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Epigenetic mechanisms such as DNA methylation are hypothesized to play a pivotal role in the pathogenesis of anxiety disorders and to predict as well as relate to treatment response. An epigenome-wide association study (EWAS) (Illumina MethylationEPIC BeadChip) was performed at baseline (BL), post-treatment (POST) and 6-month follow-up (FU) in the so far largest longitudinal sample of patients with anxiety disorders (N = 415) treated with exposure-based cognitive behavioral therapy (CBT), and in 315 healthy controls. Independent of comorbidity with depression, anxiety disorders were significantly (p ≤ 6.409E–08) associated with altered DNA methylation at 148 CpGs partly mapping to genes previously implicated in processes related to anxiety, brain disorders, learning or plasticity (e.g., GABBR2, GABRD, GAST, IL12RB2, LINC00293, LOC101928626, MFGE8, NOTCH4, PTPRN2, RIMBP2, SPTBN1) or in a recent cross-anxiety disorders EWAS (TAOK1) after pre-processing and quality control (N = 378 vs. N = 295). Furthermore, BL DNA methylation at seven and three CpGs, respectively, was suggestively (p < 1E–5) associated with treatment response at POST (ABCA7, ADRA2C, LTBR, RPSAP52, SH3RF3, SLC47A2, ZNF251) and FU (ADGRD1, PRSS58, USP47). Finally, suggestive evidence for dynamic epigenome-wide DNA methylation changes along with CBT response emerged at four CpGs from BL to FU (ADIPOR2, EIF3B, OCA2, TMCC1). The identification of epigenetic biomarkers may eventually aid in developing environment-based preventive strategies aimed at increasing resilience by providing deeper molecular insights into the mechanisms underlying anxiety disorders. Defining epigenetic signatures as predictors or key mechanisms in exposure-based interventions could pave the way for more targeted and personalized treatments for anxiety disorders.

Cognitive behavioral therapy (CBT) is the first-line treatment for panic disorder and agoraphobia. Supportive digital technologies can enhance the effectiveness of CBT. This pilot randomized controlled trial (RCT) investigates if patients with panic disorder and/or agoraphobia benefit from blended cognitive behavioral therapy (bCBT), combining standard CBT with an integrated digital application. Patients were randomized into two study groups: The bCBT group, receiving standard CBT plus a digital application (elona therapy) used between sessions (n = 34), and the control group, receiving standard CBT alone (n = 22). Anxiety, depression, quality of life, work and daily functioning, and mental health literacy were assessed at baseline (T0), at 6 weeks (T1), and at 12 weeks (T2). Improvements in anxiety symptoms were descriptively larger for the bCBT group at 6 weeks (d = -.28), though not significantly. The bCBT group showed significantly greater improvement in depression symptoms than the standard CBT group at 12 weeks (d = -.46 p = .028). Improvements in other secondary outcomes were descriptively larger for bCBT but not significant. bCBT shows promise in enhancing CBT for panic disorder and/or agoraphobia, warranting further research with larger RCTs.

Adequate control over automatic responses to affective stimuli is crucial for adaptive goal-oriented behavior. However, it remains unclear how individuals overcome automatic approach-avoidance tendencies to appetitive and aversive stimuli. Here we examined free versus forced approach-avoidance decisions to four conditioned stimuli (CSs), which were previously paired with either a single aversive (avCS+) or appetitive outcome (appCS+), both (i.e., conflicting) outcomes (confCS+), or no outcome (neuCS−). These CSs were presented in an anticipation phase before participants could use a joystick to either approach and obtain CS-specific outcomes or avoid without getting anything. Response times, subjective ratings, heart rate, and eye-tracking data were recorded in N = 75 participants. Results revealed that for single outcomes, concordant responses (e.g., avoidance to the avCS+) were faster than forced discordant responses (e.g., approach to the avCS+). During anticipation, gaze fixations shifted towards the spatial location associated with the concordant response for single-outcome stimuli (e.g., upward for avoidance of avCS+). Conflicting stimuli elicited intermediate behavioral and gaze patterns at the group level, while exploratory analyses revealed substantial individual differences: High avoiders (i.e., participants showing an overall high proportion of avoidance) exhibited slower approach responses and greater threat-focused visual attention compared to low avoiders. Decreased heart rate in response to all CSs suggests a general preparation of behavioral responses, while increased pupil dilation during the anticipation of aversive stimuli indicates threat-related processing. These findings suggest that competing outcomes can amplify individual differences in motivational salience and therefore might inspire clinical interventions focused on inhibiting disorder-specific behavioral tendencies.

Fear extinction procedures serve as a laboratory model for a learning process involved in exposure treatment for anxiety disorders. Clinically, exposure is typically conducted with generalization stimuli (GSs) because originally acquired fear stimuli are inaccessible. Experimental studies, however, show limited generalization of extinction when GSs are used in extinction training (i.e., GS extinction). Stimulus variability may overcome limited extinction generalization. In a first study, we examined whether using multiple, perceptually similar GSs during fear extinction may overcome limited GS extinction generalization. A healthy sample (N = 120) underwent a two-day fear conditioning procedure, with three groups receiving extinction training with a single GS, multiple GSs or the original CS+. Surprisingly, no group differences appeared. Missing awareness of stimuli differences may explain these findings. Hence, in a second study, we aimed to manipulate awareness of stimulus differences between two groups (N = 80), using additional instructions and tasks. Results suggest that enhanced stimulus differentiation was successfully induced, and pivotally influenced extinction learning and generalization. Specifically, greater awareness of stimulus differences resulted in limited GS extinction generalization toward the original CS+. Results highlight a pivotal role of stimulus differentiation, presumably in interaction with attentional and higher-order cognitive processes, for GS extinction learning and its generalization.

In anxiety disorders, approach-avoidance behavior is typically biased towards excessive, maladaptive avoidance despite costs and impairments (i.e., costly avoidance). Yet, little is known about the underlying decision dynamics that may contribute to such imbalanced behavior. The current study tested for altered temporal decision dynamics in patients with anxiety disorders compared to matched healthy controls in a task where avoiding an aversive stimulus conflicted with obtaining rewards. Participants chose repeatedly between a fixed safe/low reward and a threat/high reward option with varying threat (probability of an aversive stimulus presentation) and reward information (reward magnitude). Structured computer mouse movements required for choosing between options were tracked to capture the temporal dynamics of the decision process (i.e., when and how strongly threat and reward information influenced decision preference). The current study replicated elevated costly threat avoidance in patients with anxiety disorders compared to matched controls. Importantly, time-continuous multiple regression of mouse movements revealed altered temporal dynamics: patients showed a faster (but not stronger) impact of threat and a weaker impact of competing rewards. These findings highlight that not only biases in threat processes but also competing rewards may guide excessive avoidance and could be important treatment targets in anxiety disorders. Future research may support the external validity of these findings in real-life decisions and try to identify therapeutic strategies that allow to specifically target the attenuated impact of rewards and the accelerated impact of threat in patients.

Contemporary exposure therapy models for anxiety argue that exposures must generate threat prediction error to be effective. More research is needed to test this claim in clinical settings. This study explored how threat prediction error learning relates to outcomes during an exposure analogue procedure. Adult undergraduate psychology students (N = 125) experiencing a broad range of social anxiety symptoms from healthy to clinical levels of social anxiety completed 667 online speech performance exposures over two testing sessions separated by a week (approx. 3 speeches/session). Self-reported anxiety, threat prediction, threat outcome, and surprise were measured for each exposure and used to derive learning indicators. These included threat prediction error, prediction change, and the extent that prediction errors were converted to prediction change (i.e., learning rate). We examined between- and within-person relationships between these learning indicators and outcomes over exposure using multilevel modelling. Average prediction change and prediction error learning rate, but not average prediction error per se, was associated with more anxiety reduction across the exposure. Within-person, anxiety was lower after exposures that triggered more prediction change. Threat prediction error was not linearly associated with anxiety at the next exposure. Higher threat prediction error during an exposure was associated with greater subjective surprise for that exposure. We concluded that exposure outcomes depend on how much the patient converts exposure-related prediction errors into threat prediction change. Future research should focus on strategies to enhance the prediction-error learning rate from exposures.

Background: Although evidence-based interventions for posttraumatic stress disorder (PTSD) are highly effective, on average about 20% of patients drop out of treatment. Despite considerable research investigating PTSD treatment dropout in randomized controlled trials (RCTs), findings in naturalistic settings remain sparse. Objective: Therefore, the present study investigated the frequency and predictors of dropout in trauma-focused interventions for PTSD in routine clinical care. Method: The sample included n = 195 adults with diagnosed PTSD, receiving trauma-focused, cognitive behavioral therapy in routine clinical care in three outpatient centers. We conducted a multiple logistic regression analysis with the following candidate predictors of dropout: patient variables (e.g., basic sociodemographic status and specific clinical variables) as well as therapist’s experience level and gender match between therapist and patient. Results: Results showed a dropout rate of 15.38%. Age (higher dropout probability in younger patients) and living situation (living with parents predicted lower dropout probability compared to living alone) were significant predictors of dropout. Dropout was not significantly associated with the therapist’s experience level and gender match. Conclusions: In conclusion, routinely assessed baseline patient variables are associated with dropout. Ultimately, this may help to identify patients who need additional attention to keep them in therapy.

Objective: The efficacy of trauma-focused cognitive behaviour therapy (tf-CBT) has been well established in randomized controlled trials (RCTs). More research is needed to demonstrate the effectiveness of tf-CBT in routine clinical care settings. Method: Eighty-five patients (68 female) with a primary diagnosis of PTSD received tf-CBT at two German outpatient centres (Münster and Mannheim) between 2014 and 2016. Treatment was delivered mainly by therapists in training and treatment duration was based on symptom course. The treatment consisted of a preparation phase, a trauma-focused phase (comprising imaginal exposure, discrimination training, changing dysfunctional appraisals) and a phase of reclaiming-your-life assignments, and relapse prevention. In an intent-to-treat-analysis (ITT), linear mixed effects models were fitted for self-assessments of traumatic symptom severity using the PTSD Checklist for DSM-5 (PCL-5) and the Clinician-Administered PTSD Scale for DSM–5 (CAPS-5). Potential moderators for treatment outcome, e.g. number of suicide attempts, were investigated. Results: The observed treatment effect was large for both the CAPS-5 (ITT: Cohen’s d = 2.07, CI [1.62, 2.51]; completers d = 2.34, CI [1.84, 2.83]) and PCL-5 respectively (ITT: d = 2.02, CI [1.56, 2.48]; completers d = 2.15, CI [1.66, 2.64]), and remained stable six months and one-year post-treatment. N = 27 patients (31.48%) were defined as study dropout and of these, n = 12 (14.12%) dropped out of the study but completed treatment. None of the fixed-effect estimates for treatment predictors interacted significantly with the effect of time. Conclusions: Tf-CBT is well-tolerated and it can be effectively delivered in routine clinical care. Its large treatment effects underline the practicability and benefits of the approach. This trial demonstrates its broad applicability among individuals with diverse patterns of clinical characteristics and comorbidities.

Anxiety disorders (AD) are associated with altered connectivity in large-scale intrinsic brain networks. It remains uncertain how much these signatures overlap across different phenotypes due to a lack of well-powered cross-disorder comparisons. We used resting-state functional magnetic resonance imaging (rsfMRI) to investigate differences in functional connectivity (FC) in a cross-disorder sample of AD patients and healthy controls (HC). Before treatment, 439 patients from two German multicenter clinical trials at eight different sites fulfilling a primary diagnosis of panic disorder and/or agoraphobia (PD/AG, N = 154), social anxiety disorder (SAD, N = 95), or specific phobia (SP, N = 190) and 105 HC underwent an 8 min rsfMRI assessment. We performed categorical and dimensional regions of interest (ROI)-to-ROI analyses focusing on connectivity between regions of the defensive system and prefrontal regulation areas. AD patients showed increased connectivity between the insula and the thalamus compared to controls. This was mainly driven by PD/AG patients who showed increased (insula/hippocampus/amygdala—thalamus) and decreased (dorsomedial prefrontal cortex/periaqueductal gray—anterior cingulate cortex) positive connectivity between subcortical and cortical areas. In contrast, SAD patients showed decreased negative connectivity exclusively in cortical areas (insula—orbitofrontal cortex), whereas no differences were found in SP patients. State anxiety associated with the scanner environment did not explain the FC between these regions. Only PD/AG patients showed pronounced connectivity changes along a widespread subcortical-cortical network, including the midbrain. Dimensional analyses yielded no significant results. The results highlighting categorical differences between ADs at a systems neuroscience level are discussed within the context of personalized neuroscience-informed treatments. PROTECT-AD’s registration at NIMH Protocol Registration System: 01EE1402A and German Register of Clinical Studies: DRKS00008743. SpiderVR’s registration at ClinicalTrials.gov: NCT03208400.

Background This paper reports on the outcomes of a proof-of-principle study for the Exposure Therapy Consortium, a global network of researchers and clinicians who work to improve the effectiveness and uptake of exposure therapy. The study aimed to test the feasibility of the consortium’s big-team science approach and test the hypothesis that adding post-exposure processing focused on enhancing threat reappraisal would enhance the efficacy of a one-session large-group interoceptive exposure therapy protocol for reducing anxiety sensitivity. Methods The study involved a multi-site cluster-randomized controlled trial comparing exposure with post-processing (ENHANCED), exposure without post-processing (STANDARD), and a stress management intervention (CONTROL) in students with elevated anxiety sensitivity. Feasibility was assessed using site performance metrics (e.g., timeline, sample size, missing data). Efficacy was assessed up to 1-month follow-up using the Anxiety Sensitivity Index-3. Results Despite challenges posed by unforeseen global crises, a standardized protocol for screening, assessment, and treatment at 12 research sites across four continents was successfully implemented, resulting in a total sample size of 400 with minimal missing data. Challenges in recruitment and adherence to the projected timelines were encountered. Significant reductions in anxiety sensitivity were observed in all conditions. Contrary to hypotheses, group differences were only observed at post-treatment, when ENHANCED and CONTROL outperformed STANDARD but were not significantly different from each other. Conclusions This study demonstrates the feasibility of the Exposure Therapy Consortium. Findings raise questions regarding the efficacy of large group exposure interventions and underscore the importance of careful research site selection and an iterative approach to treatment development.

Background. The Personalized Advantage Index (PAI) shows promise as a method for identifying the most effective treatment for individual patients. Previous studies have demonstrated its utility in retrospective evaluations across various settings. In this study, we explored the effect of different methodological choices in predictive modelling underlying the PAI. Methods. Our approach involved a two-step procedure. First, we conducted a review of prior studies utilizing the PAI, evaluating each study using the Prediction model study Risk Of Bias Assessment Tool (PROBAST). We specifically assessed whether the studies adhered to two standards of predictive modeling: refraining from using leave-one-out cross-validation (LOO CV) and preventing data leakage. Second, we examined the impact of deviating from these methodological standards in real data. We employed both a traditional approach violating these standards and an advanced approach implementing them in two large-scale datasets, PANIC-net (n = 261) and Protect-AD (n = 614). Results. The PROBAST-rating revealed a substantial risk of bias across studies, primarily due to inappropriate methodological choices. Most studies did not adhere to the examined prediction modeling standards, employing LOO CV and allowing data leakage. The comparison between the traditional and advanced approach revealed that ignoring these standards could systematically overestimate the utility of the PAI. Conclusion. Our study cautions that violating standards in predictive modeling may strongly influence the evaluation of the PAI’s utility, possibly leading to false positive results. To support an unbiased evaluation, crucial for potential clinical application, we provide a low-bias, openly accessible, and meticulously annotated script implementing the PAI.

Exposure-based CBT is effective in treating anxiety disorders, but individual responses vary substantially, underlining the need to identify and boost mechanisms underlying exposure. In this study, the role of positive emotions occurring after exposure was examined. In an analysis of 8,416 exposure records of 648 anxiety patients undergoing exposure therapy, the degree of positive emotions hope and joy occurring after exposure exercises, their predictors, and their role regarding treatment success were investigated. Positive emotions after exposure were medium to high and increased slightly across repeated exposure exercises. They were associated with exposure-related learning indicators (i.e., expectancy violation and change as well as the prediction-error learning rate) and were mainly predicted by adjusted threat expectancy assessed after completing exposure, controlling for baseline depressive …