For anxiety disorders (ADs), the preferred treatment is cognitive-behavioural therapy (CBT), with in vivo exposure (IVE) as its main component. IVE aims to gradually expose the patient to feared stimuli and situations to encourage habituation. Despite its effectiveness, it is a hard component for patients, especially when applied on their own. Therefore, a (co-)therapist usually supports the exposure requiring considerable time and resources. Meanwhile, smartphones have become a promising tool to complement and deliver psychological treatments.

Background/Objectives: Glucocorticoids have been shown to improve fear extinction learning in preclinical and human studies. We hypothesized an impact of the circadian rhythm of cortisol on exposure therapy in patients with anxiety spectrum disorders. Methods: Sixteen patients suffering from obsessive-compulsive disorder and eight with agoraphobia participated in a pilot randomized prospective cohort study. During two therapist-guided sessions of exposure therapy with response prevention, both starting either at 08:00 (morning group) or at 16:00 (late afternoon group), subjective units of distress (SUD) and salivary cortisol levels were assessed repeatedly. Results: While expected significant diurnal differences in salivary cortisol emerged between daytime groups, after controlling for chronotype, no significant differences were detected in our exposure process indicators of within-session and between-session habituation and distress-related expectancy violation towards maximal SUD and SUD at end. Nearly one-hundred subjects in each group would be needed to gain statistically significant daytime differences for these indicators as per case number estimation. Conclusions: Our preliminary results from this transdiagnostic sample do not provide support for scheduling exposure sessions in the morning. Further research should consider cortisol administration before exposure sessions to test whether different doses of exogenous glucocorticoids can augment exposure therapy outcomes.

Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD (diagnosis (SE)=0.70 (0.37) years, p=0.061). In a subgroup of participants with SAD with comorbid anxiety disorders (n=184 SAD, n=1 355 HCs), a brain-PAD of +2.39 (0.93) years (Cohen's d=0.23, pFDR=0.003) was observed. This brain-PAD became smaller after exclusion of participants with comorbid agoraphobia and specific phobia, suggesting that these disorders may partly drive the advanced brain-PAD. In conclusion, this ENIGMA-Anxiety mega-analysis did not find evidence of advanced brain ageing in the full sample of adult participants with SAD relative to HCs. However, a sub-analysis suggested that SAD with co-occurring phobic disorders, or the phobic disorders themselves, are associated with neurostructural patterns typical of older brains. Future research could utilise transdiagnostic samples with information on age of onset and disorder duration to further clarify this relation.

Twin studies reveal high genetic overlap between anxiety disorders and depression, contributing to the internalising spectrum. Some genetic specificity for fear-based anxiety disorders (fear), distinct from general anxiety and depression (distress), has also emerged. Limited datasets with detailed phenotyping across anxiety disorders have restricted most genome-wide association studies (GWAS) to "any anxiety diagnosis". Additional genome-wide evidence to discern genetic differences between fear and distress is required. We conducted GWAS meta-analyses of fear (panic, agoraphobia, specific phobia, social anxiety disorder) and generalised anxiety disorder (GAD), measured using brief single-item and detailed symptom-based diagnoses from three datasets. We explored two control group criteria: phenotype-specific (fear/GAD) or broader anxiety/depression screening. We identified one independent genome-wide significant locus and three gene-level associations with fear (up to 35,523 Ncases; 157,447 Ncontrols). Four genome-wide significant loci and three gene-level associations were identified for GAD (up to 60,879 Ncases; 117,064 Ncontrols). The genetic correlation between fear and GAD was significantly different from unity only when excluding a depression-enriched dataset and using phenotype-specific control screening (rg = 0.87; P = 9.32 × 10[-3]). Most complex traits had statistically similar genetic correlations with fear and GAD, including depression. Exceptions included general cognitive ability, educational attainment, and coronary artery disease, showing statistically stronger genetic correlations with fear than GAD, while bipolar disorder type I, anorexia nervosa, and neuroticism displayed the opposite pattern. Our findings partially support a distress-fear genetic distinction, but show stronger evidence for an overarching genetic liability to internalising psychopathology driving comorbidity across anxiety disorders and depression.

Individuals with a Diagnostic and Statistical Manual of Mental Disorders (DSM) anxiety or depressive disorder tend to report a lack of agency in social situations. Agency represents one dimension in the interpersonal circumplex model while communion represents the other dimension. In the present study, we mapped six anxiety and depressive disorders examined within the Netherlands Study of Depression and Anxiety (NESDA) onto this model. To this end, we used the structural summary method to reduce Inventory of Interpersonal Problems scores of NESDA Wave 6 participants with a current diagnosis (n = 412) to interpersonal profiles for each of the six examined disorders. The Displacement parameter represents the blend of agency and communion and provided insight into which interpersonal problem theme is most characteristic for a disorder. Amplitude represents the distinctiveness of this theme, and Elevation provides an indication of the level of general interpersonal distress associated with the disorder. Unexpectedly, general interpersonal distress was highest for dysthymia, not major depressive disorder. As expected, however, all disorders (social phobia, generalized anxiety disorder, panic disorder, agoraphobia, dysthymia, and major depressive disorder) were primarily characterized by a submissive interpersonal style. Additionally, we found greater general interpersonal distress among participants with comorbid anxiety and depression than among participants with depression or anxiety alone. The main finding was that the different anxiety and depressive disorders had comparable interpersonal profiles. This supports the notion that interpersonal style may be a transdiagnostic factor in the emergence and maintenance of these disorders, contributing to interpersonal distress particularly in individuals with comorbid disorders.