The heritability of clinically diagnosed attention-deficit/hyperactivity disorder in children and adults

Background: No prior twin study has explored the heritability of clinically diagnosed ADHD. Such studies are needed to resolve conflicting results regarding the importance of genetic effects for ADHD in adults. We aimed to estimate the relative contribution of genetic and environmental influences for clinically diagnosed ADHD across the life-span with a specific focus on ADHD in adults. Method: Information about zygosity and sex was obtained from 59,514 twins born between 1959 and 2001 included in the nation-wide population-based Swedish Twin Register. Clinical data of ADHD diagnosis was obtained from the Prescribed Drug (i.e., stimulant or non-stimulant medication for ADHD) and National Patient Registers (i.e., ICD-10 diagnosis of ADHD). Twin methods were applied to clinical data of ADHD diagnosis using structural equation modeling with monozygotic and dizygotic twins. Results: The best-fitting model revealed a high heritability of ADHD (0.88; 95% CI, 0.83-0.92) for the entire sample. Shared environmental effects, on the other hand, were non-significant and of minimal importance. The heritability of ADHD in adults was also substantial (0.72; 95% CI, 0.56-0.84). Conclusion: This study showed that the heritability of clinically diagnosed ADHD is high across the life span. Our finding of high heritability for clinically diagnosed ADHD in adults indicate that the previous reports of low heritability is best explained by rater effects and that gene-identification studies of ADHD in adults needs to consider pervasiveness (e.g., multiple raters) and developmentally (e.g., childhood onset criteria) informative data.ForteVetenskapsrådetManuscrip

Codevelopment of ADHD and externalizing behavior from childhood to adulthood

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) frequently co-occurs with externalizing disorders, but a clear understanding of the etiologic underpinnings is hampered by the limited understanding of the codevelopment of the traits from childhood into early adulthood. METHODS: Using a birth cohort of 2600 twins, the Swedish Twin study of Child and Adolescent Development study, assessed at ages 8-9, 13-14, 16-17, and 19-20, we investigated the codevelopment of ADHD and externalizing behavior from childhood to adulthood. The analyses examined ADHD-like and externalizing traits, as rated by twins and their parents using the Attention Problems scale and Externalizing scale of the Child Behavior Checklist, and estimated cross-lagged effects (one trait at one time-point predicting the other at the next). The covariation between the traits were decomposed into stable (effects carried over from the prior time-points) and innovative (new effects for each time-point) sources; each source was further decomposed into additive genetics, shared and nonshared environment. RESULTS: The analysis suggested that externalizing traits in middle childhood (age 8-9) predicted ADHD-like traits in early adolescence (age 13-14), whereas the reverse association was nonsignificant. In contrast, ADHD-like traits in lateadolescence (age 16-17) predicted externalizing traits in early adulthood (age 19-20). The correlation between ADHD-like and externalizing traits increased over time. At all time-points, innovative sources contributed substantially to maintained comorbidity. Genetic effects explained 67% of the covariation at each time-point; importantly, nearly 50% of these effects were innovative. CONCLUSIONS: This study challenges the belief that ADHD generally precedes externalizing behaviors; rather, change in the etiologic factors across the development is the rule. The effects were due to both new genetic and environmental factors emerging up to young adulthood. Clinicians and researchers needs to consider complex etiologic and developmental models for the comorbidity between ADHD and externalizing behaviors.The Swedish Research CouncilThe Swedish Research Council for Health, Working Life and WelfareThe Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM)National Institute of Child Health and Human DevelopmentAccepte

Familial confounding of the association between maternal smoking during pregnancy and ADHD in offspring

Background: Maternal Smoking During Pregnancy (SDP) has consistently been associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring, but recent studies indicate that this association might be due to unmeasured familial confounding. Methods: A total of 813,030 individuals born in Sweden between 1992 and 2000 were included in this nationwide population-based cohort study. Data on maternal SDP and ADHD diagnosis were obtained from national registers and patients were followed up from the age of 3 to the end of 2009. Hazard Ratios (HRs) were estimated using stratified Cox regression models. Cousin and sibling data were used to control for unmeasured familial confounding. Results: At the population level maternal SDP predicted ADHD in offspring (HRModerateSDP = 1.89; HRHighSDP = 2.50). This estimate gradually attenuated toward the null when adjusting for measured confounders (HRModerateSDP = 1.62; HRHighSDP = 2.04), unmeasured confounders shared within the extended family (i.e., cousin comparison) (HRModerateSDP = 1.45; HRHighSDP = 1.69), and unmeasured confounders within the nuclear family (i.e., sibling comparison) (HRModerateSDP = 0.88; HRHighSDP = 0.84). Conclusions: Our results suggest that the association between maternal SDP and offspring ADHD are due to unmeasured familial confounding.ForteVetenskapsrådetNational Insitute of Child Health and Human Develoment, NICHDAccepte

Attention-deficit/hyperactivity disorder medication and seizures

OBJECTIVE: Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of seizures, but there is uncertainty about whether ADHD medication treatment increases risk among patients with and without preexisting seizures. METHODS: We followed a sample of 801,838 patients with ADHD who had prescribed drug claims from the Truven Health MarketScan Commercial Claims and Encounters databases to examine whether ADHD medication increases the likelihood of seizures among ADHD patients with and without a history of seizures. First, we assessed overall risk of seizures among patients with ADHD. Second, within-individual concurrent analyses assessed odds of seizure events during months when a patient with ADHD received ADHD medication compared with when the same individual did not, while adjusting for antiepileptic medications. Third, within-individual long-term analyses examined odds of seizure events in relation to the duration of months over the previous 2 years patients received medication. RESULTS: Patients with ADHD were at higher odds for any seizure compared with non-ADHD controls (odds ratio [OR] = 2.33, 95% confidence interval [CI] = 2.24-2.42 males; OR = 2.31, 95% CI = 2.22-2.42 females). In adjusted within-individual comparisons, ADHD medication was associated with lower odds of seizures among patients with (OR = 0.71, 95% CI = 0.60-0.85) and without (OR = 0.71, 95% CI = 0.62-0.82) prior seizures. Long-term within-individual comparisons suggested no evidence of an association between medication use and seizures among individuals with (OR = 0.87, 95% CI = 0.59-1.30) and without (OR = 1.01, 95% CI = 0.80-1.28) a seizure history. CONCLUSIONS: Results reaffirm that patients with ADHD are at higher risk of seizures. However, ADHD medication was associated with lower risk of seizures within individuals while they were dispensed medication, which is not consistent with the hypothesis that ADHD medication increases risk of seizures

Health, behavior, and social outcomes among offspring of parents with criminal convictions: a register‐based study from Sweden

Background: There is currently insufficient understanding of the health and behavior of children whose parents engage in criminal behavior. We examined associations between parental criminal convictions and wide range of offspring health, behavioral, and social outcomes by age 18 in a large, national sample, aiming to get a comprehensive picture of the risks among children of offending parents. Methods: We studied 1,013,385 individuals born in Sweden between 1987 and 1995, and their parents. Using data from several longitudinal nationwide registers, we investigated parental convictions and 85 offspring outcomes until the end of 2013, grouped into birth‐related conditions, psychiatric and somatic disorders, accidents and injuries, mortality, school achievement, violent victimization, and criminality. Cox proportional hazards regression and logistic regression models were used to examine the associations. The role of genetic factors in intergenerational associations was studied in children‐of‐siblings analyses. We also examined the co‐occurrence of multiple outcomes using Poisson regression. Results: A total of 223,319 (22.0%) individuals had one parent convicted and 31,241 (3.1%) had both parents convicted during the first 18 years of their life. The strongest associations were found between parental convictions and offspring behavioral problems, substance use disorders, poor school achievement, violent victimization, and criminality, with an approximately 2 to 2.5‐fold increased risk in children with one convicted parent and 3‐ to 4‐fold increased risk in children with two convicted parents. The risks were particularly elevated among children of incarcerated parents with a history of violent convictions. The associations appeared to be at least partly explained by genetic influences. Parental convictions were also associated with an increased likelihood of experiencing multiple outcomes. Conclusions: Our findings help to calibrate the risks of a wide range of adverse outcomes associated with parental convictions and may be used to guide prevention efforts and identify key areas for future research

Associations between β-blockers and psychiatric and behavioural outcomes: a population-based cohort study of 1.4 million individuals in Sweden

Background β-blockers are widely used for treating cardiac conditions and are suggested for the treatment of anxiety and aggression, although research is conflicting and limited by methodological problems. In addition, β-blockers have been associated with precipitating other psychiatric disorders and suicidal behaviour, but findings are mixed. We aimed to examine associations between β-blockers and psychiatric and behavioural outcomes in a large population-based cohort in Sweden. Methods and findings We conducted a population-based longitudinal cohort study using Swedish nationwide high-quality healthcare, mortality, and crime registers. We included 1,400,766 individuals aged 15 years or older who had collected β-blocker prescriptions and followed them for 8 years between 2006 and 2013. We linked register data on dispensed β-blocker prescriptions with main outcomes, hospitalisations for psychiatric disorders (not including self-injurious behaviour or suicide attempts), suicidal behaviour (including deaths from suicide), and charges of violent crime. We applied within-individual Cox proportional hazards regression to compare periods on treatment with periods off treatment within each individual in order to reduce possible confounding by indication, as this model inherently adjusts for all stable confounders (e.g., genetics and health history). We also adjusted for age as a time-varying covariate. In further analyses, we adjusted by stated indications, prevalent users, cardiac severity, psychiatric and crime history, individual β-blockers, β-blocker selectivity and solubility, and use of other medications. In the cohort, 86.8% (n = 1,215,247) were 50 years and over, and 52.2% (n = 731,322) were women. During the study period, 6.9% (n = 96,801) of the β-blocker users were hospitalised for a psychiatric disorder, 0.7% (n = 9,960) presented with suicidal behaviour, and 0.7% (n = 9,405) were charged with a violent crime. There was heterogeneity in the direction of results; within-individual analyses showed that periods of β-blocker treatment were associated with reduced hazards of psychiatric hospitalisations (hazard ratio [HR]: 0.92, 95% confidence interval [CI]: 0.91 to 0.93, p < 0.001), charges of violent crime (HR: 0.87, 95% CI: 0.81 to 0.93, p < 0.001), and increased hazards of suicidal behaviour (HR: 1.08, 95% CI: 1.02 to 1.15, p = 0.012). After stratifying by diagnosis, reduced associations with psychiatric hospitalisations during β-blocker treatment were mainly driven by lower hospitalisation rates due to depressive (HR: 0.92, 95% CI: 0.89 to 0.96, p < 0.001) and psychotic disorders (HR: 0.89, 95% CI: 0.85 to 0.93, p < 0.001). Reduced associations with violent charges remained in most sensitivity analyses, while associations with psychiatric hospitalisations and suicidal behaviour were inconsistent. Limitations include that the within-individual model does not account for confounders that could change during treatment, unless measured and adjusted for in the model. Conclusions In this population-wide study, we found no consistent links between β-blockers and psychiatric outcomes. However, β-blockers were associated with reductions in violence, which remained in sensitivity analyses. The use of β-blockers to manage aggression and violence could be investigated further

Association of parental substance use disorder with offspring cognition : a population family-based study

Aims To assess whether parental substance use disorder (SUD) is associated with lower cognitive ability in offspring, and whether the association is independent of shared genetic factors. Design A population family-based cohort study utilizing national Swedish registries. Linear regression with increased adjustment of covariates was performed in the full population. In addition, the mechanism of the association was investigated with children-of-sibling analyses using fixed-effects regression with three types of sibling parents with increasing genetic relatedness (half-siblings, full siblings and monozygotic twins). Setting and participants A total of 3 004 401 people born in Sweden between 1951 and 1998. Measurements The exposure variable was parental SUD, operationalized as having a parent with life-time SUD diagnosis or substance-related criminal conviction in the National Patient Register or Crime Register, respectively. Outcomes were cognitive test score at military conscription and final school grades when graduating from compulsory school. Covariates included in the analyses were sex, birth year, parental education, parental migration status and parental psychiatric comorbid diagnoses. Findings In the full population, parental SUD was associated with decreased cognitive test stanine scores at conscription [4.56, 95% confidence interval (CI) = 4.55-4.57] and lower Z-standardized school grades (-0.43, 95% CI = -0.43 to -0.42) compared to people with no parental SUD (cognitive test: 5.17, 95% CI = 5.17-5.18; grades: 0.09, 95% CI = 0.08-0.09). There was evidence of a dose-response relationship, in that having two parents with SUD (cognitive test: 4.17, 95% CI = 4.15-4.20; grades: -0.83, 95% CI = -0.84 to -0.82) was associated with even lower cognitive ability than having one parent with SUD (cognitive test: 4.60, 95% CI = 4.59-4.60; grades: -0.38, 95% CI = -0.39 to -0.380). In the children-of-siblings analyses when accounting for genetic relatedness, these negative associations were attenuated, suggestive of shared underlying genetic factors. Conclusions There appear to be shared genetic factors between parental substance use disorder (SUD) and offspring cognitive function, suggesting that cognitive deficits may constitute a genetically transmitted risk factor in SUD.Peer reviewe

Childhood attention-deficit/hyperactivity disorder symptoms and the development of adolescent alcohol problems : a prospective, population-based study of Swedish twins.

Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of problematic alcohol and other substance use in adolescence. This study used data from an ongoing, prospective, population-based twin study of Swedish children and adolescents to evaluate the extent to which the association between ADHD symptoms and alcohol problems reflects a unique source of genetic or environmental risk related to ADHD versus a broader predisposition to youth externalizing behavior. We used all available data from same-sex MZ and DZ twins on ADHD symptoms in childhood (age 9/12; N = 15,549) and alcohol problems in late adolescence (age 18; N = 2,564). Consistent with prior longitudinal studies, the phenotypic association between hyperactive/impulsive ADHD symptoms and alcohol problems was small in magnitude, whereas the association for inattentive symptoms was even weaker. Additive genetic influences explained 99.8% of the association between hyperactive/impulsive symptoms and alcohol problems. Furthermore, we found that the genetic risk specifically associated with hyperactive/impulsive symptoms was attenuated when estimated in the context of externalizing behavior liability during childhood, of which ADHD symptoms were specific expressions. In sensitivity analyses exploring hyperactivity in mid-adolescence, we found a similar pattern of genetic associations. These results are consistent with previous findings of genetically driven overlap in the etiology of ADHD and problematic alcohol use. At least some of this cooccurrence may result from a general predisposition to externalizing behaviors in youth.National Institutes of Health (NIH), MH102221, TR001107Swedish Initiative for Research on Microdata in the Social and Medical Sciences (SIMSAM)Swedish Research Council for Health Working Life & Welfare (Forte)Swedish Research CouncilSöderström-Königska FoundationEuropean Commission, 602768NIH National Center for Advancing Translational Sciences (NCATS), TL1TR001107, UL1TR001108NIH National Institute of Mental Health (NIMH), R01MH102221Manuscrip

Use of central nervous system drugs in combination with selective serotonin reuptake inhibitor treatment: a Bayesian screening study for risk of suicidal behavior

Background: Using other central nervous system (CNS) medications in combination with selective serotonin reuptake inhibitor (SSRI) treatment is common. Despite this, there is limited evidence on the impact on suicidal behavior of combining specific medications. We aim to provide evidence on signals for suicidal behavior risk when initiating CNS drugs during and outside of SSRI treatment. Materials and methods: Using a linkage of Swedish national registers, we identified a national cohort of SSRI users aged 6–59 years residing in Sweden 2006–2013. We used a two-stage Bayesian Poisson model to estimate the incidence rate ratio (IRR) of suicidal behavior in periods up to 90 days before and after a CNS drug initiation during SSRI treatment, while accounting for multiple testing. For comparison, and to assess whether there were interactions between SSRIs and other CNS drugs, we also estimated the IRR of initiating the CNS drug without SSRI treatment. Results: We identified 53 common CNS drugs initiated during SSRI treatment, dispensed to 262,721 individuals. We found 20 CNS drugs with statistically significant IRRs. Of these, two showed a greater risk of suicidal behavior after versus before initiating the CNS drug (alprazolam, IRR = 1.39; flunitrazepam, IRR = 1.83). We found several novel signals of drugs that were statistically significantly associated with a reduction in the suicidal behavior risk. We did not find evidence of harmful interactions between SSRIs and the selected CNS drugs. Conclusion: Several of the detected signals for reduced risk correspond to drugs where there is previous evidence of benefit for antidepressant augmentation (e.g., olanzapine, quetiapine, lithium, buspirone, and mirtazapine). Novel signals of reduced suicidal behavior risk, including for lamotrigine, valproic acid, risperidone, and melatonin, warrant further investigation

Longitudinal Associations of Childhood Internalizing Psychopathology With Substance Misuse : A Register-Based Twin and Sibling Study

Objective: The pathways from internalizing psychopathology to substance misuse remain largely unclear. We estimated associations between childhood internalizing problems and subsequent substance misuse in 2 family-based samples. We also investigated sex differences and the role of externalizing comorbidity. Method: We studied associations of childhood internalizing psychopathology with register-based substance misuse after age 13 years. Sample 1 included all individuals born in Sweden from 1984 to 2000 (N = 1,768,516). Depressive and anxiety disorders were included as register-based International Classification of Diseases Ninth Revision (ICD-9) or Tenth Revision (ICD-10) diagnoses before age 13. Sample 2 was a subsample within the population sample, the Child and Adolescent Twin Study in Sweden (CATSS) twin cohort (n = 12,408; born 1992-1998), with mood and anxiety problems assessed at age 9/12 by parents. In both samples, substance misuse was defined as an ICD-9/10 alcohol/drug use disorder or an alcohol/drug-related criminal conviction until December 2013. To account for familial effects, stratified analyses were conducted within siblings and twin pairs. Results: In the population sample, both depressive (hazard ratio [HR] = 2.75, 95% CI = 2.36-3.20) and anxiety disorders (HR = 1.52, 95% CI = 1.35-1.73) were associated with substance misuse. Childhood mood problems (HR = 2.28, 95% CI = 1.69-3.08) were associated with substance misuse in the CATSS sample. The associations were partially explained by familial factors, and comorbid externalizing disorders explained the associations in men but not in women. Conclusion: Childhood mood problems were associated with substance misuse, but familial factors shared by siblings partially explained the associations. The relationship of anxiety with substance misuse was complex and depended on measurement and the type of anxiety disorder. Internalizing problems may be especially important for substance misuse risk in women.Peer reviewe