To Örebro University

Importance: Adults with attention-deficit/hyperactivity disorder (ADHD) are at greater risk for unemployment. Pharmacological treatment is effective in reducing the core symptoms of ADHD, but whether it helps to reduce the unemployment rate among adult patients remains unclear.

Objective: To investigate the association between use of ADHD medication and long-term unemployment in working-age adults with ADHD.

Design, Setting, and Participants: Data for this population-based cohort study were extracted from Swedish national registers. Among 25 358 individuals with ADHD born from 1958 to 1978, 12 875 middle-aged adults among the workforce were included. The longitudinal cohort was followed up from January 1, 2008, to December 31, 2013. Data were analyzed from March 1, 2020, through May 31, 2021.

Exposures: Use of medication for ADHD during the previous 2 years was the main exposure, as both categorical and continuous variables.

Main Outcomes and Measures: Yearly accumulated unemployed days were derived from the Public Employment Service, and long-term unemployment was defined as 90 or more days of unemployment per year. Overall and sex-specific relative risks (RRs) with 95% CIs were estimated using generalized estimating equations.

Results: Among 12 875 individuals with ADHD (5343 women [41.50%] and 7532 men [58.50%]; mean [SD] age, 37.9 [5.6] years), the use of ADHD medications during the previous 2 years was associated with a 10% lower risk of long-term unemployment in the following year (adjusted RR, 0.90 [95% CI, 0.87-0.95]). An association between use of ADHD medications and long-term unemployment was found among women (RR, 0.82 [95% CI, 0.76-0.89]) but not men (RR, 0.96 [95% CI, 0.91-1.01]). Longer treatment duration was associated with a lower risk of subsequent long-term unemployment among women (RR for use of 1-6 months, 0.86 [95% CI, 0.78-0.95]; RR for use of 18-24 months, 0.72 [95% CI, 0.58-0.90]; P < .001 for trend). Within-individual comparisons showed that the long-term unemployment rate was lower during periods of ADHD medication treatment compared with nontreatment periods (RR, 0.89; 95% CI, 0.85-0.94).

Conclusions and Relevance: The findings of this cohort study suggest that the use of ADHD medication is associated with a lower risk of subsequent long-term unemployment for middle-aged women. These findings should be considered together with the existing knowledge of risks and benefits of ADHD medication when developing treatment plans for working-age adults.

PURPOSE: Intrauterine exposures influence offspring health and development. Here we investigated maternal intake of sweetened carbonated beverages (SCB) during pregnancy and its association with ADHD symptoms in the offspring.

METHODS: This study was based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway. Maternal diet mid-pregnancy was assessed using a food frequency questionnaire (FFQ). All mothers who responded to the FFQ and a questionnaire when their child was 8 years of age were included (n = 39,870). The exposure was defined as maternal intake (daily servings) of SCB, using no daily intake as reference. Outcome was offspring ADHD symptoms, evaluated as a continuous standardized ADHD score and as a binary outcome of six or more ADHD symptoms vs. five symptoms or less. Associations were analysed using log-binomial regression and linear mixed regression models with adjustment for covariates.

RESULTS: The adjusted regression coefficients for the standardized ADHD offspring symptom score were 0.31 [95% confidence intervals (0.001, 0.62)] and 0.46 (0.15, 0.77) for maternal daily intake of ≥ 1 glasses of SCB, when the models included adjustments for total energy intake or energy intake from other sources than SCBs and sweet drinks, respectively. The corresponding adjusted relative risks were 1.16 (1.004, 1.34) and 1.21. (1.05, 1.39) for drinking ≥ 1 glasses daily.

CONCLUSION: In a large pregnancy cohort with offspring followed until 8 years of age, we found an association between maternal daily intake of SCB and offspring ADHD symptoms. These results suggest a weak positive relationship between prenatal exposure to SCB and offspring ADHD.

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.

Background: Available prediction models ofcardiovascular diseases (CVDs) may not accuratelypredict outcomes among individuals initiatingpharmacological treatment for attention-deficit/hyperactivity disorder (ADHD).

Objective: To improve the predictive accuracyof traditional CVD risk factors for adults initiatingpharmacological treatment of ADHD, by consideringnovel CVD risk factors associated with ADHD (comorbidpsychiatric disorders, sociodemographic factors andpsychotropic medication).

Methods: The cohort composed of 24 186 adultsresiding in Sweden without previous CVDs, born between1932 and 1990, who started pharmacological treatmentof ADHD between 2008 and 2011, and were followedfor up to 2 years. CVDs were identified using diagnosesaccording to the International Classification of Diseases,and dispended medication prescriptions from Swedishnational registers. Cox proportional hazards regressionwas employed to derive the prediction model.

Findings: The developed model included eighttraditional and four novel CVD risk factors. Themodel showed acceptable overall discrimination (Cindex=0.72, 95% CI 0.70 to 0.74) and calibration(Brier score=0.008). The Integrated DiscriminationImprovement index showed a significant improvementafter adding novel risk factors (0.003 (95% CI 0.001 to0.007), p<0.001).

Conclusions: The inclusion of the novel CVD riskfactors may provide a better prediction of CVDs in thispopulation compared with traditional CVD predictorsonly, when the model is used with a continuous riskscore. External validation studies and studies assessingclinical impact of the model are warranted.

Clinical implications: Individuals initiatingpharmacological treatment of ADHD at higher risk ofdeveloping CVDs should be more closely monitored.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by inattention or hyperactivity–impulsivity, or both. ADHD is a multifactorial disorder influenced by the complex interplay between genetic and environmental risk factors, but a detailed understanding of the causal status of these factors is lacking. ADHD is associated with many psychiatric disorders, but somatic comorbidity in ADHD has received less attention in the research literature. Pharmacological treatment is effective in reducing the core symptoms of ADHD, but the effects on occupational outcomes remain unclear. The overarching aim of this thesis is to extend previous knowledge on the early risk factors of ADHD, and to increase the awareness and the understanding on somatic and occupational outcomes of ADHD in adults.

In Study I, we combined a systematic review and mate-analysis with a population based cohort of 971,501 individuals born between 1992 and 2004 in Sweden. The meta-analysis revealed a positive association between maternal pre-pregnancy overweight/obesity and risk of ADHD in offspring. However, these associations gradually attenuated toward the null when adjusted for measured confounders,unmeasured factors shared by cousins and unmeasured factors shared by siblings. In Study II, by using a Swedish population-based twin study with 17,999 individuals aged 20–47 years, we found both inattention and hyperactivity/impulsivity was associated with higher consumption of high-sugar food and unhealthy dietary habits, although these associations were generally weak. Further, the observed associations was explained by both genetic and non-shared environmental factors.In Study III, we explored the prospective associations between ADHD and a broad range of cardiovascular diseases in 5,389,519 adults from Sweden, and found that ADHD may be a novel and independent risk factor for cardiovascular diseases. In Study IV, based on the longitudinal cohort of 12,875 middle-aged adults with ADHD, we found the use of ADHD medications during the previous two years was associated with a 10% reduction in the risk of long-term unemployment in the following year.

Taken together, findings from the thesis highlight the need of future studies with various study designs, to fully understand the aetiology and long-term health outcomes of ADHD across the lifespan.

BACKGROUND AND PURPOSE: Results from previous studies that linking vitamin B12 to risk of chronic diseases or mortality are inconsistent. We hereby explore the association between serum concentration of vitamin B12 and all-cause mortality risk in elderly adults.

METHODS: Participants aged over 65 years in the Chinese Longitudinal Healthy Longevity Survey were included in present prospective cohort study. Serum vitamin B12 was assessed at the 2011-2012 and 2014 wave, respectively. Participants were divided into three groups based on two cut-off points - 10th and 90th percentiles of vitamin B12 concentrations - in the whole population. Cox regression model was used to calculate the hazard ratio (HR) and 95 % confidence intervals (95 % CIs), and restricted cubic spline function was further modelled to investigate their dose-response associations.

RESULTS: Among 2,086 participants [mean ± SD: 87.74 ± 11.24 years, 908 (43.53 %) males], 943 (45.21 %) died during an average follow-up of 3.34 (SD: 1.63) years. Comparing with participants with middle concentration of serum vitamin B12, participants with high concentration had an increased risk of all-cause mortality [HR (95 %CIs): 1.30 (1.03-1.64)], whereas participants with low concentration had an insignificantly decreased risk of all-cause mortality (0.96, 0.76-1.20). The positive association between high concentration of serum vitamin B12 and all-cause mortality was also observed among the male and in a series of sensitivity analyses. In the dose-response analysis, a J-shape pattern was observed, but the non-linear association was only significant in males (P_{non-linearity} = 0.0351).

CONCLUSIONS: High concentration of serum vitamin B12 was associated with an increased risk of all-cause mortality in a J-shaped pattern. The precise mechanisms underlying the association remain to be explored.

As a symptomatic predementia stage with progressive cognitive decline, mild cognitive impairment (MCI) is common with aging. How changes in self-reported sleep duration affect MCI risk in the older adults remains unclear. Participants aged ≥ 65 years and enrolled at least two waves in the Chinese Longitudinal Healthy Longevity Survey were included in present longitudinal study. Changes in sleep duration were calculated as the difference between two waves and categorized into five groups: decreased >2 h, decreased 0-2h, stable, increased 0-2 h, and increased >2 h. MCI was measured by the Chinese version of the Mini-Mental State Examination. Generalized estimating equation model and restricted cubic spline function was applied to investigate the association. Among 9,005 participants (mean age, 81.19 years; 4,391 male), 2,877 developed MCI. Comparing with individuals with stable sleep duration, MCI risk [odds ratio (95% confidence intervals)] was: 1.15 (0.99-1.34) for decreased >2 h, 0.99 (0.87-1.13) for decreased 0-2h, 1.09 (0.95-1.24) for increased 0-2 h, and 1.57 (1.36-1.81) for increased >2 h, respectively. Similar patterns were observed among subgroup analyses by sex, age, and sleep quality at baseline. For participants with long sleep duration at baseline (>8h), further increased >2 h was associated with higher MCI risk [2.23 (1.55-3.21)]. Either in the whole or subgroup population, a U-shaped association was observed (Pnon-linearity<0.05). In conclusion, changes in self-reported sleep duration were associated with MCI risk in a U-shaped pattern. Strategies that shifting sleep duration into normal range and keeping it stable are essential to prevent MCI in clinical practice. 

Disinhibition is a prominent feature of multiple psychiatric disorders, and has been associated with poor long-term somatic outcomes. Modifiable lifestyle factors including diet and moderate-to-vigorous physical activity (MVPA) may be associated with disinhibition, but their contributions have not previously been quantified among middle-aged/older adults. Here, among N = 157,354 UK Biobank participants aged 40-69, we extracted a single disinhibition principal component and four dietary components (prudent diet, elimination of wheat/dairy/eggs, meat consumption, full-cream dairy consumption). In addition, latent profile analysis assigned participants to one of five empirical dietary groups: prudent-moderate, unhealthy, restricted, meat-avoiding, low-fat dairy. Disinhibition was regressed on the four dietary components, the dietary grouping variable, and self-reported MVPA. In men and women, disinhibition was negatively associated with prudent diet, and positively associated with wheat/dairy/eggs elimination. In men, disinhibition was also associated with consumption of meat and full-cream dairy products. Comparing groups, disinhibition was lower in the prudent-moderate diet (reference) group compared to all other groups. Absolute βs ranged from 0.02-0.13, indicating very weak effects. Disinhibition was not associated with MVPA. In conclusion, disinhibition is associated with multiple features of diet among middle-aged/older adults. Our findings foster specific hypotheses (e.g., early malnutrition, elevated immune-response) to be tested in alternative study designs.

BACKGROUND & AIMS: Overall diet quality may partially mediate the detrimental effects of stress and neuroticism on common mental health problems: stressed and/or neurotic individuals may be more prone to unhealthy dietary habits, which in turn may contribute to depression and anxiety. Lifestyle interventions for depressed, anxious or at-risk individuals hinge on this idea, but evidence to support such pathway is missing. Here, we aim to prospectively evaluate the role of overall diet quality in common pathways to developing depression and anxiety.

METHODS: At baseline, N = 121,008 individuals from the general population (age 18-93) completed an extensive food frequency questionnaire, based on which overall diet quality was estimated. Participants also reported on two established risk factors for mental health problems, i.e. past-year stress exposure (long-term difficulties, stressful life-events) and four neuroticism traits (anger-hostility, self-consciousness, impulsivity, vulnerability). Depression and anxiety were assessed at baseline and follow-up (n = 65,342, +3.6 years). Overall diet quality was modeled as a mediator in logistic regression models predicting the development of depression and anxiety from common risk factors.

RESULTS: High stress and high neuroticism scores were - albeit weakly - associated with poorer diet quality. Poor diet quality, in turn, did not predict mental health problems. Overall diet quality did not mediate the relationship between stress/neuroticism and common mental health problems: effects of stress, neuroticism and stress-by-neuroticism interactions on mental health problems at follow-up consisted entirely of direct effects (98.6%-100%).

CONCLUSIONS: Diet quality plays no mediating role in two established pathways to common mental health problems. As overall diet quality was reduced in stressed and neurotic individuals, these groups may benefit from dietary interventions. However, such interventions are unlikely to prevent the onset or recurrence of depression and anxiety.

Background: Dietary habits were investigated as environmental risk factors for Attention-Deficit/Hyperactivity Disorder (ADHD). However, no previous studies explored the effects of dietary factors on modifying the role of genetic factors on ADHD.

Methods: Based on a Swedish population-based twin study with 1518 twin pairs aged 20-47 years, we tested whether the importance of genetic and environmental effects on ADHD varied as a function of dietary habits. Self-reported dietary habits and ADHD symptoms were collected. Twin methods were used to test the degree to which high-sugar and unhealthy food intake moderated the genetic and environmental influences on ADHD symptoms.

Results: In middle-aged adults, genetic influences on inattention symptoms were statistically significantly higher among individuals with higher levels of high-sugar (45%, 95%CI: 25-54%) and unhealthy food intake (51%, 95%CI: 31-60%), compared with those with lower levels of consumption of high-sugar (36%, 95%CI: 25-47%) and unhealthy foods (30%, 95%CI: 20-41%). Similar patterns were also found for the associations between hyperactivity/impulsivity and high-sugar/unhealthy food intake, even though the moderation effects were not statistically significant.

Conclusion: The present study suggests that genetic factors play a more prominent role in individual differences of ADHD symptoms in the presence of the high consumption of sugar and unhealthy foods. Future longitudinal studies with multiple assessments of ADHD and dietary habits are needed to replicate our findings.