Judith Rosmalen

Neuroticism: a non-informative marker of vulnerability to psychopathology

Abstract.Background:Neuroticism measures are very popular in psychopathological research, but it is unclear how useful neuroticism is in studies of the aetiology of psychopathology.Method:A conceptual examination was made of the literature on the association of neuroticism and psychopathology, the ontological status of neuroticism, the purport of neuroticism questionnaires, and causal issues.Results:The research on which neuroticism is built has historically been based solely on the factor analyses of the common adjectives used to describe usual behaviours. An abundance of studies have shown that neuroticism scores predict life stress, psychological distress, emotional disorders, psychotic symptoms, substance abuse, physical tension-related symptoms, medically unexplained physical symptoms, and health care utilisation. This evidence suggests that neuroticism scales index vulnerability to many forms of negative affect and psychiatric disorder. However, the associations do not clarify the nature of this vulnerability nor the underlying psychobiological mechanisms. We present evidence that neuroticism scores reflect a person’s characteristic (or mean) level of distress over a protracted period of time. In this perspective, even prospective associations of neuroticism with mental health outcomes are basically futile, and largely tautological since scores on any characteristic with substantial within-subject stability will predict, by definition, that characteristic and related variables at later points in time.Conclusion:Neuroticism is not an explanatory concept in the aetiology of psychopathology, since it measures a person’s characteristic level of distress over a protracted period of time. This situation will not change until knowledge becomes available about: (i) the mechanisms that produce high neuroticism scores (and, therefore, also psychopathology) and (ii) its neurobiological substrate. Only then will we understand why neuroticism appears to ‘predict’ the outcomes it predicts.

Determinants of salivary cortisol levels in 10–12 year old children; a population-based study of individual differences

The hypothalamic-pituitary-adrenal (HPA)-axis is a central component of the bodys neuroendocrine response to stress. Its major end-product cortisol has profound effects on mood and behavior. Although it has often been suggested, it remains unknown whether differences in HPA-axis physiology are part of an individuals vulnerability to psychopathology, and constitute a causal factor in its development. In order to study the contribution of HPA-axis physiology to the development of psychopathology, we measured HPA-axis physiology in a community-cohort of 1768 10-12 year-old children. The aims of the here presented study were twofold: (1) to obtain data on HPA-axis function in a large cohort of pre- and early-adolescent children, both in terms of total hormonal output and in terms of the dynamics of cortisol secretion (by means of the cortisol awakening response); and (2) to study potential confounders of the cortisol-psychopathology relationship in this age group, such as season of sampling, age, gender, pubertal development, perinatal variables and BMI. We found a wide interindividual variability in HPA-axis function. An increase in cortisol in the first 30 min after awakening was present in 70.7% of children, but the increase appears lower in children than in adults. In addition, this study suggests that season of sampling and gender may act as potential confounders in the cortisol-psychopathology relationship. We will follow these children longitudinally for the development of psychopathology in the period from childhood into adulthood. This period covers adolescence, which is a critical time for the appearance and development of psychiatric disorders.

Universal risk factors for multifactorial diseases: LifeLines: a three-generation population-based study.

The risk for multifactorial diseases is determined by risk factors that frequently apply across disorders (universal risk factors). To investigate unresolved issues on etiology of and individual’s susceptibility to multifactorial diseases, research focus should shift from single determinant-outcome relations to effect modification of universal risk factors. We present a model to investigate universal risk factors of multifactorial diseases, based on a single risk factor, a single outcome measure, and several effect modifiers. Outcome measures can be disease overriding, such as clustering of disease, frailty and quality of life. “Life course epidemiology” can be considered as a specific application of the proposed model, since risk factors and effect modifiers of multifactorial diseases typically have a chronic aspect. Risk factors are categorized into genetic, environmental, or complex factors, the latter resulting from interactions between (multiple) genetic and environmental factors (an example of a complex factor is overweight). The proposed research model of multifactorial diseases assumes that determinant-outcome relations differ between individuals because of modifiers, which can be divided into three categories. First, risk-factor modifiers that determine the effect of the determinant (such as factors that modify gene-expression in case of a genetic determinant). Second, outcome modifiers that determine the expression of the studied outcome (such as medication use). Third, generic modifiers that determine the susceptibility for multifactorial diseases (such as age). A study to assess disease risk during life requires phenotype and outcome measurements in multiple generations with a long-term follow up. Multiple generations will also enable to separate genetic and environmental factors. Traditionally, representative individuals (probands) and their first-degree relatives have been included in this type of research. We put forward that a three-generation design is the optimal approach to investigate multifactorial diseases. This design has statistical advantages (precision, multiple-informants, separation of non-genetic and genetic familial transmission, direct haplotype assessment, quantify genetic effects), enables unique possibilities to study social characteristics (socioeconomic mobility, partner preferences, between-generation similarities), and offers practical benefits (efficiency, lower non-response). LifeLines is a study based on these concepts. It will be carried out in a representative sample of 165,000 participants from the northern provinces of the Netherlands. LifeLines will contribute to the understanding of how universal risk factors are modified to influence the individual susceptibility to multifactorial diseases, not only at one stage of life but cumulatively over time: the lifeline.

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.

Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is the most investigated biological risk marker in functional somatic disorders (FSDs), such as chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS). Our aim was to assess whether there is an association between basal hypocortisolism and FSD and to identify potential moderators of this association. Meta-analysis on 85 studies revealed that although basal cortisol levels were generally lower in FSD subjects compared to controls, this association did not reach statistical significance (SMD -0.07, 95% CI -0.17 to 0.04, p=0.241). However, when the three FSD were assessed separately, statistically significant basal hypocortisolism was observed in CFS subjects compared to controls (SMD -0.14, 95% CI -0.28 to 0.00, p=0.047), but not in FM or IBS. When all potential moderators were entered into a meta-regression analysis, only type of FSD and female gender were significant independent predictors of basal hypocortisolism. In conclusion, we did not find evidence to consider all three main FSD as hypocortisolemic disorders, as significant reduction in basal cortisol compared to healthy controls was only found in CFS and in females with FM, but not in IBS.

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.

How to assess common somatic symptoms in large-scale studies: A systematic review of questionnaires

OBJECTIVE Many questionnaires for assessment of common somatic symptoms or functional somatic symptoms are available and their use differs greatly among studies. The prevalence and incidence of symptoms are partially determined by the methods used to assess them. As a result, comparison across studies is difficult. This article describes a systematic review of self-report questionnaires for somatic symptoms for use in large-scale studies and recommends two questionnaires for use in such studies. METHODS A literature search was performed in the databases Medline, PsycINFO and EMBASE. Articles that reported the development, evaluation, or review of a self-report somatic symptom measure were included. Instrument evaluation was based on validity and reliability, and their fitness for purpose in large scale studies, according to the PhenX criteria. RESULTS The literature search identified 40 questionnaires. The number of items within the questionnaires ranged from 5 to 78 items. In 70% of the questionnaires, headaches were included, followed by nausea/upset stomach (65%), shortness of breath/breathing trouble (58%), dizziness (55%), and (low) back pain/backaches (55%). Data on validity and reliability were reported and used for evaluation. CONCLUSION Questionnaires varied regarding usability and burden to participants, and relevance to a variety of populations and regions. Based on our criteria, the Patient Health Questionnaire-15 and the Symptom Checklist-90 somatization scale seem the most fit for purpose for use in large-scale studies. These two questionnaires have well-established psychometric properties, contain relevant symptoms, are relatively short, and are available in multiple languages.

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.

Psychophysiological biomarkers explaining the association between depression and prognosis in coronary artery patients: a critical review of the literature.

This paper aims to provide an overview of the current state of affairs on psychophysiological factors that may explain the link between depression and adverse outcome in coronary artery disease (CAD) patients. Factors discussed include heart rate variability, inflammation, platelet function, hypothalamus-pituitary-adrenal axis activity, serotonin metabolism and polyunsaturated fatty acids. Evidence suggests the involvement of each of these factors in both depression and CAD, together contributing to the prospective association between depression and cardiac outcome. Unfortunately, the involvement of above factors has been evaluated mostly in isolation, despite their functional interrelations and associations with behavioral factors. Moreover, there may be specific relations between individual symptoms of depression and certain psychophysiological mechanisms, rather than with general depression, further complicating the notion of depression as a cardiotoxic factor. The relatively understudied complexity of the relation between depression and CAD may serve as an explanation for the finding that depression treatment does not or barely affect cardiac outcome. Future studies should focus on the network of psychophysiological (and behavioral) factors to elucidate their precise role and timing in depressed cardiac patients.

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.