2015 › Trails



Internalizing and externalizing problems: Ghrelin-reactive immunoglobulins and anxiety, depression and stress-induced cortisol response in adolescents. The TRAILS study

Authors: Marie François, Johanna M. Schaefer, Christine Bole-Feysota, Pierre Déchelottea, Frank C. Verhulstb, Sergueï O. Fetissov.

Background. Ghrelin, a hunger hormone, has been implicated in the regulation of stress-response, anxiety and depression. Ghrelin-reactive immunoglobulins (Ig) were recently identified in healthy and obese humans showing abilities to increase ghrelin's stability and orexigenic effects. Here we studied if ghrelin-reactive Ig are associated with anxiety and depression and with the stress-induced cortisol response in a general population of adolescents. Furthermore, to test the possible infectious origin of ghrelin-reactive Ig, their levels were compared with serum IgG against common viruses. Methods. We measured ghrelin-reactive IgM, IgG and IgA in serum samples of 1199 adolescents from the Dutch TRAILS study and tested their associations with 1) anxiety and depression symptoms assessed with the Youth Self-Report, 2) stress-induced salivary cortisol levels and 3) IgG against human herpesvirus 1, 2, 4 and 6 and Influenza A and B viruses. Results. Ghrelin-reactive IgM and IgG correlated positively with levels of antibodies against Influenza A virus. Ghrelin-reactive IgM correlated negatively with antibodies against Influenza B virus. Ghrelin-reactive IgM correlated positively with anxiety scores in girls and ghrelin-reactive IgG correlated with stress-induced cortisol secretion, but these associations were weak and not significant after correction for multiple testing. Conclusion. These data indicate that production of ghrelin-reactive autoantibodies could be influenced by viral infections. Serum levels of ghrelin-reactive autoantibodies probably do not play a role in regulating anxiety, depression and the stress-response in adolescents from the general population.

Copyright © 2015 Elsevier Inc. All rights reserved.

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Internalizing and externalizing problems: Autonomic and Adrenocortical Interactions Predict Mental Health in Late Adolescence: The TRAILS Study

Authors: Nederhof E, Marceau K, Shirtcliff EA, Hastings PD, Oldehinkel AJ

The present study is informed by the theory of allostatic load to examine how multiple stress responsive biomarkers are related to mental health outcomes. Data are from the TRAILS study, a large prospective population study of 715 Dutch adolescents (50.9 % girls), assessed at 16.3 and 19.1 years. Reactivity measures of the hypothalamic pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) biomarkers (heart rate, HR; respiratory sinus arrhythmia, RSA; and pre-ejection period, PEP) to a social stress task were used to predict concurrent and longitudinal changes in internalizing and externalizing symptoms. Hierarchical linear modeling revealed relatively few single effects for each biomarker with the exception that high HR reactivity predicted concurrent internalizing problems in boys. More interestingly, interactions were found between HPA-axis reactivity and sympathetic and parasympathetic reactivity. Boys with high HPA reactivity and low RSA reactivity had the largest increases in internalizing problems from 16 to 19 years. Youth with low HPA reactivity along with increased ANS activation characterized by both decreases in RSA and decreases in PEP had the most concurrent externalizing problems, consistent with broad theories of hypo-arousal. Youth with high HPA reactivity along with increases in RSA but decreases in PEP also had elevated concurrent externalizing problems, which increased over time, especially within boys. This profile illustrates the utility of examining the parasympathetic and sympathetic components of the ANS which can act in opposition to one another to achieve, overall, stress responsivity. The framework of allostasis and allostatic load is supported in that examination of multiple biomarkers working together in concert was of value in understanding mental health problems concurrently and longitudinally. Findings argue against an additive panel of risk and instead illustrate the dynamic interplay of stress physiology systems.

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Internalizing and externalizing problems: Methylation of NR3C1 and SLC6A4 and internalizing problems. The TRAILS study

Authors: Van der Knaap L.J., van Oort F.V.A., Verhulst F.C., Oldehinkel A.J., Riese H.

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.


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.

Copyright © 2015 Elsevier B.V. All rights reserved.

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Internalizing and externalizing problems: Predicting mental disorders from hypothalamic-pituitary-adrenal axis functioning: a three-year follow-up in the TRAILS study

Authors: Nederhof E, Van Oort F, Bouma E, Laceulle O, Oldehinkel AJ, Ormel J

Background. Hypothalamic-pituitary-adrenal axis functioning, with cortisol as its major output hormone, has been presumed to play a key role in the development of psychopathology. Predicting affective disorders from diurnal cortisol levels has been inconclusive, whereas the predictive value of stress-induced cortisol concentrations has not been studied before. The aim of this study was to predict mental disorders over a 3-year follow-up from awakening and stress-induced cortisol concentrations. Method. Data were used from 561 TRAILS (TRacking Adolescents' Individual Lives Survey) participants, a prospective cohort study of Dutch adolescents. Saliva samples were collected at awakening and half an hour later and during a social stress test at age 16. Mental disorders were assessed 3 years later with the Composite International Diagnostic Interview (CIDI). Results. A lower cortisol awakening response (CAR) marginally significantly predicted new disorders [odds ratio (OR) 0.77, p = 0.06]. A flat recovery slope predicted disorders with a first onset after the experimental session (OR 1.27, p = 0.04). Recovery revealed smaller, non-significant ORs when predicting new onset affective or anxiety disorders, major depressive disorder, or dependence disorders in three separate models, corrected for all other new onsets. Conclusions. Our results suggest that delayed recovery and possibly reduced CAR are indicators of a more general risk status and may be part of a common pathway to psychopathology. Delayed recovery suggests that individuals at risk for mental disorders perceived the social stress test as less controllable and less predictable.

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Internalizing and externalizing problems: Mental health problems are associated with low-frequency fluctuations in reaction time in a large general population sample. The TRAILS study

Authors: Bastiaansen J.A., van Roon A.M., Buitelaar J.K., Oldehinkel A.J.

Background. Increased intra-subject reaction time variability (RT-ISV) as coarsely measured by the standard deviation (RT-SD) has been associated with many forms of psychopathology. Low-frequency RT fluctuations, which have been associated with intrinsic brain rhythms occurring approximately every 15-40s, have been shown to add unique information for ADHD. In this study, we investigated whether these fluctuations also relate to attentional problems in the general population, and contribute to the two major domains of psychopathology: externalizing and internalizing problems. Methods.  RT was monitored throughout a self-paced sustained attention task (duration: 9.1 ± 1.2 min) in a Dutch population cohort of young adults (n=1455, mean age: 19.0 ± 0.6 years, 55.1% girls). To characterize temporal fluctuations in RT, we performed direct Fourier Transform on externally validated frequency bands based on frequency ranges of neuronal oscillations: Slow-5 (0.010-0.027 Hz), Slow-4 (0.027-0.073 Hz), and three additional higher frequency bands. Relative magnitude of Slow-4 fluctuations was the primary predictor in regression models for attentional, internalizing and externalizing problems (measured by the Adult Self-Report questionnaire). Additionally, stepwise regression models were created to investigate (a) whether Slow-4 significantly improved the prediction of problem behaviors beyond the RT-SD and (b) whether the other frequency bands provided important additional information. Results. The magnitude of Slow-4 fluctuations significantly predicted attentional and externalizing problems and even improved model fit after modeling RT-SD first (R(2) change=0.6%, P<.01). Subsequently, adding Slow-5 explained additional variance for externalizing problems (R(2) change=0.4%, P<.05). For internalizing problems, only RT-SD made a significant contribution to the regression model (R(2)=0.5%, P<.01), that is, none of the frequency bands provided additional information. Conclusions. Low-frequency RT fluctuations have added predictive value for attentional and externalizing, but not internalizing problems beyond global differences in variability. This study extends previous findings in clinical samples of children with ADHD to adolescents from the general population and demonstrates that deconstructing RT-ISV into temporal components can provide more distinctive information for different domains of psychopathology.

Copyright © 2014 Elsevier Masson SAS. All rights reserved.

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Internalizing and externalizing problems: Mental health in Dutch adolescents: a TRAILS report on prevalence, severity, age of onset, continuity and co-morbidity of DSM disorders

Authors: Ormel J., Raven D., van Oort F., Hartman C.A., Reijneveld S.A., Veenstra R., Vollebergh W.A.M., et al.

Background. With psychopathology rising during adolescence and evidence suggesting that adult mental health burden is often due to disorders beginning in youth, it is important to investigate the epidemiology of adolescent mental disorders. Method. We analysed data gathered at ages 11 (baseline) and 19 years from the population-based Dutch TRacking Adolescents' Individual Lives Survey (TRAILS) study. At baseline we administered the Achenbach measures (Child Behavior Checklist, Youth Self-Report) and at age 19 years the World Health Organization's Composite International Diagnostic Interview version 3.0 (CIDI 3.0) to 1584 youths. Results.
Lifetime, 12-month and 30-day prevalences of any CIDI-DSM-IV disorder were 45, 31 and 15%, respectively. Half were severe. Anxiety disorders were the most common but the least severe whereas mood and behaviour disorders were less prevalent but more severe. Disorders persisted, mostly by recurrence in mood disorders and chronicity in anxiety disorders. Median onset age varied substantially across disorders. Having one disorder increased subjects' risk of developing another disorder. We found substantial homotypic and heterotypic continuity. Baseline problems predicted the development of diagnosable disorders in adolescence. Non-intact families and low maternal education predicted externalizing disorders. Most morbidity concentrated in 5-10% of the sample, experiencing 34-55% of all severe lifetime disorders. Conclusions. At late adolescence, 22% of youths have experienced a severe episode and 23% only mild episodes. This psychopathology is rather persistent, mostly due to recurrence, showing both monotypic and heterotypic continuity, with family context affecting particularly externalizing disorders. High problem levels at age 11 years are modest precursors of incident adolescent disorders. The burden of mental illness concentrates in 5-10% of the adolescent population.

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Internalizing and externalizing problems: Multifinality of peer victimization: maladjustment patterns and transitions from early to mid-adolescence

Authors: Tina Kretschmer, Edward D. Barker, Jan Kornelis Dijkstra, Albertine J. Oldehinkel, René Veenstra

Peer victimization is a common and pervasive experience in childhood and adolescence and is associated with various maladjustment symptoms, including internalizing, externalizing, and somatic problems. This variety suggests that peer victimization is multifinal where exposure to the same risk leads to different outcomes. However, very little is known about the relative likelihood of each form of maladjustment. We used a latent profile approach to capture multiple possible outcomes and examined prediction by peer victimization. We also examined the role of peer victimization with regard to stability and change in maladjustment. Maladjustment symptoms and peer victimization were assessed from the participants of the large cohort study TRacking Adolescents' Individual Lives Survey in early and mid-adolescence. Latent profile and latent transition analyses were conducted to examine associations between victimization and maladjustment profile and to test the role of victimization in maladjustment profile transitions. Four maladjustment profiles were identified for early adolescence (Low, Internalizing, Externalizing, Comorbid) and three profiles (Low, Internalizing, Externalizing) were identified for mid-adolescence. Internalizing problems were more likely in victimized adolescents than low symptom levels or externalizing problems. Victimized adolescents were at greater risk to develop internalizing problems between early and mid-adolescence than non-victimized adolescents. Peer victimization is multifinal mostly when outcomes are examined separately. If multiple outcomes are tested simultaneously, internalizing problems seem to be the most likely outcome.

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Internalizing and externalizing problems: Early life adversities and adolescent antisocial behavior: The role of cardiac autonomic nervous system reactivity in the TRAILS study

Authors: Sijtsema J.J., Van Roon A.M., Groot P.F.C., Riese H.

In the current study, the role of pre-ejection period (PEP) and respiratory sinus arrhythmia (RSA) was studied in the association between prior adversities and antisocial behavior in adolescence. PEP and RSA task reactivity and recovery to a public speaking task were assessed in adolescents from a longitudinal population-based study (N=624, Mage=16.14 years, 49.2% boys). Perinatal adversities were unrelated to antisocial behavior, but experiencing more stressful adversities between age 0 and 15 was associated with antisocial behavior at age 16 in boys with blunted PEP reactivity and smaller PEP differences from rest to recovery. Number of adversities between age 0 and 15 was associated with antisocial behavior in boys with blunted and girls with heightened RSA reactivity and larger PEP differences from rest to recovery. The association between prior adversities and antisocial behavior were small in effect size and depended upon sex and PEP and RSA reactivity and recovery.

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Internalizing and externalizing problems: The Structured Assessment of Violence Risk in Youth in a large community sample of young adult males and females: The TRAILS study

Authors: Sijtsema J.J., Kretschmer T., Van Os T.

This study examined associations between the Structured Assessment of Violence Risk in Youth (SAVRY; Borum, Bartel, & Forth, 2002) risk and protective items, identified clusters of SAVRY items, and used these clusters to predict police contact and violence. SAVRY items were assessed in a community sample of adolescent boys and girls (N = 963, 46.5% boys) via self-, parent, and teacher reports at ages 11 and 13.5 as part of a longitudinal cohort study. Police contact and violence were assessed at age 19. Correlations between risk and protective items and police contact and violence were largely similar in boys and girls, though there were some differences with regard to outcome measure. Principal factor analysis on the SAVRY items yielded a 2-factor model, distinguishing between History of Violence/Dysregulation and Social Support factors. Follow-up analyses showed incremental validity of the Social Support factor over and beyond the History of Violence/Dysregulation factor and sex in the prediction of violence. The findings provide new insights into the SAVRY factor structure and show that the SAVRY was able to predict violence in a community sample of adolescents over a period of 4 to 7 years.

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