Sex-dependent association of DNA methylation of HPA axis-related gene FKBP5 with obsessive-compulsive disorder.

AIMS: Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation in obsessive-compulsive disorder (OCD) has been reported, epigenetic changes in HPA axis-related genes have not been well studied in OCD. The present study investigated whether the epigenetic regulation of FK506-binding protein 51 gene (FKBP5) intron 7 is associated with OCD status in each sex. In addition, relationships among the DNA methylation levels of FKBP5 intron 7, OCD status and early-life trauma were explored. METHODS: A total of 267 patients with OCD and 201 controls aged between 18 and 40 years were recruited. Demographic and clinical assessment, FKBP5 rs1360780 genotyping, and pyrosequencing of FKBP5 intron 7 were conducted. DNA was extracted from peripheral blood leucocytes. First, multivariate analysis of covariance for differential DNA methylation levels between OCD patients and controls was conducted with adjustment for FKBP5 rs1360780 genotype, early-life trauma, depressive symptoms, and age as covariates in each sex. Next, path analysis was conducted to determine the mediation effects of DNA methylation levels of FKBP5 between early-life trauma and OCD status. In addition, sensitivity analyses for medication and lifetime major depression were also performed. RESULTS: DNA methylation at the FKBP5 intron 7 CpG site was significantly lower in men with OCD, compared to controls (mean difference -1.33%, 95% CI -2.11 to -0.55, p < 0.001). The results remained significant for drug naïve or free subjects (mean difference -1.27%, 95% CI -2.18 to -0.37, p = 0.006, in men) and for subjects without lifetime major depressive disorder (mean difference -1.60%, 95% CI -2.54 to -0.66, p < 0.001, in men). The mediation effect of DNA methylation levels was not significant between early-life trauma and OCD status. CONCLUSION: These findings suggest that epigenetic factors of HPA axis-related gene FKBP5 may play a role in the pathogenesis of OCD. Further studies are needed to determine how altered DNA methylation of FKBP5 intron 7 and HPA axis function are involved in OCD.

Microbiome analysis of circulating bacterial extracellular vesicles in obsessive-compulsive disorder.

AIM: The present study examined the microbiome abundance and composition of drug-naive or drug-free patients with obsessive-compulsive disorder (OCD) compared with healthy controls. In addition, in the OCD group, the microbiome composition was compared between early-onset and late-onset OCD. METHODS: Serum samples were collected from 89 patients with OCD and 107 age- and sex-matched healthy controls. Bacterial DNA was isolated from bacteria-derived extracellular vesicles in serum and then amplified and quantified using primers specific to the V3-V4 hypervariable region of the 16S ribosomal RNA gene. The 16S ribosomal DNA gene amplicon sequencing was performed. RESULTS: The pooled estimate showed that α-diversity was significantly reduced in patients with OCD compared with that in healthy controls (PShannon = 0.00015). In addition, a statistically significant difference was observed in ß-diversity between patients with OCD and healthy controls at the order (P = 0.012), family (P = 0.003), genus (P < 0.001), and species (P = 0.005) levels. In the microbiome composition, Pseudomonas, Caulobacteraceae (f), Streptococcus, Novosphingobium, and Enhydrobacter at the genus level were significantly less prevalent in patients with OCD than in controls. In addition, among patients with OCD, the microbial composition in the early-onset versus late-onset types was significantly different with respect to the genera Corynebacterium and Pelomonas. CONCLUSION: The present study showed an aberrant microbiome in patients with OCD, suggesting a role of the microbiota-brain interaction in the pathophysiology of OCD. Further longitudinal studies with larger sample sizes adjusting for various confounders are warranted.

Psychological factors associated with COVID-19 related anxiety and depression in young adults during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic and the corresponding lockdown have drastically changed our lives and led to high psychological distress and mental health problems. This study examined whether psychological factors such as loneliness, perfectionism, and health anxiety are associated with COVID-19 related anxiety and depression during the pandemic in young Korean adults, after controlling for various socio-demographic factors and early life stress. METHODS: A total of 189 participants (58.2% women) completed a cross-sectional online survey including the Fear of COVID-19 Scale, Center for Epidemiologic Studies Depression Scale, 3-item Revised UCLA Loneliness Scale, Frost Multidimensional Perfectionism Scale, and Whiteley Index-6. Hierarchical linear regression analyses with three blocks were employed to identify the factors that contributed to COVID-19 related anxiety and depressive symptoms. RESULTS: Hierarchical regression analyses showed that higher health anxiety was significantly associated with more severe COVID-19 related anxiety (standardized regression coefficient, ß = 0.599, p < 0.001). Additionally, higher levels of loneliness (ß = 0.482, p < 0.001), perfectionism (ß = 0.124, p = 0.035), and health anxiety (ß = 0.228, p < 0.001) were significantly associated with higher depression scores. The three psychological factors explained 32.8% of the total variance in depressive symptom scores, after taking all covariates into account. CONCLUSION: The results showed that health anxiety was a risk factor for both COVID-19 related anxiety and depression in young adults. Loneliness was the strongest predictor of depressive symptoms during the COVID-19 pandemic. These findings highlight the importance of identifying vulnerable individuals and encouraging psychological counselling and social connections to reduce the burden of psychiatric disorders during the pandemic.

Core clinical symptoms and suicidal ideation in patients with obsessive-compulsive disorder: A network analysis.

INTRODUCTION: Suicidality in obsessive-compulsive disorder (OCD) is underestimated and it is important for clinicians to understand the factors that contribute to suicidal ideation. The present study aimed to estimate a network of the core clinical symptoms of OCD including obsessions, compulsions, and obsessive-compulsive (OC) symptom dimensions, depressive symptoms, and psychological traits, and to examine which symptoms contribute to suicidal ideation in patients with a primary diagnosis of obsessive-compulsive disorder. METHODS: A total of 444 patients with OCD were assessed with the Yale-Brown Obsessive-Compulsive Scale, the Montgomery-Asberg Depression Rating Scale, and various other measures. Network analysis was conducted to estimate the network of obsessive-compulsive and depressive symptoms, psychological traits including alexithymia and impulsivity, and demographic covariates. Symptoms directly related to suicidal ideation in the network were examined for their relative contribution to suicidal ideation. RESULTS: Suicidal ideation was directly related to degree of control over compulsive behaviors, distress associated with compulsive behaviors, time spent performing compulsive behaviors, and unacceptable thoughts, along with depressive symptoms and alexithymia. In the network of OC and depressive symptoms the most central symptoms among the former were interference due to compulsive behaviors and interference due to obsessive thoughts, and among the latter were pessimistic thoughts and reported sadness. CONCLUSION: The findings suggest that along with depressive symptoms and alexithymia, compulsions and unacceptable thoughts dimension may contribute to suicidality, and thus, should be carefully monitored in patients with OCD.

Dysfunctional coronavirus anxiety in nonpsychotic psychiatric outpatients during the COVID-19 pandemic: A network analysis.

BACKGROUND: The 2019 coronavirus disease (COVID-19) pandemic has had a profound impact on the mental health of people worldwide. This study examined dysfunctional coronavirus anxiety in nonpsychotic psychiatric outpatients during the pandemic using the coronavirus anxiety scale (CAS) and examined the relationship between coronavirus anxiety and clinical symptoms using network analysis. METHODS: In this cross-sectional study, 192 patients who first visited the psychiatric outpatient clinic of Severance Hospital during the COVID-19 pandemic with chief complaints of depressed mood, anxiety, somatic symptoms, or insomnia were included. We compared the clinical characteristics of patients with and without dysfunctional coronavirus anxiety. Network analysis was conducted to estimate the network of coronavirus anxiety and depressive, anxious, and hypochondriacal psychopathology. RESULTS: The results showed that 7.8% of patients exhibited dysfunctional coronavirus anxiety (CAS ≥ 5). Patients with dysfunctional coronavirus anxiety showed higher levels of health worry, somatic preoccupation, and subjective anxiety compared to patients without dysfunctional coronavirus anxiety. In the network analysis, the health worry node (Item 6 of the WI) showed the greatest number of connections with coronavirus anxiety nodes. CONCLUSIONS: These findings suggest that health worry may be an important bridge symptom that connects coronavirus anxiety and other clinical psychopathology. Patients with elevated health worries should be carefully monitored during the COVID-19 pandemic for exacerbation of previous symptoms and COVID-19-related psychopathology. Understanding the psychological factors in the face of the pandemic and their relationships with clinical psychiatric symptoms would help people prevent and overcome mental health problems during the pandemic.

Dysfunctional Metacognitive Beliefs in Patients With Obsessive-Compulsive Disorder and Pattern of Their Changes Following a 3-Month Treatment.

Introduction: Metacognitions are considered to be crucial factors for the development and maintenance of pathologic anxiety. The present case-control study aimed to examine how metacognitive beliefs are associated with the diagnostic status and subtypes of obsessive-compulsive disorder (OCD). In addition, we examined the pattern of changes in metacognitive beliefs after a 3-month pharmacological treatment in patients with OCD. Methods: A total of 562 cases with OCD and 236 healthy controls were assessed with the Metacognitions Questionnaire (MCQ) and various measures of OC symptom severity. Multivariate analyses of variance (MANOVAs) with covariates were conducted to explore the relationship between subdimensions of metacognitive beliefs and OCD disease status. In addition, for the OCD patients, Pearson's correlation was performed between baseline MCQ subdimensions and Obsessive-Compulsive Inventory-Revised-Korean subscales (OCI-R-K). Finally, in a subset of drug-free OCD patients (n = 144), the MCQ was reassessed after 3 months of treatment and patterns of changes in subdimensions of the MCQ were examined. Results: Patients with OCD scored significantly higher on the four dimensions of the MCQ. There were significant associations between all MCQ subdimensions and OCI-R-K subscales. In the repeated-measure MANOVA, a significant group (non-responders vs. responders)-by-time interaction effect was found only for the negative beliefs about the uncontrollability and danger of worry (NB) subdimension (F = 10.75; η2 = 0.072; p = 0.001). Conclusion: The presence of dysfunctional metacognitive beliefs in OCD subjects and their association with OCD characteristics suggest that dysfunctional metacognitions may play a crucial role in the pathophysiology of OCD. Improvement of metacognitive beliefs in the NB dimension may be a clinically meaningful correlate of good treatment response in the pharmacological treatment of OCD.

Metacognitive beliefs predict early response to pharmacological treatment in patients with obsessive-compulsive disorder.

RATIONALE: Metacognitions, beliefs that monitor or control thoughts and coping, are considered to be important components for development and maintenance of obsessive-compulsive disorder (OCD). OBJECTIVES: This study prospectively investigated whether metacognitive beliefs can predict early treatment response after serotonin reuptake inhibitor (SRI) initiation in patients with OCD. METHODS: Drug-naïve or medication-free patients with OCD (N = 156) were assessed for various characteristics, including metacognitions. In total, 132 patients were followed for 4 weeks, and their clinical responses to pharmacological treatment were assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Early treatment response was defined as a 20% or greater reduction from the baseline Y-BOCS score at 4 weeks. Logistic and linear regression analyses were performed to identify major determinants for the early treatment outcome. RESULTS: Among participants with OCD, 53 patients (40.15%) were early responders. The logistic regression model revealed two significant predictors, age (beta = - 0.113, p < 0.001) and "positive beliefs about worry," which refers to metacognitive beliefs concerning the benefits of engaging in worry (beta = - 0.067, p = 0.001), for identifying early responders. Moreover, in the linear regression model, lower "positive beliefs about worry" was also shown as a significant predictor for the degree of better early improvement (beta = - 0.566, p = 0.001). CONCLUSIONS: These results suggest that lower metacognition of "positive beliefs about worry" predicts improvement of obsessive-compulsive symptoms seen early on in the SRI treatment, and that pathological metacognitive belief would lead to delayed response to SRI treatment in OCD.

Reduced DNA methylation of the oxytocin receptor gene is associated with obsessive-compulsive disorder.

BACKGROUND: Oxytocin is an important neuromodulator involved in cognition and socio-emotional processing that exerts its central activities via oxytocin receptors. Epigenetic alterations in the oxytocin receptor gene (OXTR) may be a molecular mechanism in the pathogenesis of obsessive-compulsive disorder (OCD). This study investigated the association between OXTR DNA methylation and the OCD status of a Korean population. RESULTS: Quantitative leukocyte DNA methylation levels of three cytosine-phosphate-guanine (CpG) sites in the 5' untranslated region (UTR) of OXTR exon 2 and eight CpG sites within OXTR exon 3 were analyzed using the pyrosequencing method in 151 patients with OCD (including 45 drug-naïve patients) and 108 healthy controls. DNA methylation levels were compared between the groups using multiple analyses of covariance separately by sex after controlling for age and educational level. Patients with OCD showed significantly lower methylation levels at CpG1 and CpG2 sites on the UTR of OXTR exon 2 than those of healthy controls for both sexes. In a subset of 45 drug-naïve patients with OCD, the DNA methylation levels also remained significantly lower than those in the controls and their CpG1 methylation levels were significantly negatively associated with the ordering symptom dimension. CONCLUSIONS: Our findings suggest that epigenetic OXTR alterations may affect the pathophysiology of OCD. The potential role of the oxytocin system in OCD development and treatment warrants further investigation.