To Örebro University

Background

Randomised controlled trials (RCTs) evaluating ADHD medications often use strict eligibility criteria, potentially limiting generalisability to patients in real-world clinical settings. We aimed to identify the proportion of individuals with ADHD who would be ineligible for medication RCTs and evaluate differences in treatment patterns and clinical and functional outcomes between RCT-eligible and RCT-ineligible individuals.

Methods

We used multiple Swedish national registries to identify individuals with ADHD, aged at least 4 years at the age of diagnosis, initiating pharmacological treatment between Jan 1, 2007, and Dec 31, 2019, with follow-up up to Dec 31, 2020. Hypothetical RCT ineligibility was established using exclusion criteria from the international MED-ADHD dataset, including 164 RCTs of ADHD medications. Cox models evaluated differences in medication switching and discontinuation within 1 year between eligible and ineligible individuals. Quasi-Poisson models compared eligible and ineligible individuals on rates of psychiatric hospitalisations, injuries or accidents, and substance use disorder within 1 year of initiating ADHD medications. People with lived experience of ADHD were not involved in the research and writing process.

Findings

Of 189 699 individuals included in the study cohort (112 153 men and boys [59%] and 77 546 women and girls [41%]; mean age 21·52 years [SD 12·83; range 4–68]) initiating ADHD medication, 53% (76 477 [74%] of 103 023 adults [aged >17 years], 12 658 [35%] of 35 681 adolescents [aged 13–17 years], and 10 643 [21%] of 50 995 children [aged <13 years]) would have been ineligible for RCT participation. Ethnicity data were not available. Ineligible individuals had a higher likelihood of treatment switching (hazard ratio 1·14, 95% CI 1·12–1·16) and a decreased likelihood of medication discontinuation (0·96, 0·94–0·98) compared with eligible individuals. Individuals ineligible for RCTs had significantly higher rates of psychiatric hospitalisations (ncidence rate ratio 9·68, 95% CI 9·57–9·78) and specialist care visits related to substance use disorder (14·78, 14·64–14·91), depression (6·00, 5·94–6·06), and anxiety (11·63, 11·56–11·69).

Interpretation

Individuals ineligible for ADHD medication trials face higher risks of adverse outcomes. This study provides the first empirical evidence for the limited generalisability of ADHD RCTs to real-world clinical populations, by applying eligibility criteria extracted from a comprehensive dataset of RCTs to a large real-world cohort. Triangulating evidence from RCTs and real-world studies is crucial to inform rigorous evidence-based treatment guidelines.

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 ADHD onsets in early life, it has been hypothesized that ADHD may cause MDD.

METHODS: In this study, we examined the association of ADHD with MDD using three different genetically informed methods to disentangle causality from confounding: 1) a nationwide longitudinal register-based full sibling comparison (N=1,018,489) adjusting for shared familial confounding; 2) a prospective co-twin control study comprising 16,447 twins (5,084 monozygotic and 11,393 dizygotic); and 3) a two-sample Mendelian randomization analysis using the largest available ADHD (N=225,534) and MDD (N=500,199) genome wide association (GWAS) summary statistics, adjusting for correlated and uncorrelated horizontal pleiotropy.

RESULTS: Sibling and twin comparisons indicated that individuals with ADHD have an increased risk for subsequent development of MDD (HR=4.12 [3.62-4.69]) after adjusting for shared genetic and familial factors, and that ADHD scores endorsed by parents are positively associated with subsequent MDD scores at ages 15 and 18 years (b=0.07 [0.05-0.08]) and b=0.09 [0.08-0.11], respectively). Mendelian randomization analyses showed that genetic liability for ADHD is causally related to MDD (OR=1.15 [1.08-1.23]).

CONCLUSIONS: Our study provided consistent results across three different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.

IMPORTANCE: Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades. However, the potential risk of cardiovascular disease (CVD) associated with long-term ADHD medication use remains unclear.

OBJECTIVE: To assess the association between long-term use of ADHD medication and the risk of CVD.

DESIGN, SETTING, AND PARTICIPANTS: This case-control study included individuals in Sweden aged 6 to 64 years who received an incident diagnosis of ADHD or ADHD medication dispensation between January 1, 2007, and December 31, 2020. Data on ADHD and CVD diagnoses and ADHD medication dispensation were obtained from the Swedish National Inpatient Register and the Swedish Prescribed Drug Register, respectively. Cases included individuals with ADHD and an incident CVD diagnosis (ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease). Incidence density sampling was used to match cases with up to 5 controls without CVD based on age, sex, and calendar time. Cases and controls had the same duration of follow-up.

EXPOSURE: Cumulative duration of ADHD medication use up to 14 years.

MAIN OUTCOMES AND MEASURES: The primary outcome was incident CVD. The association between CVD and cumulative duration of ADHD medication use was measured using adjusted odds ratios (AORs) with 95% CIs.

RESULTS: Of 278 027 individuals with ADHD aged 6 to 64 years, 10 388 with CVD were identified (median [IQR] age, 34.6 [20.0-45.7] years; 6154 males [59.2%]) and matched with 51 672 control participants without CVD (median [IQR] age, 34.6 [19.8-45.6] years; 30 601 males [59.2%]). Median (IQR) follow-up time in both groups was 4.1 (1.9-6.8) years. Longer cumulative duration of ADHD medication use was associated with an increased risk of CVD compared with nonuse (0 to ≤1 year: AOR, 0.99 [95% CI, 0.93-1.06]; 1 to ≤2 years: AOR, 1.09 [95% CI, 1.01-1.18]; 2 to ≤3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ≤5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and >5 years: AOR, 1.23 [95% CI, 1.12-1.36]). Longer cumulative ADHD medication use was associated with an increased risk of hypertension (eg, 3 to ≤5 years: AOR, 1.72 [95% CI, 1.51-1.97] and >5 years: AOR, 1.80 [95% CI, 1.55-2.08]) and arterial disease (eg, 3 to ≤5 years: AOR, 1.65 [95% CI, 1.11-2.45] and >5 years: AOR, 1.49 [95% CI, 0.96-2.32]). Across the 14-year follow-up, each 1-year increase of ADHD medication use was associated with a 4% increased risk of CVD (AOR, 1.04 [95% CI, 1.03-1.05]), with a larger increase in risk in the first 3 years of cumulative use (AOR, 1.08 [95% CI, 1.04-1.11]) and stable risk over the remaining follow-up. Similar patterns were observed in children and youth (aged <25 years) and adults (aged ≥25 years).

CONCLUSIONS AND RELEVANCE: This case-control study found that long-term exposure to ADHD medications was associated with an increased risk of CVDs, especially hypertension and arterial disease. These findings highlight the importance of carefully weighing potential benefits and risks when making treatment decisions about long-term ADHD medication use. Clinicians should regularly and consistently monitor cardiovascular signs and symptoms throughout the course of treatment.

Background: Over the last decades, the prevalence of Attention-deficit/hyperactivity disorder (ADHD) has increased. However, the underlying explanation for this increase remains unclear. We aimed to assess whether there has been a secular change in how parents perceive the impairment conferred by ADHD symptomatology.

Methods: Data for this study were obtained from the Child and Adolescent Twin Study in Sweden, involving 27,240 individuals whose parents answered a questionnaire when the children were 9 years old. We assessed the relationship between parentally perceived impairment caused by ADHD symptoms scores over time. The analysis was performed separately for five different birth cohorts, spanning three-year periods from 1995 to 2009 and for ADHD inattention and hyperactivity/impulsivity dimensions.

Results: We found a consistent upward trend of parents reporting impairment in relation to ADHD symptomatology across birth cohorts. Over a 12-year period, comparing those born 2007–2009 (assessed 2016–2018) with those born 1995–1997 (assessed 2004–2006), impairment scores increased by 27% at clinically relevant levels of ADHD symptomatology. Notably, when specifically evaluating the hyperactivity/impulsivity dimension, the disparity was even more striking, with an increase of up to 77%.

Conclusions: This study revealed a significant secular change in parental perception of impairment attributed to ADHD symptomatology over recent decades, providing new insights into the increased prevalence of ADHD. It underscores the need to better understand the factors that have contributed to the increased perception of impairment related to ADHD symptoms.

Background: Individuals with Attention-Deficit/Hyperactivity Disorder (ADHD) face an elevated risk of criminal convictions compared to those without ADHD. However, understanding this link involves considering sex differences, coexisting psychiatric conditions, and unmeasured familial factors. This study aimed to explore the connection between ADHD and criminal convictions (both violent and non-violent) in males and females, while also assessing the impact of comorbid psychiatric disorders and familial factors.

Methods: Using Swedish national registers, we identified individuals born between 1986 and 1997 (635,391 males and 600,548 females). ADHD was defined through clinical diagnosis and prescribed medications, while criminal convictions were determined based on Swedish lower court records. Unmeasured familial factors were accounted for using a sibling design approach.

Results: Findings revealed that individuals with ADHD had a notably higher absolute and relative risk of both violent and non-violent criminal convictions compared to those without ADHD. While criminal convictions were more frequent among males with ADHD, females with ADHD exhibited higher relative risks (HR violent 10.50, non-violent 4.04) than their male counterparts (HR violent 6.03, non-violent 3.57). Additionally, lower socioeconomic status (SES) in individuals with ADHD was associated with increased relative risks for criminal convictions compared to individuals with ADHD who had higher SES. Adjusting for childhood and internalizing psychiatric disorders partially attenuated these associations, while substance use disorders (SUD) substantially attenuated them. SUD also contributed to an elevated absolute risk of criminal convictions in both male and female individuals with ADHD. Accounting for unmeasured shared familial factors slightly reduced the estimates, but the association between ADHD and criminal convictions persisted.

Conclusion: In conclusion, ADHD remains a potent independent risk factor for criminal convictions, with varying effects based on gender. This underscores the importance of tailored crime prevention strategies and early interventions for individuals with ADHD, especially when comorbid SUD is present.

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder, and phobias) are highly prevalent, often onset early, persist throughout life, and cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant ANX risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 of the 58 associated variants were replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism, and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism underlying ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

There have been increasing efforts to develop prediction models supporting personalised detection, prediction, or treatment of ADHD. We overviewed the current status of prediction science in ADHD by: (1) systematically reviewing and appraising available prediction models; (2) quantitatively assessing factors impacting the performance of published models. We did a PRISMA/CHARMS/TRIPOD-compliant systematic review (PROSPERO: CRD42023387502), searching, until 20/12/2023, studies reporting internally and/or externally validated diagnostic/prognostic/treatment-response prediction models in ADHD. Using meta-regressions, we explored the impact of factors affecting the area under the curve (AUC) of the models. We assessed the study risk of bias with the Prediction Model Risk of Bias Assessment Tool (PROBAST). From 7764 identified records, 100 prediction models were included (88% diagnostic, 5% prognostic, and 7% treatment-response). Of these, 96% and 7% were internally and externally validated, respectively. None was implemented in clinical practice. Only 8% of the models were deemed at low risk of bias; 67% were considered at high risk of bias. Clinical, neuroimaging, and cognitive predictors were used in 35%, 31%, and 27% of the studies, respectively. The performance of ADHD prediction models was increased in those models including, compared to those models not including, clinical predictors (β = 6.54, p = 0.007). Type of validation, age range, type of model, number of predictors, study quality, and other type of predictors did not alter the AUC. Several prediction models have been developed to support the diagnosis of ADHD. However, efforts to predict outcomes or treatment response have been limited, and none of the available models is ready for implementation into clinical practice. The use of clinical predictors, which may be combined with other type of predictors, seems to improve the performance of the models. A new generation of research should address these gaps by conducting high quality, replicable, and externally validated models, followed by implementation research.

BACKGROUND: BIPCOM aims to (1) identify medical comorbidities in people with bipolar disorder (BD); (2) examine risk factors and clinical profiles of Medical Comorbidities (MC) in this clinical group, with a special focus on Metabolic Syndrome (MetS); (3) develop a Clinical Support Tool (CST) for the personalized management of BD and medical comorbidities.

METHODS: The BIPCOM project aims to investigate MC, specifically MetS, in individuals with BD using various approaches. Initially, prevalence rates, characteristics, genetic and non-genetic risk factors, and the natural progression of MetS among individuals with BD will be assessed by analysing Nordic registers, biobanks, and existing patient datasets from 11 European recruiting centres across 5 countries. Subsequently, a clinical study involving 400 participants from these sites will be conducted to examine the clinical profiles and incidence of specific MetS risk factors over 1 year. Baseline assessments, 1-year follow-ups, biomarker analyses, and physical activity measurements with wearable biosensors, and focus groups will be performed. Using this comprehensive data, a CST will be developed to enhance the prevention, early detection, and personalized treatment of MC in BD, by incorporating clinical, biological, sex and genetic information. This protocol will highlight the study's methodology.

DISCUSSION: BIPCOM's data collection will pave the way for tailored treatment and prevention approaches for individuals with BD. This approach has the potential to generate significant healthcare savings by preventing complications, hospitalizations, and emergency visits related to comorbidities and cardiovascular risks in BD. BIPCOM's data collection will enhance BD patient care through personalized strategies, resulting in improved quality of life and reduced costly interventions. The findings of the study will contribute to a better understanding of the relationship between medical comorbidities and BD, enabling accurate prediction and effective management of MetS and cardiovascular diseases.

TRIAL REGISTRATION: ISRCTN68010602 at https://www.isrctn.com/ISRCTN68010602 . Registration date: 18/04/2023.

Importance:  There are concerns about the safety of medications for treatment of attention-deficit/hyperactivity disorder (ADHD), with mixed evidence on possible cardiovascular risk.

Objective:  To assess whether short-term methylphenidate use is associated with risk of cardiovascular events.

Design, Setting, and Participants:  This retrospective, population-based cohort study was based on national Swedish registry data. Participants were individuals with ADHD aged 12 to 60 years with dispensed prescriptions of methylphenidate between January 1, 2007, and June 30, 2012. Each person receiving methylphenidate (n = 26 710) was matched on birth date, sex, and county to up to 10 nonusers without ADHD (n = 225 672). Statistical analyses were performed from September 13, 2022, to May 16, 2023.

Main Outcomes and Measures:  Rates of cardiovascular events, including ischemic heart disease, venous thromboembolism, heart failure, or tachyarrhythmias, 1 year before methylphenidate treatment and 6 months after treatment initiation were compared between individuals receiving methylphenidate and matched controls using a bayesian within-individual design. Analyses were stratified by history of cardiovascular events.

Results:  The cohort included 252 382 individuals (15 442 [57.8% men]; median age, 20 (IQR, 15-31) years). The overall incidence of cardiovascular events was 1.51 per 10 000 person-weeks (95% highest density interval [HDI], 1.35-1.69) for individuals receiving methylphenidate and 0.77 (95% HDI, 0.73-0.82) for the matched controls. Individuals treated with methylphenidate had an 87% posterior probability of having a higher rate of cardiovascular events after treatment initiation (incidence rate ratio [IRR], 1.41; 95% HDI, 1.09-1.88) compared with matched controls (IRR, 1.18; 95% HDI, 1.02-1.37). The posterior probabilities were 70% for at least a 10% increased risk of cardiovascular events in individuals receiving methylphenidate vs 49% in matched controls. No difference was found in this risk between individuals with and without a history of cardiovascular disease (IRR, 1.11; 95% HDI, 0.58-2.13).

Conclusions and Relevance:  In this cohort study, individuals receiving methylphenidate had a small increased cardiovascular risk vs matched controls in the 6 months after treatment initiation. However, there was little evidence for an increased risk of 20% or higher and for differences in risk increase between people with and without a history of cardiovascular disease. Therefore, before treatment initiation, careful consideration of the risk-benefit trade-off of methylphenidate would be useful, regardless of cardiovascular history.

Background: The diagnosis of attention-deficit/hyperactivity disorder (ADHD) in preschool years (before age 6 years) is a marker of severity and poor prognosis. This study investigated a broad range of predictors of ADHD diagnosis during preschool age.

Methods: Population-based cohort study using Swedish registers. The final sample consisted of all children born in Sweden between 2001 and 2007 who could be linked to both of their biological parents, excluding those who died or emigrated (n = 631,695). Follow-up was completed December 31, 2013. Cox proportional-hazards models for survival analysis were used to identify the predictors that increased the risk of receiving a clinical diagnosis of ADHD from 3 to 5 years. Hazard ratios (HR) with 95% confidence intervals (CI) were presented for each of the 41 selected predictors covering early-onset psychiatric comorbidities, nonpsychiatric medical conditions, parental history and perinatal factors.

Results: At the end of follow-up, 1,686 preschoolers (2.7% of the whole sample) had received a diagnosis of ADHD. We found that 39 out of 41 predictors were associated with increased risk of a later diagnosis of preschool ADHD. Novel associations with preschool ADHD diagnosis were found for gastroesophageal reflux disease (HR = 3.48), premature contractions during pregnancy (HR = 2.03), and criminal conviction history from any parent (HR = 2.14).

Conclusions: A large number of novel and well-established predictors of preschool ADHD diagnosis were identified. This broad set of early predictors may direct future clinical research and assist in early identification of preschool ADHD.