Lineke M. Tak

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.

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.

Dysfunction of stress responsive systems as a risk factor for functional somatic syndromes

The etiology of functional somatic syndromes or disorders (FSDs) is generally considered to be a multifactorial interplay between psychological, biological, and social factors. One of the most investigated biological factors is stress responsive system dysfunction. Despite more than twenty years of research of the autonomic nervous system and the hypothalamic-pituitary-adrenal axis, however, it is yet unknown whether dysfunctions in these systems play a causal role in the etiology of FSDs and whether they are generic or FSD-specific. In this review, we will give an overview of available evidence on whether or not alterations in these stress responsive systems can be considered causal risk factors of FSDs. We conclude that although not necessary factors for FSDs in general, lowered cardiac vagal activity and hypocortisolism may be pivotal in the etiology and treatment strategy in subgroups of subjects with a FSD. Such subgroups need to be better identified.

Empirical foundations for the diagnosis of somatization: implications for DSM-5.

BACKGROUND The aim of this study was to develop empirically validated criteria for the diagnoses of clinically relevant somatization. METHOD This study was performed in a population-representative cohort consisting of 461 males (47.8%) and 503 females (52.2%), with an average age of 55.8 years (s.d.=11.1). Somatization, anxiety and depression were derived from the Composite International Diagnostic Interview. Mplus was used to perform confirmative factor analyses on the current DSM-IV symptom groups; on alternative symptom clusters previously suggested; and to perform latent class analysis in order to define an empirically derived cut-off for somatization. RESULTS The existence of symptom groups as described in DSM-IV was not supported by our data, whereas a differentiation between cardiopulmonary, musculoskeletal, gastrointestinal and general somatic symptoms did fit our data. Latent class analysis revealed two classes characterized by few (n=859) and many (n=105) symptoms. The class of subjects could be approached by a simple cut-off of four functional symptoms (sensitivity 79%, specificity 98%, positive predictive value 82%, negative predictive value 97%) regardless of the number of organ systems involved. CONCLUSIONS This study in a large population-representative cohort suggests that a simple symptom count can be used as a dimensional diagnosis of somatization. In those instances in which a categorical diagnosis is preferred, a simple cut-off of four out of 43 functional symptoms best fitted our data. We did not find any added value for incorporating the number of symptom clusters into the diagnostic criteria.

Intelligence is negatively associated with the number of functional somatic symptoms

Background: Functional somatic symptoms (FSS), that is, symptoms that cannot be conclusively explained by organic pathology, have a poorly understood aetiology. Intelligence was studied as a risk factor for FSS. It was hypothesised that intelligence is negatively associated with the number of FSS. To investigate the specific role of intelligence in FSS as opposed to medically explained symptoms (MES), the association of intelligence with FSS was compared with that of intelligence with MES. It was also hypothesised that lifestyle factors and socioeconomic factors mediate the relationship between intelligence and both FSS and MES, whereas psychological distress is especially important for FSS. Methods: All analyses were performed in a longitudinal study with two measurement waves in a general population cohort of 947 participants (age 33–79 years, 47.9% male). The Generalized Aptitude-Test Battery was used to derive an index for general intelligence, and the somatisation section of the Composite International Diagnostic Interview was used to measure the number of FSS and MES. Results: General intelligence was significantly associated with the number of FSS. The association of intelligence and FSS but not MES was mediated by work situation: participants of lower intelligence who reported more FSS were more often (unwanted) economically inactive. No evidence was found for a mediating role of psychological distress in the association of intelligence with FSS, even though distress was an important predictor of FSS. Conclusion: Intelligence is negatively associated with the number of FSS in the general population. Part of the association of intelligence with FSS is explained by a more unfavourable work situation for adults of lower intelligence.

Age-specific associations between cardiac vagal activity and functional somatic symptoms: a population-based study

Background: Functional somatic symptoms (FSS) are symptoms not explained by underlying organic pathology. It has frequently been suggested that dysfunction of the autonomic nervous system (ANS) contributes to the development of FSS. We hypothesized that decreased cardiac vagal activity is cross-sectionally and prospectively associated with the number of FSS in the general population. Methods: This study was performed in a population-based cohort of 774 adults (45.1% male, mean age ± SD 53.5 ± 10.7 years). Participants completed the somatization section of the Composite International Diagnostic Interview surveying the presence of 43 FSS. ANS function was assessed by spectral analysis of heart rate variability in the high-frequency band (HRV-HF), reflecting cardiac vagal activity. Follow-up measurements of HRV-HF and FSS were performed approximately 2 years later. Results: Linear regression analyses, with adjustments for gender, age, body mass index, anxiety, depression, smoking, alcohol use, and frequency of exercise, revealed an interaction of cardiac vagal activity with age: HRV-HF was negatively associated with FSS in adults ≤52 years of age (β = –0.12, t = –2.37, p = 0.018), but positively with FSS in adults aged >52 years (β = 0.13, t = 2.51, p = 0.012). Longitudinal analysis demonstrated a similar pattern. Conclusions: Decreased cardiac vagal activity is associated with a higher number of FSS in adults aged ≤52 years in the general population. The unexpected association between increased cardiac vagal activity and FSS in adults aged >52 years needs further exploration. The role of age should be acknowledged in future studies on ANS function in the etiology of FSS.

More than the sum of its parts: meta-analysis and its potential to discover sources of heterogeneity in psychosomatic medicine.

Meta-analyses may contribute to more reliable knowledge about the existence of certain relations in the area of psychosomatic research. Surprisingly, the increasing popularity of meta-analysis is not reflected in the number of meta-analyses of observational studies published in Psychosomatic Medicine. This may be due to the specific difficulties that apply to meta-analyses of observational research. The aim of this paper is to provide a nontechnical overview of the principles of meta-analysis applied to observational research. We will highlight general principles of meta-analysis and discuss the major threats to its validity, with an emphasis on its specific merits and pitfalls for psychosomatic research, using several examples. We conclude that meta-analysis is a relatively simple technique, leaving little reason for not routinely applying it when performing a systematic review. An adequately conducted meta-analysis may not only provide a summary estimate of a certain association, but it has additional value in discovering relevant confounders, mediators, and moderators, as well as identifying areas of research that require more attention. BMI = body mass index; IL = interleukin; IPD = individual patient data; OR = odds ratio; PTSD = posttraumatic stress disorder; SEM = standard error of the mean; SMD = standardized mean difference.

Dysfunction of the hypothalamic-pituitary-adrenal axis and functional somatic symptoms: a longitudinal cohort study in the general population.

In persons with functional somatic symptoms (FSS), no conventionally defined organic pathology is apparent. It has been suggested that complex interactions of psychological, physiological, and social factors are involved in the etiology of FSS. One of the physiological mechanisms that may contribute to FSS is the function of the hypothalamic-pituitary-adrenal (HPA)-axis. This study investigates the association of HPA-axis function with cross-sectional presence and prospective development of FSS in the general population. This study was performed in a population-based cohort of 741 male and female adults (mean age 53.1, S.D. 10.9). Participants completed the somatization section of the Composite International Diagnostic Interview (CIDI) in which the presence of 43 FSS is surveyed. In addition to the total number of FSS, bodily system FSS clusters with musculoskeletal, gastrointestinal, cardiorespiratory, and general symptoms were constructed. HPA-axis function was assessed by measuring 24-h urinary free cortisol (24-h UFC) excretion. Follow-up measurements were performed approximately 2 years later. All analyses were adjusted for age, gender, body mass index, smoking, alcohol use, depression, exercise frequency, and urinary volume. Regression analysis detected no cross-sectional association between 24-h UFC excretion and the number of FSS (beta=-0.021, t=-0.521, p=0.603). In addition, 24-h UFC excretion was not associated with any of the bodily system FSS clusters (all p>0.050). Furthermore, 24-h UFC excretion did not predict new-onset FSS in the 2-year follow-up period (beta=0.021, t=0.566, p=0.572). We conclude that this study does not provide evidence for an association between altered HPA-axis function, as indexed by 24-h UFC, and FSS in the general population. We conclude that this study does not provide evidence for an association between altered HPA-axis function, as indexed by 24-h UFC, and FSS in the general population.

Is high-sensitive C-reactive protein a biomarker for functional somatic symptoms? A population-based study

Functional somatic symptoms (FSS) are symptoms unexplained in terms of underlying organic pathology. Alterations in the immune system function may be associated with FSS via induction of sickness behavior. We aimed to investigate whether low-grade immune system activation is positively associated with FSS in a population-based cohort of 881 adults (46% male, mean age 53.0, SD 11.4). Participants completed the somatization section of the Composite International Diagnostic Interview surveying the presence of 43 FSS. Innate immune function was assessed by measuring high-sensitive C-reactive protein (hs-CRP). Follow-up measurements of hs-CRP and FSS were performed approximately 2years later. Regression analyses, with adjustments for gender, age, body mass index, anxiety, depression, smoking, alcohol use, and frequency of exercise, did not reveal a cross-sectional association (beta=0.01, t=0.40, p=0.693) or longitudinal association (beta=-0.03, t=-0.93, p=0.352) between hs-CRP and the total number of FSS. When examining different bodily clusters of FSS, hs-CRP was not associated with the gastrointestinal FSS cluster, but the association approached statistical significance for the general FSS cluster (OR 1.08, 95% CI 0.98-1.18) and musculoskeletal FSS cluster (OR 1.08, 95% CI 0.99-1.17). For the latter association, exploratory analyses revealed that mainly the pure musculoskeletal complaints were responsible (OR 1.12, 95% CI 1.03-1.21). We conclude that the level of hs-CRP is not a biomarker for the total number of FSS in the general population. The association between hs-CRP and musculoskeletal and general FSS needs further study.

Effects of adverse life events on heart rate variability, cortisol, and C-reactive protein

Our objective was to assess whether self‐reported adverse life events during childhood or over the lifespan are associated with altered activity of the autonomic nervous system (ANS), the hypothalamic‐pituitary‐adrenal axis (HPA axis), and the immune system.