Understanding importance of clinical biomarkers for diagnosis of anxiety disorders using machine learning models.

Anxiety disorders are a group of mental illnesses that cause constant and overwhelming feelings of anxiety and fear. Excessive anxiety can make an individual avoid work, school, family get-togethers, and other social situations that in turn might amplify these symptoms. According to the World Health Organization (WHO), one in thirteen persons globally suffers from anxiety. It is high time to understand the roles of various clinical biomarker measures that can diagnose the types of anxiety disorders. In this study, we apply machine learning (ML) techniques to understand the importance of a set of biomarkers with four types of anxiety disorders-Generalized Anxiety Disorder (GAD), Agoraphobia (AP), Social Anxiety Disorder (SAD) and Panic Disorder (PD). We used several machine learning models and extracted the variable importance contributing to a type of anxiety disorder. The study uses a sample of 11,081 Dutch citizens' data collected by the Lifelines, Netherlands. The results show that there are significant and low correlations among GAD, AP, PD and SAD and we extracted the variable importance hierarchy of biomarkers with respect to each type of anxiety disorder which will be helpful in designing the experimental setup for clinical trials related to influence of biomarkers on type of anxiety disorder.

Cortisol reactivity in social anxiety disorder: A highly standardized and controlled study.

In order to understand the psychopathology of the social anxiety disorder (SAD) at the neuroendocrine level, standardized experimental studies on endocrine and physiological markers are necessary, especially since empirical data are still ambiguous. Hence, differences in both, the autonomic nervous system (ANS) and the endocrine stress responses (ACTH, salivary and plasma cortisol) were investigated in a particularly homogenous sample after a standardized stressor (Trier Social Stress Test). The sample consisted of n = 35 patients with SAD, age, and gender matched to n = 35 healthy controls (HC). In terms of the heart rate, the response pattern was comparable in both groups. Concerning ACTH, no significant group differences in the response pattern nor in the total output (AUCG) were exhibited. Significant differences were noticeable only in the plasma cortisol response pattern with less total output (AUCG) in patients suggesting a blunted response. The salivary cortisol response indicated comparable patterns between groups. However, the patients' total output (AUCG) was significantly smaller relative to the controls. In sum, evidence for a hypo-responsiveness of the HPA-axis in SAD by means of blood cortisol was observed, with no differences in ACTH between the two groups. This reduced reactivity of the HPA-axis might be associated with an inability to elicit an adequate hormone release, possibly accompanied by an enhanced perception of the stress stimulus. This might be explained by an adaptation of the adrenocortical system due to prolonged repeated stress exposure such as social evaluation.

Improvement in indices of cellular protection after psychological treatment for social anxiety disorder.

Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen's d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety.

Prospective associations of androgens and sex hormone-binding globulin with 12-month, lifetime and incident anxiety and depressive disorders in men and women from the general population.

BACKGROUND: Findings on associations of androgens and sex hormone-binding globulin (SHBG) with anxiety and depressive disorders in the general population remain inconclusive. METHODS: We used data of n = 993 men and n = 980 women from the Study of Health in Pomerania (SHIP, a prospective-longitudinal general population study from northeastern Germany). Immunoassay-measured serum concentrations of total testosterone, androstenedione and SHBG were assessed when participants were aged 20-80. 12-month, lifetime and incident DSM-IV anxiety and depressive disorders were assessed with the DIA-X/M-CIDI at 10-year follow-up, when participants were aged 29-89. Logistic regressions were adjusted for age, smoking, alcohol consumption, physical activity, waist circumference, hypertension and oral contraceptive use (women only) at baseline and follow-up interval. RESULTS: In men and women, androgens and SHBG were not associated significantly with incident anxiety and depressive disorders. In men, higher total testosterone predicted any 12-month (OR = 1.46) and lifetime (OR = 1.34) anxiety disorder, lifetime social phobia (OR = 2.15), and 12-month (OR = 1.48) and lifetime (OR = 1.39) specific phobia, but neither 12-month nor lifetime depression. Moreover, androstenedione in men interacted with age in predicting lifetime anxiety disorders (OR = 0.98): Higher androstenedione more strongly predicted lifetime anxiety in younger vs. older men. These findings, however, did not survive correction for multiple testing. In women, androgens and SHBG were not associated significantly with 12-month and lifetime anxiety and depressive disorders. LIMITATIONS: The follow-up period was relatively long and other factors might have affected the examined associations. CONCLUSIONS: Higher serum total testosterone in men and androstenedione in younger men may relate to an increased risk of anxiety disorders.

Emotional neglect in childhood shapes social dysfunctioning in adults by influencing the oxytocin and the attachment system: Results from a population-based study.

Early life maltreatment (ELM) is the major single risk factor for impairments in social functioning and mental health in adulthood. One of the most prevalent and most rapidly increasing forms of ELM is emotional neglect. According to bio-behavioral synchrony assumptions, the oxytocin and attachment systems play an important mediating role in the interplay between emotional neglect and social dysfunctioning. Therefore, the aim of the present study was to investigate whether fear and avoidance of social functioning, two important and highly prevalent facets of social dysfunctioning in adulthood, are shaped by emotional neglect, plasma oxytocin levels and attachment representations. We assessed emotional neglect as well as other forms of ELM with the Childhood Trauma Questionnaire, current attachment representations with the Adult Attachment Projective Picture System, and fear and avoidance of social situations with the Liebowitz Social Anxiety Scale in a population-based sample of N = 121 men and women. Furthermore, 4.9 ml blood samples were drawn from each participant to assess peripheral plasma oxytocin levels. Applying a sequential mediation model, results revealed that emotional neglect was associated with lower plasma oxytocin levels which in turn were associated with insecure attachment representations which were related to elevated fear and avoidance of social situations (a1d21b2: F3,117 = 20.84, P < .001). Plasma oxytocin and current attachment representations hence fully and sequentially mediate the effects of emotional neglect on social fear and avoidance, two important facets of adult social dysfunctioning, confirming bio-behavioral synchrony assumptions.

Anxiety disorders and CRP in a population cohort study with 54,326 participants: The LifeLines study.

OBJECTIVES: Growing evidence indicates that inflammatory processes may play a role in the pathogenesis of anxiety disorders. Nevertheless, much remains to be learned about the involvement of inflammation, including C-reactive protein (CRP), in specific anxiety disorders. This study examines the relation between anxiety disorders and CRP. METHODS: Associations of serum CRP with anxiety disorders were determined in a large population study (n = 54,326 participants, mean age = 47 years; 59% female), the LifeLines cohort. Depressive and anxiety disorders (generalized anxiety disorder, social anxiety phobia, panic disorder with or without agoraphobia and agoraphobia without panic disorder) were assessed using the Mini-International Neuropsychiatric Interview. RESULTS: Anxiety disorders, with the exception of social anxiety disorder, were significantly associated with increased CRP. After adjusting for demographics, life style factors, health factors, medication use, depression, and psychological stressors, CRP remained significantly associated with panic disorder with agoraphobia (ß = 0.01, P = .013). Moreover, CRP levels were significantly higher in people with panic disorder with agoraphobia compared to other anxiety disorders, independent of all covariates (F = 3.00, df = 4, P = .021). CONCLUSIONS: Panic disorder with agoraphobia is associated with increased CRP, although the effect size of this association is small. This indicates that neuroinflammatory mechanisms may play a potential role in its pathophysiology.

Daily fluctuation of emotions and memories thereof: Design and methods of an experience sampling study of major depression, social phobia, and controls.

Symptom fluctuations and the dynamic contexts provoking these are poorly understood. This deficit is compounded by people's limited ability to accurately report about such dimensions in retrospect. Utilizing the advantages of experience sampling methodology (ESM), this study rigorously describes and tests proximal environmental, neurobiological and psychological factors associated with symptoms and mood states. Participants were assigned to three diagnostic groups: Major Depressive Disorder (MDD; n = 118), Social Phobia (SP; n = 47), or a Control Group without SP or MDD (CG; n = 119). Laboratory assessments included cognitive abilities, memory, constructs, and brain derived neurotrophic factor (BDNF). ESM lasted seven days, with six assessments per day covering symptoms, affect, daily events, social interactions, post-event processing, well-being, etc. Morning cortisol and actigraphy were also assessed during ESM. Thereafter, participants provided subjective retrospective recall estimates of the emotions they reported during ESM. The multi-level data of >10,000 observations will allow for thorough examination of fluctuations of psychopathology and well-being in two highly prevalent disorders. Using two clinical groups and a non-affected control group, the clinical specificity versus generalizability of processes can be directly tested, thus providing stimulating information about the overlap and differences between anxiety and affective disorders. This research informs about the development, fluctuation, and maintaining factors of emotions and symptoms and examines the accuracy with which participants recall these dimensions.