Filip Van Den Eede

Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression

Dysregulation of the hypothalamic-pituitary-adrenal axis, one of the stress-response systems, is one of the key neurobiological features of major depression (MDD). Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in MDD come from a multitude of studies demonstrating nonsuppression of cortisol secretion following administration of the synthetic glucocorticoid dexamethasone. We examined whether genetic variations in the glucocorticoid receptor gene (Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1) could be associated with increased susceptibility for MDD using a whole gene-based association analysis of single nucleotide polymorphisms (SNPs). Four SNPs were identified in NR3C1 and genotyped in two well-diagnosed samples of patients with MDD ascertained in Belgium and northern Sweden, and matched control samples. In total, 314 MDD patients and 354 control individuals were included in the study. In the Belgian sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with an SNP in the promoter region (NR3C1-1); in the Swedish sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with the R23K SNP. The haplotype association studies showed modest evidence for an involvement of the 5′ region of the NR3C1 gene in the genetic vulnerability for MDD. This study suggests that polymorphisms in the 5′ region of the NR3C1 gene may play a role in the genetic vulnerability for MDD.

Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome

There is evidence for a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in a proportion of the patients with chronic fatigue syndrome (CFS), despite the negative studies and methodological difficulties. In this review, we focus on challenge studies and on the role of the HPA axis in the pathogenesis of CFS. Mild hypocortisolism, blunted adrenocorticotropin response to stressors and enhanced negative feedback sensitivity to glucocorticoids are the main findings. Several underlying mechanisms have been proposed. Currently, it is a matter of debate whether these disturbances have a primary role in the pathogenesis of CFS. However, even if the HPA axis dysfunctions are secondary to other factors, they are probably a relevant factor in symptom propagation in CFS.

Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a 'crash' in the stress system?

The etiopathogenesis of chronic fatigue syndrome (CFS) remains poorly understood. Although neuroendocrine disturbances - and hypothalamic-pituitary-adrenal (HPA) axis hypofunction in particular - have been found in a large proportion of CFS patients, it is not clear whether these disturbances are cause or consequence of the illness. After a review of the available evidence we hypothesize that that HPA axis hypofunction in CFS, conceptualized within a system-biological perspective, primarily reflects a fundamental and persistent dysregulation of the neurobiological stress system. As a result, a disturbed balance between glucocorticoid and inflammatory signaling pathways may give rise to a pathological cytokine-induced sickness response that may be the final common pathway underlying central CFS symptoms, i.e. effort/stress intolerance and pain hypersensitivity. This comprehensive hypothesis on HPA axis hypofunction in CFS may stimulate diagnostic refinement of the illness, inform treatment approaches and suggest directions for future research, particularly focusing on the neuroendocrine-immune interface and possible links between CFS, early and recent life stress, and depression.

Corticotropin-releasing factor-binding protein, stress and major depression

Major depressive disorder (MDD) is characterized by a dysregulation of the stress response system. A corticotropin-releasing factor (CRF) hyperdrive is a consistent and well-documented finding. CRF-binding protein (CRF-BP) may play a role in the pathogenesis of MDD. CRF-BP reduces the availability of CRF by binding free CRF and inhibits CRF function at the pituitary level. Moreover, CRF-BP expression increases in the pituitary and amygdala in response to acute stress, providing an additional feedback mechanism to maintain the homeostasis of the stress response. There are different regulatory elements of the expression of CRF-BP gene that are implicated in the pathophysiology of MDD, including CRF, glucocorticoids, cytokines and estrogens. A specific haplotype within the CRF-BP gene has been associated with MDD, but confirmation of this finding is necessary. Currently, the possible role of CRF-BP in the pathophysiology of conditions that have been associated with a hypofunction of the CRF system and immune dysfunctions is unclear. Implications of the function of CRF-BP for therapeutic strategies in MDD are being discussed. An important advantage of ligands that target CRF-BP is that concentrations of free CRF can be altered without acting directly on the transmission of CRF through its receptor.

Use of the Temperament and Character Inventory (TCI) for Assessment of Personality in Chronic Fatigue Syndrome

BACKGROUND Chronic fatigue syndrome (CFS) is characterized by severe and prolonged fatigue, along with a set of nonspecific symptoms and signs, such as sore throat, muscle pain, headaches, and difficulties with concentration or memory. OBJECTIVE The study examined whether CFS is associated with specific dimensions of Cloningers psychobiological model of personality. METHOD Personality profiles were compared between 38 CFS patients and 42 control subjects by means of the Temperament and Character Inventory (TCI). RESULTS The CFS group showed significantly higher scores on Harm-Avoidance and Persistence. CONCLUSION The current study shows a significant association between specific personality characteristics and CFS. These personality traits may be implicated in the onset and/or perpetuation of CFS and may be a productive focus for psychotherapy.

Turning the pink cloud grey: Dampening of positive affect predicts postpartum depressive symptoms

OBJECTIVE Maladaptive response styles to negative affect have been shown to be associated with prospective (postpartum) depression. Whether maladaptive styles to positive affect are also critically involved is understudied, even though anhedonia (a correlate of low positive affectivity) is a cardinal symptom of depression. The present study is the first to investigate the predictive value of cognitive response styles to both negative (depressive rumination) and positive affect (dampening) for postpartum depressive symptoms. METHODS During the third trimester of pregnancy, 210 women completed self-report instruments assessing depression (symptom severity and current and/or past episodes) and scales gauging the presence of depressive rumination and dampening. Of these women, 187 were retained for postpartum follow-up, with depressive symptoms being reassessed at 12 (n=171) and 24 (n=176) weeks after delivery. RESULTS Regression analyses showed that higher levels of dampening of positive affect during pregnancy predicted higher levels of depressive symptoms at 12 and 24 weeks postpartum, irrespective of initial symptom severity, past history of depression and levels of rumination to negative affect. Prepartum trait levels of rumination, however, did not predict postpartum symptomatology when controlled for baseline symptoms and history of major depressive episode(s). CONCLUSIONS The results of this investigation suggest that the way women cognitively respond to positive affect contributes perhaps even more to the development of postpartum depression than maladaptive response styles to negative affect.

Dissociative symptoms and sleep parameters — an all-night polysomnography study in patients with insomnia

BACKGROUND Dissociative disorders encompass a range of symptoms varying from severe absent-mindedness and memory problems to confusion about ones own identity. Recent studies suggest that these symptoms may be the by-products of a labile sleep-wake cycle. METHODS In the current study, we explored this issue in patients suffering from insomnia (N=46). We investigated whether these patients have raised levels of dissociative symptoms and whether these are related to objective sleep parameters. Patients stayed for at least one night in a specialized sleep clinic, while sleep EEG data were obtained. In addition, they completed self-report measures on dissociative symptoms, psychological problems, and sleep characteristics. RESULTS Dissociative symptom levels were elevated in patients suffering from insomnia, and were correlated with unusual sleep experiences and poor sleep quality. Longer REM sleep periods and less time spent awake during the night were predictive of dissociation. CONCLUSIONS This is the first study to show that insomnia patients have raised dissociative symptom levels and that their dissociative symptoms are related to objective EEG parameters. These findings are important because they may inspire sleep-related treatment methods for dissociative disorders.

Interpersonal violence against children in sport in the Netherlands and Belgium

The current article reports on the first large-scale prevalence study on interpersonal violence against children in sport in the Netherlands and Belgium. Using a dedicated online questionnaire, over 4,000 adults prescreened on having participated in organized sport before the age of 18 were surveyed with respect to their experiences with childhood psychological, physical, and sexual violence while playing sports. Being the first of its kind in the Netherlands and Belgium, our study has a sufficiently large sample taken from the general population, with a balanced gender ratio and wide variety in socio-demographic characteristics. The survey showed that 38% of all respondents reported experiences with psychological violence, 11% with physical violence, and 14% with sexual violence. Ethnic minority, lesbian/gay/bisexual (LGB) and disabled athletes, and those competing at the international level report significantly more experiences of interpersonal violence in sport. The results are consistent with rates obtained outside sport, underscoring the need for more research on interventions and systematic follow-ups, to minimize these negative experiences in youth sport.

Chronic Fatigue Syndrome and DNA Hypomethylation of the Glucocorticoid Receptor Gene Promoter 1F Region: Associations With Hypothalamic-Pituitary-Adrenal Axis Hypofunction and Childhood Trauma

Objectives Chronic fatigue syndrome (CFS) has been associated with hypothalamic-pituitary-adrenal axis hypofunction and enhanced glucocorticoid receptor (GR) sensitivity. In addition, childhood trauma is considered a major risk factor for the syndrome. This study examines DNA methylation of the GR gene (NR3C1) in CFS and associations with childhood sexual and physical trauma. Methods Quantification of DNA methylation within the 1F promoter region of NR3C1 was performed in 76 female patients (46 with no/mild and 30 with moderate/severe childhood trauma) and 19 healthy controls by using Sequenom EpiTYPER. Further, we examined the association of NR3C1-1F promoter methylation with the outcomes of the low-dose (0.5 mg) dexamethasone/corticotropin-releasing factor test in a subset of the study population. Mann-Whitney U tests and Spearman correlations were used for statistical analyses. Results Overall NR3C1-1F DNA methylation was lower in patients with CFS than in controls. After cytosine guanine dinucleotide (CpG)-specific analysis, CpG_1.5 remained significant after Bonferroni correction (adjusted p = .0014). Within the CFS group, overall methylation (&rgr; = 0.477, p = .016) and selective CpG units (CpG_1.5: &rgr; = 0.538, p = .007; CpG_12.13: &rgr; = 0.448, p = .025) were positively correlated with salivary cortisol after dexamethasone administration. There was no significant difference in NR3C1-1F methylation between traumatized and nontraumatized patients. Conclusions We found evidence of NR3C1 promoter hypomethylation in female patients with CFS and the functional relevance of these differences was consistent with the hypothalamic-pituitary-adrenalaxis hypofunction hypothesis (GR hypersuppression). However, we found no evidence of an additional effect of childhood trauma on CFS via alterations in NR3C1 methylation.

Single nucleotide polymorphism analysis of corticotropin-releasing factor-binding protein gene in recurrent major depressive disorder

Corticotropin-releasing factor-binding protein (CRF-BP) regulates the availability of free CRF and is a functional candidate gene for affective disorders. Previous research showed an association between polymorphisms in the CRF-BP gene and recurrent major depression (MDD) in a Swedish sample. The purpose of the current study was to re-evaluate the previous findings in an extended Swedish sample and in an independent Belgian sample of patients with recurrent MDD and in control samples. In total, 317 patients and 696 control individuals were included. Five single nucleotide polymorphisms (SNPs) and a deletion polymorphism in the CRF-BP gene were genotyped and the haplotype block structure of the gene was assessed. In the extended Swedish population, there was a trend towards an association between two SNPs and MDD. The subsequent gender analysis showed significant associations of three SNPs (CRF-BPs2 T; CRF-BPs11 T and CRF-BPs12 C) and haplotype G_T_C_T_C with MDD in Swedish males. However, these findings did not withstand correction for multiple testing and there were no significant SNP or haplotype associations in the Belgian MDD sample. In conclusion, this study does not provide confirmatory evidence for a role of the CRF-BP gene in the vulnerability for MDD in general. The association between genetic CRF-BP variants and MDD may be sexually dimorphic, but this issue requires further investigation in a larger sample.