Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients.

OBJECTIVE: Although the precise mechanisms are not yet understood, previous studies have suggested that chronic fatigue syndrome (CFS) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and trauma in early childhood. Consistent with findings suggesting that early life stress-induced DNA methylation changes may underlie dysregulation of the HPA axis, we previously found evidence for the involvement of glucocorticoid receptor (GR) gene (NR3C1) methylation in whole blood of CFS patients. METHODS: In the current study, we assessed NR3C1-1F region DNA methylation status in peripheral blood from a new and independent sample of 80 female CFS patients and 91 female controls. In CFS patients, history of childhood trauma subtypes was evaluated using the Childhood Trauma Questionnaire short form (CTQ-SF). RESULTS: Although absolute methylation differences were small, the present study confirms our previous findings of NR3C1-1F DNA hypomethylation at several CpG sites in CFS patients as compared to controls. Following multiple testing correction, only CpG_8 remained significant (DNA methylation difference: 1.3% versus 1.5%, p<0.001). In addition, we found associations between DNA methylation and severity of fatigue as well as with childhood emotional abuse in CFS patients, although these findings were not significant after correction for multiple testing. CONCLUSIONS: In conclusion, we replicated findings of NR3C1-1F DNA hypomethylation in CFS patients versus controls. Our results support the hypothesis of HPA axis dysregulation and enhanced GR sensitivity in CFS.

Cortisol and Subjective Stress Responses to Acute Psychosocial Stress in Fibromyalgia Patients and Control Participants.

OBJECTIVE: Hypothalamic-pituitary-adrenal axis dysfunction may play a role in fibromyalgia (FM) pathogenesis but it remains understudied in this disorder. Furthermore, early childhood adversities (ECA) are common in FM, but whether they moderate stress reactivity is unknown. Hence, we investigated cortisol and subjective responses to acute psychosocial stress in FM and controls, while adjusting for ECA. METHODS: Twenty-seven female FM patients and 24 age-matched female controls were recruited in a tertiary care center and through advertisements, respectively. The Childhood Trauma Questionnaire was used to measure ECA history. Salivary cortisol levels and subjective stress ratings were measured at multiple time points before and after the Trier Social Stress Test (TSST) was administered. RESULTS: Significant main effects of group [F(1,43) = 7.04, p = .011, lower in FM] and ECA [F(1,43) = 5.18, p = .028, higher in participants with ECA] were found for cortisol responses. When excluding controls with ECA (n = 5), a significant group-by-time interaction was found [F(6,39) = 2.60, p = .032], driven by a blunted response to the stressor in FM compared with controls (p = .037). For subjective stress responses, a significant main effect of group [F(1,45) = 10.69, p = .002, higher in FM] and a trend toward a group-by-time interaction effect [F(6,45) = 2.05, p = .078, higher in FM 30 minutes before and 30 and 75 minutes after the TSST, and impaired recovery (difference immediately after - 30 minutes after the TSST) in FM] were found. CONCLUSIONS: Blunted cortisol responsivity to the TSST was observed in FM patients compared with controls without ECA. FM patients had higher subjective stress levels compared with controls, particularly at baseline and during recovery from the TSST. In FM patients, ECA history was not associated with cortisol or subjective stress levels or with responsivity to the TSST. Future research should investigate the mechanisms underlying hypothalamic-pituitary-adrenal axis dysregulation in FM.

High prevalence of fatigue in adults with a 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with high phenotypic variability, including somatic disorders like congenital heart disease and psychiatric disorders such as schizophrenia, anxiety disorders, and mood disorders. Clinical observations suggest that many patients with 22q11.2DS suffer from severe fatigue. However, to the best of our knowledge, no previous study has investigated the potential association between 22q11.2DS and fatigue. Twenty-nine patients (mean age 26.8, 18-38 y) with 22q11.2DS completed the multidimensional fatigue inventory (MFI) measuring severity of fatigue. The results of the study group were compared with published population norms. In addition, cross-sectional associations between fatigue, depression (Beck Depression Inventory-BDI), and a quality of life questionnaire (WHO) in patients with 22q11.2 DS were examined. Subscales and total MFI scores were significantly higher in adults with 22q11.2DS. Approximately 80% of the study group had a total MFI score above the mean of the norms. A significant correlation between depressive symptoms and fatigue was found. Fatigue was also significantly associated with quality of life scores, specifically the general score, psychological health, and environment. This is the first report of high levels of fatigue in adults with the 22q11.2DS. Fatigue is a frequent complaint in this age group and should get the necessary attention given its association with quality of life and depression severity. Taking into account the multisystem nature of the 22q11.2DS, we recommend a systematic clinical examination to exclude underlying somatic or psychiatric causes of fatigue. © 2017 Wiley Periodicals, Inc.

Cognitive Alexithymia Mediates the Association Between Avoidant Attachment and Interpersonal Problems in Patients With Somatoform Disorder.

Patients with somatoform disorder (SFD) are characterized by the presence of chronic physical complaints that are not fully explained by a general medical condition or another mental disorder. Insecure attachment patterns are common in this patient group, which are often associated with interpersonal difficulties. In the present study, the mediational role of two types of alexithymia and negative affectivity (NA) was examined in the association between attachment styles and interpersonal problems in a group of 120 patients with SFD. Patients were requested to fill out several self-report questionnaires for the assessment of attachment strategies, alexithymia, NA, and interpersonal problems. Cognitive alexithymia (i.e., the inability to identify and verbalize emotions) mediated the relationship between avoidant attachment patterns and interpersonal problems, even after controlling for NA. Preliminary findings also suggested that NA acted as a moderator of the mediator cognitive alexithymia. These results have important implications for clinical practice, as this study clearly shows that interpersonal problems do not automatically follow from insecure attachment strategies, but are contingent upon alexithymic features. It is recommended to target alexithymic features in patients with SFD, particularly in the context of negative emotions. Therefore, cognitive alexithymia may be an important therapeutic focus, specifically in the treatment of avoidant ptients with SFD.

Self-critical perfectionism predicts lower cortisol response to experimental stress in patients with chronic fatigue syndrome.

OBJECTIVE: Previous studies have suggested that self-critical perfectionism (SCP) may play a role in the development and maintenance of Chronic Fatigue Syndrome (CFS). In this study we investigated whether SCP is related to a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis, which has been shown to be a key factor in the pathophysiology of CFS. METHOD: We conducted a quasi-experimental study to examine the association between SCP (as measured with the Depressive Experiences Questionnaire) and stress reactivity in a sample of 41 female CFS patients. Participants were exposed to the Trier Social Stress Test (TSST). Both subjective stress and salivary cortisol levels were measured until 90 min after the TSST. We also examined the relationship between stress reactivity and illness characteristics (i.e., duration and severity of symptoms). RESULTS: The results showed that SCP was associated with increased subjective stress reactivity, but with decreased HPA-axis reactivity as indicated by a blunted cortisol response to the TSST. Furthermore, we found an inverse relationship between cortisol reactivity and symptom severity. There was no relationship between cortisol reactivity and illness duration. CONCLUSION: Our findings suggest that SCP is associated with loss of resilience of the neurobiological stress response system in CFS.

Effects of early childhood trauma on hypothalamic-pituitary-adrenal (HPA) axis function in patients with Chronic Fatigue Syndrome.

BACKGROUND: There is a paucity of studies that have investigated the assumption that early childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction in Chronic Fatigue Syndrome (CFS). The current study is the first to simultaneously investigate relationships among early childhood trauma, cortisol activity, and cortisol stress reactivity to psychosocial stress in a sample of well-screened CFS patients. We also examined whether self-critical perfectionism (SCP) plays a mediating role in the potential relationship between early trauma and neurobiological stress responses. METHODS: A total of 40 female patients diagnosed with CFS were asked to provide morning saliva cortisol samples (after awakening, 30min later, and 1h later) for seven consecutive days as a measure of cortisol activity. In addition, patients were exposed to the Trier Social Stress Test, a well-validated stress test, to investigate the relationship between early childhood trauma and cortisol stress reactivity. Before the start of the study, patients completed the Childhood Trauma Questionnaire-Short form (CTQ-SF) as a measure of early childhood trauma (i.e. sexual, physical and emotional traumatic experiences). SCP was measured with the Depressive Experiences Questionnaire (DEQ). Data were analyzed by calculating several indices of cortisol secretion (i.e. Cortisol Awakening Response and Area Under the Curve). RESULTS: There was no association between early childhood trauma and cortisol as measured over the 7-day period. However, emotional neglect was significantly negatively related to cortisol reactivity in the TSST. SCP did not significantly mediate this association. CONCLUSION: Findings of this study suggest that emotional neglect is associated with blunted HPA axis reactivity, congruent with the assumption that CFS may reflect loss of adaptability of the neuroendocrine stress response system in at least a subgroup of patients.

Self-critical perfectionism predicts outcome in multidisciplinary treatment for chronic pain.

BACKGROUND: Self-critical perfectionistic personality features have been shown to influence the onset and perpetuation of pain symptoms. However, no study to date has investigated whether these personality features are associated with treatment response in chronic pain. METHODS: Using a naturalistic pre-post design, the present study examined the effect of self-critical perfectionism on treatment outcome in terms of self-reported pain. The study was conducted in a sample of 53 chronic non-cancer pain patients who followed Multidisciplinary Pain Education Program (MPEP), a brief, 2-week cognitive-behaviorally based psycho-educational intervention for chronic pain that was recently found to be effective in reducing pain severity. Pre- and post-treatment pain intensity levels were assessed with the visual analog scale of the McGill Pain Questionnaire-Short Form. RESULTS: Pretreatment self-critical perfectionism was significantly associated with negative treatment outcome, even after taking into account pretreatment levels of depression. CONCLUSION: Results suggest that self-critical perfectionistic personality features may negatively interfere with treatment response in patients with chronic pain. Thus, findings indicate that chronic pain patients with high levels of self-critical perfectionism may benefit less from brief interventions such as MPEP, and therefore may need more intensive and tailored treatment.

Hospitalization-based treatment for postpartum depressed mothers and their babies: rationale, principles, and preliminary follow-up data.

This paper describes the rationale and treatment principles of a mother-infant unit for severely depressed mothers and their infants in Flanders (Belgium). The unit integrates systemic, psychodynamic, and cognitive behavioral treatment approaches, and aims at improvements on three levels: (1) improving mood and interpersonal relationships in depressed mothers, (2) fostering a positive mother infant relationship, and (3) establishing a supportive environment outside the treatment setting for both mother and infant. In addition, we present preliminary data of a 3.5-year naturalistic follow-up study of postpartum depressed mothers (n = 41) admitted at this mother-infant unit between April 2003 and April 2005. Results showed that at 3.5-year follow-up a considerable subgroup of mothers (61%) were functioning relatively well, as indicated by low levels of depressive symptoms, anxiety and anger, negative affect, and relatively high levels of positive affect. Yet, in line with other studies, a relatively large subgroup of mothers (39%) continued to suffer from (severe) depression during follow-up. Using a Life History Calendar method, it was found that, compared to currently nondepressed mothers, mothers who were depressed at follow-up did not have more depressive episodes but had longer depressive episodes, received more psychotherapy after hospitalization, and experienced more negative life events during the 3.5-year follow-up period. Implications of these findings for future research and intervention strategies in postpartum depression are discussed.

The prevalence and impact of early childhood trauma in Chronic Fatigue Syndrome.

BACKGROUND: Although some studies have found high rates of early childhood trauma in Chronic Fatigue Syndrome (CFS), the role of early trauma in this condition remains controversial. METHODS: This study examined the prevalence of early childhood trauma and its impact on daily fatigue and pain levels over a 14-day period in a sample of 90 carefully screened CFS patients using a diary method approach. Data were analyzed using multilevel analysis. RESULTS: More than half of the patients (54.4%) had experienced at least one type of early trauma, with the majority of these patients reporting multiple traumas. Prevalence rates were particularly high for emotional trauma (i.e., emotional abuse and/or emotional neglect) (46.7%). Moreover, total trauma scores and emotional abuse significantly predicted higher levels of daily fatigue and pain over the 14-day period, even when controlling for demographic features and depressed mood. CONCLUSIONS: This is the first study to demonstrate that early childhood trauma predicts increasing levels of core symptoms of CFS in the daily flow of life. Moreover, findings of this study suggest that emotional trauma may be particularly important in CFS.

Prevalence of DSM-IV personality disorders in patients with chronic fatigue syndrome: a controlled study.

BACKGROUND: It is not yet clear whether chronic fatigue syndrome (CFS) is associated with elevated levels of personality disorders. PURPOSE: This study aims to determine the prevalence of DSM-IV axis II personality disorders among patients with CFS. METHODS: We examined the prevalence of personality disorders in a sample of 92 female CFS patients and in two well-matched control groups, i.e., normal community individuals (N = 92) and psychiatric patients (N = 92). Participants completed the assessment of DSM-IV personality disorders questionnaire (ADP-IV), which yields a categorical and dimensional evaluation of personality disorder features. RESULTS: The prevalence of personality disorders in CFS patients (16.3 %) was significantly lower than in psychiatric patients (58.7 %) and was similar to that in the community sample (16.3 %). Similar results were found for dimensional and pseudodimensional scores, except for the Depressive (DE) and Obsessive-Compulsive Personality Disorder (O-C) subscales. Patients with CFS had significantly higher levels of DE features compared to normal controls and similar dimensional scores on the O-C scale compared to psychiatric controls. CONCLUSIONS: Although the CFS sample was characterized by depressive and obsessive-compulsive personality features, this study provides no evidence for the assumption that these patients generally show a higher prevalence of axis II pathology. Given the conflicting findings in this area, future studies using multiple measures to assess personality disorders in CFS are needed to substantiate these findings.

Multidisciplinary pain education program (MPEP) for chronic pain patients: preliminary evidence for effectiveness and mechanisms of change.

OBJECTIVE: There is a need for effective brief interventions in chronic pain patients, and the identification of mechanisms of change. METHOD: In the present study, we tested the effectiveness of MPEP (Multidisciplinary Pain Education Program), a very brief, four-session cognitive-behaviorally based psycho-educational intervention for chronic pain using a pre-and post-test design. In addition, pre- to post-treatment change scores were calculated to investigate factors associated with change in pain. Participants of the study were 53 patients with chronic non-cancer pain. Primary outcome measures were (1) pain severity, (2) health perception, and (3) severity of depression. Secondary outcome measures included factors that have been implicated in the maintenance of chronic pain and that might be associated with worse treatment outcome: (1) catastrophizing, (2) kinesiophobia, and (3) action-proneness. RESULTS: Findings provided preliminary evidence for the effectiveness of MPEP in that patients showed significant and clinically meaningful improvements in pain symptoms (F = 24.503, p < 0.001, d = 0.59) and action-proneness (F = 178.504, p < 0.001, d = 1.95), and small improvements in health perception (F = 7.116, p < 0.05, d = 0.30). Furthermore, results showed that changes in catastrophizing (ß = -0.455, p = 0.001) and severity of depression (ß = -0.300, p < 0.05) were independently and significantly associated with changes in pain. However, changes in health perception, kinesiophobia, and action-proneness were not significantly associated with changes in pain (ß = 0.203, ns; ß = 0.003, ns; and ß = 0.154, ns, respectively). Importantly, duration of chronic pain was not related to treatment outcome (ß = 0.070, ns). CONCLUSIONS: Overall, this study provides preliminary evidence for the effectiveness of MPEP and possible mechanisms through which MPEP is effective. Yet, further research is needed to investigate the efficacy of MPEP.

Self-esteem mediates the relationship between maladaptive perfectionism and depression in chronic fatigue syndrome.

Patients with chronic fatigue syndrome (CFS) often experience depression which may negatively affect prognosis and treatment outcome. Research has shown that depression in CFS is associated with maladaptive or self-critical perfectionism. However, currently, little is known about factors that may explain this relationship, but studies in nonclinical samples suggest that low self-esteem may be an important mediator of this relationship. The present study therefore examined whether self-esteem mediated the cross-sectional association between maladaptive perfectionism and severity of depression in 192 patients meeting Centres for Disease Control and Prevention criteria for CFS. Patients completed self-report measures of maladaptive perfectionism, self-esteem, depression, and fatigue. Regression analyses and more direct tests of indirect effects (i.e., the Sobel test and bootstrapping) were used to test for mediation. Congruent with expectations, we found that self-esteem fully mediated the relationship between maladaptive perfectionism and depression in CFS. Findings from this study suggest that self-esteem may explain the link between maladaptive perfectionism and depression in CFS, which may have important implications for the treatment and prevention of depression in these patients.

Self-critical perfectionism, stress generation, and stress sensitivity in patients with chronic fatigue syndrome: relationship with severity of depression.

Chronic Fatigue Syndrome (CFS) is a highly disabling disorder that is part of a broader spectrum of chronic pain and fatigue disorders. Although the etiology and pathogenesis of CFS largely remain unclear, there is increasing evidence that CFS shares important pathophysiological disturbances with mood disorders in terms of disturbances in the stress response and the stress system. From a psycho-dynamic perspective, self-critical perfectionism and related personality factors are hypothesized to explain in part impairments of the stress response in both depression and CFS. Yet, although there is ample evidence that high levels of self-critical perfectionism are associated with stress generation and increased stress sensitivity in depression, evidence supporting this hypothesis in CFS is currently lacking. This study therefore set out to investigate the relationship between self-critical perfectionism, the active generation of stress, stress sensitivity, and levels of depression in a sample of 57 patients diagnosed with CFS using an ecological momentary assessment approach. Results showed, congruent with theoretical assumptions, that self-critical perfectionism was associated with the generation of daily hassles, which in turn predicted higher levels of depression. Moreover, multilevel analyses showed that self-critical perfectionism was related to increased stress sensitivity in CFS patients over a 14-day period, and that increased stress sensitivity in turn was related to increased levels of depression. The implications of these findings for future research and particularly for the development of psychodynamic treatment approaches of CFS and related conditions are discussed.

Was Freud partly right on obsessive-compulsive disorder (OCD)? Investigation of latent aggression in OCD.

Inflated responsibility is increasingly regarded a pathogenetic mechanism in obsessive-compulsive disorder (OCD). In seeming contrast, there is mounting evidence that latent aggression is also elevated in OCD. Building upon psychodynamic theories that an altruistic façade including exaggerated concerns for others is partly a defense against latent aggression, evidence was recently obtained for high interpersonal ambivalence in OCD patients relative to psychiatric and healthy controls using a newly developed instrument entitled the Responsibility and Interpersonal Behaviors and Attitudes Questionnaire (RIBAQ). A total of 46 OCD patients and 23 healthy participants took part in the present study. OCD patients displayed a higher social responsibility than controls. At the same time, patients also disclosed more latent aggression/calculating behavior and interpersonal distrust. While the pathogenic role of latent aggression is still not fully uncovered, it may deserve more consideration in treatment in view of frequent tensions in the families of OCD patients. Longitudinal studies with at-risk sample are needed to assess the relationship between problems with anger expression as well as (exaggerated) moral standards in OCD.

Unraveling the role of perfectionism in chronic fatigue syndrome: is there a distinction between adaptive and maladaptive perfectionism?

In the current study, we investigated whether the distinction between adaptive (i.e. high personal standards) and maladaptive (i.e. concern over mistakes and doubt about actions) perfectionism that has been found in the literature, is also valid in patients with chronic fatigue syndrome (CFS). We hypothesized that maladaptive, but not adaptive, perfectionism would be significantly and positively related to severity of fatigue and depression in CFS. We examined this hypothesis in a sample of 192 CFS patients using structural equation modelling (SEM). Although the two perfectionism dimensions were related to each other, results supported a model in which only maladaptive perfectionism was positively related to severity of fatigue and depression. Further, we found that depression fully mediated the effect of maladaptive perfectionism on fatigue. The results suggest that adaptive and maladaptive perfectionism are two distinct, albeit related, dimensions in CFS. Findings of this study have important implications for theory and treatment of CFS, particularly for cognitive-behavioral treatment.

Psychiatric aspects of chronic fatigue syndrome and fibromyalgia.

Chronic fatigue syndrome and/or fibromyalgia (CFS/FM) consists of highly overlapping, medically unexplained symptoms, including long-lasting fatigue, effort intolerance, cognitive dysfunction, and widespread pain and tenderness. CFS/FM often seems to be triggered by infections and physical trauma, but depression, sleep disturbances, and personality may also be involved. Moreover, dysregulation of the stress system, the immune system, and central pain mechanisms may determine the pathophysiology of the illness, leading to a loss of capacity to adapt to all kind of stressors. CFS/FM patients can be best helped by a pragmatic and individualized approach aimed at adjusting lifestyle and optimizing self-care, which in the long run may contribute to a restoration of physical and mental adaptability. Future psychiatric research into CFS/FM should focus on the complex interrelationships among pain/fatigue, stress/depression, and personality, as well as on processes of therapeutic change and the advantages of customized treatment.

Predictors of outcome in a multi-component treatment program for chronic fatigue syndrome.

BACKGROUND: Little is known about factors predicting treatment outcome in chronic fatigue syndrome (CFS). METHODS: Based on Vercoulen et al.'s (1998) cognitive-behavioral model of perpetuating factors in CFS, the predictive value of the following patient characteristics were examined in a sample of 178 CFS patients who followed a multi-component treatment program: (1) somatic attributions, (2) psychological attributions, (3) sense of control over symptoms, (4) physical activity, (5) functional impairment, (6) somatic focus, and (7) severity of depression. RESULTS: Only pre-treatment severity of depression was associated with negative treatment outcome defined in terms of post-treatment fatigue and improvement in fatigue. LIMITATIONS: The study was conducted at a tertiary care centre and did not include a control group or a long-term follow-up. CONCLUSIONS: Level of depression may be the most important factor of the cognitive-behavioral model predicting post-treatment fatigue in CFS. Hence, findings suggest that treatment of CFS should include a focus on severity of depression.

Stability and change in levels of depression and personality: a follow-up study of postpartum depressed mothers that were hospitalized in a mother-infant unit.

This prospective longitudinal study investigated the role of the personality dimensions of dependency and self-criticism in the course of depressive symptoms in a sample of inpatient severely postpartum depressed mothers (n = 55). Depressive symptoms and personality were measured during hospitalization and on average 3 1/2 years later. In line with previous research, a considerable subgroup of mothers (39%) reported moderate to severe symptoms of depression at time 2. In addition, although these mothers did not exhibit more depressive episodes during follow-up period compared with mothers with a less chronic course of depression, their depressive episodes were considerably longer, and they had higher levels of severity of depression as well as of dependency and self-criticism at Time 1. Finally, self-criticism, but not dependency, assessed at Time 1, predicted both depression diagnosis and levels of depression at follow-up, supporting a vulnerability model positing that self-criticism confers vulnerability for depression over time.

A comparison of patients with chronic fatigue syndrome in two "ideologically" contrasting clinics.

Aim of the present study was to compare chronic fatigue syndrome (CFS) patients, attending 2 "ideologically" contrasting clinics for CFS, on various patient and illness characteristics. Fifty-nine CFS patients of each clinic, located in Leuven and Brussels (Belgium), participated. Patients did not differ with regard to age, levels of fatigue, psychopathology, and self-efficacy. However, patients from the psychosocially-oriented clinic had a lower level of education, reported more progressive illness onset, and attributed their illness more to psychological causes. Patients in the biologically-oriented clinic reported more pain, and showed higher levels of social functioning, motivation and vitality, as well as fewer limitations related to emotional problems. It is concluded that CFS patients attending the 2 clinics could not be distinguished along dualistic biological/psychosocial lines, but those reporting sudden illness onset and making somatic attributions were more likely to be represented in the biologically-oriented clinic.

Treatment of chronic fatigue syndrome: findings, principles and strategies.

Chronic fatigue syndrome (CFS) is a debilitating condition characterized by serious medically unexplained mental and physical fatigue. The high prevalence and both direct and indirect health costs of CFS patients represent a huge problem for contemporary health care. Moreover, the prognosis of CFS, even when treated, is often poor. In this paper, we first critically review current evidence based treatments of CFS. Second, we discuss the growing insights into the etiopathogenesis of CFS, and the need to translate and integrate these insights into future treatments. In particular, we formulate a pragmatic and empirically testable treatment approach, tailored to the individual needs of patients, which aims at restoring the mental and physical equilibrium of CFS patients by trying to bring about sustained life style changes.