Harriette Riese

Neuroticism and common mental disorders: meaning and utility of a complex relationship.

Neuroticisms prospective association with common mental disorders (CMDs) has fueled the assumption that neuroticism is an independent etiologically informative risk factor. This vulnerability model postulates that neuroticism sets in motion processes that lead to CMDs. However, four other models seek to explain the association, including the spectrum model (manifestations of the same process), common cause model (shared determinants), state and scar models (CMD episode adds temporary/permanent neuroticism). To examine their validity we reviewed literature on confounding, operational overlap, stability and change, determinants, and treatment effects. None of the models is able to account for (virtually) all findings. The state and scar model cannot explain the prospective association. The spectrum model has some relevance, especially for internalizing disorders. Common causes are most important but the vulnerability model cannot be excluded although confounding of the prospective association by baseline symptoms and psychiatric history is substantial. In fact, some of the findings, such as interactions with stress and the small decay of neuroticisms effect over time, are consistent with the vulnerability model. We describe research designs that discriminate the remaining models and plea for deconstruction of neuroticism. Neuroticism is etiologically not informative yet but useful as an efficient marker of non-specified general risk.

The biological and psychological basis of neuroticism: Current status and future directions

Neuroticism (N) is believed to reflect a stable disposition involving specific biological and psychological mechanisms that produce its robust association with psychopathology. The nature of these mechanisms remains unclear, however. Based on an extensive review of published evidence, we argue that three interesting leads are emerging. First, N may reflect individual differences in brain circuits involved in perception of and cognitive control over negative stimuli. More specifically, reduced connectivity between the left amygdala and ACC may impair extinction of the amygdala response to anxiety-eliciting stimuli. Second, the neural evidence matches the psychological findings, which associate N with a negative bias in attention, interpretation and recall of information, increased reactivity, and ineffective coping, and is consistent with findings of decreased cardiovascular flexibility. Third, current studies suggest that HPA-axis influences mood independently of N. Strong claims on Ns biological basis, however, are not yet justified due to inconsistencies and lack of replication which are in part due to methodological limitations and Ns heterogeneity. We discuss potential methodological improvements and substantive directions for future research.

As good as it gets? A meta-analysis and systematic review of methodological quality of heart rate variability studies in functional somatic disorders

Autonomic nervous system (ANS) dysfunction is a potential mechanism connecting psychosocial stress to functional somatic disorders (FSD), such as chronic fatigue syndrome, fibromyalgia and irritable bowel syndrome. We present the first meta-analysis and systematic review of methodological study quality on the association between cardiac ANS dysfunction, measured as parasympathetic nervous system (PNS) activity using heart rate variability (HRV), and FSD. Literature search revealed 23 available studies including data on 533 FSD patients. Meta-analysis on a subgroup of 14 studies with suitable outcome measures indicated lower PNS activity in FSD patients compared to controls (weighted standardized mean difference (SMD)=-0.32, 95% CI -0.63 to -0.01, p=0.04). The reliability of this summary estimate was, however, significantly limited by unexplained heterogeneity in the effect sizes and potential publication bias (weighted SMD after correction for funnel plot asymmetry=0.01, 95% CI -0.34 to 0.36, p=0.95). The systematic review of overall methodological quality of HRV studies in FSD demonstrates that there is substantial room for improvement, especially in selection of healthy control subjects, blinding of researchers performing HRV measurements, report of adequate HRV outcomes, and assessment of and adjustment for potential confounders. Methodological study quality was, however, not a significant predictor of study findings. We conclude that current available evidence is not adequate to firmly reject or accept a role of ANS dysfunction in FSD. Quality criteria and recommendations to improve future research on HRV in FSD are provided.

Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study.

Stress early in life is a known risk factor for the development of affective disorders later in life. Epigenetic mechanisms, such as DNA methylation, may have an important role in mediating that risk. Recent epigenetic research reported on the long-term relationship between traumatic stress in childhood and DNA methylation in adulthood. In this study, we examined the impact of various types of stress (perinatal stress, stressful life events (SLEs) and traumatic youth experiences) on methylation of the glucocorticoid receptor gene (NR3C1) in the blood of a population sample of 468 adolescents (50.4% female, mean age 16.1 years). Second, we determined whether stress at different ages was associated with higher NR3C1 methylation. NR3C1 methylation rates were higher after exposure to SLEs and after exposure to traumatic youth experiences. NR3C1 methylation in adolescence was not higher after exposure to perinatal stress. Experience of SLEs in adolescence was associated with a higher NR3C1 methylation, independently of childhood SLEs. We demonstrate that not only traumatic youth experiences but also (more common) SLEs are associated with higher NR3C1 methylation. In addition, our findings underline the relevance of adolescent stress for epigenetic changes in the NR3C1 gene.

Rejection sensitivity relates to hypocortisolism and depressed mood state in young women

Rejection sensitivity and the associated fear of negative social evaluation (FNSE) trait are characteristics of hypocortisolemic syndromes such as atypical depression. However, a meta-analysis showed that acute FNSE evokes strong cortisol responses in humans. This is consistent with suggestions that hypocortisolism reflects a protective adaptation to a history of high cortisol responses. This leads us to hypothesize that measures of trait FNSE relate to hypocortisolism. Moreover, because FNSE relates positively to depressed mood state, but negatively to cortisol, we expect that the positive relationship between depressed mood state and cortisol will show up most clearly when controlling for the confounding effect of FNSE on this relationship. In the present study we measured salivary cortisol awakening response and psychological variables in 194 community women aged 18-30 years. The results confirmed our hypotheses. We propose that dispositional FNSE is associated with a history of frequent high cortisol responses, leading to long-term protective inhibition of further cortisol and energy mobilization. The present results have special relevance for mental health problems that have high prevalence among young women.

Mutual reinforcement between neuroticism and life experiences: a five-wave, 16-year study to test reciprocal causation.

High neuroticism predicts psychopathology and physical health problems. Nongenetic factors, including major life events and experiences, explain approximately half of the variance in neuroticism. Conversely, neuroticism also predicts these life experiences. In this study, we aimed to quantify the reciprocal causation between neuroticism and life experiences and to gauge the magnitude and persistence of these associations. This longitudinal cohort study included 5 assessment waves over 16 years in a random sample of 296 Dutch participants (47% women) with a mean age of 34 years (SD = 12, range 16-63 years). Neuroticism was assessed with the Amsterdam Biographic Questionnaire. The experiences measured included positive and negative life events, long-term difficulties (LTDs), and change in life quality, all assessed by contextual rating procedures adapted from the Life Event and Difficulties Schedule. We fit structural equation models in Mplus. Results showed that neuroticism consistently predicted negative experiences, decreased life quality, and LTDs (β = 0.15 to 0.39), whereas effects on positive experiences were variable (β = 0.14). LTDs and deteriorated life quality each predicted small but persistent increases in neuroticism (β = 0.18), whereas improved life quality predicted small but persistent decreases (β = -0.13). This suggests set point change in neuroticism. Life event aggregates showed no persistent effects on the neuroticism set point. Neuroticism and life experiences showed persistent, bidirectional associations. Experience-driven changes in neuroticism lasted over a decade. Results support the corresponsive principle (reciprocal causation), suggesting a mixed model of change in neuroticism that distinguishes temporary changes in neuroticism from persistent changes in an individuals neuroticism set point.

Negative and positive life events are associated with small but lasting change in neuroticism

BACKGROUND High neuroticism is prospectively associated with psychopathology and physical health. However, within-subject changes in neuroticism due to life experiences (LEs) or state effects of current psychopathology are largely unexplored. In this 2-year follow-up study, four hypotheses were tested: (1) positive LEs (PLEs) decrease and negative LEs (NLEs) increase neuroticism; (2) LE-driven change in neuroticism is partly long-lasting; and (3) partly independent of LE-driven changes in anxiety/depression; and (4) childhood adversity (before age 16 years) moderates the influence of NLEs/PLEs on neuroticism scores in adult life. METHOD Data came from the Netherlands Study of Depression and Anxiety [NESDA, n = 2981, mean age 41.99 years (s.d. = 13.08), 66.6% women]. At follow-up (T₂) we assessed PLEs/NLEs with the List of Threatening Experiences (LTE) over the prior 24 months and categorized them over recent and distant PLE/NLE measures (1-3 and 4-24 months prior to T₂ respectively) to distinguish distant NLE/PLE-driven change in trait neuroticism (using the Dutch version of the Neuroticism-Extroversion-Openness Five Factor Inventory, NEO-FFI) from state deviations due to changes in symptoms of depression (self-rated version of the 30-item Inventory of Depressive Symptomatology, IDS-SR30) and anxiety (Beck Anxiety Inventory, BAI). RESULTS Distant NLEs were associated with higher and distant PLEs with lower neuroticism scores. The effects of distant LEs were weak but long-lasting, especially for distant PLEs. Distant NLE-driven change in neuroticism was associated with change in symptoms of anxiety/depression whereas the effect of distant PLEs on neuroticism was independent of any such changes. Childhood adversity weakened the impact of distant NLEs but enhanced the impact of distant PLEs on neuroticism. CONCLUSIONS Distant PLEs are associated with small but long-lasting decreases in neuroticism regardless of changes in symptom levels of anxiety/depression. Long-lasting increases in neuroticism associated with distant NLEs are mediated by anxiety/depression.

Filling the Gap: Relationship Between the Serotonin-Transporter-Linked Polymorphic Region and Amygdala Activation

The alleged association between the serotonin-transporter-linked polymorphic region (5-HTTLPR) and amygdala activation forms a cornerstone of the common view that carrying the short allele of this polymorphism is a potential risk factor for affective disorders. The authors of a recent meta-analysis showed that this association is statistically significant (Hedges’s g = 0.35) but warned that estimates might be distorted because of publication bias. Here, we report a replication study of this relationship in 120 participants. We failed to find an association of 5-HTTLPR variation with amygdala activation during a widely used emotional-face-matching paradigm. Moreover, when we conducted a meta-analysis that included unpublished studies and data from the current study, the pooled meta-analytic effect size was no longer significant (g = 0.20, p = .06). These findings cast doubt on previously reported substantial effects, suggesting that the 5-HTTLPR–amygdala association is either much smaller than previously thought, conditional on other factors, or nonexistent.

Genetic influences on heart rate variability at rest and during stress.

We tested whether the heritability of heart rate variability (HRV) under stress is different from rest and its dependency on ethnicity or gender. HRV indexed by root mean square of successive differences (RMSSD) and high-frequency (HF) power was measured at rest and during 3 stressors in 427 European and 308 African American twins. No ethnic or gender differences were found for any measures. There was a nonsignificant increase in heritability of RMSSD (from 0.48 to 0.58) and HF (from 0.50 to 0.58) under stress. Up to 81% and 60% of the heritabilities of RMSSD and HF under stress could be attributed to genes influencing rest levels. The heritabilities due to genes expressed under stress were 0.11 for RMSSD and 0.23 for HF. The findings suggest that, independent of ethnicity and gender, HRV regulation at rest and under stress is largely influenced by the same genes with a small but significant contribution of stress-specific genetic effects.

Spontaneous baroreflex sensitivity in (pre)adolescents

Objective To present normal spontaneous baroreflex sensitivity (BRS) values and investigate the influence of posture, sex, age, pubertal stage, body mass index (BMI), and physical activity level on BRS in (pre)adolescents. BRS is a sensitive measure of both sympathetic and parasympathetic cardiovascular regulation that may help detect early subclinical autonomic dysfunction. Design A cross-sectional cohort study in a large sample of 10–13-year-old Dutch (pre)adolescents from the general population. Methods Short-term spontaneous BRS was determined non-invasively by Portapres in both the supine and standing position. BRS was calculated by power spectral analysis using the discrete Fourier method (frequency band 0.07–0.14 Hz). Univariate statistical methods and multiple regression analyses were applied. Results BRS in a standing position was lower than in a supine position (9.0 ± 4.9 versus 15.3 ± 9.1 ms/mmHg; t = 27.8, P < 0.001). Girls had lower BRS values than boys in both postures (supine 14.3 ± 8.7 versus 16.4 ± 9.4 ms/mmHg, β = 0.12, P < 0.001; standing 8.4 ± 4.4 versus 9.5 ± 5.4 ms/mmHg, β = 0.08, P = 0.012), independent of age, pubertal stage, BMI, and physical activity. Lower limits (P2.5) for normal BRS values in supine and standing positions were for girls 3.6 and 2.2 ms/mmHg and for boys 3.9 and 2.5 ms/mmHg, respectively. BRS declined with age in the standing position (β = −0.13, P < 0.001). In obese (pre)adolescents, BMI was negatively associated with BRS during standing (Kendalls τ = −0.26, P = 0.010). Conclusion The BRS of (pre)adolescents was negatively related to female sex, age, and obesity. A reduced BRS in obese (pre)adolescents might be a candidate predictor of future cardiovascular health, and therefore warrants further exploration.