Glucocorticoid receptor gene methylation and HPA-axis regulation in adolescents. The TRAILS study.

Early life adversity and psychopathology are thought to be linked through HPA-axis deregulation. Changes in methylation levels of stress reactivity genes such as the glucocorticoid receptor gene (NR3C1) can be induced by adversity. Higher NR3C1 methylation levels have been associated with a reduced NR3C1 expression, possibly leading to impaired negative feedback regulation of the HPA-axis. In this study we tested whether methylation levels of NR3C1 were associated with HPA-axis regulation, operationalized as cortisol responses. In 361 adolescents (mean age 16.1, SD=0.6), salivary cortisol samples were collected before, during, and after a social stress task, from which response measures (cortisol activation and recovery) were calculated. Higher NR3C1 methylation levels were associated with a flattened cortisol recovery slope, indicating a delayed recovery time. Cortisol response activation was not associated with NR3C1 methylation. These results suggest that methylation of NR3C1 may impair negative feedback of the HPA-axis in adolescents.

Methylation of NR3C1 and SLC6A4 and internalizing problems. The TRAILS study.

BACKGROUND: The relationship between early adverse life events and later internalizing problems could be mediated by DNA methylation. Adversity has been associated with higher methylation levels in the glucocorticoid receptor gene (NR3C1) and the serotonin transporter gene (SLC6A4) in adolescents. We investigated cross-sectional and prospective associations of NR3C1 and SLC6A4 methylation with adolescents׳ clinical diagnoses of internalizing disorders and internalizing symptom scores. METHODS: In a population sample (mean age=16.2) we measured DNA methylation in three regions of NR3C1 (NR3C1_1, N=454; NR3C1_2, N=904; NR3C1_3, N=412) and one region of SLC6A4 (N=939) at baseline. Internalizing problems were operationalized as clinical DSM-IV diagnoses, assessed at 3 year follow-up with a diagnostic interview, and internalizing symptom scores, assessed with Self-Report questionnaires at baseline and follow-up. RESULTS: Only NR3C1_1 methylation was positively associated with risk of lifetime internalizing disorders, and with symptom scores at follow-up. However, after accounting for baseline symptom scores there was only a tendency for association with internalizing symptom scores at follow-up. There was no association between SLC6A4 methylation and risk of lifetime internalizing disorders. SLC6A4 methylation and internalizing symptom scores showed a tendency for association, also after accounting for baseline symptom scores. LIMITATIONS: There was no repeated measure of DNA methylation to study causality between methylation and internalizing problems. Gene expression data were not available. CONCLUSIONS: Although the role of gene methylation in the development of internalizing problems remains unclear, our findings suggest that gene methylation, particularly of NR3C1, may be involved in the development of internalizing problems in adolescence.

Adverse life events and allele-specific methylation of the serotonin transporter gene (SLC6A4) in adolescents: the TRAILS study.

OBJECTIVES: Adverse life events increase vulnerability to affective disorders later in life, possibly mediated by methylation of the serotonin transporter gene (SLC6A4). We investigated the relationship of SLC6A4 methylation with various types of adversity (perinatal adversity, traumatic youth experiences and stressful life events [SLEs]), as well as with the timing of SLEs (during childhood [0-11 years] or during adolescence [12-15 years]). In addition, we investigated whether different serotonin-transporter-linked polymorphic region genotypes were equally sensitive to SLE-related methylation. METHODS: In a population sample of 939 adolescents (mean age = 16.2 years), we assessed SLC6A4 methylation, SLC6A4 functionality (serotonin-transporter-linked polymorphic region "long" and "short" alleles, and rs25531), and adverse life events. RESULTS: Only a higher number of SLEs was positively associated with higher SLC6A4 methylation (B = 0.11, p = .011). Adolescent SLEs were associated with higher SLC6A4 methylation (B = 0.13, p = .004) independently of childhood SLEs (B = 0.02, p = .57). L-allele homozygotes showed a greater impact of SLEs on methylation (B = 0.37, p < .001) than did s-allele carriers (B = 0.04, p = .66), resulting in higher levels of SLC6A4 methylation for l-allele homozygotes among those experiencing high levels of SLEs. CONCLUSIONS: Our findings demonstrate a higher level of SLC6A4 methylation after SLEs in adolescents, with a more pronounced association for SLEs during adolescence than during childhood. Considering the allele-specific sensitivity of SLC6A4 methylation to SLEs, this study may help clarify the role of SLC6A4 in the development of affective disorders.

Emotion recognition specialization and context-dependent risk of anxiety and depression in adolescents.

BACKGROUND: Some adolescents function poorly in apparently benign environments, while others thrive despite hassles and difficulties. The aim of this study was to examine if adolescents with specialized skills in the recognition of either positive or negative emotions have a context-dependent risk of developing an anxiety or depressive disorder during adolescence, depending on exposure to positive or harsh parenting. METHODS: Data came from a large prospective Dutch population study (N = 1539). At age 11, perceived parental rejection and emotional warmth were measured by questionnaire, and emotion recognition skills by means of a reaction-time task. Lifetime diagnoses of anxiety and depressive disorders were assessed at about age 19, using a standardized diagnostic interview. RESULTS: Adolescents who were specialized in the recognition of positive emotions had a relatively high probability to develop an anxiety disorder when exposed to parental rejection (Bspecialization*rejection = 0.23, P < 0.01) and a relatively low probability in response to parental emotional warmth (Bspecialization*warmth = -0.24, P = 0.01), while the opposite pattern was found for specialists in negative emotions. The effect of parental emotional warmth on depression onset was likewise modified by emotion recognition specialization (B = -0.13, P = 0.03), but the effect of parental rejection was not (B = 0.02, P = 0.72). In general, the relative advantage of specialists in negative emotions was restricted to fairly uncommon negative conditions. CONCLUSIONS: Our results suggest that there is no unequivocal relation between parenting behaviors and the probability to develop an anxiety or depressive disorder in adolescence, and that emotion recognition specialization may be a promising way to distinguish between various types of context-dependent reaction patterns.

Ethnicity, socioeconomic position and severity of problems as predictors of mental health care use in 5- to 8-year-old children with problem behaviour.

BACKGROUND: Empirical research on mental health care use and its determinants in young school-aged children is still scarce. In this study, we investigated the role of ethnicity, socioeconomic position (SEP) and perceived severity by both parents and teachers on mental health care use in 5- to 8-year old children with emotional and/or behavioural problems. METHODS: Data from 1,269 children with a high score([P90) on the Strengths and Difficulties Questionnaire (SDQ) in the school year 2008­2009 were linked to psychiatric case register data over the years 2010­2011. Cox proportional hazards models were used to predict mental health care use from ethnicity, SEP and perceived severity of the child's problems. RESULTS: During the follow-up period, 117 children with high SDQ scores (9.2 %) had used mental health care for the first time. Ethnic minority children were less likely to receive care than Dutch children (HR Moroccan/Turkish:0.26; 95 % CI 0.13-0.54, HR other ethnicity: 0.26; 95 %CI 0.12-0.58). No socioeconomic differences were found.After correction for previous care use, ethnicity and parental perceived severity, impact score as reported by teachers was significantly associated with mental healthcare use (HR 1.58; 95 % CI 1.01­2.46). CONCLUSIONS: Ethnicity is an important predictor of mental health care use in young children. Already in the youngest school-aged children, ethnic differences in the use of mental health care are present.A distinct predictor of care use in this age group is severity of emotional and behavioural problems as perceived by teachers. Therefore, teachers may be especially helpful in the process of identifying young children who need specialist mental health care.

Ethnic differences in problem perception and perceived need as determinants of referral in young children with problem behaviour.

An underrepresentation of ethnic minority children in mental health care settings is consistently reported. Parents of ethnic minority children are, however, less likely to perceive problem behaviour in their children. Our hypothesis was that, as a result of ethnic differences in problem perception, referral to care by a child health professional (CHP) would be lower for 5- to 6-year-old (high-risk) children from ethnic minority backgrounds than for their peers from the ethnic majority (Dutch origin). For 10,951 children in grade two of elementary school, parents and/or teachers completed the Strengths and Difficulties Questionnaire (SDQ) as well as questions on problem perception (PP) and perceived need for professional care (PN). Referral information was obtained from the Electronic Child Records (ECR) for 1,034 of these children. These children had a high (>90th percentile) SDQ score, and were not receiving mental health care. CHP's referred 144 children (14 %) during the routine health assessments. A lower problem perception was reported by parents of ethnic minority children (40-72 %) than by parents of the ethnic majority group (80 %; p < 0.001), but there were no ethnic differences in referral (OR range 0.9-1.9-p > 0.05). No ethnic differences were found for parental PN, nor for teacher's PP or PN. Despite a lower problem perception in ethnic minority parents when compared to ethnic majority parents, no ethnic differences were found in referral of children with problem behaviour in a preventive health care setting.

Validation of the SDQ in a multi-ethnic population of young children.

BACKGROUND: The Strengths and Difficulties Questionnaire (SDQ) is a valuable screening tool for identifying psychosocial problems. Its performance in a multi-ethnic society, common to many paediatric health care workers, has not been investigated. Because it is important that screening instruments are valid and reliable for all ethnic groups within one society, we examined differences in the SDQ's psychometric properties in a multi-ethnic society. METHODS: The SDQ parent (n = 8114) and teacher form (n = 9355) were completed as part of a preventive health check for children aged 5-6 years of Dutch and non-Dutch ethnic backgrounds. The Child Behaviour Checklist (CBCL)/Teacher Report Form (TRF) was administered to a subsample. RESULTS: Factor analysis of the parent-rated SDQ showed different rating patterns for two of the five subscales for non-Dutch children as compared with Dutch children. Cronbach's alpha for the total difficulties score varied by ethnic group (0.73-0.78 parent-rated SDQ, 0.80-0.83 teacher-rated SDQ), and coefficients were generally smaller for non-Dutch than for Dutch children (P < 0.05). Alpha coefficients for subscales varied between 0.31-0.85 for ethnic groups. Inter-rater correlations between parents and teachers for the total difficulties score varied between 0.20-0.41 between ethnic groups and were larger for Dutch than for non-Dutch children (P < 0.05). Concurrent validity was acceptable for most scales and most ethnic groups. CONCLUSION: The total difficulties score of the parent- and teacher-rated SDQ is valid and reliable for different ethnic groups within Dutch society. However, there are differences in reliability and validity of the subscales, which makes interpretation of the subscales difficult for certain ethnic groups.

Corticotropin (ACTH)-reactive immunoglobulins in adolescents in relation to antisocial behavior and stress-induced cortisol response. The TRAILS study.

Elevated levels of corticotropin (ACTH)-reactive immunoglobulins (ACTH IgG) were found in males with conduct disorder, suggesting their involvement in the biology of antisocial behavior. We first aimed to confirm these findings in a large general population sample of adolescents. Secondly, we studied the association between ACTH IgG levels and hypothalamic-pituitary-adrenal (HPA) axis response to stress. Free and total ACTH IgG levels were measured in sera of 1230 adolescents (15-18 years). HPA axis activity was determined by measuring salivary cortisol before, during, and after a social stress test. Antisocial behavior was assessed using the Antisocial Behavior Questionnaire. ACTH peptide and IgG affinity kinetics for ACTH were assayed in a subsample of 90 adolescents selected for high or low ACTH IgG levels. In boys, higher total ACTH IgG levels were associated with higher antisocial behavior scores (ß=1.05, p=0.04), especially at high levels of free ACTH IgG. In girls, antisocial behavior was associated with low free ACTH IgG levels (ß=-0.20, p=0.04). Stress-induced cortisol release was associated with free ACTH IgG in boys (ßareaunderthecurve=-0.67, p<0.01), and with total ACTH IgG in girls (ßrecovery=0.84, p=0.05). The affinity kinetics assay showed that ACTH IgG association rates were lower in both boys and girls with high ACTH IgG levels. These data show that ACTH IgG levels are related to antisocial behavior and HPA axis response to stress in adolescents. The mechanisms behind these associations, including different ACTH binding properties of IgG in subjects with antisocial behavior, deserve further attention.

Does the Revised Child Anxiety and Depression Scale (RCADS) measure anxiety symptoms consistently across adolescence? The TRAILS study.

We assessed if the Revised Child Anxiety and Depression Scale (RCADS) measures anxiety symptoms similarly across age groups within adolescence. This is crucial for valid comparison of anxiety levels between different age groups. Anxiety symptoms were assessed biennially in a representative population sample (n = 2226) at three time points (age range 10-17 years) using the RCADS anxiety subscales (generalized anxiety disorder [GAD], obsessive-compulsive disorder [OCD], panic disorder [PD], separation anxiety [SA], social phobia [SP]). We examined longitudinal measurement invariance of the RCADS, using longitudinal confirmatory factor analysis, by examining the factor structure (configural invariance), factor loadings (metric invariance) and thresholds (strong invariance). We found that all anxiety subtypes were configural invariant. Metric invariance held for items on the GAD, OCD, PD and SA subscales; yet, for the SP subscale three items showed modest longitudinal variation at age 10-12. Model fit decreased modestly when enforcing additional constraints across time; however, model fit for these models was still adequate to excellent. We conclude that the RCADS measures anxiety symptoms similarly across time in a general population sample of adolescents; hence, measured changes in anxiety symptoms very likely reflect true changes in anxiety levels. We consider the instrument suitable to assess anxiety levels across adolescence.

Gender-Specific Developmental Trajectories of Anxiety during Adolescence: Determinants and Outcomes. The TRAILS Study.

OBJECTIVE: To identify developmental trajectories of anxiety symptoms for adolescent girls and boys. Trajectories were compared with regard to early-adolescent risk factors and psychiatric outcomes during adolescence and in young adulthood. METHOD: A community sample of 2,230 adolescents was assessed three times across a six-year interval (10-17 years). Symptom scores of anxiety were analyzed with growth mixture models, stratified by gender. RESULTS: Three gender-specific anxiety trajectories were identified for both girls (93.3% low, 4.1% mid-adolescence limited, 2.6% mid-adolescence increasing) and boys (84.4% low, 9.5% mid-adolescence limited, 6.1% early-adolescence decreasing). Child, family and peer factors at baseline predicted group membership of the mid-adolescence limited anxiety trajectory and the early-adolescence decreasing anxiety trajectory in boys. Parental emotional problems predicted the early-adolescence anxiety increase trajectory in girls. Prevalence of anxiety disorders and depression during adolescence and in early adulthood was higher in both the mid-adolescence limited and the mid-adolescence anxiety increase trajectory. CONCLUSIONS: The longitudinal course of anxiety symptoms during adolescence was characterized by three distinct gender-specific developmental trajectories. The most at-risk trajectory in girls was the mid-adolescence anxiety increase trajectory, and in boys the mid-adolescence limited trajectory. None of the environmental (i.e., child, family and peer) factors distinguished the at-risk trajectories from the other trajectories.

Résumé OBJECTIF: Identifier les trajectoires développementales des symptômes d'anxiété pour les adolescents et les adolescentes. Les trajectoires ont été comparées à l'égard des facteurs de risque du début de l'adolescence et des résultats psychiatriques durant l'adolescence et le jeune âge adulte. MÉTHODE: Un échantillon communautaire de 2 230 adolescents (de 10 à 17 ans) a été évalué à trois reprises sur un intervalle de six ans. Les scores des symptômes d'anxiété ont été analysés à l'aide de modèles de croissance mixtes, stratifiés par sexe. RÉSULTATS: Trois trajectoires d'anxiété sexospécifiques ont été identifiées pour les filles (93,3 % faibles, 4,1 % limitées à la mi-adolescence, 2,6 % croissantes à la mi-adolescence) et les garçons (84,4 % faibles, 9,5 % limitées à la mi-adolescence, 6,1 % décroissantes au début de l'adolescence). Les facteurs environnementaux des enfants, de la famille et des pairs au départ prédisaient l'appartenance du groupe à la trajectoire d'anxiété limitée de la mi-adolescence ainsi qu'à la trajectoire d'anxiété décroissante du début de l'adolescence chez les garçons. Les problèmes émotionnels parentaux prédisaient la trajectoire d'anxiété croissante du début de l'adolescence chez les filles. La prévalence des troubles anxieux et de la dépression durant l'adolescence et au jeune âge adulte était plus élevée tant dans la trajectoire d'anxiété limitée de mi-adolescence que dans la trajectoire d'anxiété croissante de mi-adolescence. CONCLUSIONS: L'évolution longitudinale des symptômes d'anxiété durant l'adolescence était caractérisée par trois trajectoires développementales sexospécifiques distinctes. Chez les filles, la trajectoire la plus à risque était la trajectoire d'anxiété croissante de mi-adolescence, et chez les garçons, la trajectoire d'anxiété limitée de mi-adolescence. Aucun des facteurs environnementaux (c.-à-d., enfants, famille, pairs) ne distinguait les trajectoires à risque des autres trajectoires.

Structured shared decision-making using dialogue and visualization: a randomized controlled trial.

OBJECTIVE: The aim of this study is to evaluate a method, "Counseling in Dialogue" (CD), developed to increase the quality of counseling in youth mental health. Decisional conflict was used as indicator of the quality of counseling and shared decision-making. METHODS: 94 children aged 2-12 years were randomized into a CD group and a care as usual (CU) group. In a before-and-after design decisional conflict was measured using the decisional conflict scale (DCS) for parents (N=133) and the Provider Decision Process Assessment Instrument for therapists (PDPAI, N=20). 81 children had follow-up data. RESULTS: Compared with parents of the CU group, parents of the CD group reported significantly less decisional conflict after counseling (difference mothers: -0.38 (95%CI -0.56; -0.19), p<.001; fathers: -0.22 (95%CI -0.44; -0.01), p=.045). 98% of the mothers and 96% of the fathers in the CD group accepted the recommended treatment, compared to 71% (fathers) and 77% (mothers) in the CU group, p<0.05. Decisional conflict of the therapists was low in both groups after counseling (difference: -0.03 (95%CI -0.19; 0.14), p=.741). CONCLUSION: The counseling procedure significantly lowered decisional conflict of the parents and promoted the acceptance of the recommended treatment.

Childhood internalizing and externalizing problems predict the onset of clinical panic attacks over adolescence: the TRAILS study.

BACKGROUND: Panic attacks are a source of individual suffering and are an independent risk factor for later psychopathology. However, much less is known about risk factors for the development of panic attacks, particularly during adolescence when the incidence of panic attacks increases dramatically. We examined whether internalizing and externalizing problems in childhood predict the onset of panic attacks in adolescence. METHOD: This study is part of the TRacking Adolescents' Individual Lives Survey (TRAILS), a Dutch longitudinal population cohort study (N = 1,584). Internalizing and Externalizing Problems were collected using the Youth Self-Report (YSR) and the parent-report Child Behavior Checklist (CBCL) at baseline (age 10-12). At age 18-20, DSM-IV defined panic attacks since baseline were assessed with the Composite International Diagnostic Interview (CIDI). We investigated whether early adolescent Internalizing and Externalizing Problems predicted panic attacks between ages 10-20 years, using survival analysis in univariate and multivariate models. RESULTS: There were N = 314 (19.8%) cases who experienced at least one DSM-IV defined panic attack during adolescence and N = 18 (1.2%) who developed panic disorder during adolescence. In univariate analyses, CBCL Total Problems, Internalizing Problems and three of the eight syndrome scales predicted panic attack onset, while on the YSR all broad-band problem scales and each narrow-band syndrome scale predicted panic attack onset. In multivariate analyses, CBCL Social Problems (HR 1.19, p<.05), and YSR Thought Problems (HR 1.15, p<.05) and Social Problems (HR 1.26, p<.01) predicted panic attack onset. CONCLUSION: Risk indicators of panic attack include the wide range of internalizing and externalizing problems. Yet, when adjusted for co-occurring problem behaviors, Social Problems were the most consistent risk factor for panic attack onsets in adolescence.

Ethnic differences in problem perception and perceived need for care for young children with problem behaviour.

BACKGROUND: Problem perception and perceived need for professional care are important determinants that can contribute to ethnic differences in the use of mental health care. Therefore, we studied ethnic differences in problem perception and perceived need for professional care in the parents and teachers of 5- to 6-year-old children from the general population who were selected for having emotional and behavioural problems. METHODS: A cross-sectional study with data of 10,951 children from grade two of the elementary schools in the Rotterdam-Rijnmond area, The Netherlands. Parents and teachers completed the strengths and difficulties questionnaire (SDQ) as well as questions on problem perception and perceived need for care. The SDQ was used to identify children with emotional and behavioural problems. We included Dutch, Surinamese, Antillean, Moroccan and Turkish children in our sample with high (>P90) SDQ scores (N = 1,215), who were not currently receiving professional care for their problems. RESULTS: Amongst children with high SDQ scores, problem perception was lower in non-Dutch parents than in Dutch parents (49% vs. 81%, p < 0.01). These lower rates of problem perception could not be explained by differences in socioeconomic position or severity of the problems. No ethnic differences were found in parental perceived need and in problem perception and perceived need reported by teachers. Higher levels of problem perception and perceived need were reported by teachers than by parents in all ethnic groups (PP: 87% vs. 63% and PN: 48% vs. 23%). CONCLUSIONS: Child health professionals should be aware of ethnic variations in problem perception as low problem perception in parents of non-Dutch children may lead to miscommunication and unmet need for professional care for the child.

When parent and teacher ratings don't agree: the Tracking Adolescents' Individual Lives Survey (TRAILS).

OBJECTIVES: A commonly encountered situation for evaluating clinicians is a history of significant problems in one setting with little or no difficulties in another. This study aims to describe this phenomenon and to examine its relations with other child and family characteristics. METHOD: A total of 1,730 children (mean age 11.05 years) was studied from the first wave of the Tracking Adolescents' Individual Lives Survey (TRAILS), a large population-based study of Dutch youth. Parent and teacher ratings of aggression, rule breaking, inattention, and hyperactivity were obtained. Children were assigned to groups according to the presence of clinically relevant problems at home only, at school only, or in both settings. The rate of setting specific problems was calculated and comparisons between groups were made. RESULTS: Setting specific, especially home-specific, problems were quite common. Among children whom parents rated as having at least borderline-clinical problems, teachers reported clear or very clear behaviors at school at the following rates: aggression (22%), rule breaking (12.5%), inattention (55%), and hyperactivity/impulsivity (33%). Compared with the school-specific group, the home-specific group contained a significantly higher percentage of girls with regard to inattention or hyperactivity and a significantly lower percentage of girls with regards to rule breaking. Logistic regression analyses revealed that home- versus school-specific problems were related to sex, child effortful control, and parental stress. CONCLUSION: Externalizing problems are frequently encountered only in one setting between home and school and are related to sex, child effortful control, and parental stress.

Trajectories of CBCL attention problems in childhood.

The first aim of this study was to identify developmental trajectories of Attention Problems in twins followed from age 6 to 12 years. Second, we investigated whether singletons follow similar trajectories. Maternal longitudinal ratings on the Attention Problems (AP) subscale of the Child Behavior Checklist were obtained for a sample of 12,486 twins from the Netherlands Twin Register and for a general population sample of 1,346 singletons. Trajectories were analyzed by growth mixture modeling in twins, and compared with singletons. Teacher ratings on the AP subscale of the Teachers' Report Form were available for 7,179 twins and 1,211 singletons, and were used for cross-sectional mean comparisons at each age. All analyses were conducted for boys and girls separately. We identified three linear trajectories in both boys and girls, i.e., stable low (62-71%), low-increasing (15-18%), and high-decreasing (14-21%). Singletons followed three identical trajectories, with similar class proportions. Teacher ratings yielded no differences in mean levels of Attention Problems between twins and singletons. The development of Attention Problems from age 6 to 12 years can be characterized by stable low, low-increasing, and high-decreasing developmental trajectories. Twins and singletons are comparable with respect to the development of Attention Problems in childhood.

Cross-national comparison of the link between socioeconomic status and emotional and behavioral problems in youths.

INTRODUCTION: In previous longitudinal studies in the US, lower socioeconomic status (SES) was associated with more emotional and behavioral problems. It remains unclear whether these findings can be generalized outside the US, as different countries vary in their health care systems and prevention of psychopathology in youth. Therefore, we studied the same associations in a comparable sample in The Netherlands and directly tested for differences between the US and The Netherlands. METHODS: The US (N=833) and Dutch (N=708) population samples were followed-up for 9 years. Age at baseline ranged from 8 to 16 years. Parents filled out behavior checklists. RESULTS: Analyses revealed very few differences between the two countries. In both countries, SES predicted syndrome scores and cumulative prevalence rates for internalizing and externalizing problems (withdrawn and aggressive behavior) and for thought and attention Problems. The SES gradient in syndrome scores was stable over time. Only for withdrawn behavior, the gradient was larger in young adulthood. CONCLUSION: Although the health care systems differ between the US and The Netherlands, the socioeconomic disparities in emotional and behavioral problems were similar.

A twin-singleton comparison of developmental trajectories of externalizing and internalizing problems in 6- to 12-year-old children.

Research on twin-singleton differences in externalizing and internalizing problems in childhood is largely cross-sectional and yields contrasting results. The goal of this study was to compare developmental trajectories of externalizing and internalizing problems in 6- to 12-year-old twins and singletons. Child Behavior Checklist (CBCL) maternal reports of externalizing and internalizing problems were obtained for a sample of 9651 twins from the Netherlands Twin Register and for a representative general population sample of 1351 singletons. Latent growth modeling was applied to estimate growth curves for twins and singletons. Twin-singleton differences in the intercepts and slopes of the growth curves were examined. The developmental trajectories of externalizing problems showed a linear decrease over time, and were not significantly different for twins and singletons. Internalizing problems seem to develop similarly for twins and singletons up to age 9. After this age twins' internalizing symptoms start to decrease in comparison to those of singletons, resulting in less internalizing problems than singletons by the age of 12 years. Our findings confirm the generalizability of twin studies to singleton populations with regard to externalizing problems in middle and late childhood. The generalizability of studies on internalizing problems in early adolescence in twin samples should be addressed with care. Twinship may be a protective factor in the development of internalizing problems during early adolescence.

Anxiety and depression are risk factors rather than consequences of functional somatic symptoms in a general population of adolescents: the TRAILS study.

BACKGROUND: It is well known that functional somatic symptoms (FSS) are associated with anxiety and depression. However, evidence is lacking about how they are related to FSS. The aim of this study was to clarify these relationships and examine whether anxiety and depression are distinctly related to FSS. We hypothesized that anxiety contributes to the development of FSS and that depression is a consequence of FSS. METHODS: FSS, anxiety, and depression were measured in adolescents (N = 2230, 51% women) by subscales of the Youth Self-Report during three assessment waves (adolescents successively aged: 10-12, 12-14, and 14-17) and by corresponding subscales of the Child Behavior Checklist. Using structural equation models, we combined trait and state models of FSS with those of anxiety and depression, respectively. We identified which relationships (contemporaneous and two-year lagged) significantly connected the states of FSS with the states of anxiety and depression. RESULTS: Trait variables were all highly interrelated (r = .54-.63). Contrary to our hypothesis, both state anxiety (beta = .35) and state depression (beta = .45) had a strong contemporaneous effect on state FSS. In turn, state FSS had a weak two-year lagged effect on state anxiety (beta = .11) and an even weaker effect on state depression (beta = .06). CONCLUSIONS: While the effect of anxiety and depression on FSS is strong and immediate, FSS exert a weaker and delayed influence on anxiety and depression. Further research should be done to detect the exact ways in which anxiety and depression lead to FSS, and FSS lead to anxiety and depression.

Prospective community study of family stress and anxiety in (pre)adolescents: the TRAILS study.

For prevention of anxiety in children and adolescents, it is important to know whether family stress is a predictor of anxiety. We studied this in 1,875 adolescents from the Tracking Adolescents' Individual Lives Survey (TRAILS) who were followed up for 2 years, from age 10-12 to 12-14 years. Adolescents reported anxiety and depression symptoms at both assessments, and parents reported family stress (family dysfunction and parenting stress) at the first assessment. Family dysfunction was not associated with future anxiety, whereas high parenting stress was. Furthermore, family dysfunction was more strongly associated with anxiety than with depression, whereas parenting stress was more strongly associated with depression. Level of parental psychopathology explained part of the association of family stress with anxiety. The associations were modest and the understanding of the origins of adolescents' anxiety will require identifying other factors than family stress that account for more of the variance.

Gender and body size affect the response of erythrocyte folate to folic acid treatment.

The recommended dietary allowance (RDA) differs between men and women for some vitamins, but not for folate. The RDA for folate is derived mainly from metabolic studies in women. We assessed if men differ from women in their response of erythrocyte folate to folic acid supplementation. We used data from 2 randomized placebo-controlled trials with folic acid: a 3-y trial in which subjects ingested 800 mug/d of folic acid (294 men and 112 women) and a 12-wk trial in which 187 men and 129 women ingested 0, 50, 100, 200, 400, 600, or 800 microg/d of folic acid in a parallel design (n = 38-42 per treatment group). In the 3-y trial, the erythrocyte folate concentration increased 10% (143 nmol/L, [95%CI 46, 241]) less in men than in women. In the 12-wk trial, regression analysis showed that the response of erythrocyte folate upon folic acid intake for men was 47 nmol/L lower than for women (P for beta(gender) = 0.022); for an intake of 800 microg/d folic acid, this resulted in a 5% lower response in men than in women. Differences in lean body size explained 56% of the difference in response of erythrocyte folate between men and women in the 3-y trial and 70% in the 12-wk trial. Men need more folic acid than women to achieve the same erythrocyte folate concentration, mainly because men have a larger lean body mass. This could be an indication that the RDA for folate should be higher for men than for women, or that the RDA should be expressed per kilogram of lean body mass.