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Research

Publications

On this page, we show you all research publications of the TIMESPAN consortium. These publications report on the research output of the project. For each publication, we provide a brief summary. To read the full article, simply click on the title of the publication.

TIMESPAN publications

2025

  • Attention-deficit/hyperactivity disorder and cardiometabolic risk profile in patients with acute myocardial infarction: data from the SWEDEHEART registry
    Honghui Yao, Isabell Brikell, Henrik Larsson, Lin Li, et al., European Journal of Preventive Cardiology
    Published: 11 April 2025
    Abstract:
    Aims

    Attention-deficit/hyperactivity disorder (ADHD) is increasingly diagnosed in adults and is associated with cardiometabolic diseases. Yet, the associations between ADHD and cardiometabolic risk profile, participation in non-pharmacological interventions, and long-term outcomes in patients with myocardial infarction (MI) remain unclear.
    Methods and results
    This observational study involved patients from the SWEDEHEART (the Swedish Web-system for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated According to Recommended Therapy) registry, aged 18–74 years old, diagnosed with their first acute MI from 2006 to 2020. We assessed the associations between ADHD and cardiometabolic risk profile (clinical parameters, disease histories, and behavioural factors), engagement in guideline-recommended non-pharmacological interventions, recurrent cardiovascular events, and mortality. We analysed adults with MI with ADHD (n = 582) and without ADHD (n = 2704). Most clinical parameters and disease histories did not differ significantly between groups. However, patients with ADHD had higher risks of smoking (risk ratio, RR = 1.53; 95% confidence interval 1.36–1.71] and snus use (RR = 1.65; 1.36–1.99), were less likely to participate in follow-up evaluations (RR = 0.87; 0.79–0.96), or to stop smoking after MI (RR = 0.76; 0.63–0.91). They had a higher rate of all-cause mortality (hazard ratio = 2.02; 1.05–3.88) after discharge, but not recurrent cardiovascular events.
    Conclusion
    Adults with MI and ADHD present similar cardiometabolic risk profiles but poorer lifestyle behaviours, lower engagement in recommended interventions, and higher mortality compared with those without ADHD, underscoring the need for integrated cardiology care with psychiatric services.

2024

  • The contribution of attention-deficit/hyperactivity disorder polygenic load to metabolic and cardiovascular health outcomes: a large-scale population and sibling study
    Ebba Du Rietz, Tian Xie, Rujia Wang, Rosa Cheesman, et al., Translational Psychiatry
    Published: 13 November 2024
    Abstract:
    Emerging evidence suggests that ADHD is associated with increased risk for metabolic and cardiovascular (cardiometabolic) diseases. However, an understanding of the mechanisms underlying these associations is still limited. In this study we estimated the associations of polygenic scores (PGS) for ADHD with several cardiometabolic diseases and biomarkers. Furthermore, we investigated to what extent the PGS effect was influenced by direct and indirect genetic effects (i.e., shared familial effects). We derived ADHD-PGS in 50,768 individuals aged 18–90 years from the Dutch Lifelines Cohort study. Using generalised estimating equations, we estimated the association of PGS with cardiometabolic diseases, derived from self-report and several biomarkers measured during a physical examination. We additionally ran within-sibling PGS analyses, using fixed effects models, to disentangle direct effects of individuals’ own ADHD genetic risk from confounding due to indirect genetic effects of relatives, as well as population stratification. We found that higher ADHD-PGS were statistically significantly associated with several cardiometabolic diseases (R-squared [R2] range = 0.03–0.50%) and biomarkers (related to inflammation, blood pressure, lipid metabolism, amongst others) (R2 range = 0.01–0.16%) (P < 0.05). Adjustment for shared familial factors attenuated the associations between ADHD-PGS and cardiometabolic outcomes (on average 56% effect size reduction), and significant associations only remained for metabolic disease. Overall our findings suggest that increased genetic liability for ADHD confers a small but significant risk increase for cardiometabolic health outcomes in adulthood. These associations were observable in the general population, even in individuals without ADHD diagnosis, and were partly explained by familial factors shared among siblings.
  • Mediating pathways between attention deficit hyperactivity disorder and type 2 diabetes mellitus: evidence from a two-step and multivariable Mendelian randomization study
    J Zhang, Z K Chen, R D Triatin, H Snieder, C H L Thio, C A Hartman, Epidemiology and Psychiatric Sciences
    Published: October 2024
    Abstract:
    Aims: Type 2 diabetes (T2D) is a global health burden, more prevalent among individuals with attention deficit hyperactivity disorder (ADHD) compared to the general population. To extend the knowledge base on how ADHD links to T2D, this study aimed to estimate causal effects of ADHD on T2D and to explore mediating pathways.
    Methods: We applied a two-step, two-sample Mendelian randomization (MR) design, using single nucleotide polymorphisms to genetically predict ADHD and a range of potential mediators. First, a wide range of univariable MR methods was used to investigate associations between genetically predicted ADHD and T2D, and between ADHD and the purported mediators: body mass index (BMI), childhood obesity, childhood BMI, sedentary behaviour (daily hours of TV watching), blood pressure (systolic blood pressure, diastolic blood pressure), C-reactive protein and educational attainment (EA). A mixture-of-experts method was then applied to select the MR method most likely to return a reliable estimate. We used estimates derived from multivariable MR to estimate indirect effects of ADHD on T2D through mediators.
    Results: Genetically predicted ADHD liability associated with 10% higher odds of T2D (OR: 1.10; 95% CI: 1.02, 1.18). From nine purported mediators studied, three showed significant individual mediation effects: EA (39.44% mediation; 95% CI: 29.00%, 49.73%), BMI (44.23% mediation; 95% CI: 34.34%, 52.03%) and TV watching (44.10% mediation; 95% CI: 30.76%, 57.80%). The combination of BMI and EA explained the largest mediating effect (53.31%, 95% CI: -1.99%, 110.38%) of the ADHD-T2D association.
    Conclusions: These findings suggest a potentially causal, positive relationship between ADHD liability and T2D, with mediation through higher BMI, more TV watching and lower EA. Intervention on these factors may thus have beneficial effects on T2D risk in individuals with ADHD.

  • The impact of genetic factors on stimulant medication treatment in ADHD
    Janne Thirstrup, Jinjie Duan, TIMESPAN Consortium, Anders Børglum, Isabell Brikell, Ditte Demontis, European Neuropsychopharmacology
    Published: 16 October 2024
    Abstract:
    Stimulant medications are first-line treatment for attention deficit hyperactivity disorder (ADHD) and considered effective to treat ADHD symptoms and safe in majority of patients. However,>50% of individuals with ADHD discontinue stimulant treatment within two years, and there is limited knowledge about the underlying biological mechanisms. This study aimed to characterize the genetic architecture of stimulant medication discontinuation in individuals with ADHD.
    We analyzed data from 18,362 individuals with ADHD receiving stimulant medication in the iPSYCH cohort, a Danish population-based case-cohort linked to register data. Individuals with stimulant discontinuation were defined by a gap ≥180 days between redeemed prescriptions in the first year of treatment (7,202 discontinued; 11,260 continued). We estimated SNP-heritability (h2SNP) using GCTA, performed a genome-wide association study (GWAS), calculated polygenic scores for phenotypes previously linked to ADHD or medication side effects using LDpred2, and estimated the association of PRSs with discontinuation using logistic regression. Furthermore, we evaluated the impact of rare deleterious variants on medication discontinuation in specific gene-sets using whole-exome sequencing data from 5,999 individuals, and finally we explored if genetic factors underlying discontinuation differed between children (< 16 years of age at first prescription) and adolescents/adults (≥16 years of age at first prescription).
    No genome-wide significant loci were identified. Our results points to potential differences in the genetic architecture underlying medication discontinuation in children vs adolescents/adults, as the genetic correlation (rg) was significantly different from 1 (rg = 0.23, [95%CI = 0.37 – 0.83]) and the h2SNP was higher in adults (h2SNP = 0.14 [95%CI=0.02 – 0.27]) compared to children h2SNP = 0.08 (95%CI=0.02 – 0.14). Overall, ten of the 36 evaluated PRSs were associated with discontinuation, with higher PRS for psychiatric disorders associated with increased liability of discontinuation, whereas PRSs for educational attainment and BMI showed opposite effects across age groups. ADHD individuals who discontinued stimulants had a decreased load of rare deleterious variants in a set of genes involved in dopamine response compared to those who continued medication, and the effect was more pronounced in adolescents/adults.
    Common and rare variants contribute modestly to stimulant discontinuation in ADHD, with potential underlying genetic differences between children and adolescents/adults in heritability, PRS-associations and rare burden. Our results could indicate that genetics seem to have a slightly stronger impact on medication discontinuation in adults compared to children. It can be hypothesized that adults are better at evaluating and responding to the biological effect of stimulant treatment than children, from whom treatment discontinuation may to a larger extent be influenced by environmental factors (their parents or teachers).

  • Cumulative ADHD medication use and risk of type 2 diabetes in adults: a Swedish Register study
    Zihan Dong, Le Zhang, Lin Li, Shengxin Liu, et al., BMJ Mental Health
    Published: 25 September 2024
    Abstract:
    Background
    Little is known about the impact of cumulative attention-deficit/hyperactivity disorder (ADHD) medication use on the risk of type 2 diabetes (T2D).
    Objective
    The objective is to examine the association between cumulative use of ADHD medication and risk of incident T2D.
    Methods
    A nested case–control study was conducted in a national cohort of individuals aged 18–70 years with incident ADHD (n=138 778) between 2007 and 2020 through Swedish registers. Individuals with incident T2D after ADHD were selected as cases (n=2355) and matched with up to five controls (n=11 681) on age at baseline, sex and birth year. Conditional logistic regression models examined the association between cumulative duration of ADHD medication use and T2D.
    Findings
    Compared with no use, a decreased risk of T2D was observed for those on cumulative use of ADHD medications up to 3 years (ORs: 0<duration≤1 year, 0.79 (95% CI, 0.69 to 0.91); 1<duration≤3 years, 0.80 (95% CI, 0.69 to 0.92); duration>3 years, 0.97 (95% CI, 0.84 to 1.12)). When investigating medication types separately, methylphenidate showed results similar to main analyses, lisdexamfetamine showed no association with T2D, whereas long-term (>3 years) use of atomoxetine was associated with an increased risk of T2D (OR: 1.44 (95% CI, 1.01 to 2.04)).
    Conclusion
    Cumulative use of ADHD medication does not increase the risk for T2D, with the exception of long-term use of atomoxetine.
    Clinical implications
    Findings suggest that clinicians should be aware of the potential risk of T2D associated with the cumulative use of atomoxetine among patients with ADHD; however, further replication is strongly needed.
  • Somatic burden of attention-deficit/hyperactivity disorder across the lifecourse
    Berit Libutzki, Benno Neukirch, Andreas Reif, Catharina A. Hartman, Acta Psychiatrica Scandinavica
    Published: 28 May 2024
    Abstract:
    Objective
    A thorough and comprehensive knowledge base on the extent of comorbidity of attention-deficit/hyperactivity disorder (ADHD) and somatic conditions is needed.
    Method
    We compared the prevalence of a wide range of somatic conditions in individuals with and without ADHD and described sex and lifecourse differences. Individuals with an ADHD diagnosis (N = 87,394) and age and sex-matched individuals without an ADHD diagnosis were identified from a large health claims dataset representative of the general German population, including both primary and specialized care (N = 4.874,754). Results were provided for the full sample as well as stratified for sex and age (<12 years, 13–17 years, 18–29 years, 30–59 years, ≥60 years).
    Results
    The results showed that ADHD is associated with a wide variety of somatic conditions across the entire lifecourse. Specifically neurological disorders such as Parkison’s disease (odds ratio [OR]: 5.21) and dementia (OR: 2.23), sleep-related disorders (OR: 2.38) and autoimmune disorders affecting the musculoskeletal, digestive, and endocrine system (fibromyalgia OR: 3.33; lupus OR: 2.17) are strongly and significantly associated with ADHD. Additionally, ADHD is associated with higher occurrence of common acute diseases typically treated by the general practitioner, hinting at an overall general lower health status. Sex differences in somatic comorbidity were not prominent. Age differences, in contrast, stood out: in particular endocrine, cardiovascular, and neurological disorders had an early onset in individuals with compared to individuals without ADHD.
    Conclusion
    This research underlines the high burden of disease due to somatic conditions among individuals with ADHD. The findings indicate the need for preventive measures to reduce comorbidity.

  • Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother–child pairs
    Adrienne Y. L. Chan, Le Gao, Miyuki Hsing-Chun Hsieh, Lars J. Kjerpeseth, et al. nature medicine
    Published: 8 April 2024
    Abstract:
    Previous studies report an association between maternal diabetes mellitus (MDM) and attention-deficit/hyperactivity disorder (ADHD), often overlooking unmeasured confounders such as shared genetics and environmental factors. We therefore conducted a multinational cohort study with linked mother–child pairs data in Hong Kong, New Zealand, Taiwan, Finland, Iceland, Norway and Sweden to evaluate associations between different MDM (any MDM, gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (PGDM)) and ADHD using Cox proportional hazards regression. We included over 3.6 million mother–child pairs between 2001 and 2014 with follow-up until 2020. Children who were born to mothers with any type of diabetes during pregnancy had a higher risk of ADHD than unexposed children (pooled hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 1.08-1.24). Higher risks of ADHD were also observed for both GDM (pooled HR = 1.10, 95% CI = 1.04-1.17) and PGDM (pooled HR = 1.39, 95% CI = 1.25-1.55). However, siblings with discordant exposure to GDM in pregnancy had similar risks of ADHD (pooled HR = 1.05, 95% CI = 0.94-1.17), suggesting potential confounding by unmeasured, shared familial factors.
    Our findings indicate that there is a small-to-moderate association between MDM and ADHD, whereas the association between GDM and ADHD is unlikely to be causal. This finding contrast with previous studies, which reported substantially higher risk estimates, and underscores the need to reevaluate the precise roles of hyperglycemia and genetic factors in the relationship between MDM and ADHD.

  • Associations between attention-deficit hyperactivity disorder genetic liability and ICD-10 medical conditions in adults: utilizing electronic health records in a Phenome-Wide Association Study
    Ellis Haan et al. Psychological Medicine
    Published: 2 April 2024
    Abstract:
    Background: Attention-deficit hyperactivity disorder (ADHD) is often comorbid with other medical conditions in adult patients. However, ADHD is extremely underdiagnosed in adults and little is known about the medical comorbidities in undiagnosed adult individuals with high ADHD liability. In this study we investigated associations between ADHD genetic liability and electronic health record (EHR)-based ICD-10 diagnoses across all diagnostic categories, in individuals without ADHD diagnosis history.Methods: We used data from the Estonian Biobank cohort (N = 111 261) and generated polygenic risk scores (PRS) for ADHD (PRSADHD) based on the ADHD genome-wide association study. We performed a phenome-wide association study (PheWAS) to test for associations between standardized PRSADHD and 1515 EHR-based ICD-10 diagnoses in the full and sex-stratified sample. We compared the observed significant ICD-10 associations to associations with (1) ADHD diagnosis and (2) questionnaire-based high ADHD risk analyses.Results: After Bonferroni correction (p = 3.3 × 10−5) we identified 80 medical conditions associated with PRSADHD. The strongest evidence was seen with chronic obstructive pulmonary disease (OR 1.15, CI 1.11–1.18), obesity (OR 1.13, CI 1.11–1.15), and type 2 diabetes (OR 1.11, CI 1.09–1.14). Sex-stratified analysis generally showed similar associations in males and females. Out of all identified associations, 40% and 78% were also observed using ADHD diagnosis or questionnaire-based ADHD, respectively, as the predictor.Conclusions: Overall our findings indicate that ADHD genetic liability is associated with an increased risk of a substantial number of medical conditions in undiagnosed individuals. These results highlight the need for timely detection and improved management of ADHD symptoms in adults.
  • Distal-to-proximal etiologically relevant variables associated with the general (p) and specific factors of psychopathology
    Jonah Ormel et al. Journal of Child Psychology and Psychiatry
    Published: 19 March 2024
    Abstract:
    Background
    The general factor of psychopathology, often denoted as p, captures the common variance among a broad range of psychiatric symptoms. Specific factors are co-modeled based on subsets of closely related symptoms. This paper investigated the extent to which wide-ranging genetic, personal, and environmental etiologically relevant variables are associated with p and specific psychopathology factors.
    Methods
    Using data from four waves (ages 11–19) of TRAILS, we modeled a bifactor model of p and four specific factors [internalizing, externalizing, ADHD, Autism Spectrum Disorder (ASD)]. Next, we examined the associations of 19 etiologically relevant variables with these psychology factors using path models that organized the variables according to the distal-to-proximal risk principle.
    Results
    Collectively, the etiologically relevant factors, including temperament traits, accounted for 55% of p’s variance, 46% in ADHD, 35% in externalizing, 19% in internalizing, and 7% in ASD. The low 7% is due to insufficient unique variance in ASD indicators that load more strongly on p. Excluding temperament, variables accounted for 29% variance in p, 9% ADHD, 14% EXT, 7% INT, and 4% ASD. Most etiologically relevant factors were generic, predicting p. In addition, we identified effects on specific factors in addition to effects on p (e.g., parental SES, executive functioning); only effects on specific factors (e.g., parental rejection); opposite effects on different factors [e.g., diurnal cortisol (high INT but low EXT, p); developmental delay (high ASD and p but low EXT)]. Frustration, family functioning, parental psychopathology, executive functioning, and fearfulness had strong effects on p.
    Conclusions
    (1) Strong generic effects on p suggest that etiologically relevant factors and psychopathology tend to cluster in persons. (2) While many factors predict p, additional as well as opposite effects on specific factors indicate the relevance of specific psychopathology factors in understanding mental disorder. (3) High frustration, neurodevelopmental problems, and a disadvantaged family environment primarily characterize p.
  • ADHD Pharmacotherapy and Mortality in Individuals With ADHD
    Lin Li et al. JAMA
    Published: 12 March 2024
    Key Points:
    Question: Is initiation of attention-deficit/hyperactivity disorder (ADHD) medication associated with a reduced mortality risk in individuals with ADHD?
    Findings: In this observational, target trial emulation analysis that included 148 578 individuals diagnosed with ADHD in Sweden, initial dispensation of ADHD medication was significantly associated with lower all-cause (hazard ratio [HR], 0.79) and unnatural-cause (HR, 0.75) mortality, whereas the association with natural-cause mortality was not significant (HR, 0.86).
    Meaning: Among individuals diagnosed with ADHD, medication initiation was significantly associated with lower mortality, in particular for unnatural causes.
  • Methylphenidate and Short-Term Cardiovascular Risk
    Miguel Garcia-Arigbay, et al. JAMA Network Open.
    Published: 6 March 2024
    Key Points:
    Question: What is the cardiovascular risk associated with short-term methylphenidate use?
    Findings: In this cohort study of 252 382 individuals, methylphenidate-treated individuals showed a higher (10%) cardiovascular event rate compared with non-treated matched controls in the 6 months after treatment. However, there was no evidence for a more substantial difference (≥20%) or difference based on preexisting cardiovascular disease.
    Meaning: The findings of this study suggest that the small cardiovascular risk associated with short-term methylphenidate use should not be a reason to withhold treatment but suggest the need for individualized risk-benefit assessment and risk monitoring.

  • Effects of ADHD and ADHD treatment on glycemic management in type 1 diabetes: A systematic review and meta-analysis of observational studies
    Ali Zare Dehnavi, Islam Elmitwalli, et al. Diabetes Research and Clinical Practice.
    Published: March 2024
    Highlights:

    • People with a dual diagnosis of Type 1 Diabetes Mellitus (T1D) and ADHD exhibit suboptimal HbA1c levels compared to those with T1D without ADHD.
    • T1D individuals with ADHD experienced more diabetic ketoacidosis (DKA), hypoglycemia, and hospitalizations than those without ADHD.
    • Receiving ADHD treatment was not associated with lower HbA1c levels.
    • Identifying and addressing ADHD symptoms in T1D can improve glycemic management.
    • Identifying and addressing ADHD symptoms in T1D can help prevent acute diabetes-related complications.
  • Disentangling the shared genetics of ADHD, cannabis use disorder and cannabis use and prediction of cannabis use disorder in ADHD
    Trine Tollerup Nielsen et al. medRxiv
    Published: 24 February 2024
    Abstract:
    Cannabis use disorder (CUD) and cannabis use (CU) are prevalent conditions cooccurring with ADHD, but not much is known about the underlying shared genetics. Here we perform cross-disorder GWAS meta-analyses of ADHD and CUD or CU to identify pleiotropic risk loci and evaluate differences in the genetics of ADHD-CUD and ADHD-CU, and subsequently we dissect the polygenic architecture of CUD comorbidity in ADHD in the iPSYCH cohort. There was a higher genetic overlap of ADHD and CUD than observed for ADHD and CU and we found a significant direct effect of ADHD genetic risk on CUD with only a minor part (12%) mediated by the genetics of CU. We identified 36 genome-wide significant loci for ADHD-CUD and 10 loci for ADHD-CU, with concordant direction of effect on the phenotypes. Three different approaches identified DRD2, which encodes the dopamine 2 receptor, as a risk gene for ADHD-CUD and, overall, ADHD-CUD risk genes were associated with high expression across several brain tissues and brain developmental stages, which was not observed for ADHD-CU genes. ADHD-CUD and ADHD-CU demonstrated similar genetic correlations with substance use phenotypes, while they differed significantly with respect to substance use disorder (SUD) phenotypes. ADHD-CUD individuals had significantly increased polygenic score (PGS) for psychiatric disorders compared to ADHD without CUD and increased burden of rare deleterious variants. Stratifying individuals with ADHD by their CUD-PGS revealed an absolute risk of 22% for comorbid CUD among the 20% of cases with the highest CUD-PGS, which was strikingly higher than the absolute risk of 1.6% observed among the 20% of controls with the highest CUD-PGS. Sex-specific analyses identified substantial differences in the absolute risk of comorbid CUD between males and females with ADHD, with a ∼10% higher CUD risk among males than females in the high-risk CUD-PGS group (24% risk for males and 14% risk for females).
  • Attention-deficit/hyperactivity disorder
    Stephen V. Faraone, et al. Nature Reviews Disease Primers
    Published: 22 February 2024
    Abstract:
    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.
  • Genomic Machine Learning Meta-regression: Insights on Associations of Study Features With Reported Model Performance
    Eric J. Barnett, Daniel G. Onete, Asif Salekin and Stephen V Faraone IEEE/ACM Transactions on Computational Biology and Bioinformatics
    Published: January-February 2024
    Abstract:
    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.
  • A primer on the use of machine learning to distil knowledge from data in biological psychiatry
    Thomas P. Quinn, et al. Nature Molecular Psychiatry
    Published: 4 January 2024
    Abstract:
    The integration of machine learning in biomedical sciences is expanding rapidly, driven by collaborative efforts, widespread access to large datasets, enhanced analytic tools, and powerful computing resources. As machine learning gains prominence, there is a shared responsibility for education and a deeper comprehension of its nuances, involving both data scientists and biomedical researchers. This article offers an accessible and critical overview of machine learning, emphasizing its applications in psychiatry. It covers definitions, commonly used methods, and historical trends in psychiatric research. Additionally, the article introduces Guidelines for REporting Machine Learning Investigations in Neuropsychiatry (GREMLIN) as a set of standards for designing and reporting machine learning studies. Finally, it proposes the formation of the Machine Learning in Psychiatry (MLPsych) Consortium, outlining its objectives and highlighting future opportunities for machine learning in biological psychiatry. Serving as a cautiously optimistic primer, this review is tailored for those on the brink of entering the field, whether as methodological practitioners or informed consumers.

2023

  • Using real-world data to generate evidence to improve quality use of psychotropic medicines in priority populations
    Claudia Bruno Thesis
    Published: 15 December 2023
    Abstract:
    Quality (or rational) use of medicines is embedded in Australia’s National Medicines Policy to ensure that patients receive appropriate treatment without harm. Still, clinical trials often exclude priority populations that are at greater risk of medicine-related harm, resulting in limited evidence to guide real-world prescribing in such populations. This evidence gap has led to considerable variation in prescribing and concerns about the appropriate use and safety of psychotropic medicines. Through exemplar studies using real-world data, this thesis generates evidence to address the quality use and safety of psychotropic medicines among people with mental health and neurodevelopmental disorders, children, and pregnant women. The first three studies (Chapters 2-4) use Australia-wide dispensing data and linked data to address several concerns around attention-deficit/hyperactivity disorder (ADHD) medicine use in Australia. Key findings include: (i) that school children who were the youngest in their school grade were more likely to use ADHD medicines than older students in most Australian jurisdictions, except in New South Wales where children often delay school start for one year; (ii) ADHD medicine use doubled in Australia between 2013 and 2020, with largest increases among young females. However, this level of use remains below the prevalence of ADHD; (iii) in 2021, changes to populations eligible for publicly subsidised lisdexamfetamine led to increased use among adults and improved access for those previously ineligible for publicly subsidised treatment. These results informed ongoing government inquiries into ADHD and treatment in Australia. The fourth study (Chapter 5), using register data from the Nordic countries, found that antipsychotic use during pregnancy did not increase the risk of child neurodevelopmental disorders or learning difficulties. These findings will assist clinicians and women managing mental illness during pregnancy and demonstrate the benefits of global collaboration. The findings of this thesis are of public and clinical interest and have both local and international implications. The thesis demonstrates the utility of real-world data to address and promote quality use of medicines and safety in priority populations. The thesis also considers the challenges of using real-world data in evidence generation and explores how appropriate study designs, global collaboration, and open science may help overcome these challenges.
  • Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals
    Hang Zhou, Rachel L. Kember, Joseph D. Deak et al. Nature Medicine
    Published: 7 December 2023
    Abstract:
    Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights—together with neuroscience, biology and data science—closer.
  • ADHD medication discontinuation and persistence across the lifespan: a multinational study
    Isabell Brikell, Honghui Yao, Lin Li, et al. The Lancet Psychiatry
    Published: 27 November 2023
    Abstract:
    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.
    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.
  • Nonlinear associations between insomnia symptoms and circadian preferences in the general population: Symptom-specific and lifespan differences in men and women
    Dina Sarsembayeva et al. Sleep Health
    Published: 24 November 2023
    Abstract:
    This study investigated (non)linear associations between different eveningness characteristics (bedtime, wake time, morning affect, and peak performance time) and insomnia symptoms (difficulties initiating sleep, difficulties maintaining sleep, and nonrestorative sleep) in a large general population sample. The data came from digital surveys about insomnia (Minimal Insomnia Scale) and circadian preferences (Children’s Chronotype Questionnaire/Composite Scale of Morningness) completed by the Dutch general population (37,389 participants aged 4-91 years, 42.4% men) in the Lifelines cohort substudy Comorbid Conditions of ADHD. Using generalized additive modeling, we found that different characteristics of eveningness related to insomnia either exponentially (later wake time/peak performance time, worse morning affect) or quadratically (early and late bedtime/midpoint of sleep). While difficulties initiating sleep and nonrestorative sleep were strongly associated with all eveningness characteristics, difficulties maintaining sleep related only to earlier bedtimes. These relationships were similar for men and women but varied partly in shapes and strengths across the lifespan. Additional analyses showed that bedtime and wake time were associated with insomnia symptoms only when their combination would result in an unusually long or short preferred time in bed. The association between eveningness and insomnia symptoms highly depends on whether eveningness is reflected by daytime performance or sleep-wake time. The pattern and strength of these associations also vary depending on age and insomnia symptom, but less so on sex. Future sleep-related research and policies relying on circadian preferences should account for the nonlinearity, dimension/symptom-related specificity and age-related differences in the association between eveningness and insomnia symptoms.
  • Attention-deficit/hyperactivity disorder symptoms and subsequent cardiometabolic disorders in adults: investigating underlying mechanisms using a longitudinal twin study
    Maja Dobrosavlejevic, et al. BMC Medicine.
    Published: 22 November 2023
    Abstract    :
    Background: Emerging research suggests that attention-deficit/hyperactivity disorder (ADHD) increases the risk for cardiovascular (CVDs) and metabolic disorders (i.e., cardiometabolic disorders) in adulthood. Yet, available studies are scarce and have mainly been focused on individuals receiving clinical ADHD diagnoses. We aimed to investigate the prospective associations of ADHD symptoms in young and mid-adulthood with subsequent cardiometabolic disorders and the underlying mechanisms.
    Conclusions: ADHD symptom score is associated with a higher risk for cardiometabolic disorders, which may be explained by lower educational attainment, adverse lifestyle factors, and psychiatric comorbidities. Moreover, the associations appear to be partly confounded by shared genetic factors, especially for CVDs. Further research is needed to investigate the identified associations at the level of individual cardiometabolic disorders and to follow-up participants until a more advanced older age.
  • Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases
    Le Zhang, et al. JAMA Psychiatry.
    Published: 22 November 2023
    Abstract:
    Question: Is long-term use of attention-deficit/hyperactivity disorder (ADHD) medication associated with an increased risk of cardiovascular disease (CVD)?
    Findings: In this case-control study of 278 027 individuals in Sweden aged 6 to 64 years who had an incident ADHD diagnosis or ADHD medication dispensation, longer cumulative duration of ADHD medication use was associated with an increased risk of CVD, particularly hypertension and arterial disease, compared with nonuse.
    Meaning: Findings of this study suggest that long-term exposure to ADHD medications was associated with an increased risk of CVD; therefore, the potential risks and benefits of long-term ADHD medication use should be carefully weighed.
  • Psychiatric comorbidities in women with cardiometabolic conditions with and without ADHD: a population‑based study
    Unnur Jakobsdottir Smari, et al. BMC Medicine
    Published: 20 November 2023
    Abstract:
    Background: Leveraging a large nationwide study of Icelandic women, we aimed to narrow the evidence gap around female attention-deficit/hyperactivity disorder (ADHD) and cardiometabolic comorbidities by determining the prevalence of obesity, hypertension, type 2 diabetes, and cardiovascular diseases among women with ADHD and examine the association between cardiometabolic conditions and co-occurring ADHD with anxiety and mood disorders, alcoholism/substance use disorder (SUD), self-harm, and suicide attempts.
    Conclusion: ADHD is overrepresented among women with cardiometabolic conditions and contributes substantially to other psychiatric comorbidities among women with cardiometabolic conditions.
  • How can we improve the management of individuals with attention deficit hyperactivity disorders and co-occurring cardiometabolic disease?
    Henrik Larsson. Expert Review of Cardiovascular Therapy.
    Published: 1 November 2023
    Abstract: Cardiometabolic diseases, including obesity, type-2 diabetes (T2D) and cardiovascular disease (CVD), are well-known chronic conditions that frequently co-occur. Each of these conditions are associated with premature death, as well as high levels of health care costs. Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental condition, characterized by hyperactivity, inattention, impulsivity, that often persist from childhood into adulthood. ADHD is a costly disorder that often co-occurs with substance use disorders, bipolar disorder, and depression and individuals with ADHD presents with an increased risk for criminality, occupational problems, and premature death, including suicide . A small but growing literature also suggest an increased risk of cardiometabolic diseases and risk factors in those with ADHD.
  • Genetic architecture of ADHD and overlap with other psychiatric disorders and cognition-related phenotypes
    M. Ribasés et al. Neuroscience and Biobehavioral Reviews
    Published: October 2023
    Abstract:
    Attention-deficit/hyperactivity disorder (ADHD) co-occurs with many other psychiatric disorders and traits. In this review, we summarize and interpret the existing literature on the genetic architecture of these comorbidities based on hypothesis-generating approaches. Quantitative genetic studies indicate that genetic factors play a substantial role in the observed co-occurrence of ADHD with many different disorders and traits. Molecular genetic correlations derived from genome-wide association studies and results of studies based on polygenic risk scores confirm the general pattern but provide effect estimates that are smaller than those from twin studies. The identification of the specific genetic variants and biological pathways underlying co-occurrence using genome-wide approaches is still in its infancy. The first analyses of causal inference using genetic data support causal relationships between ADHD and comorbid disorders, although bidirectional effects identified in some instances point to complex relationships. While several issues in the methodology and inferences from the results are still to be overcome, this review shows that the co-occurrence of ADHD with many psychiatric disorders and traits is genetically interpretable.
  • Machine learning classification of attention deficit hyperactivity disorder using genomic context informed genotype data and within-model ancestry adjustment
    Eric Barnett, et al. European Neuropsychopharmacology
    Published: October 2023
    Abstract:
    Classification models using genetic data in ADHD do not perform as well as expected given the high heritability of the disorder. One possibility in improving performance is better using the accumulated knowledge about the genome to help machine learning models find patterns among the disorder’s heterogeneous and complex genetic architecture. In a study of 2,455 people with ADHD and 8,432 without ADHD across 9 cohorts, we collected and calculated genomic annotations related to the functional and structural qualities of each genotyped single nucleotide polymorphism. We used this genomic context alongside genotype data as input into a convolutional neural network models aiming to predict ADHD diagnosis. We implemented an adversarial ancestry task, which forces the model to unlearn features that would otherwise be helpful in predicting ancestry, to test within-model ancestry adjustment. We used additional adversarial tasks to test hypotheses on the differences between models with and without genomic context. Using the same methods in type 2 diabetes, a neural network using genotype data (AUC: 0.66) and a convolutional neural network using context informed genotype data (AUC: 0.65) both outperformed a polygenic risk score approach (AUC: 0.57). Adversarial ancestry tasks effectively eliminated the predictability of ancestry without changing model performance. Analyses are underway in ADHD and will be compared to previous results in the same dataset where a gene set polygenic risk score model had an AUC of 0.72, a traditional PRS model had an AUC of 0.62, and a PRS-CS model had an AUC of 0.66. Our current results suggest that context informed genotype models can find novel risk features. They also suggest that enriching machine learning models with annotation rich genotype data is useful in improving classification performance. Adversarial ancestry adjustment can effectively adjust for ancestry within each model and report any remaining ability of the model to use ancestry as a predictor.
  • Cardiovascular Medicine Use in Adults with ADHD: A Nationwide Study in Australia
    Masako Araki, Helga Zoega, Malcolm Gillies, Juliana de Oliveira Costa Thesis
    Published: 16 September 2023
    Abstract:
    Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children, increasingly recognised among adults. Although recent evidence suggests that ADHD can double the incidence of cardiovascular diseases (CVDs) in adulthood, little is known about cardiovascular medicine use. In this cross-sectional study, we used a nationally representative sample of dispensing claims to identify 14,753 adults (aged ≥18) with ADHD (defined as ≥2 dispensings of ADHD medicines). We randomly selected 1:4 age- and sex-matched adults without ADHD (N=59,012). We estimated the prevalence of cardiovascular medicine use among adults with and without ADHD by sex and age, and cardiovascular medicine. To examine the association of ADHD with cardiovascular medicine use, we calculated odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression models.
  • Attention-Deficit/Hyperactivity Disorder and Major Depressive Disorder: Evidence From Multiple Genetically Informed Designs
    Miguel Garcia‑Argibay, et al. Biological Psychiatry.
    Published: 8 August 2023
    Abstract:
    Background: Attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are two highly prevalent disorders that frequently co-occur. Prior evidence from genetic and cohort studies supports an association between ADHD and MDD. However, the direction and mechanisms underlying their association remain unclear. As onset of ADHD occurs in early life, it has been hypothesized that ADHD may cause MDD.
    Conclusion: Our study provides consistent results across 3 different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.
  • Epidemiology of ADHD coming of age and a plea for prospective research on causes and consequences of ADHD throughout the lifespan in multidisciplinary team science
    Catharina A. Hartman, JCPP Advances
    Published: 1 June 2023
    Highlights:

    • ADHD research historically focused on diagnosed children, neglecting pre-onset causes.
    • Prospective research from conception to ADHD onset is crucial for understanding its causes.
    • Identifying pre-onset risk factors aids in developing interventions for ADHD.
    • Consortium formation and research collaboration are vital for obtaining large samples in ADHD research.
    • Adults with ADHD have a heightened risk of cardiovascular diseases (CVD), necessitating investigation into risk factors.
    • Risk factors for ADHD and its comorbidities may change over the lifespan, requiring longitudinal research.
    • Not all ADHD risk factors are disorder-specific, indicating transdiagnostic vulnerability.
    • Multidisciplinary team research is essential for comprehensive understanding of ADHD.
  • Nonstimulant Medications for Attention-Deficit/Hyperactivity Disorder (ADHD) in Adults: Systematic Review and Meta-analysis
    Nevena V. Radonjić, et al. CNS Drugs
    Published: 11 May 2023
    Abstract:
    Background:     For some adults with Attention-Deficit/Hyperactivity Disorder (ADHD), nonstimulants need to be considered either as a monotherapy or as an adjunct to stimulants.
    Conclusion: All investigated nonstimulants were more efficacious in the treatment of ADHD in adults, than placebo, while the placebo had better acceptability and tolerability.
  • Expanded access to publicly subsidised lisdexamfetamine treatment for adults with attention-deficit/hyperactivity disorder: An interrupted time-series analysis
    Claudia Bruno, et al. The Australian and New Zealand Journal of Psychiatry
    Published: 25 April 2023
    Abstract:
    Attention-deficit/hyperactivity disorder (ADHD) and related impairments persist into adulthood for approximately two-thirds of people diagnosed in childhood (Di Lorenzo et al., 2021). ADHD medicine use among Australian adults doubled between 2013 and 2020 (Bruno et al., 2022); however, rates of publicly subsidised ADHD pharmacotherapy (0.3–1.0%) in 2020 have remained lower than the global prevalence of persistent adult ADHD from childhood (2.6%) (Song et al., 2021). While a proportion of adults may have been accessing privately funded pharmacotherapy not captured in prior Australian analyses, other barriers are likely contributing to this apparent treatment gap (Bisset et al., 2023). Until recently, Australian adults with ADHD diagnosed after the age of 18 years were only eligible for subsidised access to immediate-release forms of dexamfetamine and methylphenidate. On the contrary, adults who were diagnosed in childhood could access all publicly subsidised ADHD medicines, including atomoxetine, guanfacine, lisdexamfetamine and long-acting methylphenidate. On 1 February 2021, Australia’s Pharmaceutical Benefits Scheme (PBS) listing for lisdexamfetamine was expanded to allow use in adults with ADHD persisting from childhood, even when diagnosed after 18 years of age. Lisdexamfetamine, a pro-drug of dexamfetamine, with a 12–13 hour duration of action is taken once daily, compared with immediate-release stimulants that require dosing two to three times per day. Prior to these subsidy changes, an estimated 20,000 Australian adults were paying more than $1200 (AUD) per person each year for privately funded lisdexamfetamine treatment (Department of Health and Aged Care, 2021). Expansion of the PBS-listing for lisdexamfetamine was intended to increase treatment access for people who were diagnosed in adulthood; however, little is known about the actual impact on dispensing of lisdexamfetamine and other ADHD medicines. Here, we provide contemporary prevalence and incidence estimates for ADHD medicine use among adults in Australia for 2021. We describe the changes in dispensing of subsidised lisdexamfetamine and other subsidised ADHD medicines for adults following the expanded PBS-listing of lisdexamfetamine.
  • Association of ADHD symptoms with type 2 diabetes and cardiovascular comorbidities in adults receiving outpatient diabetes care
    Ali Zare Dehnavi, Yanli Zhang-James, et al.  Journal of Clinical & Translational Endocrinology
    Published: 11 April 2023
    Abstract:
    Background: The relationship between attention-deficit/hyperactivity disorder (ADHD) symptoms and type 2 diabetes mellitus (T2D) and its cardiovascular outcomes have not been sufficiently studied.
    Conclusion: Our results suggest that adults with T2D attending a tertiary care diabetes clinic are at risk for having ADHD-like symptoms, highlighting the importance of screening for ADHD symptoms in this specialty setting and referring undiagnosed adult patients for further assessment and treatment of ADHD. Larger studies are needed to clarify the relationship between ADHD-like symptoms, executive dysfunction, and emotional control with diabetic control and comorbidities.
  • Attention-deficit/hyperactivity disorder is associated with increased risk of cardiovascular diseases: A systematic review and meta-analysis
    Lin Li, Honghui Yao, Le Zhang et al. JCPP Advances
    Published: 5 April 2023
    Abstract: Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with other psychiatric and physical diseases. However, available evidence on associations between ADHD and cardiovascular diseases (CVDs) is mixed. To systematically review, quantitatively synthesize, and appraise available evidence on the link between ADHD with CVDs, we searched relevant articles in PubMed, Embase, PsycINFO, and Web of Science from inception to May 1, 2022.
    Key Points:

    • Evidence on the associations between ADHD and CVDs is mixed.
    • Individuals with ADHD were nearly twice as likely to develop at least one CVD, compare with non-ADHD.
    • The observed strength of associations was largely comparable to estimates of associations between severe mental illness and CVDs.
    • More studies are needed to explore the role of ADHD medications.
  • Growth Trajectories in Stimulant-Treated Children Ages 6 to 12: An Electronic Medical Record Analysis
    Joseph Biederman, et al.     Journal of Developmental & Behavioral Pediatrics
    Published: February/March 2023
    Abstract    :
    Objective: The aim of this study was to evaluate growth trajectories in stimulant-exposed and stimulant-unexposed children using electronic medical record data from a large health care organization attending to moderating effects of the magnitude of exposure to stimulants, sex, and race.
    Conclusion: This comprehensive analysis of an ecologically informative sample attending to key covariates of the magnitude of exposure to stimulants, sex, and race extends previous findings, showing that effects on growth trajectories are small and do not appear to pose a significant clinical concern for most children with ADHD treated with stimulants from childhood onto adolescent years.
  • Progress and Pitfalls in the Provision of Quality Care for Adults With Attention Deficit Hyperactivity Disorder in Primary Care
    Elisabeth F Callen, et al. Journal of Attention Disorders
    Published: 18 February 2023
    Abstract:
    Objective: Quality care for attention deficit hyperactivity disorder (ADHD) in adults has lagged behind other psychiatric disorders. We sought to assess how the achievement of quality measures (QMs) for diagnosing and treating ADHD in adults has changed over time.
    Conclusion: Increase in quality care from 2010 to 2020 along with clear evidence that more efforts are needed to improve quality of care for adults with ADHD seen in primary care.
  • The association between type 2 diabetes and attention- deficit/hyperactivity disorder: A systematic review, meta-analysis, and population-based sibling study
    Miguel Garcia-Argibay,  et al. Neuroscience & Biobehavioral Reviews
    Published online: 6 February 2023
    Abstract: We conducted a systematic review and a meta-analysis to quantitatively summarize evidence on the association between attention-deficit/hyperactivity disorder (ADHD) and type 2 diabetes (T2D). Moreover, a register-based sibling study was conducted to simultaneously control for confounding factors. A systematic search identified four eligible observational studies (N = 5738,287). The meta-analysis showed that individuals with ADHD have a more than doubled risk of T2D when considering adjusted estimates (OR=2.29 [1.48–3.55], d=0.46). Results from the register-based Swedish data showed a significant association between ADHD and T2D (HR=2.35 [2.14–2.58]), with substance use disorder, depression, and anxiety being the main drivers of the association, and cardiovascular and familiar risk playing a smaller role. While results from the meta-analysis provide evidence for an increased risk of T2D in individuals with ADHD, the register-based analyses show that the association between ADHD and T2D is largely explained by psychiatric comorbidities. Pending further evidence of causal association, our findings suggest that early identification and treatment of ADHD comorbidities might greatly reduce the risk of developing T2D in individuals with ADHD.
  • Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains
    Ditte Demontis, et al. Nature Genetics
    Published: 26 January 2023
    Abstract: Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84–98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.
  • Machine Learning and MRI-based Diagnostic Models for ADHD: Are We There Yet?
    Yanli Zhang-James, et al. Journal of Attention Disorders
    Published: 18 January 2023
    Abstract:
    Objective: Machine learning (ML) has been applied to develop magnetic resonance imaging (MRI)-based diagnostic classifiers for attention-deficit/hyperactivity disorder (ADHD). This systematic review examines this literature to clarify its clinical significance and to assess the implications of the various analytic methods applied.
    Conclusion: Ultimately, large multi-modal imaging datasets, and potentially the combination with other types of data, like cognitive data and/or genetics, will be essential to achieve the goal of developing clinically useful imaging classification tools for ADHD in the future.

2022

  • ADHD Remote Technology study of cardiometabolic risk factors and medication adherence (ART-CARMA): a multi-centre prospective cohort study protocol
    Hayley Denyer, et al. BMC Psychiatry
    Published: 20 December 2022
    Abstract:
    Background: Emerging evidence points at substantial comorbidity between adult attention deficit hyperactivity disorder (ADHD) and cardiometabolic diseases, but our understanding of the comorbidity and how to manage cardiometabolic disease in adults with ADHD is limited. The ADHD Remote Technology study of cardiometabolic risk factors and medication adherence (ART-CARMA) project uses remote measurement technology to obtain real-world data from daily life to assess the extent to which ADHD medication treatment and physical activity, individually and jointly, may influence cardiometabolic risks in adults with ADHD. Our second main aim is to obtain valuable real-world data on adherence to pharmacological treatment and its predictors and correlates during daily life from adults with ADHD.
    Discussion: The long-term goal is to use these data to improve the management of cardiometabolic disease in adults with ADHD, and to improve ADHD medication treatment adherence and the personalisation of treatment.
  • Predicting childhood and adolescent attention-deficit/hyperactivity disorder onset: a nationwide deep learning approach
    Miguel Garcia-Argibay, et al. Molecular Psychiatry
    Published: 19 December 2022
    Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder with a high degree of psychiatric and physical comorbidity, which complicates its diagnosis in childhood and adolescence. We analyzed registry data from 238,696 persons born and living in Sweden between 1995 and 1999. Several machine learning techniques were used to assess the ability of registry data to inform the diagnosis of ADHD in childhood and adolescence: logistic regression, random Forest, gradient boosting, XGBoost, penalized logistic regression, deep neural network (DNN), and ensemble models. The best fitting model was the DNN, achieving an area under the receiver operating characteristic curve of 0.75, 95% CI (0.74–0.76) and balanced accuracy of 0.69. At the 0.45 probability threshold, sensitivity was 71.66% and specificity was 65.0%. There was an overall agreement in the feature importance among all models (τ > .5). The top 5 features contributing to classification were having a parent with criminal convictions, male sex, having a relative with ADHD, number of academic subjects failed, and speech/learning disabilities. A DNN model predicting childhood and adolescent ADHD trained exclusively on Swedish register data achieved good discrimination. If replicated and validated in an external sample, and proven to be cost-effective, this model could be used to alert clinicians to individuals who ought to be screened for ADHD and to aid clinicians’ decision-making with the goal of decreasing misdiagnoses. Further research is needed to validate results in different populations and to incorporate new predictors.
  • Risk of Cardiovascular Diseases Associated With Medications Used in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis
    Le Zhang L, Honghui Yao, Lin Li et al. JAMA Network Open.
    Published: 23 November 2022
    Abstract:
    Question: Are attention-deficit/hyperactivity disorder (ADHD) medications associated with the risk of cardiovascular disease (CVD)?
    Findings: This systematic review and meta-analysis based on 19 observational studies with more than 3.9 million participants suggested that there was no statistically significant association between ADHD medications and the risk of cardiovascular events among children and adolescents, young and middle-aged adults, or older adults.
    Meaning: Despite no statistically significant association between ADHD medications and CVD, more evidence is needed for the potential risk of cardiac arrest and tachyarrhythmias, the cardiovascular risk in female patients and in those with preexisting CVD, and long-term risk.
  • Association between Attention Deficit Hyperactivity Disorder and outcomes after metabolic and bariatric surgery: a nationwide propensity matched cohort study
    Erik Stenberg, et al. Surgery for Obesity and Related Diseases.
    Published online: 2 November 2022
    Abstract:
    Background: The risks and benefits of metabolic and bariatric surgery for patients with attention deficit hyperactivity disorder (ADHD) remain to be investigated.
    Objective: The aim of this study was to assess short- and long-term outcomes after metabolic and bariatric surgery in patients with previous ADHD compared with matched control individuals.
    Conclusion: Compared with patients without ADHD, patients treated pharmacologically for ADHD experience similar weight loss and remission of obesity-related diseases without an increased risk for serious complications but report a lower health-related quality of life and have an increased risk of substance abuse and self-harm. This further emphasizes the need for close follow-up care for this group of individuals
  • Association Between ADHD and COVID-19 Infection and Clinical Outcomes: A Retrospective Cohort Study From Electronic Medical Records
    Kathleen P. Heslin, et al. Journal of Attention Disorders.
    Published: 20 October 2022
    Abstract:
    Objectives: Though psychiatric illnesses have been associated with increased COVID-19 infection risk, limited information exists about the relationship between ADHD and COVID-19.
    Conclusion: ADHD poses increased risk for COVID-19, but may reduce risk of severe outcomes. ADHD medications modestly impacted COVID-19 risk.
  • Attention-deficit/hyperactivity disorder as a risk factor for cardiovascular diseases: a nationwide population-based cohort study
    Lin Li, et al.     World Psychiatry
    Published: 8 September 2022
    Abstract: Accumulating evidence suggests a higher risk for cardiovascular diseases among individuals with mental disorders, but very little is known about the risk for overall and specific groups of cardiovascular diseases in people with attention-deficit/hyperactivity disorder (ADHD). To fill this knowledge gap, we investigated the prospective associations between ADHD and a wide range of cardiovascular diseases in adults. In a nationwide population-based cohort study, we identified 5,389,519 adults born between 1941 and 1983, without pre-existing cardiovascular diseases, from Swedish registers. The study period was from January 1, 2001 to December 31, 2013. Incident cardiovascular disease events were identified according to ICD codes. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox proportional hazards regression model, with ADHD as a time-varying exposure. After an average 11.80 years of follow-up, 38.05% of individuals with ADHD versus 23.57% of those without ADHD had at least one diagnosis of cardiovascular disease (p<0.0001). ADHD was significantly associated with increased risk of any cardiovascular disease (HR=2.05, 95% CI: 1.98-2.13) after adjusting for sex and year of birth. Further adjustments for education level, birth country, type 2 diabetes mellitus, obesity, dyslipidemia, sleep problems and heavy smoking attenuated the association, which however remained significant (HR=1.84, 95% CI: 1.77-1.91). Further adjustment for psychiatric comorbidities attenuated but could not fully explain the association (HR=1.65, 95% CI: 1.59-1.71). The strongest associations were found for cardiac arrest (HR=2.28, 95% CI: 1.81-2.87), hemorrhagic stroke (HR=2.16, 95% CI: 1.68-2.77), and peripheral vascular disease/arteriosclerosis (HR=2.05, 95% CI: 1.76-2.38). Stronger associations were observed in males and younger adults, while comparable associations were found among individuals with or without psychotropic medications and family history of cardiovascular diseases. These data suggest that ADHD is an independent risk factor for a wide range of cardiovascular diseases. They highlight the importance of carefully monitoring cardiovascular health and developing age-appropriate and individualized strategies to reduce the cardiovascular risk in individuals with ADHD.
  • Risk prediction model for cardiovascular diseases in adults initiating pharmacological treatment for attention-deficit/hyperactivity disorder
    Maja Dobrosavljevic, et al. BMJ Mental Health
    Published: 5 September 2022
    Abstract:
    Background: Available prediction models of cardiovascular diseases (CVDs) may not accurately predict outcomes among individuals initiating pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD).
    Conclusion: The inclusion of the novel CVD risk factors may provide a better prediction of CVDs in this population compared with traditional CVD predictors only, when the model is used with a continuous risk score. External validation studies and studies assessing clinical impact of the model are warranted.
  • Patterns of attention deficit hyperactivity disorder medicine use in the era of new non-stimulant medicines: A population-based study among Australian children and adults (2013–2020)
    Claudia Bruno, et al. The Australian and New Zealand Journal of Psychiatry
    Published: 23 August 2022
    Abstract:
    Background: New therapeutic options such as lisdexamfetamine and guanfacine have recently become available for the treatment of attention deficit hyperactivity disorder. We described contemporary patterns of attention deficit hyperactivity disorder medicine use among children, adolescents and adults in Australia.
    Conclusion: We observed increasing attention deficit hyperactivity disorder medicine use in Australia, especially among young females. Nevertheless, treatment rates remain lower than the estimated prevalence of attention deficit hyperactivity disorder across all subpopulations. Poor long-term treatment persistence in adolescence may warrant improved clinical monitoring of attention deficit hyperactivity disorder in patients transitioning from paediatric to adult care. Reassuringly, use of newly approved guanfacine appeared to be in accordance with guidelines among children.
  • Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease
    Jiahui Hou, et al. Nature Translational Psychiatry.
    Published: 25 July 2022
    Abstract: Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast “resilient” unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.
  • Cardiovascular risk factors in attention deficit/hyperactivity disorder: A family design study of Swedish conscripts
    Miguel Garcia-Argibay, et al. International Journal of Methods in Psychiatric Research
    Published: 29 June 2022
    Abstract:
    Objective: (1) investigate the associations of attention-deficit/hyperactivity disorder (ADHD) with systolic and diastolic blood pressure, resting heart rate, pulse pressure (PP), physical fitness, and BMI; (2) explore whether cardiovascular risk factors and ADHD share genetic and environmental influences; (3) assess if pharmacological treatment for ADHD influences these associations.
    Conclusion: Individuals with several cardiovascular risk factors are more often diagnosed with ADHD, regardless of psychiatric comorbidity. These association are not explained by ADHD pharmacotherapy, rather, they are in part due to shared familial risk factors.
  • The role of ADHD genetic risk in mid-tolate life somatic health conditions
    Miguel Garcia-Argibay, et al. Translational Psychiatry.
    Published: 21 April 2022
    Abstract: Growing evidence suggests that ADHD, an early onset neurodevelopmental disorder, is associated with poor somatic health in adulthood. However, the mechanisms underlying these associations are poorly understood. Here, we tested whether ADHD polygenic risk scores (PRS) are associated with mid-to-late life somatic health in a general population sample. Furthermore, we explored whether potential associations were moderated and mediated by life-course risk factors. We derived ADHD-PRS in 10,645 Swedish twins born between 1911 and 1958. Sixteen cardiometabolic, autoimmune/inflammatory, and neurological health conditions were evaluated using self-report (age range at measure 42–88 years) and clinical diagnoses defined by International Classification of Diseases codes in national registers. We estimated associations of ADHD-PRS with somatic outcomes using generalized estimating equations, and tested moderation and mediation of these associations by four life-course risk factors (education level, body mass index [BMI], tobacco use, alcohol misuse). Results showed that higher ADHD-PRS were associated with increased risk of seven somatic outcomes (heart failure, cerebro- and peripheral vascular disease, obesity, type 1 diabetes, rheumatoid arthritis, and migraine) with odds ratios ranging 1.07 to 1.20. We observed significant mediation effects by education, BMI, tobacco use, and alcohol misuse, primarily for associations of ADHD-PRS with cardiometabolic outcomes. No moderation effects survived multiple testing correction. Our findings suggests that higher ADHD genetic liability confers a modest risk increase for several somatic health problems in mid-to-late life, particularly in the cardiometabolic domain. These associations were observable in the general population, even in the absence of medical treatment for ADHD, and appear to be in part mediated by life-course risk factors.
  • Rare coding variants in ten genes confer substantial risk for schizophrenia.
    Tarjinder Singh, et al. Nature
    Published: 8 April 2022
    Abstract: Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.