association of America, Zynerba. Mai Uchida has received honorarium from American Physicians Institute and Mochida Pharmaceuticals and royalties from the book “Ask The Geniuses About the Future” (Magazine House Publishing) and has consulted to Moderna and Guidepoint. Timothy Wilens receives or has received grant support from NIH(NIDA). Dr. Timothy Wilens has co/edited books: Straight Talk About Psychiatric Medications for Kids (Guilford Press), ADHD in Adults and Children (Cambridge University Press), Massachusetts General Hospital Comprehensive Clinical Psychiatry (Elsevier), Massachusetts General Hospital Psychopharmacology and Neurotherapeutics (Elsevier), and Update on Pharmacotherapy of ADHD (Elsevier Press). Dr. Wilens has a licensing agreement with Ironshore (BSFQ Questionnaire) and 3D Therapy. Dr. Wilens is Chief, Division of Child and Adolescent Psychiatry and (Co) Director of the Center for Addiction Medicine at Massachusetts General Hospital. He serves as a clinical consultant to U.S. Minor/Major League Baseball, Gavin Foundation and Bay Cove Human Services. Craig Surman has received, in his lifetime, consulting fees from Eisai, Ironshore, Kaylon, Mcneil, NLS Pharma, Neurocentria, Nutricia, Otsuka, Pfizer, Adlon/Purdue, Rhodes, Shire, Somaxon, Sunovion, Supernus, Takeda, and Teva. He has also received payments for lectures for Alcobra, Arbor, McNeil, Janssen, Janssen-Ortho, Novartis, Shire, and Reed/MGH Academy (funded by multiple companies) as well as GME CME (funded by multiple companies). Royalties have been given to Craig B. H. Surman from Berkeley/Penguin for ““FASTMINDS” How to Thrive if You have ADHD (or think you might)” and from Humana/Springer for “ADHD in Adults: A Practical Guide to Evaluation and Management.” Additionally, Dr. Surman has conducted clinical research at Massachusetts General Hospital supported by Abbot, Cephalon, Hilda and Preston Davis Foundation, Eli Lilly, Magceutics/Neurocentria, Jazz, Johnson & Johnson/McNeil, Lundbeck, Merck, Nordic Naturals, Shire, and Takeda. Thomas J. Spencer receives royalties from Cambridge University Press for book publication and from MGH Corporate Licensing for ADHD rating scales, holds a US patent (#14/027,676) for a nonstimulant treatment for ADHD (no license fees), and has a patent pending (#61/233,686) for a method to prevent stimulant abuse (no license fees).

Background: Accumulating evidence suggests that sleep disordered breathing (SDB) is under-recognized in youth and adults with ADHD. SDB may contribute to exacerbating pre-existing ADHD symptoms and may play a role in the development of cognitive deficits that may mimic ADHD symptoms., Method: We conducted a focused review of publications on cross-prevalence, overlapping clinical and neurobiological characteristics and possible mechanisms linking SDB and ADHD., Results: Exiting studies suggest that co-occurrence of SDB and ADHD is as high as 50%, with frequent overlap of clinical symptoms such as distractibility and inattention. Mechanisms linking these conditions may include hypoxia during sleep, sleep fragmentation and activation of inflammation, all of which may affect brain structure and physiology to produce disturbances in attention., Conclusions: The relationship between SDB and ADHD symptoms appear well-supported and suggests that more research is needed to better optimize procedures for SDB assessment in youth being evaluated and/or treated for ADHD., 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. Ben Miraglia – no conflicts. Dana Prodanova – 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.

Objective: There is growing evidence of involvement of inflammatory mechanisms in ADHD. Previous studies found significantly higher rates of ADHD among children with FMF. The present study examined the rate of exposure to FMF in children with a later (within a 5-year period) diagnosis of ADHD compared to non-ADHD children., Methods: A population-based case-control study of all children (<18 years) registered in Leumit Health Services during 01.01.2006 to 06.30.2021. All cases met ICD-9/10 criteria for ADHD. They were matched by age, sex, and socioeconomic status on a 1:2 rate to randomly selected non-ADHD controls., Results: Fifty-six (0.30%) children with ADHD ( N  = 18,756) were previously diagnosed with FMF compared to 65 of 37,512 controls (0.17%). A significant, independent association existed between a preceding FMF diagnosis and a later ADHD diagnosis [OR = 1.72 (95% CI 1.18-2.51); p  = .003]., Conclusions: The mechanisms underlying the association w between FMF and later ADHD diagnosis merit further elucidation., 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: Over the past 3 years Dr. Eugene Merzon received support for continuing medical education programs or advisory boards meetings sponsored by: SK-Pharma, Medison Israel, Teva Israel, AstraZeneca Israel, and Merk Israel. Over the past 3 years Dr. Ariel Israel has No disclosure. Dr. Beth Krone: Over the past 3 years, Dr. Krone has received financial compensation as a scientific consultant to HIPPO T & C and MaxisHealth, makers of digital health technologies for ADHD. Dr. Krone also provides clinical review for Signant Health, a company that provides rater training for clinical trials. Over the past 3 years Ms. Shani Medvejer has no disclosure. Over the past 3 years Ms. . Shira Cohen has no disclosure. Over the past 3 years Dr. Ilan Green has no disclosure. Over the past 3 years Dr. Avivit Golan-Cohen has no disclosure. Over the past 3 years Prof. Shlomo Vinker has no disclosure. Over the past 3 years Prof. Stephen V. Faraone received income, travel expenses, research support, continuing medical education programs, or advisory boards, sponsored by: Aardvark, Aardwolf, Akili, Atentiv, Corium, Genomind, Ironshore, Medice, Noven, Otsuka, Sandoz, Sky Therapeutics, Supernus, Tris, and Vallon. In previous years, he received support from: Alcobra, Arbor, Aveksham, Axsome, CogCubed, Eli Lilly, Enzymotec, Impact, Janssen, KemPharm, Lundbeck/Takeda, Shire/Takeda, McNeil, NeuroLifeSciences, Neurovance, Novartis, Pfizer, Rhodes, Shire, and Sunovion. 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. In addition, he is the program director of www.adhdinadults.com and www.ADHDEvidence.org Dr. Faraone is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 965381; NIMH grants U01AR076092-01A1, 1R21MH1264940, R01MH116037, and 1R01NS128535—01; Oregon Health and Science University. Over the past 3 years, Prof. Jeff Newcorn has received financial compensation as a consultant, advisory board member, and lecturer from Shire Pharmaceuticals (the study sponsor and manufacturer of the study drug Vyvanse (Lisdexamfetamine)). Dr. Newcorn also receives financial compensation from other companies which either develop or assess medicines used for the treatment of ADHD. Over the past 3 years Prof. Shai Ashkenazi has no disclosure relevant to this manuscript. Over the past 3 years Prof Abraham Weizman declares honoraria for educational lectures from the following pharmaceutical companies: Pfizer, Novartis, Janssen, Lundbeck, Teva, Unipharm, Dexcel, and Medison. None of these are relevant to the submitted manuscript. Over the past 3 years, Prof. Iris Manor has received financial compensation as a consultant, advisory board member, and lecturer from Madison Ltd. (the distributor of the study drug Vyvance (Lisdexamfetamine) in Israel) and Teva Israel (the manufacturer and the distributor in Israel of the study drug attent (Mixed Amphetamine Salts), and attent XR (Mixed Amphetamine Salts—Extended Release). She was a lecturer for Takeda Ltd. Dr. Manor is a consultant to the startup companies Peri and Vizo, which either develop or assess medicines used to treat ADHD. She also served/serves as a PI (as a part of her position in Geha MHC) in several startups: Nuance Ltd and Mindtension Ltd.

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.

Attention-deficit/hyperactivity disorder (ADHD; also known as hyperkinetic disorder) is a common neurodevelopmental condition that affects children and adults worldwide. ADHD has a predominantly genetic aetiology that involves common and rare genetic variants. Some environmental correlates of the disorder have been discovered but causation has been difficult to establish. The heterogeneity of the condition is evident in the diverse presentation of symptoms and levels of impairment, the numerous co-occurring mental and physical conditions, the various domains of neurocognitive impairment, and extensive minor structural and functional brain differences. The diagnosis of ADHD is reliable and valid when evaluated with standard diagnostic criteria. Curative treatments for ADHD do not exist but evidence-based treatments substantially reduce symptoms and/or functional impairment. Medications are effective for core symptoms and are usually well tolerated. Some non-pharmacological treatments are valuable, especially for improving adaptive functioning. Clinical and neurobiological research is ongoing and could lead to the creation of personalized diagnostic and therapeutic approaches for this disorder., (© 2024. Springer Nature Limited.)

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.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (© 2022 Association for Child and Adolescent Mental Health.)

Objective: Genetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination., Methods: A possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8-9 from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD., Results: Perinatal inflammation ( β [SE], 0.263 [0.017]; P < 0.001), ADHD-PRS ( β [SE], 0.116[0.042]; P = 0.006), and an interaction between the two ( β [SE], 0.031[0.011]; P = 0.010) were associated with ADHD symptoms. The association between perinatal inflammation and ADHD symptoms measured by ADHD-PRS was evident only in the two higher genetic risk groups ( β [SE], 0.623[0.122]; P < 0.001 for the medium-high risk group; β [SE], 0.664[0.152]; P < 0.001 for the high-risk group)., Conclusion: Inflammation in the perinatal period both directly elevated ADHD symptoms and magnified the impact of genetic vulnerability on ADHD risk particularly among children aged 8-9 with genetically higher risk for ADHD., Competing Interests: Dr. Takahashi reported receiving research grants from the Japan Society for the Promotion of Science (JSPS) (21K07479, 21H02848, and 19H03582), the Japan Agency for Medical Research and Development (AMED) (20dk0307094h0001) and SENSHIN Medical Research Foundation, as well as personal fees from Janssen, Takeda, Otsuka, Shionogi, and Pfizer for lectures. He also owns a stake in Johnson & Johnson. Dr. Nishimura reported receiving research grants from JSPS (20K03307, 20K07941 and 19H03582). Dr. Harada reported receiving research grants from JSPS (20K02628, 20K03363, 20K07941 and 19H03582). Dr.Iwabuchi reported receiving research grants from JSPS (20K03363, 20K03438, 20K07941, 19K08042, 19K14175 and 19H03582). Dr. Kuwabara reported receiving grants from JSPS (20H03601, 20K03456, 19K08043, 19K08013, 19K08014, 19K08042, 19K08070 and 19H03582). Dr. Takagai reported receiving a grant from JSPS (20K03438). Dr. Usui reported receiving grants from JSPS (20K21654, 20K06855, 20K06872 and 19K11440), JST (JPMJCE1310), Uehara Memorial Foundation, Takeda Science Foundation, SENSHIN Medical Research Foundation,; Osaka Medical Research Foundation for Intractable Diseases, Public Health Science Foundation, and an Eli Lilly Japan Research Grant. Dr. Makinodan reported receiving grants from (20H03604, 19H03539 and 18H02754) and AMED (20gm6310015h0001, 21wm04250XXs0101, 21uk1024002s0201). Dr. Matsuzaki reported receiving grants from JSPS (21K06752, 19K08041, 19K21754, 19H00617, 19H03406 and 19H03581). Dr. Itoh reported receiving grants from JSPS (JP20H03823, JP20K09666 and JP20K16886) and AMED (JP20gm1310009s0101). Dr. Nomura reported receiving research grants from the National Institute of Mental Health (R01 MH102729). Dr. Ozaki reported receiving grants from JSPS (21H04815 and 20K20602), AMED (JP20dk0307077, JP21wm0425007, JP21dm0207075 and JP21dk0307103), as well as research support or speakers' honoraria from, or has served as a consultant to, Sumitomo Dainippon, Eisai, Otsuka, KAITEKI, Mitsubishi Tanabe, Shionogi, Eli Lilly, Mochida, DAIICHI SANKYO, Nihon Medi-Physics, Takeda, Meiji Seika Pharma, Kyowa, EA Pharma, Viatris, Kyowa Kirin, MSD, Janssen and Nippon Boehringer Ingelheim. Dr. Newcorn is/has been an advisor and/or consultant for Adlon Therapeutics, Akili Interactive, Arbor, Enzymotec, Ironshore, Medice, NLS, OnDosis, Pfizer, Rhodes, Shire and Supernus. He was a DSMB member for Pfizer and Sunovion, and received research funds from Enzymotec, Otsuka, Shire and Supernus. He also has received speaker fees from Shire for disease-state presentations and served as a consultant for the US National Football League. Dr. Tsuchiya reported receiving research grants from JSPS (19H03582, 19K10997, 20K02628, 20K07941, 21K19639 and 21KK0145) and AMED (JP21gk0110039h0003), speakers’ honoraria from Sumitomo Dainippon and has served as an advisor to the City of Hamamatsu., (© 2023 Published by Elsevier Inc.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2022 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Many of the non-pharmacological treatments, which are preferred to drug-treatment by some patients, either lack efficacy for core symptoms or are associated with small effect sizes. No evidence-based decision tools are currently available to allocate pharmacological or psychosocial treatments based on the patient's clinical, environmental, cognitive, genetic, or biological characteristics. We systematically reviewed potential biomarkers that may help in diagnosing ADHD and/or stratifying ADHD into more homogeneous subgroups and/or predict clinical course, treatment response, and long-term outcome across the lifespan. Most work involved exploratory studies with cognitive, actigraphic and EEG diagnostic markers to predict ADHD, along with relatively few studies exploring markers to subtype ADHD and predict response to treatment. There is a critical need for multisite prospective carefully designed experimentally controlled or observational studies to identify biomarkers that index inter-individual variability and/or predict treatment response., Competing Interests: JB has been in the past 3 years a consultant to/member of advisory board of / and/or speaker for Shire, Roche, Medice, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. LR has received grant or research support from, served as a consultant to, and served on the speakers' bureau of Eli Lilly and Co., Janssen, Medice, Novartis and Shire. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by LR have received unrestricted educational and research support from the following pharmaceutical companies: Eli Lilly and Co., Janssen, and Novartis. LR has received authorship royalties from Oxford Press and ArtMed and travel grants from Shire to take part in the 2018 APA annual meeting and from Novartis to take part of the 2016 AACAP annual meeting. Barbara Franke has received educational speaking fees from Medice and Shire. SB discloses that he has in the last 5 years acted as an author, consultant or lecturer for Shire, Medice, Roche, Eli Lilly, Prima Psychiatry, GLGroup, System Analytic, Ability Partner, Kompetento, Expo Medica, Clarion Healthcare, and Prophase. He receives royalties for text books and diagnostic tools from Huber/Hogrefe, Kohlhammer and UTB. DB serves as an unpaid scientific advisor for an EU-funded neurofeedback trial unrelated to the present work. TB served in an advisory or consultancy role for Actelion, Hexal Pharma, Lilly, Lundbeck, Medice, Neurim Pharmaceuticals, Novartis, Shire. He received conference support or speaker's fee by Lilly, Medice, Novartis and Shire. He has been involved in clinical trials conducted by Shire & Viforpharma. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. The present work is unrelated to the above grants and relationships. DC served in an advisory or consultancy role for Medice, Novartis, Shire/Takeda. He received conference support or speaker's fee by Medice, Servier and Shire/Takeda. He has been involved in clinical trials conducted by Shire. He received royalties from Oxford University Press. The present work is unrelated to the above grants and relationships. In the past year, SF received income, potential income, travel expenses continuing education support and/or research support from Tris, Otsuka, Arbor, Ironshore, Shire, Akili, 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. In previous years, he received support from: Shire, Ironshore, Neurovance, Alcobra, Rhodes, CogCubed, KemPharm, Enzymotec, Akili, Neurolifesciences, Lundbeck/Takeda, Otsuka, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. 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 principal investigator of www.adhdinadults.com. Guilherme V. Polanczyk has been in the past 3 years a consultant, member of advisory board, and/or speaker for Shire/Takeda and Medice. He received travel expenses for continuing education support from Shire/Takeda and royalties from Editora Manole. In the past three years, Jeffrey Newcorn is/has been an advisor and/or consultant for Adlon Therapeutics, Akili Interactive, Alcobra, Arbor, Cingulate Therapeutics, Enzymotec, KemPharm, Lundbeck/Takeda, Medice, NLS, Rhodes, Shire, and Supernus. He was a DSMB member for Pfizer and Sunovion, and received research funds from Enzymotec, Otsuka, Shire and Supernus. He also has received speaker fees from Shire for disease-state presentations, and served as a consultant for the US National Football League. BV has served as consultant to Medice and Teva Pharm. Markus Gleitz is an employee of Medice Arzneimittel Pütter GmbH & Co. KG. MS received research support from Supernus, Shire, and Akili Interactive labs and in the past year has served in a advisory or consultancy capacity to Genomind, NLS, Shire/Takeda, Supernus, and Sunovian. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer KAJ declared a shared affiliation with the author DC to the handling editor at the time of review., (Copyright © 2022 Buitelaar, Bölte, Brandeis, Caye, Christmann, Cortese, Coghill, Faraone, Franke, Gleitz, Greven, Kooij, Leffa, Rommelse, Newcorn, Polanczyk, Rohde, Simonoff, Stein, Vitiello, Yazgan, Roesler, Doepfner and Banaschewski.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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  < .05)., Conclusion: DR/ER-MPH increased proportions of children achieving clinically meaningful improvements in BSFQ and PREMB-R.

Objective: It is estimated that childhood attention deficit hyperactivity disorder (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. The authors investigated the extent to which children with ADHD experience recovery and variable patterns of remission by adulthood., Methods: Children with ADHD (N=558) in the Multimodal Treatment Study of ADHD (MTA) underwent eight assessments over follow-ups ranging from 2 years (mean age, 10.44 years) to 16 years (mean age, 25.12 years) after baseline. The authors identified participants with fully remitted, partially remitted, and persistent ADHD at each time point on the basis of 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 follow-up period; however, a majority of them (60%) 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 time points. 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 in MTA continued to experience residual symptoms into young adulthood.

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)., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To investigate long-term (12-month) safety and symptom control of extended-release methylphenidate (MPH-MLR) in children aged 4 to <6 years after treatment optimization., Method: A total of 90 children aged 4 to <6 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., Results: 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., Conclusion: These data contribute to the understanding of the long-term safety of an extended-release stimulant in children 4 to <6 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., Clinical Trial Registration Information: A 12-Month Open Label Safety Study of Aptensio XR® in Children Ages 4-5 Years Diagnosed With ADHD (EF004); https://clinicaltrials.gov; NCT02677519., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base., Methods: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder., Results: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents., Conclusions: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Non-medical use (NMU) of prescription stimulant medications is a continuing public health concern. Stimulant medications prescribed for attention-deficit/hyperactivity disorder (ADHD) are widely available on college campuses, and, as a consequence, college students may have multiple opportunities to engage in prescription stimulant NMU. This online self-report survey examined prescription stimulant NMU among college students, including: (1) patterns of non-oral route of administration (ROA); (2) motivations for non-oral ROAs; and (3) retrospectively recalled pathways of initiation. Method: The survey sample was created from a pool of 3,379 respondents, who were matched to a sampling frame constructed from the 18-26-year-old, college student sample of the 2016 American Community Survey (ACS). About 14% ( n = 486) from the overall pool were identified as college students with self-reported prescription stimulant NMU, all of whom completed the survey. The survey covered user characteristics, prescription and illicit substance use, age of first NMU, motivations for NMU, sources of procurement, and ROAs used. Results: Among 486 students reporting prescription stimulant NMU, 43% had a lifetime diagnosis of ADHD. More than 90% reported polysubstance use, with 55% using illicit substances other than marijuana. Slightly more than 2 in 5 (43.3%) reported using illicit substances prior to prescription stimulant NMU, 24.6% used both at the same age, and 32.0% engaged in NMU of prescription stimulants prior to using illicit substances. Prescription stimulant NMU preceded prescription opioid NMU 45% of the time. More than a quarter of those engaged in prescription stimulant NMU (27.9%) initiated prescription stimulants alone or at the same age as other drugs. Most prescription stimulant NMU was oral, however 23.0% reported any non-oral use: snorting (20.4%), smoking (6.0%)and/or injection (3.5%). Non-oral use was associated with being male, obtaining medication from a dealer, use to get high, and/or a substance use disorder diagnosis. Conclusions: Prescription stimulant NMU often occurs in the larger context of other substance use among college students. Injection, an under-researched route for prescription stimulants, was associated with male gender, history of substance use and higher likelihood of illicit substance use. Nearly a quarter of college student survey respondents reported use with non-oral routes, which is associated with other high-risk behaviors. Efforts to reduce non-oral prescription stimulant NMU in college students are warranted., Competing Interests: SB is a consultant to Inflexxion, an IBH Company. Inflexxion contracts with FDA and multiple companies with interests in some of the products included in the compounds evaluated for this article. In the past year, SF received income, potential income, travel expenses continuing education support and/or research support from, Akili, Arbor, Genomind, Ironshore, Ondosis, Otsuka, Rhodes, Shire/Takeda, Sunovion, Supernus, Tris, and Vallon. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received support from: Alcobra, CogCubed, Eli Lilly, Enzymotec, Janssen, KemPharm, Lundbeck/Takeda, McNeil, Neurolifesciences, Neurovance, Novartis, Pfizer, and Vaya. In the past 2 years, JN is/has been an advisor and/or consultant for Adlon Therapeutics, Akili Interactive, Arbor, Enzymotec, Ironshore, Medice, NLS, OnDosis, Pfizer, Rhodes, Shire, and Supernus. He was a DSMB member for Pfizer and Sunovion, and received research funds from Enzymotec, Otsuka, Shire and Supernus. He also has received speaker fees from Shire for disease-state presentations and served as a consultant for the US National Football League. KA has current investigator-initiated research funding from Takeda Pharmaceutical Company and serves as an advisory board member for Arbor Pharmaceutical Company. AR reports book royalties (Routedge/Taylor Francis Group), scientific board honoraria (Shire/Takeda, Arbor), consultant honoraria (Tris Pharmaceuticals and National Football League), and CME presentations (APA, Shire/Takeda, Globala Medical Education, and US Psychiatric Congress). RR is a Senior Epidemiologist at Inflexxion, an IBH Company. Inflexxion contracts with FDA and multiple companies with interests in some of the products included in the compounds evaluated for this article. JG is the Chief Scientific Officer at Inflexxion, an IBH Company. Inflexxion contracts with FDA and multiple companies with interests in some of the products included in the compounds evaluated for this article. JG has served as an expert witness on behalf of two manufacturers of prescription opioid medications., (Copyright © 2021 Butler, Faraone, Rostain, Newcorn, Antshel, Robbins and Green.)

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 <.001). Discussion: TOVA-PR has an index-specific profile compared with CAARS-PR and TOVA-MPH-R. The partial correlation of TOVA-PR with CAARS-PR suggests that a composite score of TOVA specific indices and CAARS could have a synergic impact to improve the reliability of the response assessment in adult ADHD.

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., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

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.

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  < 0.001). The CGSQ demonstrated strong internal consistency (Cronbach's alpha = 0.93) and good test/retest reliability (ICC = 0.72). Known groups, convergent/divergent validity, and responsiveness were demonstrated from relationships between the CGSQ and the CGI-S, ADHD-RS-IV, and CGI-P. The mean anchor-based MCT for CGSQ total score was estimated as -9.0 (DR/ER-MPH vs. placebo: 53.2% vs. 29.9% p  = 0.003). Conclusions: CGSQ scores significantly decreased after 3 weeks of DR/ER-MPH treatment versus placebo, and the CGSQ was found to be a valid and reliable measure of strain in caregivers of children with ADHD. Clinical trial registration identification number: NCT02520388.

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.

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 < 0.05, β [SE], 5.815 [1.774]; P = 0.002) and inattention domain (e.g., P-value threshold < 0.05, β [SE], 5.734 [1.761]; 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.

Introduction and Objectives: Lack of consensus regarding how best to define treatment response hinders translation from trials to the clinic. These post hoc analyses examine three commonly used response criteria in six trials of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD)., Methods: Data from four short-term randomised controlled trials (RCTs) and two long-term open-label studies were analysed. Children and adolescents with ADHD received either dose-optimised (30-70 mg/day) or fixed-dose (70 mg/day) LDX. The RCTs included osmotic-release oral system methylphenidate (OROS-MPH) or atomoxetine (ATX) as a head-to-head comparator or as a reference treatment. Three definitions of response were used in these analyses: reductions of ⩾30% or ⩾50% in ADHD Rating Scale IV (ADHD-RS-IV) total score plus a Clinical Global Impressions - Improvement (CGI-I) score of 1 or 2, or an ADHD-RS-IV total score of ⩽18., Results: At the end point, LDX response rates for the least stringent criterion of ⩾30% reduction in ADHD-RS-IV total score plus a CGI-I score of 1 or 2 ranged from 69.6% to 82.6%. The proportion achieving the more stringent criterion of a reduction in ADHD-RS-IV total score of ⩾50% plus a CGI-I score of 1 or 2 at the end point ranged from 59.8% to 74.8%. An ADHD-RS-IV total score of ⩽18 at the end point was achieved by 56.7-79.9% of participants. Response rates remained stable throughout the long-term open-label studies., Conclusions: Response rates were similar for the two more stringent response criteria. The less stringent criterion resulted in higher response rates and may include partial responders.

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 <6 years with qualifying ADHD Rating Scale Fourth Edition (ADHD-RS-IV) Preschool Version scores (≥90th percentile for age/gender) participated in four behavior management training (BMT) sessions or immediately entered (based on investigator assessment of symptom severity or previous participation) into a 6-week, open-label, flexible MPH-MLR dose optimization phase. After BMT, children with <30% improvement in ADHD-RS-IV score and ≥3 score on the Clinical Global Impression-Improvement (CGI-I) scale also entered the open-label period. All children began the open-label period with MPH-MLR 10 mg once daily; weekly adjustments permitted once-daily maximum of up to 40 mg. Children with ≥30% improvement in ADHD-RS-IV total score and a CGI-I score of 1-2 at open-label completion were randomized to their optimized dose of MPH-MLR or placebo for 2 weeks (double blind [DB]). Safety measures included adverse events (AEs), vital signs, and electrocardiograms. Results: Open-label enrollment was 119 children. Mean (SD) ADHD-RS-IV total scores at open-label start and open-label end was 40.8 (10.4) and 19.5 (11.1), respectively. Ninety children were enrolled in the DB phase. Mean (SD) ADHD-RS-IV total scores for the MPH-MLR and placebo group were similar at DB beginning and was 25.8 (14.6) and 34.9 (14.1), respectively, at DB end. Mean change from baseline in ADHD-RS-IV total score during DB was significantly greater in children randomized to placebo compared with MPH-MLR; least squares mean change difference from baseline was -11.2, p  = 0.002. During open-label dosing, the most common AEs (≥10%) were decreased appetite, decreased weight, insomnia, hypertension, emotional disorder, and affect lability. Conclusion: Results demonstrate MPH-MLR efficacy in preschool children and a safety profile consistent with known AEs of methylphenidate when used for 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.

This pilot study adapted family-based treatment (FBT) for youth with potentially prodromal anorexia nervosa (AN). Fifty-nine youth with clinically significant AN symptom constellations, but who never met full Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.) (DSM-IV) criteria for AN, were enrolled in a partially randomized preference design study. Participants were offered randomization to FBT or supportive psychotherapy (SPT); those who declined to be randomized because of a strong treatment preference were entered into a parallel, non-randomized self-selected intervention study. Without accessing outcome data, an observational analysis with three diagnostic subclasses was designed based on AN symptom severity profiles, combining randomized and non-randomized participants, such that participants receiving FBT and SPT within each subclass were similar on key baseline characteristics. Outcomes of this pilot study were explored by calculating effect sizes for end-of-treatment values within each subclass, and also with a longitudinal mixed effect model that accounted for subclass. Weight trajectory was measured by percent expected body weight. Psychological outcomes were fear of weight gain, feeling fat, importance of weight, and importance of shape. Results show that the pattern of symptom observations over time was dependent on subclass of SAN (least symptomatic, moderately symptomatic, or most symptomatic) and on the target outcome variable category (weight or psychological). Results from this study, which should be considered in the context of the small sample sizes overall and within groups, can generate hypotheses for future, larger research trials on early treatment strategies. Feasibility findings illustrate how the innovative partially randomized preference design has potential broader application for AN intervention research., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT00418977., (Copyright © 2020 Loeb, Weissman, Marcus, Pattanayak, Hail, Kung, Schron, Zucker, Le Grange, Lock, Newcorn, Taylor and Walsh.)

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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study is to evaluate efficacy and safety of SPN-812 (extended-release viloxazine) for ADHD in children aged 6 to 12 years. Method: In an 8-week study, 222 participants were randomized to placebo or SPN-812 100, 200, 300, or 400 mg/day. Measurements included ADHD Rating Scale (RS)-IV total score and Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scores. Safety assessments included laboratory and electrocardiogram (ECG) measurements, suicidality monitoring (Columbia-Suicide Severity Rating Scale), and adverse event (AE) reporting. Results: Significant improvements in ADHD-RS-IV total score were observed for 200, 300, and 400 mg dose groups versus placebo ( p < .05; effect size [ES] = 0.547, 0.596, and 0.623). CGI-I score for the 300 mg group and CGI-S score for all SPN-812 groups except for 100 mg improved significantly ( p < .05) versus placebo. The most frequent AEs (≥15%) were somnolence, headache, and decreased appetite. Conclusion: SPN-812 significantly reduced the severity of ADHD symptoms and was well tolerated. The efficacy and safety of SPN-812 are being investigated in Phase III trials.

Objective: Aggressive behavior is among the most common reasons for referral to psychiatric clinics and confers significant burden on individuals. Aggression remains poorly defined; there is currently no consensus on the best ways to recognize, diagnose, and treat aggression in clinical settings. In this review, we synthesize the available literature on aggression in children and adolescents and propose the concept of impulsive aggression (IA) as an important construct associated with diverse and enduring psychopathology. Methods: Articles were identified and screened from online repositories, including PubMed, PsychInfo, the Cochrane Database, EMBase, and relevant book chapters, using combinations of search terms such as "aggression," "aggressive behavio(u)r," "maladaptive aggression," "juvenile," and "developmental trajectory." These were evaluated for quality of research before being incorporated into the article. The final report references 142 sources, published from 1987 to 2019. Results: Aggression can be either adaptive or maladaptive in nature, and the latter may require psychosocial and biomedical interventions when it occurs in the context of central nervous system psychopathology. Aggression can be categorized into various subtypes, including reactive/proactive, overt/covert, relational, and IA. IA in psychiatric or neurological disorders is reviewed along with current treatments, and an algorithm for systematic evaluation of aggression in the clinical setting is proposed. Conclusions: IA is a treatable form of maladaptive aggression that is distinct from other aggression subtypes. It occurs across diverse psychiatric and neurological diagnoses and affects a substantial subpopulation. IA can serve as an important construct in clinical practice and has considerable potential to advance research.

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.

Introduction: A laboratory classroom study in children aged 6-12 years with attention-deficit/hyperactivity disorder (ADHD) found that racemic amphetamine sulfate (RA-AMPH) significantly improved performance versus placebo from 45 min through 10 h post-dose (NCT01986062). A secondary analysis assessed gender as a potential moderator of response to treatment comparing the ADHD Rating Scale-IV (ADHD-RS-IV) and Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scales., Methods: After 8 weeks of open-label RA-AMPH dose optimization using improvement in ADHD-RS-IV symptoms as a guide, 97 subjects (38 females and 59 males) were randomized to the sequence of 2 weeks of double-blind treatment with the optimized dose of RA-AMPH followed by placebo or vice versa during a laboratory classroom day. Efficacy measures included the SKAMP and the Permanent Product Measure of Performance (PERMP). The average difference for RA-AMPH versus placebo was estimated using least-square (LS) means. Treatment interaction by gender was analyzed using a cross-sectional fixed-effects model., Results: ADHD-RS-IV scores were comparable for males and females at study entry and at the end of open-label treatment. During double-blind treatment, LS mean scores significantly improved for both genders versus placebo on the SKAMP scale and the PERMP (average p < 0.0001 for all post-dose time points). Beginning at baseline, males had significantly higher (worse) SKAMP scores than females but not worse ADHD-RS-IV or PERMP scores., Conclusion: Both genders responded well to treatment with RA-AMPH, with comparable onset and duration of effect. The ADHD-RS-IV and SKAMP scales both measure changes in attention and hyperactive-impulsive behavior, but the SKAMP scale also measures associated disruptive behaviors, such as frustration, lying, and interpersonal conflict, that are more characteristic of oppositional and conduct disorders and more prevalent in boys with ADHD. Therefore, the SKAMP may be more sensitive for measuring the range of symptoms of boys with ADHD than the ADHD-RS-IV., Funding: Arbor Pharmaceuticals, LLC.

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., (Copyright © 2019 Shire Development LLC, The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2018 Association for Child and Adolescent Mental Health.)

Longitudinal studies have shown that clinical precursors of antisocial personality disorder (ASPD) include attention-deficit/hyperactivity disorder (ADHD) and more notably comorbid ADHD and conduct disorder (CD). Despite existing evidence for the purported role of abnormal serotonergic function in aggressive youth and adults, little evidence exists on the role of serotonin in the progression from childhood disruptive behavior disorders to adult psychopathology, including ASPD. This study examined the relation between serotonergic function in children diagnosed with ADHD and the development of ASPD in early adulthood. We hypothesized that low serotonin response to a pharmacological probe in childhood would predict the development of adult ASPD. Towards this goal we divided 40 adults (M = 37, F = 3), ages 23-26 (m-24.57, sd-2.33) diagnosed with childhood ADHD into 2 groups: participants with (n = 21) and without (n = 19) ASPD. We used logistic regression to assess whether serotonergic measures in childhood assessed via prolactin and cortisol responses to a fenfluramine challenge, would selectively predict the development of ASPD in early adulthood. Logistic regression models showed that low central serotonergic response in childhood indexed by cortisol response significantly predicted adult ASPD (Wald = 4.427, p = .035) but not ADHD diagnosis in adulthood. Adults without ASPD had the highest serotonergic response whereas adults with adolescent ASPD (i.e. early onset ASPD) had the lowest response. Thus we provide new evidence of the link between low serotonergic function in childhood and the development of ASPD in adulthood, particularly for boys with adolescent onset of ASPD. These findings are relevant for understanding the contribution of childhood neurobiology to risk for later ASPD., (Copyright © 2018. Published by Elsevier B.V.)

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 < 0.0001). In conclusion, GXR was well tolerated and more than 60% of participants completed the 2-year study.

Objective: Attention-deficit/hyperactivity disorder (ADHD) is associated with elevated risk for later development of substance use disorders (SUD), specifically because youth with ADHD, similar to individuals with SUD, exhibit deficits in learning abilities and reward processing. Another known risk factor for SUD is familial history of substance dependence. Youth with familial SUD history show reward processing deficits, higher prevalence of externalizing disorders, and higher impulsivity scores. Thus, the main objective of this proof-of-concept study is to investigate whether risk loading (ADHD and parental substance use) for developing SUD in drug-naïve youth impacts reward-related learning., Methods: Forty-one drug-naïve youth, stratified into three groups: Healthy Controls (HC, n = 13; neither ADHD nor parental SUD), Low Risk (LR, n = 13; ADHD only), and High Risk (HR, n = 15; ADHD and parental SUD), performed a novel Anticipation, Conflict, and Reward (ACR) task. In addition to conventional reaction time (RT) and accuracy analyses, we analyzed computational variables including learning rates and assessed the influence of learned predictions of reward probability and stimulus congruency on RT., Results: The multivariate ANOVA on learning rate, congruence, and prediction revealed a significant main Group effect across these variables [F(3, 37) = 3.79, p = 0.018]. There were significant linear effects for learning rate (Contrast Estimate = 0.181, p = 0.038) and the influence of stimulus congruency on RTs (Contrast Estimate = 1.16, p = 0.017). Post hoc comparisons revealed that HR youth showed the most significant deficits in accuracy and learning rates, while stimulus congruency had a lower impact on RTs in this group. LR youth showed scores between those of the HC and HR youth., Conclusion: These preliminary results suggest that deficits in learning and in adjusting to task difficulty are a function of increasing risk loading for SUD in drug-naïve youth. These results also highlight the importance of developing and applying computational models to study intricate details in behavior that typical analytic methodology may not be sensitive to.