To Örebro University

Cardiovascular disease (CVD) risk prediction models for the general population may not provide accurate predictions in individuals with bipolar disorder (BD) who have elevated risks of cardiometabolic conditions and premature mortality. Therefore, we aimed to: 1) develop a five-year CVD risk prediction model in this population by using nationwide register data from Sweden, 2) investigate whether the performance improved when we considered additional risk factors, including psychiatric comorbidity, psychotropic medication, and socio-demographic variables, compared to using established CVD risk factors only, and 3) whether machine learning approach provided improvements compared to standard logistic regression models. We followed 33,933 persons with BD aged 30-82 years old, without previous CVD, from the date of BD diagnosis registered between 2007-2014, for up to five years. The logistic regression model containing only established risk factors yielded an area under the receiver operating characteristic curve (AUC) of 0.76 (95% confidence interval 0.74-0.78) in the test dataset, while the logistic regression model and the best performing machine learning model including additional predictors yielded similar results (AUC was 0.77 (0.75, 0.79) in both models). The performance of logistic regression models slightly improved with additional predictors when continuous risk scores were used. In conclusion, standard logistic regression and established CVD risk factors may be sufficient to predict CVD in individuals with BD when using population register-based data from Sweden. External validation across diverse healthcare settings and rigorous assessment of clinical impact will be crucial next steps before implementing these models in clinical practice.

BACKGROUND: Body dysmorphic disorder (BDD) is a debilitating and understudied psychiatric condition of largely unknown etiology. Emerging evidence suggests that BDD may be a familial and heritable disorder, but family studies of diagnosed individuals and their biological relatives are yet to be conducted.

METHODS: We identified 4,857,049 individuals born in Sweden between 1960 and 2008, with information on both biological parents, who were living in Sweden in 1997. From this cohort, we identified clusters of full siblings, half siblings, and cousins, and compared the risk of BDD among those with a relative diagnosed with BDD and those without. Previously validated ICD-10 diagnoses of BDD were identified through the Swedish National Patient Register. To estimate hazard ratios (HRs), we fitted a series of Cox regression models with time-varying exposures and attained age as the underlying time scale. Individuals were considered unexposed before their relative's BDD diagnosis and exposed thereafter.

RESULTS: Relatives of individuals with BDD had a higher risk of BDD compared to relatives of individuals without BDD, with the highest risk observed in full siblings (HR, 16.2; 95% CI, 9.2 - 28.7), followed by half-siblings (HR, 7.8; 95% CI, 2.5 - 23.9) and cousins (HR, 2.8; 95% CI, 1.3 - 6.2), showing a gradient by degree of genetic relatedness.

CONCLUSIONS: Our findings indicate that BDD is a familial disorder and suggest an important role for genetic factors.

BACKGROUND: Adherence to antihypertensive medication, alongside lifestyle modifications, is fundamental to managing hypertension and reducing the risk of cardiovascular disease. Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder associated with a range of cardiovascular diseases, including hypertension. ADHD medication has also been associated with hypertension. However, the influence of ADHD and ADHD medication on discontinuation and adherence to antihypertensive treatments is unknown.

METHODS: We conducted a multinational cohort study using electronic health databases from seven countries, which included adults who initiated antihypertensive medication between 2010 and 2020. ADHD was identified by a diagnosis of ADHD or dispensation of ADHD medications. The outcomes were (1) time to the first discontinuation of antihypertensive medication and (2) poor adherence, defined as the proportion of days covered (PDC) below 80% during 1-, 2-, and 5-year follow-up periods. We used Cox proportional hazards models and logistic regression to estimate associations, adjusting for age, sex, and calendar year of antihypertensive medication initiation. We pooled results from different countries via random-effects meta-analysis.

RESULTS: We identified 12,174,321 adults who initiated antihypertensive medication during the study period, including 320,691 (2.6%) with ADHD. In the pooled analysis across all countries, ADHD was associated with an increased rate of discontinuation in 5-year follow-up of antihypertensive medication (hazard ratio [HR] 1.14; 95% CI, 1.02-1.27). In age-stratified analyses, ADHD was associated with a higher rate of antihypertensive medication discontinuation in middle-aged (HR, 1.11; 95% CI, 1.01-1.23) and older adults (HR, 1.14; 95% CI, 1.01-1.29), but not in young adults. Individuals with ADHD also had higher odds of poor adherence across 1 year after treatment initiation (odds ratio [OR] 1.45, 95% CI 1.26-1.67) to 5 years (OR 1.64, 95% CI 1.34-2.00). Among those with ADHD, use of ADHD medications was associated with lower odds of poor adherence (1 year OR 0.66, 95% CI 0.60-0.73; 5 years OR 0.58, 95% CI 0.46-0.72).

CONCLUSIONS: Adults with ADHD are more likely to discontinue antihypertensive treatment and exhibit poor medication adherence. However, ADHD medication use appears to be associated with better adherence among individuals with ADHD.

OBJECTIVE: To investigate the association between attention-deficit/hyperactivity disorder (ADHD) and cardiometabolic risk profile at the time of type 2 diabetes (T2D) diagnosis and examine longitudinal changes in cardiometabolic measures following T2D diagnosis.

DESIGN AND SETTING: A nationwide cohort study using linked Swedish health registers.

PARTICIPANTS: Adults aged 18-65 years with a first recorded diagnosis of T2D between 1996 and 2020. ADHD, treated as a lifetime condition, was identified through diagnostic and prescription records.

OUTCOME MEASURES: The cardiometabolic risk profile, comprising nine clinical parameters and two behavioural factors, was assessed at T2D diagnosis and was tracked for up to 5 years post-diagnosis. Linear regression (βADHD) and Poisson regression models with robust variance (risk ratios (RRs)) compared cardiometabolic risk factors at diagnosis between individuals with and without ADHD. Generalised estimating equations (βADHD*t) assessed longitudinal changes in clinical parameters following the diagnosis.

RESULTS: Among 80 607 individuals with T2D, 1204 (1.5%) had an ADHD diagnosis. At T2D diagnosis, individuals with ADHD were younger and had statistically significantly higher body mass index (BMI) (βADHD: 1.93 (95% CI 1.54 to 2.32)), triglycerides (βADHD: 0.31 (95% CI 0.17 to 0.45)) and smoking prevalence (RR: 1.58 (95% CI 1.44 to 1.74)) compared with those without ADHD. Other cardiometabolic risk factors did not differ significantly. Over the subsequent 5 years, trajectories in cardiometabolic risk factors were broadly similar, except for a greater reduction in BMI in individuals with ADHD (βADHD*t: -0.26 (95% CI -0.34 to -0.17)), independent of baseline BMI and glucose-lowering medications. After inverse probability of treatment weighting, the BMI reduction was substantially reduced and not significant (βADHD*t: -0.05 (95% CI -0.17 to 0.07)).

CONCLUSIONS: Among adults with newly diagnosed T2D, those with co-occurring ADHD had broadly similar cardiometabolic profiles to those without ADHD but presented at a younger age with a modestly higher BMI, triglycerides and smoking prevalence. Individuals with ADHD also showed a slightly greater reduction in BMI over time following T2D diagnosis. Despite modest overall cardiometabolic differences, incorporating ADHD status into preventive diabetes care may help identify a younger, more vulnerable subgroup who could benefit from targeted risk factor management.

AIMS: Social anxiety disorder (SAD) is one of the most common anxiety disorders and is associated with significant impairment and societal costs. The association between SAD and mortality remains poorly understood, partly because in epidemiological research it is rarely studied independently from other anxiety disorders. In this population-based matched cohort and sibling control study, we estimated the risk of all-cause and cause-specific mortality in individuals with SAD.

METHODS: From a population of individuals born from 1932 and living in Sweden between 1997 and 2020, we identified all cases of SAD (Swedish ICD-10 code F40.1) in the National Patient Register. Each of these individuals was matched on sex, birth year and county of residence with 10 individuals who had never received a diagnosis. Mortality data were extracted from the Cause of Death Register. Risks were estimated using Cox proportional hazards regression models. Models adjusted for sociodemographic covariates and other lifetime psychiatric disorders. We also identified all clusters of full siblings and conducted within-sibling comparisons to account for unmeasured familial confounding.

RESULTS: The matched cohort included 57,360 individuals with SAD and 573,600 unexposed individuals. During the follow-up, 2355 deaths were registered within the exposed cohort vs. 7800 deaths in the matched cohort (crude mortality rates, 5.25 and 1.73 per 1000 person-years, respectively). The full cohort was followed up for a mean of 7.87 years (standard deviation 5.23). In models adjusting for sociodemographic variables, individuals with SAD had a 2.24-fold increased hazard of all-cause mortality (95% confidence interval [CI], 2.13-2.35). The increased risk was observed for both natural (adjusted hazard ratio [HR], 1.62; 95% CI 1.52-1.72) and unnatural causes of death (HR, 4.18; 95% CI 3.82-4.58). The results were robust to additional adjustment for psychiatric comorbidities, but the magnitude of the associations was attenuated, particularly when adjusting for substance use disorders. In the sibling cohort, 39,993 individuals with SAD were compared with their 64,640 unaffected siblings. While the estimates were also attenuated, they remained statistically significant (HR for all-cause mortality, 1.40; 95% CI 1.36-1.45).

CONCLUSIONS: Individuals with SAD face an increased risk of mortality, attributable primarily to unnatural causes of death, such as suicide, but also to natural causes, even after adjusting for socioeconomic variables. Psychiatric comorbidities, particularly substance use disorders, and shared familial factors may also contribute to this excess death. Further study of underlying mechanisms may inform prevention and early intervention strategies to reduce mortality in this vulnerable population.

The potential associations between parental ADHD and a broad spectrum of offspring health outcomes remain uncertain. We explored associations between parental ADHD and multiple adverse outcomes in offspring. We used linked Swedish national registers to identify all individuals born in Sweden between 2000 and 2014 (N = 1,164,580) and followed them from birth until emigration, death, or December 31, 2020. After matching, 56,853 individuals with parental ADHD and 544,716 individuals without parental ADHD were included in the analysis. Parental ADHD was identified through ADHD diagnoses or ADHD medication prescriptions. Offspring of parents with ADHD were matched to ten individuals whose parents had no ADHD diagnosis. Stratified Cox regression models with robust standard errors were used to estimate associations between parental ADHD and 24 offspring outcomes. Offspring of parents with ADHD had higher rates of most adverse outcomes, compared with those without parental ADHD. Parental ADHD was associated with an increased rate of offspring psychiatric disorders (range of hazard ratios [HRs]: 1.49 for intellectual disability - 4.47 for ADHD), behavioral outcomes (range of HRs: 1.08 for falls - 1.82 for assault/victimization), and somatic disorders (range of HRs: 1.04 for type 1 diabetes-2.47 for sleep disorder). After adjusting for offspring lifetime ADHD, associations weakened but remained significant, except for intellectual disability and epilepsy. Rates were elevated for both maternal and paternal ADHD and highest when both parents with ADHD. Parental ADHD was associated with elevated risks of a broad range of adverse outcomes in offspring, encompassing psychiatric, behavioral, and somatic conditions. These findings highlight the broad intergenerational impact of ADHD and the need for early identification and family-focused preventive strategies.

Background: The cumulative effect of early medical events has been shown to be associated with autism. It is unclear whether this effect is specific to autism or if it is associated to other neurodevelopmental conditions (NDCs) as well.

Methods: We established a registry-linked population-based twin cohort of 10,254 pairs within the child and adolescent twin study in Sweden. Participants were evaluated for symptoms of autism, attention deficit hyperactivity disorder, tics, and learning difficulties at age 9. Three early medical events previously associated with autism, beyond familial confounding (low birth weight, congenital malformations, and perinatal respiratory stress), were summed up creating an individual cumulative exposure load. Confirmatory Factor Analysis was performed on the measure of NDCs and a standardized common latent NDC factor was regressed on level of cumulative exposure.

Results: Cumulative exposure to early medical events was associated with a non-linear increase in the common latent NDC factor, ss = 0.12 (95% CI, 0.07-0.17) for exposure level 1, ss = 0.25 (0.17-0.33) for exposure level 2, and ss = 0.62 (0.34-0.90) for exposure level 3. In a monozygotic twin difference analysis, with familial confounding being fully accounted for, the whole exposure effect was captured by the common factor, with residual associations fully attenuated for all four NDC outcomes, at all levels of cumulative exposure.

Conclusion: The result suggests a possibly causal environmental pathway. The cumulative effect of early medical events previously associated with autism, are not specific for autism, but rather associated with NDCs in a broad sense.

BACKGROUND: Higher parental educational attainment is associated with a reduced risk of mental health problems in offspring. However, these associations might partially reflect unmeasured confounding rather than causal effects.

AIMS: To investigate the association between parental education and offspring psychiatric diagnoses, violent crimes, and suicidal behavior, after isolating unmeasured confounding.

METHODS: We analyzed data from 1,047,275 offspring to 701,350 parents born between 1945 and 1955 in 926 Swedish municipalities. The exposure was parental years of schooling. The outcomes were 14 psychiatric diagnoses, court convictions of violent crimes, and suicidal behavior in the offspring. We first estimated the association between parental years of schooling and offspring outcomes using stratified Cox regression. Subsequently, leveraging a Swedish education reform that extended compulsory schooling from 7 to 9 years as a quasi-experiment, we compared parents educated immediately before and after the reform's implementation. This approach allowed us to estimate the reform's impact on offspring outcomes while controlling for potential unmeasured confounders. To estimate the causal effect of the parental education on offspring outcomes, we applied a fuzzy regression discontinuity (RD) design, that is, we used the Swedish education reform as an instrument for parental years of schooling. If the RD model assumptions are met, this design identifies the causal effect of education among those who planned to quit school after completing the minimum compulsory requirement.

RESULTS: Parental years of schooling were negatively associated with most of the 14 psychiatric diagnoses, violent crime, and suicidal behavior in their offspring. However, when comparing children of parents exposed to the reform versus those not exposed, there were no significant differences in these outcomes (e.g., any psychiatric diagnosis: hazard ratio = 1.00, 95% CI 0.99-1.02). Consistently, RD estimates of the effect of parental years of schooling on offspring outcomes were close to the null and not statistically significant after correcting for multiple testing.

CONCLUSIONS: Among parents who planned to quit school after completing the minimum compulsory requirement, the negative association between longer years of parental schooling and offspring mental health problems and behavioral outcomes likely reflected unmeasured confounding.

BACKGROUND: Autistic people are at an increased risk of psychiatric and somatic health conditions in young adulthood, but the influence of childhood somatic conditions on adult psychiatric conditions has not been examined. This study aimed to investigate whether childhood somatic conditions are associated with adult psychiatric conditions in autistic young adults.

METHODS: This retrospective, longitudinal, population-based cohort study design used data from linking nationwide Swedish registers. From the Medical Birth Register, we identified all individuals born in Sweden between Jan 1, 1985, and Dec 31, 2004 who were residing in Sweden at age 16 years. Between Jan 1, 2001, and Dec 31, 2020, individuals were followed up from age 16 years until a psychiatric diagnosis, their 25th birthday, death, emigration, or the end of follow-up, whichever came first. Autism, psychiatric, and somatic diagnoses were obtained from the National Patient Register and Prescribed Drug Register. We extracted diagnoses of nine childhood somatic conditions (asthma, chronic pain, epilepsy, cardiovascular conditions, migraine, autoimmune conditions, infections, irritable bowel syndrome, and type 1 diabetes) before age 16 years as exposures and ten adult psychiatric conditions (anxiety, obsessive-compulsive, depressive, bipolar, psychotic, sleep, and substance use disorders, anorexia nervosa, other eating disorders, and self-harm) between ages 16 years and 24 years as outcomes. Associations between childhood somatic conditions and adult psychiatric conditions were estimated using Cox regression in autistic and non-autistic people, adjusted for birth year and sex, with additional stratified analyses by sex and co-occurring intellectual disability among autistic people. We involved people with lived experience in the study design and implementation.

FINDINGS: From nationwide registers, we identified 1 944 781 individuals born between 1985 and 2004 in Sweden, including 58 410 (3·0%) autistic people (21 758 [37·3%] females and 36 652 [62·7%] males), who were followed up from age 16 years for a mean of 7·1 years (SD 2·8). Of 58 410 autistic people, 32 828 (56·2%) had any childhood somatic condition and 29 793 (51·0%) had any adult psychiatric condition. Of 1 886 371 non-autistic people, 835 810 (44·3%) had any childhood somatic condition and 251 333 (13·3%) had any adult psychiatric condition. Autistic people with any childhood somatic condition had an increased risk of any adult psychiatric condition compared with autistic people without any childhood somatic condition (adjusted HR 1·14 [95% CI 1·11-1·17]). For non-autistic people with versus without any childhood somatic condition, the adjusted HR was 1·41 (1·40-1·43). In people with any childhood somatic condition, autistic people showed an increased risk of any adult psychiatric condition compared with non-autistic people (5·36 [5·27-5·45]). In those without any childhood somatic condition, autistic people also showed an increased risk compared with non-autistic people (6·65 [6·53-6·77]).

INTERPRETATION: Although childhood somatic conditions contribute to adult psychiatric conditions, autistic people show elevated psychiatric vulnerability regardless of childhood somatic condition status. The findings highlight the need for integrated somatic-psychiatric health care and suggest that risk in this group is likely shaped by a broader range of factors beyond childhood somatic conditions alone. FUNDING: MQ Mental Health Research.

Multiple psychiatric disorders are associated with later dementia, but it remains unclear whether these associations reflect a shared liability toward all psychiatric conditions (general psychopathology factor) or diagnosis-specific effects (specific psychopathology factors). In this Swedish register-based cohort study, we investigated these questions while adjusting for familial confounding shared by siblings (N = 2 543 621 individuals, 1 485 880 full-sibling pairs). Exposures were (i) six psychiatric diagnoses recorded by age 35 and (ii) a latent bifactor model fit to these diagnoses that identified one general and three specific (internalizing, externalizing, and psychotic) psychopathology factors. Outcomes were all-cause dementia and Alzheimer's disease recorded after age 50. For observed psychiatric diagnoses, we estimated between-individual (HR) and within-sibling hazard ratios (HRwn) using Cox regression; for latent factors, we estimated between-individual (OR) and within-sibling odds ratios (ORwn) using exploratory structural equation modelling. All psychiatric diagnoses were significantly associated with increased risk of all-cause dementia (HR range 2.03-3.59; HRwn range 1.72-2.94) and Alzheimer's disease (HR range 1.89-3.47; HRwn range 1.77-3.22). These associations were largely attributable to the general psychopathology factor, even after adjusting for familial confounding (ORwn with 95% CI: 1.25 [1.17-1.32] for dementia; 1.24 [1.16-1.32] for Alzheimer's disease). After accounting for the general factor, only the psychotic-specific factor remained associated (ORwn with 95% CI: 1.20 [1.07-1.36] for dementia; 1.20 [1.06-1.37] for Alzheimer's disease). These results suggest that liability toward general psychopathology and, independently, psychotic conditions, by early adulthood might be early markers of increased dementia risk and targets for timely identification and prevention.