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Objective: Most serum lithium (se-Li) tests do not comply with the required timing (12 hours after lithium intake). We aimed to develop an equation estimating 12-hour se-Li levels when lithium blood tests are taken at other time points than 12 hours., Methods: The equation was developed via secondary analyses using data from the Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (CHOICE) trial and verified in 2 separate proof-of-concept studies. Bipolar CHOICE included 122 lithium-treated patients (192 se-Li measurements), who had se-Li levels measured and self-reported the time since lithium intake. The proof-of concept studies tested the accuracy of the equation by measuring se-Li concentrations at different time points up to 24 hours after lithium intake and were performed in Boston, US (5 patients, 10 se-Li measurements) and Aarhus, Denmark (21 patients, 159 se-Li measurements)., Results: We present a simple equation calculating the estimated 12-hour se-Li level (eLi 12 ) based on the measured se-Li level at the patient-reported time for intake of the last lithium dose. The accuracy was confirmed in both proof-of concept studies, where eLi 12 showed a mean deviation from the 12-hour se-Li level of 10% compared to 25% for the measured se-Li ( P < .0001). For 99 out of 102 (97%) blood tests taken between 3 and 24 hours after the last lithium dose, eLi 12 was closer to the 12-hour level than the actual measured se-Li level., Conclusion: eLi 12 provides clinicians with more accurate 12-hour se-Li estimations and gives patients flexibility as to when to show up for lithium blood tests., (© Copyright 2025 Physicians Postgraduate Press, Inc.) more...

Objectives: To determine ADHD research priorities from the perspective of ADHD professionals internationally., Method: A two-stage modified Delphi design was used. In Stage 1 (qualitative), participants listed research questions relating to ADHD that they perceived to be most important ( N  = 132). In Stage 2 (quantitative), participants were then asked to rate each research question that was deemed appropriate (able to be researched and not already addressed by research) in terms of perceived importance ( N  = 180)., Results: Stage 1 generated 382 research questions with 10 broad areas identified for example, co-occurring conditions and treatment, etc. The top 20 most important questions related to ADHD in women/girls, long-term medication use, non-pharmacological interventions, ADHD measurement/rating scales, and efficacy of emotional regulation interventions., Conclusion: These results can inform an ADHD research agenda which represents the views of the individuals from major ADHD professional groups internationally. Parallel work is needed focusing on research priorities from the perspective of ADHD consumers., 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: Outside the submitted work, A/Prof Sciberras receives royalties for her published book “Sleep and ADHD: An evidence-based guide to assessment and treatment,” received honoraria for presentations in 2018 and 2019 at the National Education Summit, Australia, and was an invited speaker at the seventh World Congress on ADHD 2019 with partial travel costs covered. Prof Bellgrove reports honoraria for presentations over the last three years, outside the submitted work. Prof Coghill reports grants and personal fees from Shire/Takeda and personal fees each from Medice, Novartis, Oxford University Press, and Servier, outside the submitted work. In the past year, Prof. Faraone reports income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, AIMH, Tris, Otsuka, Ironshore, Johnson & Johnson/Kenvue, ADHDOnline, KemPharm/Corium, Akili, Supernus, Atentiv, Noven, Sky Therapeutics, Axsome, and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is Program Director of www.ADHDEvidence.org and www.ADHDinAdults.com. Prof. Faraone’s research and education programs are supported by the European Union’s Horizon 2020 research and innovation program under grant agreement 965381; NIH/NIMH grants U01AR076092-01A1, R0MH116037, 5R01AG064955-02, 1R21MH126494-01, 1R01NS128535-01, R01MH131685-01, 1R01MH130899-01A1, Corium Pharmaceuticals, Tris Pharmaceuticals, and Supernus Pharmaceutical Company. Over the past three years, Professor Manor has received financial compensation as a consultant, advisory board member, and lecturer from Madison Ltd. (the distributor of the study drug, Lisdexamfetamine (Vyvanse), in Israel) and Teva Israel (the manufacturer and distributor in Israel of the study drug Mixed Amphetamine Salts, and Mixed Amphetamine Salts—Extended Release. Additionally, she has served as a lecturer for Takeda Ltd. Further, Dr. Manor is a consultant for a startup company, Peri, which either develops or evaluates medications for treating ADHD. She has also served as a P.I. (part of her position in Geha MHC) in two startups: Nuance Ltd. and Mindtension Ltd. Prof Banaschewski TB served in an advisory or consultancy role for eye level, Infectopharm, Medice, Neurim Pharmaceuticals, Oberberg GmbH, and Takeda. He received conference support or speaker’s fee by Janssen-Cilag, Medice, and Takeda. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. Dr Stephens, Miss Summerton, Dr Bisset, Prof Middeldorp, Dr Payne, and A/Prof Silk have no financial relationships or conflicts of interest relevant to this article to disclose. more...

Background: Genetic risk factors for psychiatric and neurodegenerative disorders are well documented. However, some individuals with high genetic risk remain unaffected, and the mechanisms underlying such resilience remain poorly understood. The presence of protective resilience factors that mitigate risk could help explain the disconnect between predicted risk and reality, particularly for brain disorders, where genetic contributions are substantial but incompletely understood. Identifying and studying resilience factors could improve our understanding of pathology, enhance risk prediction, and inform preventive measures or treatment strategies. However, such efforts are complicated by the difficulty of identifying resilience that is separable from low risk., Methods: We developed a novel adversarial multi-task neural network model to detect genetic resilience markers. The model learns to separate high-risk unaffected individuals from affected individuals at similar risk while "unlearning" patterns found in low-risk groups using adversarial learning. In simulated and existing Alzheimer's disease (AD) datasets, we identified markers of resilience with a feature-importance-based approach that prioritized specificity, generated resilience scores, and analyzed associations with polygenic risk scores (PRS)., Results: In simulations, our model had high specificity and moderate sensitivity in identifying resilience markers, outperforming traditional approaches. Applied to AD data, the model generated genetic resilience scores protective against AD and independent of PRS. We identified five resilience-associated SNPs, including known AD-associated variants, underscoring their potential involvement in risk/resilience interactions., Conclusions: Our methods of modeling and evaluation of feature-importance successfully identified resilience markers that were obscured in previous work. The high specificity of our model provides high confidence that these markers reflect resilience and not simply low risk. Our findings support the utility of resilience scores in modifying risk predictions, particularly for high-risk groups. Expanding this method could aid in understanding resilience mechanisms, potentially improving diagnosis, prevention, and treatment strategies for AD and other complex brain disorders. more...

Background and Hypothesis: In the past decade, significant advances have been made in finding genomic risk loci for schizophrenia (SCZ). This, in turn, has enabled the search for SCZ resilience loci that mitigate the impact of SCZ risk genes. We identified the first genomic resilience profile for SCZ, completely independent from known risk loci for SCZ, though it remains unclear whether resilience loci foster protection against adverse states associated with SCZ involving clinical, cognitive, and brain-structural phenotypes., Study Design: We analyzed genomic and phenotypic data from 459 784 participants from the UK Biobank, using regression models to estimate interaction effects of resilience and SCZ risk scores on phenotypes spanning multiple scales., Study Results: We found that resilience loci for SCZ afforded protection against lifetime psychiatric (schizophrenia, bipolar disorder, anxiety, and depression) and medical disorders (such as type 2 diabetes, cardiovascular, and digestive and metabolic disorders). Resilience loci also moderated the impact of SCZ loci, associated with protection against self-harm behavior and greater fluid intelligence scores. The main effects of resilience are also observed in the absence of a moderating effect in some instances, such as associations with larger brain structures., Conclusions: Overall, this study highlights a wide range of phenotypes that are significantly associated with resilience loci within the general population, revealing distinct patterns separate from those associated with SCZ risk loci. Resilience loci may protect against serious psychiatric and medical outcomes, comorbidities, and cognitive impairment. Therefore, it is conceivable that resilience loci facilitate adaptive processes linked to improved health and life expectancy., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.) more...

Intermittent Explosive Disorder (IED) is characterized by repeated inability to control aggressive impulses. Although the etiology and neurobiology of impulsive anger and impulse control disorders have been reviewed, no systematic review on these aspects has been published for IED specifically. We conducted a systematic search in seven electronic databases for publications about IED, screened by two authors, and retained twenty-four studies for the review. Our findings highlight a multifactorial etiology and neurobiology of IED, emphasizing the role of the amygdala and orbitofrontal cortex in emotional regulation and impulse control, and supporting interventions that target serotonergic signaling. Research also shows that childhood trauma and adverse family environment may significantly contribute to the development of IED. Yet, genetic studies focusing on IED were largely lacking, despite many examining the genetics underlying aggression as a general trait or other related disorders. Future research using consistently defined IED as a phenotype is required to better understand the etiology and underlying mechanisms and assist in informing the development of more effective interventions for IED., Competing Interests: Declaration of competing interest SVF received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, AIMH, Akili, Atentiv, Axsome, Genomind, Ironshore, Johnson & Johnson/Kenvue, Kanjo, KemPharm/Corium, Noven, Otsuka, Sky Therapeutics, Sandoz, 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. He is Program Director of www.ADHDEvidence.org and www.ADHDinAdults.com. SVF received research support from Corium Pharmaceuticals, Tris Pharmaceuticals and Supernus Pharmaceutical Company. JS declares financial relationships with the following entities: Amneal Pharmaceuticals LLC, Viatris Inc., Organon & Co. Inc., Medtronic Inc., Bristol-Myers Squibb, and Psychological Skills Press, all of which include equity or stock holdings. Additionally, he serves as a board member for the Organization for Psychoeducational Tutoring, Inc. Joseph Strayhorn declares financial relationships with the following entities: Amneal Pharmaceuticals LLC, Viatris Inc., Organon & Co. Inc., Medtronic Inc., Bristol-Myers Squibb, and Psychological Skills Press, all of which include equity or stock holdings. Additionally, he serves as a board member for the Organization for Psychoeducational Tutoring, Inc. JP, SE, AU, ASS, JE and YZJ have no disclosures to report., (Copyright © 2025 Elsevier B.V. All rights reserved.) more...

Although the efficacy of pharmacy in the treatment of attention deficit/hyperactivity disorder (ADHD) has been well established, the lack of predictors of treatment response poses great challenges for personalized treatment. The current study employed a comprehensive approach, combining genome-wide association analyses (GWAS) and deep learning (DL) methods, to elucidate the genetic underpinnings of pharmacological treatment response in ADHD. Based on genotype data of medication-naïve patients with ADHD who received pharmacological treatments for 12 weeks, the current study performed GWAS using the percentage changes in ADHD-RS score as phenotype. Then, DL models were constructed to predict percentage changes in symptom scores using genetic variants selected based on four different genome-wide P thresholds (E-02, E-03, E-04, E-05) as inputs. The current GWAS results identified two significant loci (rs10880574, P = 2.39E-09; rs2000900, P = 3.31E-09) which implicated two genes, TMEM117 and MYO5B, that were primarily associated with both brain- and gut-related disorders. The convolutional neural network (CNN) model, using variants with genome-wide P values less than E-02 (5516 SNPs), demonstrated the best performance with mean squared error (MSE) equals 0.012 (Accuracy = 0.83; Sensitivity = 0.90; Specificity = 0.75) in the validation dataset, 0.081 in an independent test dataset (Acc = 0.61, Sensitivity = 0.81; Specificity = 0.26). Notably, the variant that contributed most to the CNN model was NKAIN2, an ADHD-related gene, which is also associated with metabolic processes. To conclude, the integration of GWAS and DL methods revealed new genes contribute to ADHD pharmacological treatment responses, and underscored the interplay between neural systems and metabolic processes, potentially providing critical insights into precision treatment. Furthermore, our CNN model exhibited good performance in an independent dataset, encouraged future studies and implied potential clinical applications., Competing Interests: Competing interests: In the past year, Dr. Faraone received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, AIMH, Akili, Atentiv, Axsome, Genomind, Ironshore, Johnson & Johnson/Kenvue, Kanjo, KemPharm/Corium, Noven, Otsuka, Sky Therapeutics, Sandoz, 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. He is Program Director of www.ADHDEvidence.org and www.ADHDinAdults.com . Dr. Faraone’s research is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement 965381; NIH/NIMH grants U01AR076092, R01MH116037, 1R01NS128535, R01MH131685, 1R01MH130899, U01MH135970, and Supernus Pharmaceuticals. His continuing medical education programs are supported by The Upstate Foundation, Corium Pharmaceuticals, Tris Pharmaceuticals and Supernus Pharmaceuticals. Ethics approval and consent to participate: The study was approved by the Institutional Review Board of the Peking University Health Science Center (2010–19; 2018–21). After complete description of the study to the subjects, written informed consent was obtained from parents of the ADHD individuals. The current research was registered in ClinicalTrials.gov (NCT01065259). All methods were performed in accordance with the relevant guidelines and regulations., (© 2025. The Author(s).) more...

Background: Randomised controlled trials (RCTs) evaluating ADHD medications often use strict eligibility criteria, potentially limiting generalisability to patients in real-world clinical settings. We aimed to identify the proportion of individuals with ADHD who would be ineligible for medication RCTs and evaluate differences in treatment patterns and clinical and functional outcomes between RCT-eligible and RCT-ineligible individuals., Methods: We used multiple Swedish national registries to identify individuals with ADHD, aged at least 4 years at the age of diagnosis, initiating pharmacological treatment between Jan 1, 2007, and Dec 31, 2019, with follow-up up to Dec 31, 2020. Hypothetical RCT ineligibility was established using exclusion criteria from the international MED-ADHD dataset, including 164 RCTs of ADHD medications. Cox models evaluated differences in medication switching and discontinuation within 1 year between eligible and ineligible individuals. Quasi-Poisson models compared eligible and ineligible individuals on rates of psychiatric hospitalisations, injuries or accidents, and substance use disorder within 1 year of initiating ADHD medications. People with lived experience of ADHD were not involved in the research and writing process., Findings: Of 189 699 individuals included in the study cohort (112 153 men and boys [59%] and 77 546 women and girls [41%]; mean age 21·52 years [SD 12·83; range 4-68]) initiating ADHD medication, 53% (76 477 [74%] of 103 023 adults [aged >17 years], 12 658 [35%] of 35 681 adolescents [aged 13-17 years], and 10 643 [21%] of 50 995 children [aged <13 years]) would have been ineligible for RCT participation. Ethnicity data were not available. Ineligible individuals had a higher likelihood of treatment switching (hazard ratio 1·14, 95% CI 1·12-1·16) and a decreased likelihood of medication discontinuation (0·96, 0·94-0·98) compared with eligible individuals. Individuals ineligible for RCTs had significantly higher rates of psychiatric hospitalisations (ncidence rate ratio 9·68, 95% CI 9·57-9·78) and specialist care visits related to substance use disorder (14·78, 14·64-14·91), depression (6·00, 5·94-6·06), and anxiety (11·63, 11·56-11·69)., Interpretation: Individuals ineligible for ADHD medication trials face higher risks of adverse outcomes. This study provides the first empirical evidence for the limited generalisability of ADHD RCTs to real-world clinical populations, by applying eligibility criteria extracted from a comprehensive dataset of RCTs to a large real-world cohort. Triangulating evidence from RCTs and real-world studies is crucial to inform rigorous evidence-based treatment guidelines., Funding: National Institute of Healthcare and Research, European Union's Horizon 2020, and Swedish Research Council., Competing Interests: Declaration of interests HL reports receiving grants from Shire/Takeda Pharmaceuticals during the conduct of the study; personal fees from and serving as a speaker for Shire/Takeda Pharmaceuticals and Evolan Pharma outside the submitted work; and sponsorship for a conference on ADHD from Shire Pharmaceuticals outside the submitted work. SC declares reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH) in relation to lectures delivered for ACAMH, the Canadian ADHD Resource Alliance, the British Association of Psychopharmacology; from Healthcare Convention for educational activity on ADHD; and has received honoraria from Medice. All other authors declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.) more...

Importance: Intermittent explosive disorder (IED) is an understudied psychiatric condition marked by impulsive aggression and poorly regulated emotional control, often resulting in interpersonal and societal consequences. Better understanding of comorbidities can improve screening, diagnosis, and treatment., Objective: To investigate the prevalence of IED and its associations with psychiatric, neurological, and somatic disorders., Design, Setting, and Participants: In this cohort study, matched groups of patients with and without IED were identified from the TriNetX Research Network (dated January 31, 2024). Electronic medical record data were analyzed. The mean (SD) time from the first to last known visits was 4.8 (5.4) years., Exposure: Lifetime diagnosis of IED., Main Outcomes and Measures: Main outcomes were International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnostic categories and root codes. Cox proportional hazard models were used to estimate and compare probabilities of acquiring other diagnoses. Key measures include the numbers and proportions of patients with these diagnoses and adjusted hazard ratios (HRs) for IED., Results: Overall, 30 357 individuals with IED and 30 357 demographically matched controls were included. In each group, 21 313 (70%) were male, with a mean (SD) age at the first visit 26 (17) years. Despite only 0.03% of the total patient population having an IED diagnosis, extensive comorbidities with psychiatric, neurological, and somatic conditions were found. A notable 95.7% of individuals with IED (29 054 individuals) had another psychiatric diagnosis. All psychiatric subcategories and 92% of the psychiatric diagnoses were significantly associated with IED, with HRs ranging from 2.1 (95% CI, 2.0-2.2) for substance use disorder to 76.6 (95% CI, 65.4-89.6) for disorders of adult personality and behavior (excluding IED). Among neurological conditions, neurodegenerative diseases (HR, 5.0; 95% CI, 4.1-6.1) and epilepsy (HR, 4.9; 95% CI, 4.3-5.6) had the highest HRs, followed by movement disorders (HR, 3.1; 95% CI, 2.8-3.5), cerebral palsy (HR, 2.6; 95% CI, 2.2-3.0), and sleep disorders (HR, 2.2; 95% CI, 2.1-2.3). Significant associations with IED were also observed for many somatic diseases, including obesity (HR, 1.6; 95% CI, 1.5-1.7), hyperlipidemia (HR, 1.5; 95% CI, 1.4-1.5), hypertension (HR, 1.6; 95% CI, 1.5-1.7), and gastroesophageal reflux disease (HR, 1.7; 95% CI, 1.7-1.9)., Conclusion and Relevance: These findings highlight the extensive comorbidities between IED and psychiatric, neurological, and somatic disorders, emphasizing the need for integrated diagnostic and treatment approaches addressing both psychological and physical health aspects of IED. Limitations related to reliance on medical records and low diagnostic rates of IED caution the generalizability of these findings, underscoring the need for further validation in prospective studies and more accurate, inclusive diagnosis of IED in patients with mental disorders. more...

Background: Despite a high heritability of schizophrenia (SZ), only limited variance was attributed to gene loci or the polygenic risk score in genome-wide association studies (GWAS). Early-onset SZ, a more homogeneous SZ subtype, may aid in bridging the genotype-phenotype gap and the identification of its hub genes is critical for early intervention in clinical practice. We aimed to examine the gene expression risk score (GeRS) in patients from both multiplex and simplex families to identify hub genes for early-onset SZ, and perform enrichment analysis to understand the biological functions of the hub genes., Methods: Based on the GWAS genotype data from patients with SZ in multiplex families (223 early-onset and 372 late-onset) and those from simplex families (matched for sex and onset age), GeRSs for SZ (SZ-GeRSs) were estimated using the SNP-expression prediction model derived from existing brain tissues of patients with psychiatric disorders. Module-based SZ-GeRS was summed over genes from empirically derived gene clusters, network analysis was conducted to identify hub genes, and enrichment analysis was used for functional mapping., Results: Among the 13 modules from existing coexpression analyses of postmortem brains of patients with psychiatric disorders, the meta-analysis revealed that associations with early-onset SZ existed for the GeRS of module 10 in subset, M10 sub -GeRS (adjusted odds ratio [aOR] = 1.38, 95% CI = 1.22-1.57), and six hub genes, M10 hub -GeRS (aOR = 1.22, 95% CI = 1.07-1.39), after adjustment for covariates. Functional mapping of the genes revealed their enrichment in excitatory neurons and immune-regulatory pathways., Conclusions: GeRS for SZ helps identify six hub genes for early-onset schizophrenia, and the enrichment analysis sheds light on their possible roles in the pathophysiology. These findings will enhance the understanding of SZ etiology and may contribute to early screening and personalized prevention efforts., Competing Interests: Competing Interests Dr. Neale reports serving as a member of the Scientific Advisory Board of Deep Genomics and as a consultant for Camp4 Therapeutics Corporation, Merck & Co., Takeda Pharmaceutical, and Avanir Pharmaceuticals, Inc. All the other authors report no biomedical financial interests or potential conflicts of interest. more...

Objective: To investigate the impact of the SARS-CoV-2 infection on the rates of mental disorders in youth., Method: The study involved 7,519,465 children and 5,338,496 adolescents from the TriNetX Research Network, all without prior mental disorder histories. Among them, 290,145 children and 223,667 adolescents had SARS-CoV-2-positive tests or confirmed COVID-19 diagnoses. Kaplan-Meier survival analysis was used to evaluate the probability of developing new mental disorders (any codes in International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) F01-F99 category and suicidal behaviors) within 2 years post infection, compared to the propensity score-matched youth who were never infected., Results: Within 2 years post SARS-CoV-2 infection, children had a probability of 0.15 in acquiring new psychiatric diagnoses, compared to 0.026 for matched non-infected children; adolescents had a 0.19 probability against 0.05 for their non-infected counterparts. The hazard ratio (HR) was 6.0 (95% CI = 5.8-6.3) for children and 4.2 for adolescents (95% CI = 4.1-4.4), with children vs adolescents HR of 1.4 (95% CI = 1.36-1.51). Elevated HRs were observed for almost all subcategories of mental disorders and suicidal behaviors, with variations based on sex, severity of SARS-CoV-2 infection, and viral variants. COVID-19 was similar to other respiratory infections and was associated with a similarly increased rate of mental disorders in adolescents, but had a significantly higher effect on children (HR = 1.57, 95% CI =1.53-1.61)., Conclusion: This study revealed significant mental health distress following SARS-CoV-2 infection in youth, which was more pronounced in children than in adolescents. These findings underscore the urgent need to support at-risk youth, particularly those who contracted SARS-CoV-2 at younger ages and had more severe infections., Plain Language Summary: The authors of this study conducted analyses using electronic medical records from the TriNetX Research Network to investigate the impact of SARS-CoV-2 infection on the rates of mental health disorders in youth. Within 2 years after SARS-CoV-2 infection, children and adolescents were 6.0 and 4.2 times more likely to acquire a new psychiatric diagnosis, respectively. While the risk of being diagnosed with a mental health disorder following SARS-CoV-2 infection in adolescents was comparable to other respiratory infections, it had a more pronounced effect on children., (Copyright © 2024 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.) more...

The comprehensive genome-wide nature of transcriptome studies in Alzheimer's disease (AD) should provide a reliable description of disease molecular states. However, the genes and molecular systems nominated by transcriptomic studies do not always overlap. Even when results do align, it is not clear if those observations represent true consensus across many studies. A couple of sources of variation have been proposed to explain this variability, including tissue-of-origin and cohort type, but its basis remains uncertain. To address this variability and extract reliable results, we utilized all publicly available blood or brain transcriptomic datasets of AD, comprised of 24 brain studies with 4007 samples from six different brain regions, and eight blood studies with 1566 samples. We identified a consensus of AD-associated genes across brain regions and AD-associated gene-sets across blood and brain, generalizable machine learning and linear scoring classifiers, and significant contributors to biological diversity in AD datasets. While AD-associated genes did not significantly overlap between blood and brain, our findings highlighted 15 dysregulated processes shared across blood and brain in AD. The top five most significantly dysregulated processes were DNA replication, metabolism of proteins, protein localization, cell cycle, and programmed cell death. Conversely, addressing the discord across studies, we found that large-scale gene co-regulation patterns can account for a significant fraction of variability in AD datasets. Overall, this study ranked and characterized a compilation of genes and molecular systems consistently identified across a large assembly of AD transcriptome studies in blood and brain, providing potential candidate biomarkers and therapeutic targets., (© 2024 Wiley Periodicals LLC.) more...

Background: Suicide and self-harm remain critical concerns in youth. This study compares patients with and without suicidality or self-harm (SOSH), suicidality (SI/SA), and COVID-19 to investigate 53 pre-existing risk factors associated with suicidality in patients with and without COVID-19., Methods: A retrospective case-control study was conducted using TriNetX data from 111,631,250 patients across 78 healthcare networks. This study included patients aged 0-21 with any healthcare visit between January 20, 2020, and May 11, 2023., Outcomes: Comparison groups shared many risk factors, with specific differences. Children with SOSH and COVID-19 had higher odds of support group problems, personality disorder, thyroid disorders, and insomnia; children with SOSH without COVID-19 had higher odds of upbringing problems, anxiety and nonpsychotic disorders, sleep disorders, and autism. Adolescents with SOSH and COVID-19 had higher odds of parent-child conflict; adolescents with SOSH without COVID-19 had higher odds of education and literacy problems. Children with SI/SA and COVID-19 had higher odds of support group problems, personality disorders, and asthma; children with SI/SA without COVID-19 had higher odds of autism. Adolescents with SI/SA and COVID-19 had higher odds of asthma. The effect size of COVID-19 was not significant. SOSH was associated with increased odds of prior SARS-CoV-2 infection in children (OR 2.42) and adolescents (OR 1.88)., Interpretation: This study confirms known SOSH risk factors and demonstrates their association with suicidality. We observed a significant association between SOSH and preceding SARS-CoV-2 infection. This underscores the need to focus on suicide risk in youth affected by COVID-19. more...

There have been increasing efforts to develop prediction models supporting personalised detection, prediction, or treatment of ADHD. We overviewed the current status of prediction science in ADHD by: (1) systematically reviewing and appraising available prediction models; (2) quantitatively assessing factors impacting the performance of published models. We did a PRISMA/CHARMS/TRIPOD-compliant systematic review (PROSPERO: CRD42023387502), searching, until 20/12/2023, studies reporting internally and/or externally validated diagnostic/prognostic/treatment-response prediction models in ADHD. Using meta-regressions, we explored the impact of factors affecting the area under the curve (AUC) of the models. We assessed the study risk of bias with the Prediction Model Risk of Bias Assessment Tool (PROBAST). From 7764 identified records, 100 prediction models were included (88% diagnostic, 5% prognostic, and 7% treatment-response). Of these, 96% and 7% were internally and externally validated, respectively. None was implemented in clinical practice. Only 8% of the models were deemed at low risk of bias; 67% were considered at high risk of bias. Clinical, neuroimaging, and cognitive predictors were used in 35%, 31%, and 27% of the studies, respectively. The performance of ADHD prediction models was increased in those models including, compared to those models not including, clinical predictors (β = 6.54, p = 0.007). Type of validation, age range, type of model, number of predictors, study quality, and other type of predictors did not alter the AUC. Several prediction models have been developed to support the diagnosis of ADHD. However, efforts to predict outcomes or treatment response have been limited, and none of the available models is ready for implementation into clinical practice. The use of clinical predictors, which may be combined with other type of predictors, seems to improve the performance of the models. A new generation of research should address these gaps by conducting high quality, replicable, and externally validated models, followed by implementation research., Competing Interests: Competing interests: Dr. Salazar de Pablo has received honoraria from Janssen Cilag, Lundbeck and Angelini. Dr Archer is supported by funding from the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. Dr. Solmi has received honoraria/has been a consultant for Abbvie, Angelini, Lundbeck, Otsuka. Prof. Fusar-Poli has received grant support from Lundbeck and honoraria fees from Angelini, Menarini, and Lundbeck. In the past year, Dr. Faraone received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, AIMH, Tris, Otsuka, Ironshore, KemPharm/Corium, Akili, Supernus, Atentiv, Noven, Sky Therapeutics, Axsome and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is Program Director of www.ADHDEvidence.org and www.ADHDinAdults.com . Prof Larsson reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals and Evolan Pharma AB; all outside the submitted work. Henrik Larsson is editor-in-chief of JCPP Advances. Prof. Cortese has declared reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH) in relation to lectures delivered for ACAMH, the Canadian AADHD Alliance Resource, the British Association of Psychopharmacology, and from Healthcare Convention for educational activity on ADHD., (© 2024. The Author(s).) more...

Background: Pediatric pain significantly affects children's lives, leading to school absenteeism, impaired social interactions, and psychological distress. The perception of sensory signals as pain is influenced by the brain's noradrenergic system, and recent evidence suggests that chronic pain may impact cognitive functioning and emotional regulation. Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with alterations in the dopaminergic/noradrenergic systems, which could affect pain perception. Pain-associated conditions and frequent analgesic use in childhood may be linked to ADHD development and could serve as early indicators, yet data on this potential association remain limited. Study Aim: This population-based case-control study in Israel aimed to assess the prevalence of pain-related diagnoses prior to ADHD diagnosis in children aged 5 to 18. The study included children registered with Leumit Health Services (LHS) between 1 January 2006, and 30 June 2021. Children diagnosed with ADHD were compared to matched controls, selected based on age, gender, socioeconomic status, and other sociodemographic factors, who were never diagnosed with ADHD during the study period. Results : Children with ADHD ( N = 18,756) and controls ( N = 37,512) were precisely matched for sociodemographic characteristics. Individuals with ADHD exhibited significantly higher frequencies of diverse pain conditions, including those associated with illness [headache, earaches, and throat pain (odds ratios [OR] = 1.156 [95%CI 1.085, 1.232], 1.295 [95%CI 1.217, 1.377], and 1.080 [95%CI 1.019, 1.145], respectively; p < 0.01)] and injury [sprains and strains (OR = 1.233 [95% CI 1.104,1.376)]. Analgesics were more frequently purchased by individuals with ADHD, particularly paracetamol (OR = 1.194 [95%CI 1.152, 1.237], p < 0.001) and ibuprofen (OR = 1.366 [95%CI 1.318, 1.416], p = 0.001). Conclusions: This study highlights a potential connection between ADHD and pediatric pain. The elevated rates of pain diagnoses and analgesic usage among children with ADHD underscore the need for further research. more...

Importance: Intermittent Explosive Disorder (IED) is an understudied psychiatric condition that presents with repeated episodes of impulsive aggression and poorly regulated emotional control, often resulting in interpersonal and societal consequences. Better understanding of comorbidities will allow for enhanced screening, diagnosis, and treatment of patients., Objective: To investigate prevalence and associations of IED with psychiatric, neurological, and somatic disorders using real-world data., Design: Matched cohorts of patients with or without IED diagnosis were identified using data from the TriNetX Research Network (until January 31, 2024). Cox proportional hazard models were used to estimate and compare the probabilities of acquiring other diagnoses using patients' available medical records., Setting: Analysis of electronic medical records from two patient populations., Participants: 30,357 individuals with IED and equal number of demographically matched individuals without IED from the TriNetX Research., Exposure: IED diagnosis identified through the associated ICD codes., Main Outcomes and Measures: The main outcomes were ICD-10-CM diagnostic categories and root codes for disorders and health conditions in both cohorts. Main measures are total numbers and proportions of patients who had the diagnostic codes, as well as adjusted hazard ratios for IED diagnosis., Results: Although only 0.03% of the total patient population had an IED diagnosis, we found extensive and widespread comorbidities with psychiatric, neurological and somatic conditions. A significant 95.7% of the individuals with IED had another psychiatric diagnosis. All psychiatric sub-categories and 95% of the psychiatric diagnoses were significantly associated with IED, with HRs ranging from 2 to 77. Among neurological conditions, neurodegenerative diseases and epilepsy had the highest HRs, followed by extrapyramidal and movement disorders, cerebral palsy and other paralytic syndromes, and sleep disorders. Notable associations with IED also includes conditions such as obesity, hyperlipidemia, hypertension, and GERD., Conclusion and Relevance: Our findings illuminate the extensive comorbid relationships between IED and psychiatric, neurological, and somatic disorders. This underscores the necessity for an integrated diagnostic and treatment approach that addresses both the psychological and physical health aspects of IED. Additionally, our work highlights the need for more accurate and inclusive diagnosis of IED in patients with mental disorders. more...

Intermittent Explosive Disorder (IED) is characterized by repeated inability to control aggressive impulses. Although the etiology and neurobiology of impulsive anger and impulse control disorders have been reviewed, no systematic review on these aspects has been published for IED specifically. We conducted a systematic search in seven electronic databases for publications about IED, screened by two authors, and retained twenty-four studies for the review. Our findings highlight a multifactorial etiology and neurobiology of IED, emphasizing the role of the amygdala and orbitofrontal cortex in emotional regulation and impulse control, and supporting interventions that target serotonergic signaling. Research also shows that childhood trauma and adverse family environment may significantly contribute to the development of IED. Yet, genetic studies focusing on IED were largely lacking, despite many examining the genetics underlying aggression as a general trait or other related disorders. Future research using consistently defined IED as a phenotype is required to better understand the etiology and underlying mechanisms and assist in informing the development of more effective interventions for IED., Competing Interests: Declaration of Interest SVF received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, AIMH, Akili, Atentiv, Axsome, Genomind, Ironshore, Johnson & Johnson/Kenvue, Kanjo, KemPharm/Corium, Noven, Otsuka, Sky Therapeutics, Sandoz, 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. He is Program Director of www.ADHDEvidence.org and www.ADHDinAdults.com. Dr. Faraone’s research is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement 965381; NIH/NIMH grants U01AR076092-01A1, R0MH116037, 5R01AG064955-02, 1R21MH126494-01, 1R01NS128535-01, R01MH131685-01, 1R01MH130899-01A1, Corium Pharmaceuticals, Tris Pharmaceuticals and Supernus Pharmaceutical Company. JP, SE, AU, JS, and YZJ have no disclosures to report. more...

Infection and lockdowns resulting from COVID-19 have been suggested to increase the prevalence and treatment rates of Attention Deficit/Hyperactivity Disorder (ADHD). To accurately estimate the pandemic's effects, pre-pandemic data can be used to estimate diagnosis and treatment rates during the COVID-19 years as if the COVID-19 pandemic did not occur. However, accurate predictions require a broad dataset, both in terms of the number of cases and the pre-pandemic timeframe. In the current study, we modeled monthly ADHD diagnosis and treatment rates over the 18 years preceding the COVID-19 pandemic. The dataset included ∼3 million cases for individuals aged 6 to 18 from the Clalit Health Services' electronic database. Using a trained model, we projected monthly rates for post-lockdown and post-infection periods, enabling us to estimate the expected diagnosis and treatment rates without the COVID-19 pandemic. We then compared these predictions to observed data, stratified by age groups, gender, and socioeconomic status. Our findings suggest no influence of the COVID-19 pandemic on ADHD diagnosis or treatment rates. We show that a narrower timeframe for pre-COVID-19 data points can lead to incorrect conclusions that COVID-19 affected ADHD diagnosis rates. Findings are discussed, given the assumed impact of the COVID-19 pandemic on ADHD., Competing Interests: Declaration of competing interest The authors declare no conflicts or competing interests relevant to this article., (Copyright © 2024. Published by Elsevier B.V.) more...

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. more...

In the past decade, significant advances have been made in finding genomic risk loci for schizophrenia (SCZ). This, in turn, has enabled the search for SCZ resilience loci that mitigate the impact of SCZ risk genes. Recently, we discovered the first genomic resilience profile for SCZ, completely independent from the established risk loci for SCZ. We posited that these resilience loci protect against SCZ for those having a heighted genomic risk for SCZ. Nevertheless, our understanding of genetic resilience remains limited. It remains unclear whether resilience loci foster protection against adverse states associated with SCZ risk related to clinical, cognitive, and brain-structural phenotypes. To address this knowledge gap, we analyzed data from 487,409 participants from the UK Biobank, and found that resilience loci for SCZ afforded protection against lifetime psychiatric (schizophrenia, bipolar disorder, anxiety, and depression) and non-psychiatric medical disorders (such as asthma, cardiovascular disease, digestive disorders, metabolic disorders, and external causes of morbidity and mortality). Resilience loci also protected against self-harm behaviors, improved fluid intelligence, and larger whole-brain and brain-regional sizes. Overall, this study sheds light on the range of phenotypes that are significantly associated with resilience loci within the general population, revealing distinct patterns separate from those associated with SCZ risk loci. Our findings indicate that resilience loci may offer protection against serious psychiatric and medical outcomes, co-morbidities, and cognitive impairment. Therefore, it is conceivable that resilience loci facilitate adaptive processes linked to improved health and life expectancy. more...

The Research Domain Criteria (RDoC) initiative was established by the US National Institute of Mental Health as a multilevel, disorder-agnostic framework for analysis of human psychopathology through designated domains and constructs, including the "Positive Valence Systems" domain focused on reward-related behavior. This study investigates the reward valuation subconstruct of "effort" and its association with genetic markers, functional neurobiological pathways, and polygenic risk scores for psychopathology in 1215 children aged 6-12 and their parents (n = 1044). All participants completed the effort expenditure for rewards task (EEfRT), which assesses "effort" according to two quantitative measures: hard-task choice and reward sensitivity. Genetic association analyses were undertaken in MAGMA, utilizing EEfRT outcome variables as genome-wide association studies phenotypes to compute SNP and gene-level associations. Genome-wide association analyses found two distinct genetic loci that were significantly associated with measures of reward sensitivity and a separate genetic locus associated with hard task choice. Gene-set enrichment analysis yielded significant associations between "effort" and multiple gene sets involved in reward processing-related pathways, including dopamine receptor signaling, limbic system and forebrain development, and biological response to cocaine. These results serve to establish "effort" as a relevant construct for understanding reward-related behavior at the genetic level and support the RDoC framework for assessing disorder-agnostic psychopathology., (© 2023 Wiley Periodicals LLC.) more...

Objectives: This review aims to present recent innovations and advancements in attention-deficit/hyperactivity disorder (ADHD) care, encompassing international consensus statement, new medication formulations, digital therapeutics, and neurostimulation devices. Methods: A comprehensive literature search of relevant articles published in the past five years was conducted, emphasizing the evidence base, efficacy, safety, and practical implications of these advancements. Results: The World Federation of ADHD Consensus Statement offers an updated diagnostic and treatment framework rooted in global scientific evidence. There are several newer ADHD medication formulations, including a nonstimulant (Viloxazine extended release) and the first transdermal amphetamine patch approved to treat ADHD. These options offer some unique benefits to personalize treatment based on symptom profile, lifestyle, preferences, and response. Digital tools offer additional means to restructure environments for individuals with ADHD, reducing impairment and reliance on others. In addition, digital therapeutics enhance access, affordability, personalization, and feasibility of ADHD care, complementing or augmenting existing interventions. Trigeminal nerve stimulation emerges as a well-tolerated nonpharmacological, device-based treatment for pediatric ADHD, with initial trials indicating effect sizes comparable to nonstimulant medications. Conclusions: These innovations in ADHD care represent clinically significant new treatment options and opportunities for personalized care. Health care professionals should integrate these developments into clinical practice, mindful of individual patient and family needs and preferences. Future research should assess long-term outcomes, cost-effectiveness, and acceptability of these innovations. more...

This commentary addresses a series of articles in Prevention Science about environmental causes of attention deficit hyperactivity disorder (ADHD). It provides an overview of their key findings and places them in a broader context to facilitate their interpretation. Each of the articles included in the special issue is a meta-analysis assessing the association of ADHD with several environmental exposures. Each of the author teams systematically searched for articles and defined eligibility criteria. They assured that the measurement of risk factors preceded the measurement of ADHD. Most of the analyses are based on many studies with many participants in the constituent studies. As is typical of any observational epidemiologic study, the constituent studies could not correct for all possible confounds because some were not measured, and some are unknown. For this reason, these meta-analyses may have documented confounded associations, which calls for cautious interpretations. None of the constituent studies assessed what might be the most important type of confounding, familial, and genetic confounding, which occurs when the environmental exposure being studied is correlated with the genetic risk of the disorder being studied or other familial risk factors. Addressing familial/genetic confounding requires a genetically informed study. Because of these issues, the results presented here are intriguing but require further examination before one can conclude that the reported associations correspond to causal events for ADHD. A pathway forward is suggested by drawing parallels between genomic and exposure research., (© 2024. Society for Prevention Research.) more...

Objective: The aim of this study was to investigate the prevalence and psychiatric correlates of symptomatic ADHD in a large metropolitan area of a middle-income country., Methods: An in-person household survey with randomly selected 2,297 adults aged 19 to 60 from Rio de Janeiro, Brazil, assessed by trained lay interviewers. The Adult Self-Rating Scale Screener (ASRS-6) was used. Chi-square and logistic regression were conducted., Results: ADHD prevalence was 4.59 (95% CI [3.56, 5.44]). Those with ADHD were younger and more often unemployed; they displayed more psychiatric symptoms (depression, anxiety, and alcohol abuse) and a history of bullying and sexual abuse. They also had worse physical health indicators. Findings remained significant when controlling for socioeconomic variables., Conclusion: Adults with symptomatic ADHD from a large metropolitan area in Brazil show a pattern of findings consistent with what has been observed in higher-income countries., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. more...

Currently, placebo-controlled clinical trials report mean change and effect sizes, which masks information about heterogeneity of treatment effects (HTE). Here, we present a method to estimate HTE and evaluate the null hypothesis (H 0 ) that a drug has equal benefit for all participants (HTE=0). We developed measure termed 'estimated heterogeneity of treatment effect' or eHTE, which estimates variability in drug response by comparing distributions between study arms. This approach was tested across numerous large placebo-controlled clinical trials. In contrast with variance-based methods which have not identified heterogeneity in psychiatric trials, reproducible instances of treatment heterogeneity were found. For example, heterogeneous response was found in a trial of venlafaxine for depression (p eHTE =0.034), and two trials of dasotraline for binge eating disorder (Phase 2, p eHTE =0.002; Phase 3, 4mg p eHTE =0.011; Phase 3, 6mg p eHTE =0.003). Significant response heterogeneity was detected in other datasets as well, often despite no difference in variance between placebo and drug arms. The implications of eHTE as a clinical trial outcomes independent from central tendency of the group is considered and the important of the eHTE method and results for drug developers, providers, and patients is discussed. more...

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). more...

Objective: Examine differences in care patterns around adult ADHD between race (White/Non-White) and ethnic (Hispanic/Non-Hispanic) groups utilizing existing quality measures (QMs), concerning diagnosis, treatment, and medication prescribing., Methods: The AAFP National Research Network in partnership with SUNY Upstate Medical used an EHR dataset to evaluate achievement of 10 ADHD QMs. The dataset was obtained from DARTNet Institute and includes 4 million patients of 873 behavioral and primary care practices with at least 100 patients from 2010 to 2020. Patients 18-years or older with adult ADHD were included in this analysis., Results: White patients and Non-Hispanic/Latinx patients were more likely to achieve these QMs than Non-White patients and Hispanic/Latinx patients, respectively. Differences between groups concerning medication and monitoring demonstrate a disparity for Non-White and Hispanic/Latinx populations., Conclusions: Using QMs in EHR data can help identify gaps in ADHD research. There is a need to continue investigating disparities of quality adult ADHD care., 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, Ms. Alai received research support from PCORI, Abbott, Eli Lilly, and Otsuka.Over the past 3 years, Dr. Callen received research support from PCORI, Merck, NIH, AAFP Foundation, Otsuka, Takeda, UnitedHealth Foundation, HRSA, GlaxoSmithKline, SAMHSA, Eli Lilly, CDC, Helmsley Foundation, and VaxCare.Over the past 3 years, Ms. Clay has received research support from NIH, Otsuka, Takeda, UnitedHealth Foundation, HRSA, SAMHSA, Eli Lilly and AAFP Foundation.Over the past 3 years, Dr. Goodman received honoraria, consulting income, potential income or travel expenses from Tris, Otsuka, Ironshore, Supernus, Sunovion, Noven, Shionogi, Ondosis, Medscape, HCPlive, Clinical Care Solutions, National Football League, WebMD, and the Neuroscience Education Institute.Over the past 3 years Dr. Adler is a consultant for Takeda, Otsuka, Bracket/Signant, Major League Baseball, the National Football League, and the State University of New York; receives grants from Takeda and Otsuka; and royalty payments from New York University School of Medicine for scales and training material for adult attention-deficit/hyperactivity disorders.Over the past 3 years, Mr. Shields received research support from PCORI, Merck, Humana, NIH, and AAFP Foundation.Over the past 3 years, Dr. Faraone received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, AIMH, Tris, Otsuka, Ironshore, Kanjo, Johnson & Johnson/Kenvue, KemPharm/Corium, Akili, Supernus, Atentiv, Noven, Sky Therapeutics, Axsome, Genomind, Shire/Takeda, Arbor, Medice, Ondosis, Rhodes, 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. He is Program Director of www.ADHDEvidence.org and www.ADHDinAdults.com. 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; 1R01NS128535—01; Oregon Health and Science University, Otsuka Pharmaceuticals, Noven Pharmaceuticals Incorporated, and Supernus Pharmaceutical Company. more...

Objective: Several studies have shown that Adult ADHD presents differently in younger and older adults. We sought to assess the difference in care between these two groups using previously identified quality measures (QMs)., Methods: Using electronic health record data, we matched a younger group of ADHD patients to an older group. We then assessed the achievement of the QMs using probit models with and without interaction terms., Results: The majority of QMs shown an increase in achievement for both groups over time. However, significant differences in quality of care between younger and older adult ADHD patients persisted. By the end of the study period, with the exception of three QMs, younger patients achieved the QMs more., Conclusion: While, in general, the quality of care for adult ADHD increased from 2010 to 2020, there were still differences in care between younger and older adult ADHD patients., 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. Callen received research support from PCORI, Merck, NIH, AAFP Foundation, Otsuka, Takeda, UnitedHealth Foundation, HRSA, GlaxoSmithKline, SAMHSA, Eli Lilly, CDC, Helmsley Foundation, and VaxCare. Over the past 3 years, Ms. Clay received research support from NIH, Otsuka, Takeda, UnitedHealth Foundation, HRSA, SAMHSA, Eli Lilly, and AAFP Foundation. Over the past 3 years, Ms. Alai received research support from PCORI, Abbott, Eli Lilly, and Otsuka. Over the past 3 years, Dr. Goodman received honoraria, consulting income, potential income, or travel expenses from Tris, Otsuka, Ironshore, Supernus, Sunovion, Noven, Shionogi, Ondosis, Medscape, HCPlive, Clinical Care Solutions, National Football League, WebMD, and the Neuroscience Education Institute. Over the past 3 years Dr. Adler is a consultant for Takeda, Otsuka, Bracket/Signant, Major League Baseball, the National Football League, and the State University of New York; receives grants from Takeda and Otsuka; and royalty payments from New York University School of Medicine for scales and training material for adult attention-deficit/hyperactivity disorders. Over the past 3 years, Mr. Shields received research support from PCORI, Merck, Humana, NIH, and AAFP Foundation. Over the past 3 years, Dr. Faraone received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, AIMH, Tris, Otsuka, Ironshore, Kanjo, Johnson & Johnson/Kenvue, KemPharm/Corium, Akili, Supernus, Atentiv, Noven, Sky Therapeutics, Axsome, Genomind, Shire/Takeda, Arbor, Medice, Ondosis, Rhodes, 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. He is Program Director of www.ADHDEvidence.org and www.ADHDinAdults.com. 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; 1R01NS128535—01; Oregon Health and Science University, Otsuka Pharmaceuticals, Noven Pharmaceuticals Incorporated, and Supernus Pharmaceutical Company. more...

Objective: To provide additional information about clinical features associated with adult ADHD in patients diagnosed in childhood compared to those first diagnosed in adulthood., Method: We stratified a sample of adults with ADHD into patients diagnosed in childhood versus adulthood and compared demographic and clinical characteristics., Results: We found similar clinical features in adults diagnosed in childhood and adults diagnosed in adulthood. Among those diagnosed in adulthood, 95% reported symptom onset in youth. Our results do not support the hypothesis that ADHD diagnosed in adulthood is due to misinterpreting symptoms of other disorders as ADHD. They also suggest incorporating behavioral signs of executive dysfunction into diagnostic criteria for ADHD in adults may increase diagnostic sensitivity., Conclusion: These results support the validity of ADHD diagnoses in adulthood, as these adults show similar clinical profiles to those diagnosed in youth. Our results also suggest that if adult-onset ADHD exists, it is rare., 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: The authors’ declarations of interest in the past 36 months are as follows: Chloe Hutt Vater, Maura DiSalvo, Dr. Alyssa Ehrlich, Haley Parker, and Hannah O’Connor have no conflicts of interest relevant to this article to disclose. In the past year, Dr. Faraone received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, AIMH, Tris, Otsuka, Ironshore, Kanjo, Johnson & Johnson/Kenvue, KemPharm/Corium, Akili, Supernus, Atentiv, Noven, Sky Therapeutics, Axsome, and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is Program Director of www.ADHDEvidence.org and www.ADHDinAdults.com. In previous years 2 and 3, he received support from: Alcobra, Arbor, Aveksham, Enzymotec, Ondosis, Lundbeck/Takeda, Shire/Takeda, Medice, Neurovance, Rhodes, Sunovion, and Vallon. 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; 1R01NS128535—01; Oregon Health and Science University, Otsuka Pharmaceuticals, Noven Pharmaceuticals Incorporated, and Supernus Pharmaceutical Company. In 2023, Dr. Joseph Biederman received research support from the following sources: AACAP, Feinstein Institute for Medical Research, Genentech, Headspace Inc., NIDA, Pfizer Pharmaceuticals, Roche TCRC Inc., Sunovion Pharmaceuticals Inc., Takeda/Shire Pharmaceuticals Inc., Tris, and NIH. Dr. Biederman and his program received royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Biomarin, Bracket Global, Cogstate, Ingenix, Medavent Prophase, Shire/Takeda, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. Through Partners Healthcare Innovation, Dr. Biederman had a partnership with MEMOTEXT to commercialize a digital health intervention to improve adherence in ADHD. Through MGH corporate licensing, Dr. Biederman held a US Patent (#14/027,676) for a non-stimulant treatment for ADHD, a US Patent (#10,245,271 B2) on a treatment of impaired cognitive flexibility, and a patent pending (#61/233,686) on a method to prevent stimulant abuse. In 2022: Dr. Biederman received honoraria from UC Davis for Grand Rounds and the MGH Psychiatry Academy for tuition-funded CME courses. In 2021: Dr. Biederman received an honorarium for a scientific presentation from Multi-Health Systems, and a one-time consultation for Cowen Healthcare Investments. He received honoraria from AACAP, the American Psychiatric Nurses Association, BIAL—Portela & Cª. S.A. (Portugal), Medscape Education, and MGH Psychiatry Academy for tuition-funded CME courses. In 2020: Dr. Biederman received an honorarium for a scientific presentation from Tris and from the Institute of Integrated Sciences—INI (Brazil), and research support from the Food & Drug Administration. He received honoraria from Medlearning Inc, NYU, and MGH Psychiatry Academy for tuition-funded CME courses. more...

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. more...

Objective: We examined the association between the number, magnitude, and frequency of febrile episodes during the 0 to 4 years of life and subsequent diagnosis of ADHD., Methods: This population-based case-control study in an Israeli HMO, Leumit Health Services (LHS), uses a database for all LHS members aged 5 to 18 years between 1/1/2002 and 1/30/2022. The number and magnitude of measured fever episodes during the 0 to 4 years were recorded in individuals with ADHD ( N  = 18,558) and individually matched non-ADHD controls in a 1:2 ratio ( N  = 37,116)., Results: A significant, independent association was found between the number and magnitude of febrile episodes during the 0 to 4 years and the probability of a later diagnosis of ADHD. Children who never had a measured temperature >37.5°C had a significantly lower rate of ADHD (OR = 0.834, 95% CI [0.802, 0.866], p  < .0001)., Conclusions: Febrile episodes during 0 to 4 years are associated with a significantly increased rate of a later diagnosis of ADHD in a doseresponse relationship., 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 board meetings sponsored by SK-Pharma, Medison Israel, Teva Israel, AstraZeneca Israel, and Merk Israel. Over the past 3 years, Dr. Ariel Israel has had 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 reviews for Signant Health, which provides rater training for clinical trials. Over the past 3 years, Ms. Shira Cohen has made 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, Dr. Faraone received income, potential income, travel expenses, continuing education support and research support from Aardvark, Aardwolf, AIMH, Tris, Otsuka, Ironshore, Kanjo, Johnson & Johnson/Kenvue, KemPharm/Corium, Akili, Supernus, Atentiv, Noven, Sky Therapeutics, Axsome and Genomind, Shire/Takeda, Arbor, Medice, Ondosis, Rhodes, and Vallon. He has a U.S. patent, US20130217707 A1, with his institution for using sodium-hydrogen exchange inhibitors to treat ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health; Oxford University Press: Schizophrenia: The Facts; and Elsevier: ADHD: Non-Pharmacologic Interventions. He is the Program Director of www.ADHDEvidence.org and 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. 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 that either develop or assess medicines used for treating ADHD. Prof. Shai Ashkenazi has not disclosed relevant to this manuscript over the past 3 years. Prof. Eli Magen has not disclosed relevant to this manuscript over the past 3 years. Over the past 3 years, Prof Abraham Weizman has declared 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 X.R. (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 P.I. (as a part of her position in Geha MHC) in several startups: Nuance Ltd and Mindtension Ltd. more...

Objective: To explore outcomes of stimulant treatment for ADHD in pediatric populations with particular attention to bipolar disorder (BPD)., Method: We conducted a literature search of PubMed articles published prior to August 25, 2022 that focused on BPD, mania, and psychosis prior to, or as result of, stimulant treatment. We excluded studies: (1) unrelated to stimulants, (2) general stimulant research, (3) articles older than 40 years, (4) study protocols, or (5) case reports., Results: A total of 11 articles met all inclusion/exclusion criteria. Some reports found stimulant treatment safe and well-tolerated in children with comorbid BPD and ADHD. Others found evidence of treatment-emergent mania (TEM), discontinuation, and other adverse events with stimulant treatment., Conclusion: Poor outcomes associated with stimulant treatment in pediatric populations with BPD necessitate work to identify patients at risk of serious stimulant-related adverse events. Our results were limited by automated search filters and a pediatric, primarily male sample., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. more...

Aims: Studies suggested a higher prevalence of Attention-deficit/hyperactivity disorder (ADHD) in individuals with Type 1 Diabetes Mellitus (T1D). However, it is unclear how ADHD impacts glycemia and diabetes-related complications. This systematic review and meta-analysis aimed to investigate the effect of ADHD and ADHD medications on HbA1c and acute complications in T1D., Methods: A literature search was conducted in PubMed, EMBASE, CINAHL, Scopus, PsycINFO, CENTRAL, and Web of Science collections up to November 22, 2023. Seventeen studies were selected for the systematic review by independent reviewers, with twelve included in the meta-analysis., Results: Mean HbA1c levels were significantly higher in T1D individuals with ADHD compared to those without ADHD (MD = 0.60; 95 % CI: 0.41, 0.79; I 2  = 90.1 %; p-value < 0.001). The rates of suboptimal HbA1c levels, hospitalization, diabetic ketoacidosis, and hypoglycemia were all substantially higher in T1D individuals with ADHD than those without ADHD. No difference was found in mean HbA1c between those who received ADHD treatment and those who did not (mean difference = -0.52; 95 % confidence interval: -1.16, 0.13; I 2  = 78.6 %; p-value = 0.12)., Conclusions: ADHD is associated with higher HbA1c and increased acute diabetes-related complications. More research is needed to assess the effects of ADHD treatments on T1D management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.) more...

Objective: To examine the effects of triple beaded mixed amphetamine salts (TB MAS) on ADHD and executive dysfunction symptoms throughout the day in adults with DSM-5 ADHD., Method: This was a 6 week, single-blind, placebo-lead in trial of TB MAS (12.5-37.5 mg/day); all participants received 2 weeks of single-blind placebo); one individual was a placebo responder and was discontinued. One of these 18 dropped after 1 week on 12.5 mg/day, while all others completed the trial and received 37.5 mg/day TB MAS., Results: There were significant effects of TB MAS on all clinical measures, including investigator overall symptoms (AISRS); self-report overall (ASRS), time-sensitive ADHD (TASS) scores throughout the day, impairment (CGI) and executive function scores (BRIEF-A). TB MAS was generally well tolerated., Conclusions: This study extends prior findings of TB MAS to adults with DSM-5 ADHD; it further re-validates findings of efficacy of TB MAS throughout the day., 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: 3 year Disclosures: Lenard A. Adler MD: has received Grant/Research support to NYU Grossman School of Medicine from Shire/Takeda, Otsuka Pharmaceuticals, Corium; Consultant to Supernus Pharmaceuticals, Bracket/Signant, SUNY, Neurocentria, National Football League, Major League Baseball, Otsuka; Royalty payments (as inventor) from NYU Grossman School of Medicine for license of adult ADHD scales and training materials since 2004.; Deepti Anbarasan MD, Taylor Sardoff BA, Terry Leon RN, Caleb A. Massimi BA have all declared no potential conflicts of interest; 3 year Disclosures: Richard Gallagher Ph.D:Research Support from NIMH and IES; Royalties from Guilford Press and NYU Grossman School of Medicine (latter for Children’s Organizational Skills Scale Project).; In the past year, Dr. Faraone received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, AIMH, Tris, Otsuka, Ironshore, Kanjo, Johnson & Johnson/Kenvue, KemPharm/Corium, Akili, Supernus, Atentiv, Noven, Sky Therapeutics, Axsome and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is Program Director of www.ADHDEvidence.org and 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. more...

Identifying heritable factors that moderate the genetic risk for schizophrenia (SCZ) could help clarify why some individuals remain unaffected despite having relatively high genetic liability. Previously, we developed a framework to mine genome-wide association (GWAS) data for common genetic variants that protect high-risk unaffected individuals from SCZ, leading to derivation of the first-ever "polygenic resilience score" for SCZ (resilient controls n = 3786; polygenic risk score-matched SCZ cases n = 18,619). Here, we performed a replication study to verify the moderating effect of our polygenic resilience score on SCZ risk (OR = 1.09, p = 4.03 × 10 -5 ) using newly released GWAS data from 23 independent case-control studies collated by the Psychiatric Genomics Consortium (PGC) (resilient controls n = 2821; polygenic risk score-matched SCZ cases n = 5150). Additionally, we sought to optimize our polygenic resilience-scoring formula to improve subsequent modeling of resilience to SCZ and other complex disorders. We found significant replication of the polygenic resilience score, and found that strict pruning of SNPs based on linkage disequilibrium to known risk SNPs and their linked loci optimizes the performance of the polygenic resilience score., (© 2023 Wiley Periodicals LLC.) more...

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.) more...

Background: Although the COVID-19 pandemic and its implications have been associated with mental health services utilization and medication consumption, there is no longitudinal study on the long-term impact on ADHD medication use trends., Methods: This study examines the European ADHD medication consumption in 2020 to 2022 compared to the predicted consumption assuming the persistence of pre-pandemic trends. Predictions are calculated using Seasonal Autoregressive Integrated Moving Average (SARIMA) models., Results: While European ADHD medication sales recorded a drop in 2020, they returned to the predicted level in 2021, even slightly exceeding it. In 2022, we found a clear exceedance of the predicted level by 16.4% on average at country level. Furthermore, the increase in consumption growth in the post-pandemic period (2021-2022) compared to the pre-pandemic period (2014-2019) was significant in 26 of the 28 European countries under consideration., Conclusion: There is strong evidence of a trend change in the ADHD medicine consumption growth throughout Europe after the COVID-19 pandemic., (© 2024. The Author(s).) more...

Objective: Studies show adult ADHD presents differently in men and women, however few studies contrast ADHD in cisgender and gender diverse adults. We assessed care differences between these groups using previously identified quality measures (QMs)., Methods: Using EHR data, we matched a group of male ADHD patients to a female group. We followed the same procedure with a cisgender group and one identified as gender diverse through a gender dysphoria diagnosis. QM achievement was measured using logistic regression models., Results: Most QMs exhibited increasing achievement over time for all groups. Variations in care quality between males and females persisted, with female patients achieving QMs more often. There were no appreciable differences between the cisgender and gender diverse groups., Conclusion: Though quality care for adult ADHD improved from 2010 to 2020, differences between male and female patients lingered. This effect was not observed in cisgender and gender diverse patients., 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, Ms. Clay received research support from NIH, Otsuka, Takeda, UnitedHealth Foundation, HRSA, SAMHSA, Eli Lilly and AAFP Foundation.Over the past 3 years, Dr. Callen received research support from PCORI, Merck, NIH, AAFP Foundation, Otsuka, Takeda, UnitedHealth Foundation, HRSA, GlaxoSmithKline, SAMHSA, Eli Lilly, CDC, Helmsley Foundation, and VaxCare.Over the past 3 years, Ms. Alai received research support from PCORI, Abbott, Eli Lilly, and Otsuka.Over the past 3 years, Dr. Goodman received honoraria, consulting income, potential income or travel expenses from Tris, Otsuka, Ironshore, Supernus, Sunovion, Noven, Shionogi, Ondosis, Medscape, HCPlive, Clinical Care Solutions, National Football League, WebMD, and the Neuroscience Education Institute.Over the past 3 years Dr. Adler is a consultant for Takeda, Otsuka, Bracket/Signant, Major League Baseball, the National Football League, and the State University of New York; receives grants from Takeda and Otsuka; and royalty payments from New York University School of Medicine for scales and training material for adult attention-deficit/hyperactivity disorders.Over the past 3 years, Mr. Shields received research support from PCORI, Merck, Humana, NIH, and AAFP Foundation.Over the past 3 years, Dr. Faraone received income, potential income, travel expenses continuing education support and/or research support from Aardvark, Aardwolf, Akili, Arbor, Atentiv, Aveksham, Axsome, Corium, Genomind, Ironshore, Medice, Noven, Otsuka, Rhodes, Sandoz, 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. more...

Applications of machine learning in the biomedical sciences are growing rapidly. This growth has been spurred by diverse cross-institutional and interdisciplinary collaborations, public availability of large datasets, an increase in the accessibility of analytic routines, and the availability of powerful computing resources. With this increased access and exposure to machine learning comes a responsibility for education and a deeper understanding of its bases and bounds, borne equally by data scientists seeking to ply their analytic wares in medical research and by biomedical scientists seeking to harness such methods to glean knowledge from data. This article provides an accessible and critical review of machine learning for a biomedically informed audience, as well as its applications in psychiatry. The review covers definitions and expositions of commonly used machine learning methods, and historical trends of their use in psychiatry. We also provide a set of standards, namely Guidelines for REporting Machine Learning Investigations in Neuropsychiatry (GREMLIN), for designing and reporting studies that use machine learning as a primary data-analysis approach. Lastly, we propose the establishment of the Machine Learning in Psychiatry (MLPsych) Consortium, enumerate its objectives, and identify areas of opportunity for future applications of machine learning in biological psychiatry. This review serves as a cautiously optimistic primer on machine learning for those on the precipice as they prepare to dive into the field, either as methodological practitioners or well-informed consumers., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.) more...

Objective: Eight percent of college students report past year prescription stimulant misuse (nonmedical use of stimulants defined as taking stimulants in a manner other than prescribed). Despite this high prevalence rate, primary prevention efforts are lacking on college campuses. Participants and Methods: A prescription stimulant misuse primary prevention intervention targeting first-year college students was developed, refined, and pilot tested. Existing substance use treatment (motivational interviewing) and time management (cognitive behavioral therapy for adult ADHD) techniques were integrated into the novel brief prevention intervention. Focus groups provided feedback to help refine the prevention intervention. Following refinements, 484 first-year college students were randomly assigned to condition (327 treatment, 157 control) and followed for 3 months. Results: Participants rated the intervention as satisfactory. After controlling for time invariant covariates, condition significantly predicted prescription stimulant misuse. There was a lower rate of past 3-month prescription stimulant misuse reported in the intervention group (4.9%) compared to the control group (11.5%). Academic expectancies remained stable in the intervention group yet increased in the control condition over time. Time management skill ratings remained stable in both groups. Changes in academic expectancies, yet not time management skills, were a partial mediator of the prevention efficacy in prescription stimulant misuse at 3-month follow-up. Conclusions: These results provide preliminary support for the acceptability and efficacy of a brief primary prevention intervention for college student prescription stimulant misuse. Changes in positive prescription stimulant expectancies, yet not time management skills, appear to be potential targets for future preventive efforts. more...

Objective: Problems with reward processing have been implicated in multiple psychiatric disorders, but psychiatric comorbidities are common and their specificity to individual psychopathologies is unknown. Here, we evaluate the association between reward functioning and general or specific psychopathologies., Method: 1,213 adults and their1,531 children (ages 6-12) completed various measures of the Positive Valence System domain from the Research Domain Criteria (RDoC). Psychopathology was assessed using the Child Behavior Checklist for children and the Adult Self Report for parents., Results: One general factor identified via principal factors factor analysis explained most variance in psychopathology in both groups. Measures of reward were associated with the general factor and most specific psychopathologies. Certain reward constructs were associated solely with specific psychopathologies but not general psychopathology. However, some prior associations between reward and psychopathology did not hold following removal of comorbidity., Conclusion: Reward dysfunction is significantly associated with both general and specific psychopathologies., 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: Authors: Ankita Saxena, Catharina A. Hartman, Steven D. Blatt, Wanda P. Fremont, Stephen J. Glatt, and Yanli Zhang-James declare no competing interests. In the past year, Dr. Faraone received income, potential income, travel expenses, and continuing education support and/or research support from Aardvark, Aardwolf, Akili, Atentiv, Corium, Genomind, Ironshore, Medice, Noven, Otsuka, Sandoz, 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. 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. 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. more...

Many studies have been conducted with the goal of correctly predicting diagnostic status of a disorder using the combination of genomic data and machine learning. It is often hard to judge which components of a study led to better results and whether better reported results represent a true improvement or an uncorrected bias inflating performance. We extracted information about the methods used and other differentiating features in genomic machine learning models. We used these features in linear regressions predicting model performance. We tested for univariate and multivariate associations as well as interactions between features. Of the models reviewed, 46% used feature selection methods that can lead to data leakage. Across our models, the number of hyperparameter optimizations reported, data leakage due to feature selection, model type, and modeling an autoimmune disorder were significantly associated with an increase in reported model performance. We found a significant, negative interaction between data leakage and training size. Our results suggest that methods susceptible to data leakage are prevalent among genomic machine learning research, resulting in inflated reported performance. Best practice guidelines that promote the avoidance and recognition of data leakage may help the field avoid biased results. more...

Objective: To investigate the associations of symptoms of attention deficit hyperactivity disorder (ADHD) with binge eating spectrum conditions (BESC) (binge eating disorder [BED], bulimia nervosa [BN], and recurrent binge eating [RBE]), psychiatric and somatic comorbidity, and healthcare utilization in a representative sample of a Brazilian city., Methods: A household survey of 2,297 adult residents of the city of Rio de Janeiro was conducted. The Adult Self-Rating Scale Screener (ASRS-6) was used to assess ADHD symptoms. BESC was assessed using the Questionnaire on Eating and Weight Patterns-5 (QEWP-5) and confirmed by telephone interview. Standardized questionnaires were used to assess psychiatric comorbidity. Closed-ended questions investigated somatic comorbidity and healthcare utilization., Results: ADHD symptoms were highly associated with BESC (BED: OR = 13.2, 95%CI 4.3-40.6; BN: OR = 27.5, 95%CI 5.9-128.7; RBE: OR = 5.8, 95%CI 2.9-11.4). However, with further adjustment for psychiatric comorbidity (depression, anxiety, alcohol use, and impulsivity), the ORs were no longer significant. Healthcare resource utilization was significantly higher in participants with ADHD and BESC but lost significance after controlling for psychiatric comorbidity., Conclusion: ADHD was associated with an increased prevalence of BESC and greater healthcare utilization. Nonetheless, there was an essential interplay among psychiatric comorbidity in the associations of ADHD and BESC., Competing Interests: JCA has received research grants, consultancy fees, and advisory board fees from Takeda Pharmaceuticals; and has received royalties/honoraria from Artmed Panamericana Editora. PH has received royalties from Hogrefe and Huber, McGraw Hill Education, and Blackwell Scientific Publications; is a consultant for Takeda Pharmaceuticals. The other authors report no conflicts of interest. more...

Background: Although often intended for long-term treatment, discontinuation of medication for ADHD is common. However, cross-national estimates of discontinuation are missing due to the absence of standardised measures. The aim of this study was to determine the rate of ADHD treatment discontinuation across the lifespan and to describe similarities and differences across countries to guide clinical practice., Methods: We did a retrospective, observational study using population-based databases from eight countries and one Special Administrative Region (Australia, Denmark, Hong Kong, Iceland, the Netherlands, Norway, Sweden, the UK, and the USA). We used a common analytical protocol approach and extracted prescription data to identify new users of ADHD medication. Eligible individuals were aged 3 years or older who had initiated ADHD medication between 2010 and 2020. We estimated treatment discontinuation and persistence in the 5 years after treatment initiation, stratified by age at initiation (children [age 4-11 years], adolescents [age 12-17 years], young adults [age 18-24 years], and adults [age ≥25 years]) and sex. Ethnicity data were not available., Findings: 1 229 972 individuals (735 503 [60%] males, 494 469 females [40%]; median age 8-21 years) were included in the study. Across countries, treatment discontinuation 1-5 years after initiation was lowest in children, and highest in young adults and adolescents. Within 1 year of initiation, 65% (95% CI 60-70) of children, 47% (43-51) of adolescents, 39% (36-42) of young adults, and 48% (44-52) of adults remained on treatment. The proportion of patients discontinuing was highest between age 18 and 19 years. Treatment persistence for up to 5 years was higher across countries when accounting for reinitiation of medication; at 5 years of follow-up, 50-60% of children and 30-40% of adolescents and adults were covered by treatment in most countries. Patterns were similar across sex., Interpretation: Early medication discontinuation is prevalent in ADHD treatment, particularly among young adults. Although reinitiation of medication is common, treatment persistence in adolescents and young adults is lower than expected based on previous estimates of ADHD symptom persistence in these age groups. This study highlights the scope of medication treatment discontinuation and persistence in ADHD across the lifespan and provides new knowledge about long-term ADHD medication use., Funding: European Union Horizon 2020 Research and Innovation Programme., Competing Interests: Declaration of interests SF reports personal fees, travel expenses, and research grants from Johnson & Johnson, Aardvark, Aardwolf, Tris, Otsuka, Ironshore, KemPharm/Corium, Akili, Supernus, Atentiv, Noven, Sky Therapeutics, Axsome, and Genomind; has a US patent (via his institution) for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD (US20130217707 A1); 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); and is program director of www.ADHDEvidence.org and www.ADHDinAdults.com. JH reports honoraria as part of continuing medical education programmes sponsored by Shire, Takeda, Medice and Biocodex, all outside the submitted work. HL reports grants from Shire Pharmaceuticals; personal fees and speaker fees from Medice, Shire/Takeda Pharmaceuticals, and Evolan Pharma AB; and sponsorship for a conference on ADHD from Shire/Takeda Pharmaceuticals and Evolan Pharma AB, all outside the submitted work; and is Editor-in-Chief of JCPP Advances. KKCM reports grants from the C W Maplethorpe Fellowship, the National Institute for Health and Care Research, Innovation and Technology Commission of the Hong Kong Special Administration Region Government, and Hong Kong Research Grant Council; and personal fees from IQVIA, all outside the submitted work. IW reports research grants outside the submitted work from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, Glaxo Smith Kline, Novartis, Takeda, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund, UK National Institute for Health Research, European Commission, and Australian National Health and Medical Research Council; and is a non-executive director of Jacobson Medical in Hong Kong and a consultant to WHO. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.) more...