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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,  imply click on the title of the publication.

TIMESPAN publications

2024

  • 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.

  • 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.
  • 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.
  • 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

  • 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.
  • 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.
  • 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.
  • 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.
  • 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 DisorderA 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.
  • 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.