Karin A.M. Janssens

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.

Mood and Anxiety Disorders in Chronic Fatigue Syndrome, Fibromyalgia, and Irritable Bowel Syndrome : Results From the LifeLines Cohort Study

Objective Functional somatic syndromes (FSSs) have often been linked to psychopathology. The aim of the current study was to compare prevalence rates of psychiatric disorders among individuals with chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS). Methods This study was conducted in 94,516 participants (mean [standard deviation] age = 44.6 [12.5] years, 58.7% women) of the general-population cohort LifeLines. FSSs were assessed by self-reports. Mood disorders (i.e., major depressive disorder and dysthymia) and anxiety disorders (i.e., generalized anxiety disorder, social phobia, panic disorder with/without agoraphobia, and agoraphobia) were assessed by means of the Mini International Neuropsychiatric Interview. Risks on psychiatric disorders were compared for individuals with CFS, FM, and IBS by using logistic regression analyses adjusted for age and sex. Results Prevalence rates of CFS, FM, and IBS were 1.3%, 3.0%, and 9.7%, respectively. Individuals with CFS, FM, and IBS had significantly more mood (odds ratios [ORs] = 1.72–5.42) and anxiety disorders (ORs = 1.52–3.96) than did individuals without FSSs, but prevalence rates were low (1.6%–28.6%). Individuals with CFS more often had mood (ORs = 2.00–4.08) and anxiety disorders (ORs = 1.63–2.32) than did individuals with FM and IBS. Major depressive disorder was more common in FM than in IBS (OR = 1.58, 95% confidence interval = 1.24–2.01), whereas these groups did not differ on dysthymia or anxiety disorders. Conclusions Mood and anxiety disorders are more prevalent in individuals with FSSs, and particularly CFS, than in individuals without FSSs. However, most individuals with FSSs do not have mood or anxiety disorders.

Functional limitations in functional somatic syndromes and well-defined medical diseases. Results from the general population cohort LifeLines.

OBJECTIVE Functional somatic syndromes (FSS), defined as physical syndromes without known underlying organic pathology, are sometimes regarded as less serious conditions than well-defined medical diseases (MD). The aims of this study were to evaluate functional limitations in FSS, and to compare the results to MD patients with the same core symptoms. METHODS This study was performed in 89,585 participants (age: 44.4±12.4 years, 58.5% female) of the general-population cohort LifeLines. Quality of Life (QoL) and work participation were examined as indicators of functional limitations. QoL was assessed with two summary scales of the RAND-36: the physical component summary (PCS) and the mental component summary (MCS). Work participation was assessed with a self-reported questionnaire. QoL and work participation were compared between FSS and MD patients, using Chi-squared tests and ANCOVA-analyses, adjusted for age, sex, educational level, and mental disorders. RESULTS Of the participants, 11.0% (n=9861) reported a FSS, and 2.7% (n=2395) reported a MD. Total QoL, PCS and MCS were significantly lower in all separate FSS and MD compared to controls (P≤.001). Clinically relevant differences in QoL were found between chronic fatigue syndrome and multiple sclerosis patients, and between fibromyalgia syndrome and rheumatoid arthritis patients. Compared to controls, FSS and MD patients reported a comparably reduced working percentage, increased sick absence, early retirement due to health-related reasons, and disability percentage (P≤.001). CONCLUSION Functional limitations in FSS patients are common, and as severe as those in patients with MD when looking at QoL and work participation, emphasizing that FSS are serious health conditions.

Individual variation in temporal relationships between stress and functional somatic symptoms.

OBJECTIVE Medically unexplained or functional somatic symptoms (FSSs) constitute a major health problem because of their high prevalence and the suffering and disability they cause. Psychosocial stress is widely believed to be a precipitating or perpetuating factor, yet there is little empirical evidence to support this notion. Prior studies mainly focused on comparing groups, which has resulted in the obscuring of temporal complexity and individual differences. The aim of this study is to elucidate the relationship between stress and FSSs over time within individual patients. METHODS Twenty patients (17 females, ages 29-59) with multiple, persistent FSSs were included in the study. They used electronic diaries to report stress and FSSs twice daily over the course of 12 weeks. For each individual data set, Vector autoregressive (VAR) modelling was used to investigate possible associations between daily average stress and FSSs scores. RESULTS In six subjects (30%), an increase in stress was followed by an increase in one or more FSSs. In three subjects (15%), an increase in FSSs was followed by an increase in stress. Additionally, negative and mixed associations were found. Only two subjects (10%) showed no cross-lagged association between stress and FSSs in either direction. We did not find specific types of symptoms to be more stress-related than others. CONCLUSION Although stress does not seem to be a universal predictor of FSSs, an increase in stress precedes an increase in symptoms in some individuals. Identifying these individuals using time-series analysis might contribute to a more patient-tailored treatment.

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.

How to assess stress biomarkers for idiographic research

Associations between stress-related biomarkers, like cortisol or catecholamines, and somatic or psychological symptoms have often been examined at the group level. Studies using this nomothetic approach reported equivocal findings, which may be due to high levels of intra-individual variance of stress biomarkers. More importantly, analyses at the group level provide information about the average patient, but do not necessarily have meaning for individual patients. An alternative approach is to examine data at the level of individual patients in so-called idiographic research. This method allows identifying individuals in whom symptoms are explained by preceding alterations in specific stress biomarkers, based on time series of symptoms and stress biomarkers. To create time series of sufficient length for statistical analysis, many subsequent stress biomarker measurements are needed for each participant. In the current paper, different matrices (i.e. saliva, urine, nail and hair) are discussed in light of their applicability for idiographic research. This innovative approach might lead to promising new insights in the association between stress biomarkers and psychological or somatic symptoms. New collection tools for stress biomarkers, like the use of sweat pads, automated microdialysis systems, dried blood spots, or smartphone applications, might contribute to the feasibility and implementation of idiographic research in the future.

Psychological Interventions for Children with Functional Somatic Symptoms: A Systematic Review and Meta-Analysis

OBJECTIVE To analyze the effectiveness of psychological treatments on symptom load and associated disability in children with functional somatic symptoms, and to explore potential moderators of effects. STUDY DESIGN Cochrane, PubMed, PsycINFO, EMBASE, and CINAHL were searched for randomized controlled trials published in peer-reviewed journals. Randomized controlled trials studying the effect of a psychological treatment on symptom load and disability in children with functional somatic symptoms were selected. Data on symptom load, disability, and school absence directly post-treatment and at follow-up were extracted by 2 assessors. Studies were appraised with the Cochrane risk of bias tool. Standardized mean differences were pooled in a random-effects model. Heterogeneity in effect-sizes was explored by use of meta-regressions. PROSPERO Registration ID: CRD42015029667. RESULTS Out of 4098 identified records, 27 studies were included in this review of which 21 were included in meta-analyses. Psychological treatments reduced symptom load (Hedges g = -0.61), disability (Hedges g = -0.42), and school absence (Hedges g = -0.51) post-treatment in children suffering from various functional somatic symptoms. Effects were maintained at follow-up. Type and duration of symptoms, age, and treatment dose did not explain heterogeneity in effect-sizes between studies. Effect-sizes should be interpreted with caution because of the variety in outcome measures, unexplained heterogeneity in found effects and potential publication bias. CONCLUSIONS Psychological interventions reduce symptom load, disability, and school absence in children with functional somatic symptoms. Future research should clarify which patient and treatment characteristics modify outcomes.

PROFSS: A screening tool for early identification of functional somatic symptoms

OBJECTIVE To develop and validate a brief screening tool for predicting functional somatic symptoms (FSS) based on clinical and non-clinical information from the general practitioner referral letter, and to assess its inter-rater reliability. METHODS The derivation sample consisted of 357 consecutive patients referred to an internal outpatient clinic by their general practitioner. Referral letters were scored for candidate predictors for the main outcome measure, which was a final diagnosis of FSS made by the internist. Logistic regression identified the following independent predictors: type of symptoms, somatic and psychiatric comorbidity, absence of abnormal physical findings by the general practitioner, previous specialist consultation, and the use of illness terminology. Temporal validation was performed in a cohort of 94 consecutive patients in whom predictors were scored by two independent raters. RESULTS In both the derivation and validation sample, the discriminatory power of the model was good with areas under the receiver operating characteristic curves of 0.84 (95%confidence interval: 0.80-0.88) after bootstrapping and 0.82 (95%confidence interval: 0.73-0.91), respectively. Calibration of the models was excellent in both samples and the interobserver agreement in the validation sample was very good (intraclass coefficient: 0.82 (95%confidence interval: 0.75-0.88)). Based on this model, we constructed the brief screening tool PROFSS (Predicted Risk Of Functional Somatic Symptoms). PROFSS identified patient groups with risks of FSS ranging from 17% (95%CI: 10-26%) to 92% (95%CI:86-96%). CONCLUSION The presence of FSS can be predicted with the brief screening tool PROFSS, based on a limited set of items present in the general practitioner referral letter.

Vitamin and mineral status in chronic fatigue syndrome and fibromyalgia syndrome: A systematic review and meta-analysis

Background Many chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) patients (35–68%) use nutritional supplements, while it is unclear whether deficiencies in vitamins and minerals contribute to symptoms in these patients. Objectives were (1) to determine vitamin and mineral status in CFS and FMS patients as compared to healthy controls; (2) to investigate the association between vitamin and mineral status and clinical parameters, including symptom severity and quality of life; and (3) to determine the effect of supplementation on clinical parameters. Methods The databases PubMed, EMBASE, Web of Knowledge, and PsycINFO were searched for eligible studies. Articles published from January 1st 1994 for CFS patients and 1990 for FMS patients till March 1st 2017 were included. Articles were included if the status of one or more vitamins or minerals were reported, or an intervention concerning vitamins or minerals was performed. Two reviewers independently extracted data and assessed the risk of bias. Results A total of 5 RCTs and 40 observational studies were included in the qualitative synthesis, of which 27 studies were included in the meta-analyses. Circulating concentrations of vitamin E were lower in patients compared to controls (pooled standardized mean difference (SMD): -1.57, 95%CI: -3.09, -0.05; p = .042). However, this difference was not present when restricting the analyses to the subgroup of studies with high quality scores. Poor study quality and a substantial heterogeneity in most studies was found. No vitamins or minerals have been repeatedly or consistently linked to clinical parameters. In addition, RCTs testing supplements containing these vitamins and/or minerals did not result in clinical improvements. Discussion Little evidence was found to support the hypothesis that vitamin and mineral deficiencies play a role in the pathophysiology of CFS and FMS, and that the use of supplements is effective in these patients. Registration Study methods were documented in an international prospective register of systematic reviews (PROSPERO) protocol, registration number: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015032528.

Are Cardiac Autonomic Nervous System Activity and Perceived Stress Related to Functional Somatic Symptoms in Adolescents? The TRAILS Study

Objective Stressors have been related to medically insufficiently explained or functional somatic symptoms (FSS). However, the underlying mechanism of this association is largely unclear. In the current study, we examined whether FSS are associated with different perceived stress and cardiac autonomic nervous system (ANS) levels during a standardized stressful situation, and whether these associations are symptom-specific. Methods We examined 715 adolescents (16.1 years, 51.3% girls) from the Dutch cohort study Tracking Adolescents’ Individual Lives Sample during the Groningen Social Stress Test (GSST). FSS were assessed by the Youth Self-Report, and clustered into a cluster of overtiredness, dizziness and musculoskeletal pain and a cluster of headache and gastrointestinal symptoms. Perceived stress levels (i.e. unpleasantness and arousal) were assessed by the Self-Assessment Manikin, and cardiac ANS activity by assessing heart rate variability (HRV-HF) and pre-ejection period (PEP). Perceived stress and cardiac ANS levels before, during, and after the GSST were studied as well as cardiac ANS reactivity. Linear regression analyses were used to examine the associations. Results Perceived arousal levels during (beta = 0.09, p = 0.04) and after (beta = 0.07, p = 0.047) the GSST, and perceived unpleasantness levels before (beta = 0.07, p = 0.048) and during (beta = 0.12, p = 0.001) the GSST were related to FSS during the past couple of months. The association between perceived stress and FSS was stronger for the FSS cluster of overtiredness, dizziness and musculoskeletal pain than for the cluster of headache and gastrointestinal symptoms. Neither ANS activity levels before, during, and after the GSST, nor maximal HF-HRV and PEP reactivity were related to FSS. Conclusions This study suggests that perceived stress levels during social stress are related to FSS, whereas cardiac ANS activity and reactivity are not related to FSS.