Risk of common psychiatric disorders, suicidal behaviours, and premature mortality following violent victimisation: A matched cohort and sibling-comparison study of 127,628 people who experienced violence in Finland and Sweden.

BACKGROUND: Associations between violent victimisation and psychiatric disorders are hypothesised to be bidirectional, but the role of violent victimisation in the aetiologies of psychiatric disorders and other adverse outcomes remains unclear. We aimed to estimate associations between violent victimisation and subsequent common psychiatric disorders, suicidal behaviours, and premature mortality while accounting for unmeasured familial confounders. METHODS AND FINDINGS: Using nationwide registers, we identified a total of 127,628 individuals born in Finland (1987 to 2004) and Sweden (1973 to 2004) who had experienced violent victimisation, defined as either hospital admissions or secondary care outpatient visits for assault-related injuries. These were age- and sex-matched with up to 10 individuals in the general population (n = 1,276,215). Additionally, we matched those who had experienced violent victimisation with their unaffected siblings (n = 132,408). Outcomes included depression, anxiety, personality disorders, alcohol use disorders, drug use disorders, suicidal behaviours, and premature mortality. Participants were followed from the victimisation date until the date of the outcome, emigration, death, or December 31, 2020, whichever occurred first. Country-specific associations were estimated using stratified Cox regression models, which also accounted for unmeasured familial confounders via sibling comparisons. The country-specific associations were then pooled using meta-analytic models. Among 127,628 patients (69.0% male) who had experienced violent victimisation, the median age at first violent victimisation was 21 (interquartile range: 18 to 26) years. Incidence of all outcomes was larger in those who were exposed to violent victimisation compared to population controls, ranging from 2.3 (95% confidence interval (CI) [2.2; 2.4]) per 1,000 person-years for premature mortality (compared with 0.6, 95% CI [0.6; 0.6], in controls) to 22.5 (95% CI [22.3; 22.8]) per 1,000 person-years for anxiety (compared with 7.3, 95% CI [7.3; 7.4], in controls). In adjusted models, people who had experienced violent victimisation were between 2 to 3 times as likely as their siblings to develop any of the outcomes, ranging from adjusted hazard ratio [aHR] 1.7 (95% CI [1.7; 1.8]) for depression to 3.0 (95% CI [2.9; 3.1]) for drug use disorders. Risks remained elevated 2 years post-victimisation, ranging from aHR 1.4 (95% CI [1.3; 1.5]) for depression to 2.3 (95% CI [2.2; 2.4]) for drug use disorders. Our reliance on secondary care data likely excluded individuals with milder assault-related injuries and less severe psychiatric symptoms, thus suggesting that our estimates may be conservative. Another limitation is the possibility of residual genetic confounding, as full siblings share on average about half of their co-segregating genes. However, the associations remained robust even after adjusting for both measured and unmeasured familial confounders. CONCLUSIONS: In this longitudinal cross-national cohort study, we observed that those who had experienced violent victimisation were at least twice as likely as their unaffected siblings to develop common psychiatric disorders (i.e., depression, anxiety, personality disorder, and alcohol and drug use disorders), engage in suicidal behaviours, and to die prematurely. Importantly, these risk elevations remained 2 years after the first victimisation event. Improving clinical assessment, management, and aftercare psychosocial support could therefore potentially reduce rates of common psychiatric disorders, suicidality, and premature mortality in individuals experiencing violent victimisation.

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.

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.

Shared familial risk for type 2 diabetes mellitus and psychiatric disorders: a nationwide multigenerational genetics study.

BACKGROUND: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM. METHODS: We linked 659 906 individuals born in Denmark 1990-2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981-2008 (n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders. RESULTS: Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35-1.42; grandparents: 1.14, 1.13-1.15; and aunts/uncles: 1.19, 1.16-1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08-1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa. CONCLUSIONS: Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.

ADHD Pharmacotherapy and Mortality in Individuals With ADHD.

Importance: Attention-deficit/hyperactivity disorder (ADHD) is associated with increased risks of adverse health outcomes including premature death, but it is unclear whether ADHD pharmacotherapy influences the mortality risk. Objective: To investigate whether initiation of ADHD pharmacotherapy was associated with reduced mortality risk in individuals with ADHD. Design, Setting, and Participants: In an observational nationwide cohort study in Sweden applying the target trial emulation framework, we identified individuals aged 6 through 64 years with an incident diagnosis of ADHD from 2007 through 2018 and no ADHD medication dispensation prior to diagnosis. Follow-up started from ADHD diagnosis until death, emigration, 2 years after ADHD diagnosis, or December 31, 2020, whichever came first. Exposures: ADHD medication initiation was defined as dispensing of medication within 3 months of diagnosis. Main Outcomes and Measures: We assessed all-cause mortality within 2 years of ADHD diagnosis, as well as natural-cause (eg, physical conditions) and unnatural-cause mortality (eg, unintentional injuries, suicide, and accidental poisonings). Results: Of 148 578 individuals with ADHD (61 356 females [41.3%]), 84 204 (56.7%) initiated ADHD medication. The median age at diagnosis was 17.4 years (IQR, 11.6-29.1 years). The 2-year mortality risk was lower in the initiation treatment strategy group (39.1 per 10 000 individuals) than in the noninitiation treatment strategy group (48.1 per 10 000 individuals), with a risk difference of -8.9 per 10 000 individuals (95% CI, -17.3 to -0.6). ADHD medication initiation was associated with significantly lower rate of all-cause mortality (hazard ratio [HR], 0.79; 95% CI, 0.70 to 0.88) and unnatural-cause mortality (2-year mortality risk, 25.9 per 10 000 individuals vs 33.3 per 10 000 individuals; risk difference, -7.4 per 10 000 individuals; 95% CI, -14.2 to -0.5; HR, 0.75; 95% CI, 0.66 to 0.86), but not natural-cause mortality (2-year mortality risk, 13.1 per 10 000 individuals vs 14.7 per 10 000 individuals; risk difference, -1.6 per 10 000 individuals; 95% CI, -6.4 to 3.2; HR, 0.86; 95% CI, 0.71 to 1.05). Conclusions and Relevance: Among individuals diagnosed with ADHD, medication initiation was associated with significantly lower all-cause mortality, particularly for death due to unnatural causes.

Early-Life and Family Risk Factors for Tic Disorder Persistence into Adulthood.

BACKGROUND: Many children with tic disorders outgrow their tics, but little is known about the proportion of individuals who will continue to require specialist services in adulthood and which variables are associated with tic persistence. OBJECTIVES: The aims were to estimate the proportion of individuals first diagnosed with tic disorders in childhood who continued to receive tic disorder diagnoses after age 18 years and to identify risk factors for persistence. METHODS: In this Swedish nationwide cohort study including 3761 individuals diagnosed with tic disorders in childhood, we calculated the proportion of individuals whose diagnoses persisted into adulthood. Minimally adjusted logistic regression models examined the associations between sociodemographic, clinical, and family variables and tic disorder persistence. A multivariable model was then fitted, including only variables that were statistically significant in the minimally adjusted models. RESULTS: Seven hundred and fifty-four (20%) children with tic disorders received a diagnosis of a chronic tic disorder in adulthood. Psychiatric comorbidity in childhood (particularly attention-deficit hyperactivity disorder, obsessive-compulsive disorder, pervasive developmental disorders, and anxiety disorders) and psychiatric disorders in first-degree relatives (particularly tic and anxiety disorders) were the strongest risk factors for persistence. We did not observe statistically significant associations with socioeconomic variables, perinatal complications, comorbid autoimmune diseases, or family history of autoimmune diseases. All statistically significant variables combined explained approximately 10% of the variance in tic disorder persistence (P < 0.0001). CONCLUSIONS: Childhood psychiatric comorbidities and family history of psychiatric disorders were the strongest risk factors associated with tic disorder persistence into adulthood. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Temporal changes in sex- and age-specific incidence profiles of mental disorders-A nationwide study from 1970 to 2016.

OBJECTIVE: Information on mental disorders over time is critical for documenting changes in population burden, and aiding understanding of potential causal and non-causal factors. The aim of this study was to provide temporal changes in the sex- and age-specific incidence rates (IR) of mental disorders diagnosed in Danish hospitals during five decades and investigate whether such changes may be attributable to changes in administrative reporting practice. METHODS: This population-based cohort study included all people living in Denmark between 1970 and 2016. Mental disorders diagnoses were obtained from the Danish Psychiatric Central Research Register. We estimated the IR of each mental disorder (all persons, and sex- and age-specific IRs) and examined the impact of two administrative changes. RESULTS: Our study included 9 107 157 people, followed for 233.0 million person-years. During follow-up, 9.5% were diagnosed with at least one mental disorder. The IR for any mental disorder was 39.0 per 10,000 person-years. Despite fluctuations, this increased between 1970-84 and 2005-2016, from 28.9 to 63.0 per 10,000 person-years. Increases were most pronounced for younger age groups. Administrative changes did appear to influence incidence rates. CONCLUSION: Mental disorder IRs have increased in Denmark since 1970, with age of diagnosis shifting downwards. Both trends were likely impacted by administrative changes, while the latter is likely to be (partly) attributable to earlier detection and increased reporting of child-onset conditions. Our findings may provide valuable context of the epidemiology of mental disorders across age groups for comparison with other studies and populations.

Temporally ordered associations between type 2 diabetes and brain disorders - a Danish register-based cohort study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is linked with several neurodegenerative and psychiatric disorders, either as a comorbid condition or as a risk factor. We aimed to expand the evidence by examining associations with a broad range of brain disorders (psychiatric and neurological disorders, excluding late-onset neurodegenerative disorders), while also accounting for the temporal order of T2DM and these brain disorders. METHODS: In a population-based cohort-study of 1,883,198 Danish citizens, born 1955-1984 and followed until end of 2016, we estimated associations between T2DM and 16 brain disorders first diagnosed between childhood and mid-adulthood. We calculated odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) in temporally ordered analyses (brain disorder diagnosis after T2DM and vice versa), adjusted for sex, age, follow-up, birth year, and parental factors. RESULTS: A total of 67,660 (3.6%) of the study population were identified as T2DM cases after age 30 and by a mean age of 45 years (SD of 8 years). T2DM was associated with most psychiatric disorders. Strongest associations were seen with other (i.e. non-anorectic) eating disorders (OR [95% CI]: 2.64 [2.36-2.94]) and schizophrenia spectrum disorder (2.73 [2.63-2.84]). Among neurological disorders especially inflammatory brain diseases (1.73 [1.57-1.91]) and epilepsy (1.67 [1.60-1.75]) were associated with T2DM. Most associations remained in both directions in the temporally ordered analyses. For most psychiatric disorders, associations were strongest in females. CONCLUSIONS: T2DM was associated with several psychiatric and neurological disorders, and most associations were consistently found for both temporal order of disorders. This suggests a shared etiology of T2DM and those brain disorders. This study can form the starting point for studies directed at further elucidating potential causal links between disorders and shared biological mechanisms.

Overlap between attention-deficit hyperactivity disorder and neurodevelopmental, externalising and internalising disorders: separating unique from general psychopathology effects.

BACKGROUND: Although attention-deficit hyperactivity disorder (ADHD) is classified as a neurodevelopmental disorder in the latest diagnostic manuals, it shows phenotypic and genetic associations of similar magnitudes across neurodevelopmental, externalising and internalising disorders. AIMS: To investigate if ADHD is aetiologically more closely related to neurodevelopmental than externalising or internalising disorder clusters, after accounting for a general psychopathology factor. METHOD: Full and maternal half-sibling pairs (N = 774 416), born between 1980 and 1995, were identified from the Swedish Medical Birth and Multi-Generation Registers, and ICD diagnoses were obtained from the Swedish National Patient Register. A higher-order confirmatory factor analytic model was fitted to examine associations between ADHD and a general psychopathology factor, as well as a neurodevelopmental, externalising and internalising subfactor. Quantitative genetic modelling was performed to estimate the extent to which genetic, shared and non-shared environmental effects influenced the associations with ADHD. RESULTS: ADHD was significantly and strongly associated with all three factors (r = 0.67-0.75). However, after controlling for a general psychopathology factor, only the association between ADHD and the neurodevelopmental-specific factor remained moderately strong (r = 0.43, 95% CI = 0.42-0.45) and was almost entirely influenced by genetic effects. In contrast, the association between ADHD and the externalising-specific factor was smaller (r = 0.25, 95% CI = 0.24-0.27), and largely influenced by non-shared environmental effects. There remained no internalising-specific factor after accounting for a general factor. CONCLUSIONS: Findings suggest that ADHD comorbidity is largely explained by genetically influenced general psychopathology, but the strong link between ADHD and other neurodevelopmental disorders is also substantially driven by unique genetic influences.

Insights into attention-deficit/hyperactivity disorder from recent genetic studies.

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder (NDD). In this narrative review, we summarize recent advances in quantitative and molecular genetic research from the past 5-10 years. Combined with large-scale international collaboration, these advances have resulted in fast-paced progress in understanding the etiology of ADHD and how genetic risk factors map on to clinical heterogeneity. Studies are converging on a number of key insights. First, ADHD is a highly polygenic NDD with a complex genetic architecture encompassing risk variants across the spectrum of allelic frequencies, which are implicated in neurobiological processes. Second, genetic studies strongly suggest that ADHD diagnosis shares a large proportion of genetic risks with continuously distributed traits of ADHD in the population, with shared genetic risks also seen across development and sex. Third, ADHD genetic risks are shared with those implicated in many other neurodevelopmental, psychiatric and somatic phenotypes. As sample sizes and the diversity of genetic studies continue to increase through international collaborative efforts, we anticipate further success with gene discovery, characterization of how the ADHD phenotype relates to other human traits and growing potential to use genomic risk factors for understanding clinical trajectories and for precision medicine approaches.

The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology.

Common genetic risk variants have been implicated in the etiology of clinical attention-deficit/hyperactivity disorder (ADHD) diagnoses and symptoms in the general population. However, given the extensive comorbidity across ADHD and other psychiatric conditions, the extent to which genetic variants associated with ADHD also influence broader psychopathology dimensions remains unclear. The aim of this study was to evaluate the associations between ADHD polygenic risk scores (PRS) and a broad range of childhood psychiatric symptoms, and to quantify the extent to which such associations can be attributed to a general factor of childhood psychopathology. We derived ADHD PRS for 13,457 children aged 9 or 12 from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. We estimated associations between ADHD PRS, a general psychopathology factor, and several dimensions of neurodevelopmental, externalizing, and internalizing symptoms, using structural equation modeling. Higher ADHD PRS were statistically significantly associated with elevated neurodevelopmental, externalizing, and depressive symptoms (R2 = 0.26-1.69%), but not with anxiety. After accounting for a general psychopathology factor, on which all symptoms loaded positively (mean loading = 0.50, range = 0.09-0.91), an association with specific hyperactivity/impulsivity remained significant. ADHD PRS explained ~ 1% (p value < 0.0001) of the variance in the general psychopathology factor and ~ 0.50% (p value < 0.0001) in specific hyperactivity/impulsivity. Our results suggest that common genetic risk variants associated with ADHD, and captured by PRS, also influence a general genetic liability towards broad childhood psychopathology in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.

Medication treatment for attention-deficit/hyperactivity disorder and the risk of acute seizures in individuals with epilepsy.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) affects 10%-30% of individuals with epilepsy, yet concerns remain regarding the safety of ADHD medication in this group. The objective of this study was to examine the risk of acute seizures associated with ADHD medication in individuals with epilepsy. METHODS: A total of 21 557 individuals with a seizure history born between 1987 and 2003 were identified from Swedish population registers. Within this study population, we also identified 6773 youth (<19 years of age) who meet criteria for epilepsy, and 1605 youth with continuous antiepileptic drug (AED) treatment. ADHD medication initiation and repeated medication periods were identified from the Swedish Prescribed Drug Register between January 1, 2006 and December 31, 2013. Acute seizures were identified via unplanned visits to hospital or specialist care with a primary seizure discharge diagnosis in the Swedish National Patient Register during the same period. Conditional Poisson regression was used to compare the seizure rate during the 24 weeks before and after initiation of ADHD medication with the rate during the same 48 weeks in the previous year. Cox regression was used to compare the seizure rate during ADHD medication periods with the rate during nonmedication periods. Comparisons were made within-individual to adjust for unmeasured, time?constant confounding. RESULTS: Among 995 individuals who initiated ADHD medication during follow-up, within-individual analyses showed no statistically significant difference in the rate of seizures during the 24 weeks before and after medication initiation, compared to the same period in the previous year. In the full study population 11 754 seizure events occurred during 136 846 person-years and 1855 individuals had at least one ADHD medication period. ADHD medication periods were associated with a reduced rate of acute seizures (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.57-0.94), compared to nonmedication periods within the same individual. Similar associations were found in youth with epilepsy and continuous AED treatment, when adjusting for AEDs, and across sex, age, and comorbid neurodevelopmental disorders. SIGNIFICANCE: We found no evidence for an overall increased rate of acute seizures associated with ADHD medication treatment among individuals with epilepsy. These results suggest that epilepsy should not automatically preclude patients from receiving ADHD medications.

Familial aggregation of attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) aggregates in families. To date, the strength, pattern, and characteristics of the familial aggregation have not been thoroughly assessed in a population-based family sample. METHODS: In this cohort study, we identified relative pairs of twins, full and half-siblings, and full and half cousins from 1,656,943 unique individuals born in Sweden between 1985 and 2006. The relatives of index persons were followed from their third birthday to 31 December 2009 for ADHD diagnosis. Birth year adjusted hazard ratio (HR), that is, the rate of ADHD in relatives of ADHD-affected index persons compared with the rate of ADHD in relatives of unaffected index persons, was estimated in the different types of relatives using Cox proportional hazards model. RESULTS: During the follow-up, 31,865 individuals were diagnosed with ADHD (male to female ratio was 3.7). The birth year adjusted HRs were as follows: 70.45 for monozygotic twins; 8.44 for dizygotic twins; 8.27 for full siblings; 2.86 for maternal half-siblings; 2.31 for paternal half-siblings; 2.24 for full cousins; 1.47 for half cousins. Maternal half-siblings had significantly higher HR than in paternal half-siblings. The HR did not seem to be affected by index person's sex. Full siblings of index persons with ADHD diagnosis present at age 18 or older had a higher rate of ADHD (HR: 11.49) than full siblings of index persons with ADHD diagnosis only before age 18 (HR: 4.68). CONCLUSIONS: Familial aggregation of ADHD increases with increasing genetic relatedness. The familial aggregation is driven by not only genetic factors but also a small amount of shared environmental factors. Persistence of ADHD into adulthood indexes stronger familial aggregation of ADHD.

Predictive validity of parent- and self-rated ADHD symptoms in adolescence on adverse socioeconomic and health outcomes.

There is scarcity of research investigating the validity of self-report of attention deficit hyperactivity disorder (ADHD) symptoms compared to other informants, such as parents. This study aimed to compare the predictive associations of ADHD symptoms rated by parents and their children across adolescence on a range of adverse socioeconomic and health outcomes in early adulthood. Parent- and self-rated ADHD symptoms were assessed in 2960 individuals in early (13-14 years) and late adolescence (16-17 years). Logistic regression analyses were used to compare the associations between parent- and self-rated ADHD symptoms at both time points and adverse life outcomes in young adulthood obtained from Swedish national registries. Both parent- and self-ratings of ADHD symptoms were associated with increased risk for adverse outcomes, although associations of parent-ratings were more often statistically significant and were generally stronger (OR = 1.12-1.49, p < 0.05) than self-ratings (OR = 1.07-1.17, p < 0.05). After controlling for the other informant, parent-ratings of ADHD symptoms in both early and late adolescence significantly predicted academic and occupational failure, criminal convictions and traffic-related injuries, while self-ratings of ADHD symptoms only in late adolescence predicted substance use disorder and academic failure. Our findings suggest that both parent- and self-ratings of ADHD symptoms in adolescence provides valuable information on risk of future adverse socioeconomic and health outcomes, however, self-ratings are not valuable once parent-ratings have been taken into account in predicting most outcomes. Thus, clinicians and researchers should prioritize parent-ratings over self-ratings.

Heritability of attention-deficit hyperactivity disorder in adults.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Symptoms often persist into adulthood, with a prevalence of 2.5-5% in adult populations. Twin studies in childhood consistently report high heritabilities of 70-80%, while studies in adult samples show only moderate heritability of 30-40% when estimated from self-ratings. This review summarizes the available research on the heritability of ADHD in adults. Three key findings are outlined: (i) self-ratings lead to relatively low heritability estimates of ADHD, independent of age and whether ratings refer to current or retrospective symptoms; (ii) studies relying on different informants to rate each twin within a pair (i.e., self-ratings and different parents/teachers rating each twin in a pair) consistently yield lower heritability estimates than studies relying on ratings from a single informant; (iii) studies using cross-informant data via either combined parent and self-ratings or clinical diagnoses information suggest that the heritability of ADHD in adults could be as high as 70-80%. Together, the reviewed studies suggest that the previously reported low heritability of ADHD in adults is unlikely to reflect a true developmental change. Instead, the drop in heritability is better explained by rater effects related to a switch from using one rater for both twins in a pair (parent/teacher) in childhood, to relying on self-ratings (where each twin rates themselves) of ADHD symptoms in adulthood. When rater effects are addressed using cross-informant approaches, the heritability of ADHD in adults appears to be comparable to the heritability of ADHD in childhood. © 2015 Wiley Periodicals, Inc.

Attention-Deficit/Hyperactivity Disorder and Major Depressive Disorder: Evidence From Multiple Genetically Informed Designs.

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. METHODS: We examined the association of ADHD with MDD using 3 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 16,477 twins (5084 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 study 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 (hazard ratio = 4.12 [95% CI 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 [95% CI 0.05-0.08] and b = 0.09 [95% CI 0.08-0.11], respectively). Mendelian randomization analyses showed that genetic liability for ADHD is causally related to MDD (odds ratio = 1.15 [95% CI 1.08-1.23]). CONCLUSIONS: Our study provides consistent results across 3 different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.

Antidepressant Use and Risk of Manic Episodes in Children and Adolescents With Unipolar Depression.

Importance: Antidepressants are increasingly prescribed to pediatric patients with unipolar depression, but little is known about the risk of treatment-emergent mania. Previous research suggests pediatric patients may be particularly vulnerable to this adverse outcome. Objective: To estimate whether pediatric patients treated with antidepressants have an increased incidence of mania/hypomania compared with patients not treated with antidepressants and to identify patient characteristics associated with the risk of mania/hypomania. Design, Setting, and Participants: In a cohort study applying the target trial emulation framework, nationwide inpatient and outpatient care in Sweden from July 1, 2006, to December 31, 2019, was evaluated. Follow-up was conducted for 12 and 52 weeks after treatment initiation, with administrative follow-up ending December 31, 2020. Data were analyzed between May 1, 2022, and June 28, 2023. Individuals aged 4 to 17 years with a diagnosis of depression, but without a prior diagnosis of mania/hypomania, bipolar disorder, or psychosis or treatment with mood stabilizer (lithium, valproate, or carbamazepine), prescriptions were included. Exposures: The treatment group included patients who initiated any antidepressant medication within 90 days of diagnosis. The control group included patients who did not initiate antidepressants within 90 days. Main Outcomes and Measures: Diagnosis of mania/hypomania or initiation of mood stabilizer therapy. Incidences were estimated with Kaplan-Meier estimator, and inverse probability of treatment weighting was used to adjust for group differences at baseline. Results: The cohort included 43 677 patients (28 885 [66%] girls); 24 573 in the treatment group and 19 104 in the control group. The median age was 15 (IQR, 14-16) years. The outcome occurred in 96 individuals by 12 weeks and in 291 by 52 weeks. The cumulative incidence of mania was 0.26% (95% CI, 0.19%-0.33%) in the treatment group and 0.20% (95% CI, 0.13%-0.27%) in the control group at 12 weeks, with a risk difference of 0.06% (95% CI, -0.04% to 0.16%). At 52 weeks, the cumulative incidence was 0.79% (95% CI, 0.68%-0.91%) in the treatment group and 0.52% (95% CI, 0.40%-0.63%) in the control group (risk difference, 0.28%; 95% CI, 0.12%-0.44%). Hospitalizations, parental bipolar disorder, and use of antipsychotics and antiepileptics were the most important predictors of mania/hypomania by 12 weeks. Conclusion: This cohort study found no evidence of treatment-emergent mania/hypomania by 12 weeks in children and adolescents. This corresponds to the time frame for antidepressants to exert their psychotropic effect. A small risk difference was found only with longer follow-up. Certain patient characteristics were associated with mania/hypomania, which warrants clinical attention.

Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases.

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.

Cumulative ADHD medication use and risk of type 2 diabetes in adults: a Swedish Register study.

BACKGROUND: Little is known about the impact of cumulative attention-deficit/hyperactivity disorder (ADHD) medication use on the risk of type 2 diabetes (T2D). OBJECTIVE: The objective is to examine the association between cumulative use of ADHD medication and risk of incident T2D. METHODS: A nested case-control study was conducted in a national cohort of individuals aged 18-70 years with incident ADHD (n=138 778) between 2007 and 2020 through Swedish registers. Individuals with incident T2D after ADHD were selected as cases (n=2355) and matched with up to five controls (n=11 681) on age at baseline, sex and birth year. Conditional logistic regression models examined the association between cumulative duration of ADHD medication use and T2D. FINDINGS: Compared with no use, a decreased risk of T2D was observed for those on cumulative use of ADHD medications up to 3 years (ORs: 03 years, 0.97 (95% CI, 0.84 to 1.12)). When investigating medication types separately, methylphenidate showed results similar to main analyses, lisdexamfetamine showed no association with T2D, whereas long-term (>3 years) use of atomoxetine was associated with an increased risk of T2D (OR: 1.44 (95% CI, 1.01 to 2.04)). CONCLUSION: Cumulative use of ADHD medication does not increase the risk for T2D, with the exception of long-term use of atomoxetine. CLINICAL IMPLICATIONS: Findings suggest that clinicians should be aware of the potential risk of T2D associated with the cumulative use of atomoxetine among patients with ADHD; however, further replication is strongly needed.

A population-based multigenerational family co-aggregation study of severe infections and obsessive-compulsive disorder.

BACKGROUND: Postinfectious autoimmune processes have been proposed as potential causal factors for obsessive-compulsive disorder (OCD). This large population-based study aimed to clarify the co-aggregation pattern between severe infections and OCD across clusters of relatives with varying degrees of relatedness. METHODS: We identified 4,916,898 individuals born in Sweden between 1960 and 2008 and followed them until 2020. Each individual was linked to their first- and second-degree relatives, including monozygotic (MZ) and dizygotic (DZ) twins, mothers, fathers, full siblings, maternal and paternal half siblings, aunts, uncles, and cousins. OCD and infection diagnoses from inpatient and specialized outpatient units were retrieved from the Swedish National Patient Register. We compared the risk of OCD in relatives of probands with severe infections to those of probands without severe infections. Cox proportional hazard regression models, incorporating time-varying exposures, were used to estimate hazard ratios (HRs). Dose-response associations were examined using logistic regression models. RESULTS: Relatives of probands with severe infections exhibited a higher risk of OCD, increasing with genetic relatedness, with HRs (95% CI) ranging from 1.46 (1.07-1.98) in MZ twins to 1.10 (1.09-1.11) in cousins. The results remained robust after adjusting for severe infections among relatives, OCD in probands, and comorbid autoimmune disorders in both probands and relatives. A dose-response association was observed between the number of infections in the probands and their odds of OCD, as well as in their relatives. CONCLUSIONS: The results strongly suggest that the association between severe infections and OCD may be largely driven by shared genetic factors.

Incident Benzodiazepine and Z-Drug Use and Subsequent Risk of Serious Infections.

BACKGROUND AND OBJECTIVES: Animal studies have suggested a link between benzodiazepine and related Z-drug (BZDR) use and immune dysfunction. Corresponding evidence in humans is limited and focuses mainly on pneumonia. This study aimed to assess the association of incident BZDR use with subsequent development of serious infections. METHODS: This Swedish register-based study included a population-based demographically matched cohort, a co-twin control cohort, and an active comparator cohort. Out of 7,362,979 individuals aged below 65 years who were BZDR naïve by 2007, 713,896 BZDR recipients with incident dispensation of any BZDRs between 2007 and 2019 were 1:1 matched to 713,896 nonrecipients from the general population; 9197 BZDR recipients were compared with their 9298 unexposed co-twins/co-multiples; and 434,900 BZDR recipients were compared with 428,074 incident selective serotonin reuptake inhibitor (SSRI) recipients. The outcomes were identified by the first inpatient or specialist outpatient diagnosis of serious infections in the National Patient Register, or death from any infections recorded as the underlying cause in the Cause of Death Register. Cox proportional hazards regression models were fitted and controlled for multiple confounders, including familial confounding and confounding by indication. To study a possible dose-response association, the cumulative dosage of BZDRs dispensed during the follow-up was estimated for each BZDR recipient and modeled as a time-varying exposure with dose categories in tertiles [≤ 20 defined daily doses (DDDs), > 20 DDDs ≤ 65, and > 65 DDDs). The risk of infections was assessed in BZDR recipients within each category of the cumulative BZDR dosage compared to their demographically matched nonrecipients. RESULTS: In the demographically matched cohort (average age at incident BZDR use 42.8 years, 56.9% female), the crude incidence rate of any serious infections in BZDR recipients and matched nonrecipients during 1-year follow-up was 4.18 [95% confidence intervals (CI) 4.13-4.23] and 1.86 (95% CI 1.83-1.89) per 100 person-years, respectively. After controlling for demographic, socioeconomic, clinical, and pharmacological confounders, BZDR use was associated with 83% relative increase in risk of any infections [hazard ratio (HR) 1.83, 95% CI 1.79-1.89]. The risk remained increased, although attenuated, in the co-twin cohort (HR 1.55, 95% CI 1.23-1.97) and active comparator cohort (HR 1.33, 95% CI 1.30-1.35). The observed risks were similar across different types of initial BZDRs and across individual BZDRs, and the risks increased with age at BZDR initiation. We also observed a dose-response association between cumulative BZDR dosage and risk of serious infections. CONCLUSIONS: BZDR initiation was associated with increased risks of serious infections, even when considering unmeasured familial confounding and confounding by indication. The exact pathways through which BZDRs may affect immune function, however, remain unclear. Further studies are needed to explore the neurobiological mechanisms underlying the association between BZDR use and serious infections, as it can lead to safer therapeutic strategies for patients requiring BZDR.