Sex differences in predicting ADHD clinical diagnosis and pharmacological treatment

In youth, ADHD is more commonly diagnosed in males than females, but higher male-to-female ratios are found in clinical versus population-based samples; suggesting a sex bias in the process of receiving a clinical diagnosis of ADHD. This study investigated sex differences in the severity and presentation of ADHD symptoms, conduct problems and learning problems in males and females with and without clinically diagnosed ADHD. We then investigated whether the predictive associations of these symptom domains on being diagnosed and treated for ADHD differed in males and females. Parents of 19,804 twins (50.64% male) from the Swedish population completed dimensional assessments of ADHD symptoms and co-occurring traits (conduct and learning problems) when children were aged 9 years old. Children from this population sample were linked to Patient Register data on clinical ADHD diagnosis and medication prescriptions. At the population level, males had higher scores for all symptom domains (inattention, hyperactivity/impulsivity, conduct, and learning problems) compared to females, but similar severity was seen in clinically diagnosed males and females. Symptom severity for all domains increased the likelihood of receiving an ADHD diagnosis in both males and females. Prediction analyses revealed significant sexby-symptom interactions on diagnostic and treatment status for hyperactivity/impulsivity and conduct problems. In females, these behaviours were stronger predictors of clinical diagnosis (hyperactivity/impulsivity: OR: 1.08, 95% CI: 1.01, 1.15; conduct: OR: 1.43, 95% CI: 1.09, 1.87), and prescription of pharmacological treatment (hyperactivity/impulsivity: OR: 1.08, 95% CI: 1.01, 1.15; conduct: OR: 1.43, 95% CI: 1.09, 1.87). Females with ADHD may be more easily missed in the ADHD diagnostic process and less likely to be prescribed medication unless they have prominent externalising problems

Investigating sex-specific effects of familial risk for ADHD and other neurodevelopmental disorders in the Swedish population

Background: Many psychiatric disorders show sex differences in prevalence. Recent studies suggest that females diagnosed with anxiety and depression carry more genetic risks related to attention deficit hyperactivity disorder (ADHD), compared to affected males. Aims: In this register-based study, we aimed to test whether females who received clinical diagnoses of anxiety, depressive, bipolar, and eating disorders are at higher familial risk for ADHD and other neurodevelopmental disorders (NDs), compared to diagnosed males. Method: We analysed data from a record-linkage of several Swedish national registers, including 151,025 sibling pairs from 103,941 unique index individuals diagnosed with anxiety, depressive, bipolar, or eating disorders, as well as data from 646,948 cousin pairs. We compared the likelihood of having a relative diagnosed with ADHD/NDs in index males and females. Results: Females with anxiety disorders were more likely than affected males to have a brother with ADHD [OR(CIs)=1.13(1.05-1.22)]. Results for broader NDs were similar and were driven by ADHD diagnoses. Follow-up analyses revealed similar point estimates for several categories of anxiety disorders, with the strongest effect observed for agoraphobia [OR(CIs)=1.64(1.12-2.39)]. No significant associations were found in individuals with depressive, bipolar, or eating disorders, or in cousins. Conclusions: These results provide modest support for the possibility that familial/genetic risks for ADHD may show sex-specific phenotypic expression. Alternatively, there could be sex-specific biases in diagnoses of anxiety and ADHD. These factors could play a small role in the observed sex differences in prevalence of ADHD and anxiety

Adverse family life events during pregnancy and ADHD symptoms in five-year-old offspring

Background Prenatal exposure to maternal adverse life events has been associated with offspring ADHD, but the role of familial confounding is unclear. We aimed to clarify if adverse life events during pregnancy are related to ADHD symptoms in offspring, taking shared familial factors into account. Method Data were collected on 34,751 children (including 6,427 siblings) participating in the population‐based Norwegian Mother and Child Cohort Study. During pregnancy, mothers reported whether they had experienced specific life events. We assessed ADHD symptoms in five‐year‐old children with the Conners’ Parent Rating Scale–Revised: short form. We modeled the associations between life events and mean ADHD scores with ordinary linear regression in the full cohort, and with fixed‐effect linear regression in sibling comparisons to adjust for familial confounding. Results Children exposed to adverse life events had higher ADHD scores at age 5, with the strongest effect observed for financial problems (mean differences 0.10 [95% CI: 0.09, 0.11] in adjusted model), and the weakest for having lost someone close (0.02 [95% CI 0.01, 0.04] in adjusted model). Comparing exposure‐discordant siblings resulted in attenuated estimates that were no longer statistically significant (e.g. mean difference for financial problems −0.03 [95% CI −0.07, 0.02]). ADHD scores increased if the mother had experienced the event as painful or difficult, and with the number of events, whereas sibling‐comparison analyses resulted in estimates attenuated toward the null. Conclusions These results suggest that the association between adverse life events during pregnancy and offspring ADHD symptoms is largely explained by familial factors

A twin study of genetic and environmental contributions to ADHD over time

Background: Attention‐deficit/hyperactivity disorder (ADHD) is an increasingly commonly diagnosed neurodevelopmental condition. One possibility is that this reflects a genuine increase in the prevalence of ADHD due to secular environmental changes, yet this hypothesis remains untested. We therefore investigated whether the genetic and environmental variance underlying ADHD, and traits of ADHD, has changed over time. Methods: We identified twins born from 1982 to 2008 from the Swedish Twin Registry (STR). We linked the STR with the Swedish National Patient Register and Prescribed Drug Register to identify diagnoses of ADHD and prescriptions of ADHD medication for these twins. We also utilized data collected from participants in the Child and Adolescent Twin Study in Sweden (CATSS), born from 1992 to 2008. Their parents completed a structured ADHD screening tool, which was used to measure traits of ADHD and assign broad screening diagnoses of ADHD. We used the classical twin design to test whether the degree to which variation in these measures was influenced by genetic and environmental variation changed over time. Results: We included 22,678 twin pairs from the STR and 15,036 pairs from CATSS. The heritability of ADHD in the STR ranged from 66% to 86% over time, although these fluctuations were not statistically significant. We observed a modest increase in variance in ADHD traits, from 0.98 to 1.09. This was driven by small increases in the underlying genetic and environmental variance, with heritability estimated as 64%–65%. No statistically significant changes in variance in screening diagnoses were observed. Conclusions: The relative contribution of genetic and environmental factors to ADHD has remained stable over time, despite its increasing prevalence. Thus, changes in the underlying etiology of ADHD over time are unlikely to explain the increase in ADHD diagnoses

Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders

If and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring’s psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F0) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F1) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F3) in the androgenized lineage. In contrast, following the male germline, F3 male offspring (mF3) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F3 females in the androgenized lineage and eight genes in the obese lineage. In mF3 male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F1 and F2 offspring in the female germline did not develop anxiety-like behavior, while the F2 male offspring (mF2) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.CC BY 4.0Correspondence: Elisabet Stener-Victorin ([email protected])</p

Association between cumulative psychosocial adversity in the family and ADHD and autism: a family-based cohort study

Abstract Cumulative exposure to psychosocial adversity at an early age has been shown to be a risk factor for attention-deficit hyperactivity disorder (ADHD) and autism that often co-occur. However, it is not clear if this association reflects a causal effect or familial confounding. We aimed to assess whether cumulative psychosocial adversity in the family increases the risk for ADHD and autism in offspring while accounting for unmeasured familial confounding. We used a population-based cohort of 1,877,901 individuals born in Sweden between 1990 and 2009. Participants were followed from the age of 3 until 2013, with a median follow up time of 13.8 years. We created a cumulative index based on 7 psychosocial adversity factors. We used Cox regression to estimate the hazard ratios (HRs) relating neurodevelopmental conditions to cumulative psychosocial adversity. To address familial confounding, the analyses were repeated in groups of relatives of different kinship: siblings and half-siblings and cousins. A dose-response relationship was observed between cumulative exposure to psychosocial adversity and ADHD at a general population level (covariate adjusted HRs (aHRs) with 95% confidence intervals ranged from 1.55 [one adversity; 1.53–1.58] to 2.65 [ ≥ 4 adversities; 1.98–3.54]). No clear dose-response relation was seen for autism (aHRs ranged from 1.04 [.59–1.84] to 1.37 [1.30–1.45]). HRs of ADHD and autism decreased with increasing level of kinship in the analysis of relatives. Cumulative exposure to psychosocial adversity was associated with both ADHD and autism in the general population, these associations were partly explained by unmeasured familial confounding between relatives. This highlights the need for using family-based designs in studies of psychosocial adversity and ADHD and autism

Attention-deficit/hyperactivity disorder and smoking habits in pregnant women

Background Attention-deficit/hyperactivity disorder (ADHD) has been associated with an increased risk of tobacco smoking, and more difficulties with smoking cessation compared to non-ADHD individuals. Women with ADHD may therefore show elevated rates of smoking during pregnancy. Aims To examine the association between ADHD and smoking habits among pregnant women in Sweden and Norway. Methods Women pregnant for the first time were identified in Sweden (n = 622,037), and Norway (n = 293,383), of which 1.2% (n = 7,444), and 1.7% (n = 4,951) were defined as having ADHD, respectively. Data on smoking habits were collected early and late in pregnancy. Results In Sweden, ADHD was associated with an increased risk of smoking early in pregnancy, adjusted risk ratio (adjRR) 2.69 (95% confidence interval, 2.58–2.81), and late in pregnancy, adjRR 2.95 (2.80–3.10). Similar findings were observed in the Norwegian data, early in pregnancy, adjRR 2.31 (2.21–2.40), and late in pregnancy, adjRR 2.56 (2.42–2.70). Women with ADHD were more likely to continue smoking during pregnancy, compared to women without ADHD, both in Sweden adjRR 1.13 (1.10–1.17), and in Norway, adjRR 1.16 (1.12–1.20). Having a sibling diagnosed with ADHD was associated with an increased risk of smoking early and late in pregnancy, in both Sweden and Norway. Conclusions Women with ADHD are considerably more likely to smoke early and late in (their first) pregnancy and are less likely to stop smoking between the two time points. Smoking, early and late in pregnancy, co-aggregates in families with ADHD. Smoking prevention and intervention programs should be targeted towards women with ADHD, specifically during their childbearing years, to ensure better mother and child outcomes