Open Access

Anxiety disorders (ADs) are one of the most prevalent mental disorders, affecting up to around 30% of the population worldwide (Jacobi et al., 2014; Szuhany & Simon, 2022). They represent pathological anxiety and fear, marked by disproportionate emotional and physiological responses in the absence of real threat, leading to avoidance behavior or safety strategies. They often include panic attacks with cardiovascular and respiratory symptoms. ADs impair functioning, reduce quality of life, and impose a major socioeconomic burden (Baxter et al., 2014; Santomauro et al., 2021). The pathogenesis of AD is multifactorial, including biological, psychological, and environmental causes. Cognitive behavioral therapy (CBT), integrating exposure to feared situations and targeting maladaptive beliefs, is a widely used and highly effective treatment for various AD (Bandelow et al., 2023; Hofmann et al., 2025). Nevertheless, approximately one-third of patients do not respond to treatment. Identifying underlying mechanisms of action for CBT treatments and disentangling biological and psychological risk factors would allow a better understanding of the etiology of ADs. Moreover, it would allow to determine the utility of biomarkers in predicting therapy response and relapse risk as well as the development of a more personalized “precision” medicine to tailor treatments to the individual's needs, which has the potential to improve treatment response rates. Hence, recent research efforts have focused more on individual differences to identify relevant factors for the prediction of therapy response: biological mechanisms, such as (epi-)genetics and stress hormones, environmental factors, such as maltreatment experiences or resulting attachment styles, as well as therapy process variables, such as therapeutic alliance (Bandelow et al., 2016; Bandelow et al., 2017; Fava & Morton, 2009; Zilcha-Mano & Fisher, 2022). However, our understanding of how psychotherapy might be influenced by, e.g., (epi-)genetics and the biological stress response, is still limited. Even less is known about the impact of CBT on biological processes. Understanding the impact of CBT as a positive and predictable environmental factor becomes even more relevant as many studies have highlighted how intertwined the environment, e.g., maltreatment experiences, is with biological mechanisms, e.g., related to stress response (Fischer et al., 2021) and epigenetics (Weber et al., 2025). Interestingly, attachment style has also emerged as a relevant risk factor for the development of ADs (Levy et al., 2011). Further, it seems likely that attachment style influences the psychotherapy success of AD via the therapeutic alliance (for a meta-analysis see Notsu et al., 2025). Hence, it seems important to understand how CBT for AD is influenced by and may influence biological mechanisms and relational processes. An integration of research results from various domains within a bio-psycho-social model could contribute to a better understanding of the contributions of several mechanisms in therapy. Aiming to address this research gap, we conducted the following studies. In Publication I, we conducted a literature review of how CBT might be related to and might influence the functioning of the hypothalamic-pituitary-adrenal (HPA) axis in patients with ADs. Since it is one of the most relevant biological systems for stress response, understanding changes within this system is particularly relevant for patients suffering from ADs. Overall, we found evidence supporting the idea that cortisol levels have the potential to indicate the AD disease status and serve as a possible biomarker in therapy response prediction. In detail, the reviewed studies suggest that persistently elevated cortisol levels seem to impede therapy response. We further focused on how CBT, specifically therapeutic exposure to feared situations, might influence HPA axis functioning. A beneficial effect of cortisol elevation during exposure or, in reverse, effects of a blunted HPA system response on an unfavorable outcome are supported. Moreover, effective CBT treatment seems to normalize HPA system hyperfunction. Additionally, cognitive processes, e.g., positive anticipatory appraisal, attribution, perceived controllability, and coping, seem to have an impact on adaptive HPA system functioning. Second, we conducted a therapy progress study with patients suffering from panic disorder (PD) undergoing CBT at the outpatient clinic of the Max Planck Institute of Psychiatry in Munich. We assessed dynamic changes in epigenetic (gene methylation and expression), metabolomic (small molecules produced by metabolism), and immune system biomarkers, as well as in relational patterns (attachment style, interpersonal distress, and therapeutic alliance). We applied several measures, including various questionnaires and taking blood samples, during a standardized short-term exposure-based CBT (12 sessions and two booster sessions) at several time points: pre-/ post-, mid-treatment, exposure sessions, and follow-up. Biological markers on different levels were analyzed: Publication II identified specific DNA methylation signatures (HECA gene), which, as time-stable heritable gene-regulatory mechanisms, might serve as biomarkers for PD, thereby revealing potential epigenetic mechanisms. Publication III found that exposure to a feared situation induced significant changes in a plasma metabolite, namely glyoxylate, linked to the experienced anxiety level. These findings suggest that the metabolome might serve as a dynamic marker for different anxiety states. The related gene expression changes during exposure therapy were subtle but may indicate biological correlates of acute panic attacks and therapy success. Publication IV found that specific DNA methylation, such as within the gene for the serotonin receptor 3A related to the regulation of panic states and fear circuitry, as well as immune system patterns related to PD and acute fear (including arginase 1 gene methylation, CD4+ T cells, CD8+ T cells, B cells, and granulocytes), were altered during and after successful exposure therapy. Further, these changes were related to therapy response. In combination, the findings of studies III and IV highlight the possible role of epigenetics in the effects of CBT and its potential as a biomarker for treatment outcome. In publication V, we analyzed psychological process variables throughout the course of the therapy, namely the relationship between attachment style changes and the working alliance. We found that an insecure, specifically anxious attachment style was reduced after treatment. Further, decreased anxious attachment was associated with improvements in symptom severity, therapeutic alliance, and interpersonal difficulties, which in turn were related to the effectiveness of CBT. Furthermore, findings showed that general attachment style and interpersonal distress seem to moderate the relation between the therapeutic alliance and subsequent symptom severity. The study highlights the dynamics and potential positive effects of standardized short-term CBT on interpersonal patterns. The publications provide insights into both the pathophysiology of AD and the treatment mechanisms involved in CBT, aiming to enhance understanding of effective treatments and personalized approaches for AD patients. They emphasize, on the one hand, biological mechanisms potentially influenced by CBT: changes in the HPA system (cortisol levels), genetics (DNA methylation and gene expression), metabolomic shifts (glyoxylate regulation), and immune system dynamics. On the other hand, psychological processes are corroborated, highlighting the importance of cognitive factors, interpersonal patterns, and therapeutic alliance in the treatment of PD. Overall, multilevel changes are shown, which support a bio-psycho-social approach to PD treatment. Despite its limitations, this work highlights the probable multifaceted impact of CBT on AD/ PD and advances understanding of treatment mechanisms which could guide a more integrative approach to mental health. Future progress lies in tailoring treatments to individual needs and tracking outcomes with both biomarkers and psychological assessments.

Error monitoring allows humans to detect errors in their performance and adapt behavior accordingly. A key neural marker of this process is the error negativity (Ne/ERN), a negative deflection at frontocentral electrodes shortly after an error, which reflects fast and automatic error processing. Theoretical accounts attributed the Ne/ERN to conflict monitoring and prediction error, but the exact mechanism remains unclear. In three studies, I investigated the Ne/ERN’s role in error monitoring and its relationship with other error-related phenomena. Study 1 found that the Ne/ERN varies with the level of post-response conflict. Study 2 showed that conscious error detection can occur without the Ne/ERN, suggesting separate neural bases for early error processing and error awareness. Study 3 explored links between the Ne/ERN and autonomic signals, showing that error-related pupil dilation is associated with the Ne/ERN while heart rate deceleration is not. These findings clarify the functional role of early error processes as reflected by the Ne/ERN and their relationship with other aspects of error processing.

Unaccompanied young refugees (UYRs) encounter a multitude of stressors prior to, during and after their flight. Consequently, they demonstrate elevated levels of psychological distress and are vulnerable to the development of mental disorders, particularly post-traumatic stress disorder (PTSD). A treatment manual that has a broad evidence base and is also suitable for the treatment of young unaccompanied refugees, is trauma-focused cognitive behavioral therapy, which was established by Cohen, Mannarino and Deblinger (2006, 2017). Despite the existence of empirically validated treatment modalities for pediatric PTSD, UYRs frequently fail to receive sufficient psychotherapeutic care. Consequently, there is a necessity to identify factors that can lead to successful psychotherapeutic treatment on the patients, psychotherapists, and the healthcare system level. The present dissertation sought to explore four main questions. The initial publication is a metaanalysis. We found substantial improvement in PTSD symptoms, depression, anxiety, and grief for young patients who participated in TF-CBT, with favorable post-treatment outcomes when compared to all control conditions. The second publication posits that a web-based training approach for TF-CBT results in substantial knowledge gain among its users and is an accessible training method of training for mental health care professionals. The third publication employed qualitative analysis to ascertain the factors that facilitate effective psychotherapy with UYRs, as perceived by psychotherapists. The identified factors encompass the presence of structured training programs, the availability of supportive caregivers and facilities, and the availability of skilled interpreters. At the patient level, the fourth publication identified age, length of stay in the host-country, and the severity of PTSD symptoms as significant correlates with the intention to utilize psychotherapeutic care. The severity of PTSD symptoms emerged as the sole significant predictor of the intention, and utilization was exclusively associated with the expressed intention. This dissertation underscores the need for continuous implementation and dissemination of knowledge among all levels of the actors involved in the process of psychotherapeutic care of UYRs. At the practitioner level, the ongoing provision of structured training in evidence-based manuals is imperative, as their efficacy in practice has been well-documented. Addressing individual barriers faced by patients and their caregivers, including self-stigma and a lack of knowledge about mental illness, through targeted interventions and educational initiatives is also essential. Additionally, it is important to address structural barriers that impede the utilization of these services.

Die vorliegende Dissertation besteht aus mehreren Publikationen, die sich mit der Entwicklung, Implementierung und Evaluation des Gruppentherapieprogrammes „Wo bin ich & wo will ich hin?“ befassen. In der psychoedukativen, kognitiv-verhaltenstherapeutisch fundierten Intervention zur beruflichen Orientierung jugendlicher Patientinnen und Patienten, in der Inhalte und Strategien vermittelt werden, geht es letztlich und entscheidend darum, anstehende Lebensaufgaben offensiv und konstruktiv anzugehen. Dies wurde im Rahmen einer randomisierten Fall-Kontroll-Studie mit insgesamt 208 Teilnehmern an einer psychosomatischen Fachklinik im stationären Setting erprobt und anschließend evaluiert. Damit einher ging die wissenschaftliche Frage, inwieweit es im Rahmen des auf sechs Sitzungen angelegten Programms gelingen kann, psychisch manifest erkrankte, sich in stationärer psychosomatischer Behandlung befindliche Jugendliche dazu zu motivieren und anzuleiten, relevante Fortschritte hinsichtlich der genannten Entwicklungsaufgaben zu machen. Prüfhypothese: Eine konkretisierte berufliche Orientierung führt bei psychisch erkrankten Jugendlichen dazu, die subjektiv erlebte Beeinträchtigung bzw. das Leiden unter der zum Entlassungszeitpunkt aus der stationären Behandlung noch vorhandenen (Rest-) Symptomatik zu verringern. Ergebnisse: Das Gruppentherapieprogramm „Wo bin ich & Wo will ich hin?“ erwies sich in der Umsetzung für Teilnehmende und Gruppenleiter als gleichermaßen praktikabel und attraktiv. Die Prüfhypothese konnte empirisch bestätigt werden. In der Synopse werden die insgesamt vier in peer-reviewed Journalen erschienenen Publikationen detailliert referenziert und im Rahmen des Projektes kontextualisiert.

Confidence, a subjective evaluation about the correctness of one's own decision, is influenced by many aspects of the decision itself, for example the level of difficulty. Empirically, the time it takes to make a decision is also related to confidence, such that faster decisions are usually accompanied with higher confidence compared to slower decisions. The mathematical framework of sequential sampling models offers a way to formalize a unified theory of the complex relationship between task difficulty, response times, and confidence judgments. The three studies in this thesis utilized the sequential sampling framework to yield insight into the decision dynamics and computations that give rise to confidence judgments in perceptual decisions. In Study 1 and 2, a variety of dynamical confidence models are compared with respect to their fit to empirical data from experiments comprising different visual discrimination tasks with a difficulty manipulation. In Study 1, I formulated the dynamical weighted evidence and visibility (dynWEV) model and in Study 2, I refined the model to the dynamical visibility, time, and evidence model (dynaViTE) model. The dynaViTE model describes the decision process as a drift diffusion model. In addition, dynaViTE assumes a period of post-decisional accumulation of evidence and a parallel accumulation of visibility evidence, which accrues evidence about task difficulty. In dynaViTE, confidence is determined by a combination of decision evidence and visibility evidence in the form of a weighted sum, penalized by the duration of evidence accumulation. In Study 1, I compared different dynamical confidence models, which are based on either a race of accumulators or the drift diffusion model, on their fit to data from two experiments comprising different visual discrimination tasks with a difficulty manipulation. The newly proposed dynWEV model outperformed all competitors suggesting that confidence is not only determined by evidence about stimulus identity but is influenced by independent evidence about task difficulty, which is conveyed by choice-irrelevant stimulus features. Study 2 examined the role of the duration of evidence accumulation in the computation of confidence. Theoretically supported by a formal analysis of confidence in a Bayesian optimal observer model, I generalized the dynWEV model to include a penalization of the time it takes to accumulate evidence and form a decision in the computation of confidence, resulting in the dynaViTE model. The dynaViTE model is compared against three of its special cases that either ignore accumulation time, visibility evidence, or both accumulation time and visibility evidence in the computation of confidence. We used previously published empirical data from four experiments, three visual discrimination tasks with a difficulty manipulation, and one visual two-alternative forced choice task with a difficulty and a speed-accuracy manipulation. The results suggest that human observers indeed explicitly consider accumulation time when making confidence judgments. However, depending on the task at hand, either visibility accumulation or accumulation time may be less relevant in the formation of confidence, which suggests that some stimuli or experimental tasks leads to different strategies in confidence computations. The third study showcases the R package dynConfiR, which includes an implementation of several dynamical confidence models together with high-level functions for parameter estimation and prediction of response time distributions. The package offers an efficient and intuitive model fitting function, which simplifies the workflow for modeling studies with confidence and response time data to calling a few lines of code. Thus, the dynConfiR package provides useful tools for analyzing response time and confidence data across a variety of experiments. In sum, the dynaViTE model forms a computational model, which formalizes the relationship between task difficulty, choice, response time, and confidence judgment. The dynaViTE model extends previous theories of confidence by including the parallel assessment of independent evidence about task difficulty and the incorporation of accumulation time in the computation of confidence. The studies presented in this thesis deliver substantial evidence in supporting both features, the parallel accumulation of visibility and the incorporation of accumulation time in the computation of confidence. This thesis thus forms an important contribution to the growing research on decision mechanics and confidence and thereby improve our understanding how confidence arises in perceptual decisions.