Has the attention deficit hyperactivity disorder phenotype become more common in children between 2004 and 2014? Trends over 10 years from a Swedish general population sample.

BACKGROUND: Studies have reported increases in clinically diagnosed and treated attention deficit hyperactivity disorder (ADHD) during the last decade, but it is unclear if this reflects an increase in the underlying ADHD phenotype. We aimed to clarify if there has been an increase in the prevalence of ADHD-like traits in the general population from 2004 to 2014. METHOD: Data were collected from 9-year-old twins (19,271), participating in the population-based Child and Adolescent Twin Study in Sweden between 2004 and 2014. We assessed lifetime ADHD symptoms using the Autism-Tics, ADHD and other Comorbidities inventory. Research proxies for diagnostic-level ADHD and subthreshold ADHD were derived from this scale. We modeled the lifetime prevalence of diagnostic-level and subthreshold ADHD with logistic regression, and assessed mean ADHD scores each year with linear regression. Lifetime prevalence of clinically diagnosed ADHD was retrieved from the National Patient Register and modeled with logistic regression. RESULTS: The prevalence of diagnostic-level ADHD based on parent ratings did not differ significantly over time from 2004 to 2014 (OR 1.37; 95% CI: 0.77-2.45; p-value .233). Both subthreshold ADHD and mean ADHD scores increased significantly over time (both p-values <.001). Clinically diagnosed ADHD increased more than fivefold from 2004 to 2014 (OR 5.27, 95% CI: 1.85-14.96). CONCLUSIONS: We found no evidence of an increase in ADHD-like traits at the extreme end of the distribution from 2004 to 2014, but small increases in normal and subthreshold variations of ADHD-like traits were observed. This suggests that the increased rates of clinically diagnosed ADHD might reflect changes in diagnostic and treatment practices of ADHD, administrative changes in reporting diagnoses, greater awareness of ADHD, better access to healthcare, or current overdiagnosis, rather than an increase in the ADHD phenotype.

Sex-specific manifestation of genetic risk for attention deficit hyperactivity disorder in the general population.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is more commonly diagnosed in males than in females. A growing body of research suggests that females with ADHD might be underdiagnosed or receive alternative diagnoses, such as anxiety or depression. Other lines of reasoning suggest that females might be protected from developing ADHD, requiring a higher burden of genetic risk to manifest the disorder. METHODS: We tested these two hypotheses, using common variant genetic data from two population-based cohorts. First, we tested whether females and males diagnosed with anxiety or depression differ in terms of their genetic risk for ADHD, assessed as polygenic risk scores (PRS). Second, we tested whether females and males with ADHD differed in ADHD genetic risk burden. We used three different diagnostic definitions: registry-based clinical diagnoses, screening-based research diagnoses and algorithm-based research diagnoses, to investigate possible referral biases. RESULTS: In individuals with a registry-based clinical diagnosis of anxiety or depression, females had higher ADHD PRS than males [OR(CI) = 1.39 (1.12-1.73)] but there was no sex difference for screening-based [OR(CI) = 1.15 (0.94-1.42)] or algorithm-based [OR(CI) = 1.04 (0.89-1.21)] diagnoses. There was also no sex difference in ADHD PRS in individuals with ADHD diagnoses that were registry-based [OR(CI) = 1.04 (0.84-1.30)], screening-based [OR(CI) = 0.96 (0.85-1.08)] or algorithm-based [OR(CI) = 1.15 (0.78-1.68)]. CONCLUSIONS: This study provides genetic evidence that ADHD risk may be more likely to manifest or be diagnosed as anxiety or depression in females than in males. Contrary to some earlier studies, the results do not support increased ADHD genetic risk in females with ADHD as compared to affected males.

Genetic and environmental contributions to the association between ADHD and affective problems in early childhood-A Swedish population-based twin study.

Few twin studies have explored the relative contribution of genetic and environmental factors to the association between attention deficit hyperactivity disorder (ADHD) and affective problems, and no study has focused on preschool children. We used the classical twin design to explore the genetic and environmental overlap between ADHD symptoms and affective problems in preschool children, based on 879 five-year-old twin pairs born in Sweden 2004-2005. Questionnaire-based parent-ratings were used to measure ADHD symptoms and affective problems. A bivariate twin design was used to decompose variance in ADHD and affective problems into genetic and environmental components, and to test the degree to which these components overlapped across the two traits. Our results showed that there was a significant correlation of 0.34 (95% Confidence Interval [CI] 0.29-0.38) between ADHD and affective problems. This correlation was mostly explained by additive genetic factors (64%, 95%CI 37-93%), and to a lesser extent by shared environmental factors (35%, 95%CI 10-59%). Nonshared environmental factors did not contribute to the correlation between ADHD and affective problems (0%, 95%CI -9 to 10%). These findings show that there is a significant association between ADHD and affective problems in preschool children that is mostly explained by genetic influences. This adds important knowledge about the etiology of both ADHD and affective problems by indicating that these phenotypes are linked from as early as preschool years. This also needs to be taken into consideration when diagnosing young children and clinicians should consider assessing both affective problems and ADHD if one is present.

Measuring tobacco dependence in the general population: Evaluation of the Cigarette Dependence Scale (CDS-12) and its adaptation to smokeless tobacco use (STDS-12) in two Swedish surveys.

AIMS: The 12-item Cigarette Dependence Scale (CDS-12) is an instrument suitable to assess tobacco dependence in non-clinical populations. The aim of this study was twofold: a) to evaluate the scale's performance in a smoking population including non-daily smokers; b) to explore the scale's adaptation to the assessment of dependence on smokeless tobacco. METHODS: In a cross-sectional study we investigated performance and construct validity of the CDS-12 and of its adaptation to smokeless tobacco (STDS-12) in two Swedish population samples. The first sample consisted of young adults (1246 ever daily smokers and 1086 ever daily snus (the Swedish type of moist oral snuff) users between 19 and 28 years of age). The second sample included 1229 current smokers and 855 current users of snus between 16 and 84 years of age. Score distribution, internal consistency, factor structure, and associations with other indicators of tobacco dependence were analysed. RESULTS: Both scales had a small amount of missing answers (below 2% in most items) and had acceptable internal consistency. Factor analyses suggested a one-factor model. CDS-12 score and proportions classified as dependent were significantly higher among daily smokers compared to non-daily smokers, positively correlated with the number of cigarettes, and negatively with quit attempts as well as their duration. The same pattern was seen for STDS-12, apart from correlation with quit attempts. CONCLUSIONS: Both the CDS-12 and its adaptation to smokeless tobacco, tested for the first time in this study, appear to perform well in population-based samples including young and non-daily tobacco users.

Exposure to maternal smoking during pregnancy as a risk factor for tobacco use in adult offspring.

Nicotine from maternal smoking during pregnancy can cross the placental barrier, possibly resulting in fetal brain sensitization, as indicated by studies in which prenatal exposure to maternal smoking was associated with an increased risk of tobacco use among adolescent offspring. We investigated whether this association persists beyond adolescence by studying cigarette smoking and the use of snus (Swedish oral moist snuff) among 983 young adults from a prospective cohort study conducted in Stockholm, Sweden, between 2006 and 2010. Self-reported questionnaire data were linked with data from national population-based registers from 1983 onward. Maternal smoking during pregnancy was consistently associated with snus use in offspring (e.g., for lifetime daily snus use, adjusted odds ratio = 2.04, 95% confidence interval: 1.32, 3.16; for use of >3 cans of snus per week vs. less, odds ratio = 3.85, 95% confidence interval: 1.57, 10.15). No association was apparent with offspring's smoking, age at onset of tobacco use, or changes in use between 2006 and 2010. These findings indicate that prenatal exposure to maternal smoking is associated with regular and heavy nicotine intake from smokeless tobacco rather than from smoking. This should be further explored in epidemiologic studies that simultaneously address the roles of genetics and social environments.

In-utero exposure to maternal smoking is not linked to tobacco use in adulthood after controlling for genetic and family influences: a Swedish sibling study.

Previous studies have linked maternal smoking during pregnancy with regular tobacco use in offspring, but findings are not consistent and confounding from genetic and environmental factors have not fully been taken into account. A comparison between siblings discordant for prenatal smoking exposure adjusts for confounding by shared familial (i.e., genetic and environmental) factors. We investigated the association between prenatal exposure to maternal smoking during pregnancy and the risk of regular smoking or snus (Swedish moist smokeless tobacco) use in young adult offspring, using a population based matched cohort study. The cohort consisted of 1,538 randomly sampled same-sex sibling pairs, discordant for maternal smoking during pregnancy, 19-27 years old, participating in a survey conducted in Sweden 2010-2011. Lifetime and current history of tobacco use was self-reported in the survey, and information about maternal smoking during pregnancy was retrieved from the Medical Birth Register. Conditional logistic regression and stratified Cox proportional hazards regression were used to calculate odds ratios, hazard ratios, and corresponding 95% confidence intervals. Analyses of exposure-discordant siblings did not reveal significant associations between prenatal exposure to maternal smoking and lifetime or current daily tobacco use, intensity of use, or time to onset of daily tobacco use. These findings suggest that the previously reported higher risks of tobacco use in offspring of mothers who smoked during pregnancy, compared with offspring of non-smoking mothers, were likely due to confounding from genetic or environmental factors.

Prenatal exposure to tobacco and future nicotine dependence: population-based cohort study.

BACKGROUND: Maternal smoking during pregnancy may increase the risk of nicotine dependence, especially in girls, but data are conflicting and confounding by other familial factors cannot be ruled out. AIMS: To clarify the relationship between prenatal tobacco exposure and adolescent tobacco uptake and dependence in boys and girls respectively, while taking confounding factors into close consideration. METHOD: We conducted a prospective longitudinal study, comprising 3020 Swedish youths followed from 11 to 18 years of age. Exposure and outcome information was elicited via self-administered parental and repeated youth questionnaires. Hazard ratios (HRs), odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated as measures of associations. RESULTS: Girls prenatally exposed to maternal tobacco use had a two- to threefold increased odds of experiencing a high number of withdrawal symptoms (OR = 2.83, 95% CI 1.68-4.87), craving for tobacco (OR = 2.04, 95% CI 1.28-3.32) and heavy tobacco use (five or more cigarettes or snus dips per day) (OR = 1.93, 95% CI 1.30-2.86). These associations were weaker among boys, and did not reach formal statistical significance. Associations between prenatal tobacco exposure and onset of regular tobacco use in both genders appeared to be mostly explained by parents' social position and postnatal smoking behaviour. CONCLUSIONS: Prenatal exposure to tobacco is linked to an increased risk of nicotine dependence among adolescent girls.

Association Between Deliberate Self-harm and Violent Criminality.

Importance: Individuals who self-harm may have an increased risk of aggression toward others, but this association has been insufficiently investigated. More conclusive evidence may affect assessment, treatment interventions, and clinical guidelines. Objective: To investigate the association between nonfatal self-harm and violent crime. Design, Setting, and Participants: This population-based longitudinal cohort study, conducted from January 1, 1997, through December 31, 2013, studied all Swedish citizens born between 1982 and 1998 who were 15 years and older (N = 1 850 252). Individuals who emigrated from Sweden before the age of 15 years (n = 104 051) or immigrated to Sweden after the age of 13 years (ie, <2 years before the beginning of the follow-up; n = 22 009) were excluded. Data analysis was performed from April 21, 2016, to June 4, 2016. Exposures: Receipt of self-harm-associated clinical care. Main Outcomes and Measures: Conviction of a violent crime according to the Swedish penal code. Results: The study cohort consisted of 1 850 525 individuals (950 382 males and 900 143 females), and the mean (SD) follow-up time was 8.1 (4.7) years (range, 0-17.0 years; minimum age, 15 years; maximum age, 32 years). During a mean follow-up period of 8.1 years, 55 185 individuals (3.0%) received clinical care for self-harm. The crude hazard ratio was 4.9 (95% CI, 4.8-5.0) for violent crime conviction in exposed individuals compared with the unexposed group. Women who self-harm were at particularly high risk for expressing violent behaviors. After adjustment for relevant psychiatric comorbidities and socioeconomic status, an almost doubled hazard of violent offense remained (hazard ratio, 1.8; 95% CI, 1.8-1.9). Conclusions and Relevance: Self-harm is associated with an increased risk of conviction for a violent offense in both sexes. The risk of violence, as well as the risk of suicide and self-harm, should be assessed among offending and self-harming individuals.

Suicide in Tourette's and Chronic Tic Disorders.

BACKGROUND: Persons with neuropsychiatric disorders are at increased risk of suicide, but there is little data concerning Tourette's and chronic tic disorders (TD/CTD). We aimed to quantify the risk of suicidal behavior in a large nationwide cohort of patients with TD/CTD, establish the contribution of psychiatric comorbidity to this risk, and identify predictors of suicide. METHODS: Using a validated algorithm, we identified 7736 TD/CTD cases in the Swedish National Patient Register during a 44-year period (1969-2013). Using a matched case-cohort design, patients were compared with general population control subjects (1:10 ratio). Risk of suicidal behavior was estimated using conditional logistic regressions. Predictors of suicidal behavior in the TD/CTD cohort were studied using Cox regression models. RESULTS: In unadjusted models, TD/CTD patients, compared with control subjects, had an increased risk of both dying by suicide (odds ratio: 4.39; 95% confidence interval [CI]: 2.89-6.67) and attempting suicide (odds ratio: 3.86; 95% CI: 3.50-4.26). After adjusting for psychiatric comorbidities, the risk was reduced but remained substantial. Persistence of tics beyond young adulthood and a previous suicide attempt were the strongest predictors of death by suicide in TD/CTD patients (hazard ratio: 11.39; 95% CI: 3.71-35.02, and hazard ratio: 5.65; 95% CI: 2.21-14.42, respectively). CONCLUSIONS: TD/CTD are associated with substantial risk of suicide. Suicidal behavior should be monitored in these patients, particularly in those with persistent tics, history of suicide attempts, and psychiatric comorbidities. Preventive and intervention strategies aimed to reduce the suicidal risk in this group are warranted.

Maternal Smoking in Pregnancy and Offspring Depression: a cross cohort and negative control study.

Previous reports suggest that offspring of mothers who smoke during pregnancy have greater risk of developing depression. However, it is unclear whether this is due to intrauterine effects. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) from the UK (N = 2,869), the Nord-Trøndelag health study (HUNT) from Norway (N = 15,493), the Pelotas 1982 Birth Cohort Study from Brazil (N = 2,626), and the Swedish Sibling Health Cohort (N = 258 sibling pairs), we compared associations of maternal smoking during pregnancy and mother's partner's smoking during pregnancy with offspring depression and performed a discordant sibling analysis. In meta-analysis, maternal smoking during pregnancy was associated with higher odds of offspring depression (OR 1.20, 95% CI:1.08,1.34), but mother's partner's smoking during pregnancy was not (OR 1.05, 95% CI:0.94,1.17). However, there was only weak statistical evidence that the odds ratios for maternal and mother's partner's smoking differed from each other (p = 0.08). There was no clear evidence for an association between maternal smoking during pregnancy and offspring depression in the sibling analysis. Findings do not provide strong support for a causal role of maternal smoking during pregnancy in offspring depression, rather observed associations may reflect residual confounding relating to characteristics of parents who smoke.

Maternal smoking during pregnancy and offspring's tobacco dependence. A study of exposure-discordant sibling pairs.

BACKGROUND: Prenatal exposure to maternal smoking has previously been linked to tobacco dependence, but confounding from genetic and early-environmental factors is of concern. The aim of this study was to clarify if maternal smoking during pregnancy may affect the onset and manifestations of tobacco dependence after taking such factors into account. METHODS: The study is based on a matched cohort of 1538 siblings discordant for prenatal exposure to maternal smoking, who participated in a survey conducted in 2010 in Sweden. Analyses were based on pairs where both siblings had been daily smokers (193 pairs) or snus users (173 pairs) at some time in their life. Participants were 19-27 years old at the time of participation. Outcomes were tobacco dependence measured with the Cigarette Dependence Scale (CDS-12) in smokers and with the adapted Smokeless Tobacco Dependence Scale (STDS-12) in snus users, and previous quit attempts. Exposure to maternal smoking during pregnancy was retrieved from the Swedish Medical Birth Register. RESULTS: There was no difference in dependence scores in exposure-discordant siblings (mean difference 0.36 on CDS-12 [95% confidence interval: -1.23 to 1.95] and 0.61 on STDS-12 [95% confidence interval: -1.20 to 2.43]). Neither did the siblings differ with regard to previous quit attempts. CONCLUSIONS: Maternal smoking during pregnancy does not appear to influence tobacco dependence in adult offspring. A potential effect of heavy maternal smoking during pregnancy cannot be excluded, but genetic and environmental influences seem to be more influential for the onset of tobacco dependence.

Association of Perinatal Risk Factors With Obsessive-Compulsive Disorder: A Population-Based Birth Cohort, Sibling Control Study.

IMPORTANCE: Perinatal complications may increase the risk of obsessive-compulsive disorder (OCD). Previous reports were based on small, retrospective, specialist clinic-based studies that were unable to rigorously control for unmeasured environmental and genetic confounding. OBJECTIVE: To prospectively investigate a wide range of potential perinatal risk factors for OCD, controlling for unmeasured factors shared between siblings in the analyses. DESIGN, SETTING, AND PARTICIPANTS: This population-based birth cohort study included all 2 421 284 children from singleton births in Sweden from January 1, 1973, to December 31, 1996, who were followed up through December 31, 2013. From the 1 403 651 families in the cohort, differentially exposed siblings from the 743 885 families with siblings were evaluated; of these, 11 592 families included clusters of full siblings that were discordant for OCD. Analysis of the data was conducted from January, 26, 2015, to September, 5, 2016. EXPOSURES: Perinatal data were collected from the Swedish Medical Birth Register and included maternal smoking during pregnancy, labor presentation, obstetric delivery, gestational age (for preterm birth), birth weight, birth weight in relation to gestational age, 5-minute Apgar score, and head circumference. MAIN OUTCOMES AND MEASURES: Previously validated OCD codes (International Statistical Classification of Diseases and Health Related Problems, Tenth Revision, code F42) in the Swedish National Patient Register. RESULTS: Of 2 421 284 individuals included in the cohort, 17 305 persons were diagnosed with OCD. Of these, 7111 were men (41.1%). The mean (SD) age of individuals at first diagnosis of OCD was 23.4 (6.5) years. An increased risk for OCD remained after controlling for shared familial confounders and measured covariates (including sex, year of birth, maternal and paternal age at birth, and parity), for smoking 10 or more cigarettes per day during pregnancy (hazard ratio [HR], 1.27; 95% CI, 1.02-1.58), breech presentation (HR, 1.35; 95% CI, 1.06-1.71), delivery by cesarean section (HR, 1.17; 95% CI, 1.01-1.34), preterm birth (HR, 1.24; 95% CI, 1.07-1.43), birth weight 1501 to 2500 g (HR, 1.30; 95% CI, 1.05-1.62) and 2501 to 3500 g (HR, 1.08; 95% CI, 1.01-1.16), being large for gestational age (HR, 1.23; 95% CI, 1.05-1.45), and Apgar distress scores at 5 minutes (HR, 1.50; 95% CI, 1.07-2.09). Gestational age and birth weight followed inverse dose-response associations, whereby an increasingly higher risk for OCD was noted in children with a shorter gestational age and lower birth weight. We also observed a dose-response association between the number of perinatal events and increased OCD risk, with HRs ranging from 1.11 (95% CI, 1.07-1.15) for 1 event to 1.51 (95% CI, 1.18-1.94) for 5 or more events. CONCLUSIONS AND RELEVANCE: A range of perinatal risk factors is associated with a higher risk for OCD independent of shared familial confounders, suggesting that perinatal risk factors may be in the causal pathway to OCD.

Is Physical Activity Causally Associated With Symptoms of Attention-Deficit/Hyperactivity Disorder?

OBJECTIVE: Emerging evidence suggests that physical activity (PA) enhances cognition and may be a protective factor for attention-deficit/hyperactivity disorder (ADHD). Yet the impact of PA on ADHD symptoms has been investigated only in a few undersized, nonrandomized, and retrospective studies. We examined the effect of PA during late adolescence on ADHD symptoms in early adulthood while controlling for unmeasured genetic and shared environmental confounding. METHOD: The effect of PA at age 16 to 17 years (baseline) on ADHD symptoms at age 19 to 20 years (follow-up) was examined using a within-monozygotic (MZ) twins fixed-effects model in 232 MZ twin pairs born in Sweden between May 1985 and December 1986. Parents rated their children's DSM ADHD symptoms at baseline and follow-up. Participants' weekly energy expenditure (in metabolic equivalent task minutes per week) was based on self-reports at baseline of PA frequency, intensity, and duration. RESULTS: Greater weekly energy expenditure in adolescence was significantly associated with reduced ADHD symptom levels in early adulthood, even when controlling for unmeasured confounding (all genetic and environmental factors shared within MZ twin pairs) as well as ADHD symptoms and body mass index (BMI) at baseline, ß = -0.21, p = .013 (95% CI = -0.38 to -0.05). Similar results were observed for the 2 ADHD subcomponents: hyperactivity/impulsivity, ß = -0.21, p = .022 (95% CI = -0.39 to -0.03), and inattention, ß = -0.19, p = .049 (95% CI = -0.36 to -0.0005). CONCLUSION: In line with a causal hypothesis, PA was inversely associated with ADHD symptoms, even after adjusting for unmeasured confounding. These findings suggest that PA in adolescence might decrease ADHD symptoms in early adulthood. However, given the size of the effect, the clinical value of this intervention needs to be explored further.