Postmortem findings, neuroimaging data, and in-vitro models suggest a decrease in number and density of oligodendrocytes is driving cognitive deficits in schizophrenia (SCZ). Second-generation antipsychotics are discussed to improve oligodendrocyte dysfunction with most conclusive evidence available for quetiapine (QET). We postulate that sustained QET treatment leads to cognitive improvement in SCZ, particularly, in tests with high demands for working memory function. We further hypothesize that these effects are moderated by polygenic factors associated with hippocampus-related brain volumes, general white matter integrity, and/or oligodendroglia-related SCZ risk. Using data of the prospective PsyCourse study, we identified 166 patients with SCZ spectrum disorder receiving QET at one or two consecutive visits plus 166 matched patients without QET. Polygenic scores were calculated for subcortical brain volumes, measures of white matter integrity, and for cell type-specific genetic SCZ risks. QET treatment was consistently associated with improved cognitive function independent of time, specifically, in tests with high, but not with low to medium working memory load. Polygenic analyses did not reveal significant moderation effects. In contrary, low genetic SCZ risk specific for genes related to human oligodendrocyte function was associated with higher cognitive performance independent from QET. While we observed improved cognitive performance under QET in high working memory tests, we did not find evidence that polygenic factors associated with hippocampus-related brain volumes, white matter integrity, or oligodendroglia-related SCZ risk moderate this association. Thus, our tentative findings do not provide evidence for the hypothesis that polygenic estimates of hippocampal remyelination capacities influence the association between QET and cognitive performance in SCZ.

Abstract Schizophrenia (SCZ) frequently co-occurs with substance use disorders (SUDs), yet the genetic basis of this comorbidity remains unclear. Using the latest European-ancestry genome-wide association studies (GWAS) for SCZ, cannabis use disorder (CanUD), opioid use disorder (OUD), problematic alcohol use (PAU), tobacco use disorder (TUD), and a general addiction factor (AF), together with two SCZ and one SUD case-control samples with individual-level genotype data, we applied multiple complementary genomic approaches to characterize their shared genetic architecture. Significant positive genome-wide genetic correlations were observed across all SCZ–SUD pairs. Local genetic correlation analyses identified multiple genomic regions contributing to this shared architecture, with both positive and negative correlations, and evidence of genomic regions shared across multiple SCZ–SUD pairs. Polygenic overlap analyses indicated substantial sharing (25-50%) of trait-associated variants between SCZ and SUDs. Genomic structural equation modelling supported a common latent factor underlying SCZ and all SUDs, accounting for approximately 23% of SCZ variance. Cross-trait polygenic risk score (PRS) analyses showed bidirectional associations between SCZ and SUD genetic liability. Mendelian randomization analyses provided evidence for a bidirectional causal relationship between SCZ and CanUD. Horizontal pleiotropy analyses identified numerous loci with concordant and discordant effects across traits, including loci shared among multiple SCZ–SUD pairs. Gene mapping and enrichment analyses indicated pathways related to neuroplasticity, synaptic transmission, immune system, metabolism and proteolysis, including both shared and SCZ–SUD-specific biological processes. Overall, these findings suggest that part of SCZ liability reflects genetic susceptibility to SUDs with potential implications for patient stratification and clinical management.

Safety behavior is used to prevent or minimize perceived threats and contributes to the maintenance of anxiety disorders. Various types of safety behavior (e.g. cognitive, interoceptive strategies, aids, substances) are prevalent. Although assumed to be counterproductive during exposure-based CBT, little is known about its frequency and course across exposure exercises and its relation to treatment outcome. This study examined safety behavior during exposure-based CBT in a large multicenter outpatient sample and investigated its association with treatment outcome and clinical and exposure characteristic correlates. Safety behavior was dichotomously assessed after each exposure exercise using standardized worksheets (7,301) from 639 patients with panic disorder/agoraphobia, social anxiety disorder, or multiple specific phobia. Despite instructions to refrain from it, approximately half of patients reported safety behavior during their first exposure, most frequently cognitive strategies. It decreased significantly across exercises. More frequent safety behavior was associated with less symptom improvement and occurred more often with higher anticipatory and actual fear. Decline was steeper in therapist-guided than self-directed exposures, although therapist-guided exposures occurred first. Safety behavior is common early in exposure-based CBT and decreases across exposure exercises. Continuous monitoring appears important given its associations with clinical variables, exposure characteristics, and treatment outcome.Trial registration: NIMH Protocol Registration System (01EE1402A), German Register of Clinical Studies (DRKS00008743).

AIMS:Winter birth (WB) is a replicated risk factor for mental health conditions, potentially due to third-trimester Vitamin D deficiency and maternal viral infections. Beyond diagnosis, WB is associated with psychopathology, cognition, and functionality as epiphenomena. We analysed these outcomes in psychosis and affective disorders, considering illness duration and sex-specific effects. METHODS:We included 535 individuals with schizophrenia-spectrum and 667 with affective disorders from the PsyCourse Study, evaluated at four time points over 18 months. Participants were stratified by the birth season: winter vs. other seasons and by duration of illness (</≥5 years). Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) for psychosis, Inventory of Depressive Symptomatology (IDS-C30) and Young Mania Rating Scale (YMRS) for affective disorders, functionality with the Global Assessment of Functioning Scale (GAF), and cognitive performance with Trail Making Tests A (TMT-A) and B (TMT-B), Verbal Digit Span, and Digit Symbol Test (DST). Linear mixed models adjusted for covariates were applied. RESULTS:No interaction effects between WB and diagnostic group or time remained significant after correction for multiple comparisons. In sex-stratified models, a significant WB × time interaction emerged for DST in females, with WB participants showing improvements over time in schizophrenia-spectrum disorders, and a crossover pattern in affective disorders. CONCLUSIONS:WB has no robust effect on long-term outcomes on schizophrenia-spectrum or affective disorders. Subtle, sex-dependent effects on cognition were observed in females, with divergent longitudinal patterns between diagnostic groups, suggesting a possible early-life influence that attenuates over the course of illness.

Background Comorbidity between anxiety and depression is highly prevalent. Network theory offers a psychometric approach to studying psychopathology and comorbidity. This study investigated connectivity between anxiety and depressive symptoms in a transdiagnostic, outpatient anxiety sample using network analysis. Method In a secondary analysis of baseline data from an RCT, enrolling patients with agoraphobia, agoraphobia with panic disorder, panic disorder, social phobia or ≥ 2 specific phobias as a primary diagnosis, a regularized partial correlation network was estimated to examine symptom connectivity and (bridge) strength centrality. Subsequently, the sample was divided into two subgroups: individuals with and without comorbid depressive disorders. We first compared anxiety symptom severity between groups, followed by the estimation of separate networks to compare network structure, edge strength, and global strength. Results Out of 726 patients, 46.56% presented a comorbid depressive disorder. Symptoms with highest strength centrality in the full-sample network were worthlessness, loss of energy and feeling burdened due to anxiety-related problems. Next to the symptom agitation, the latter also emerged as the strongest bridge symptom. The comorbid group showed higher anxiety severity, while networks did not differ in any examined measure. Conclusions Symptoms with highest strength centrality matched ICD-10 main criteria for depression and a wide range of anxiety disorders, supporting strength centrality as a clinically meaningful marker. The determination of bridge strength may highlight clinically relevant candidates for future transdiagnostic investigations. Contrary to theoretical assumptions of the network approach, higher anxiety symptom severity in the comorbid group was not accompanied by increased network density.

INTRODUCTION:Negative expectations about treatment outcomes are associated with poorer recovery in anxiety disorders. However, it remains unclear whether patients' expectations about how effective the treatment will be (treatment-specific expectations) mediate the link between generalized negative expectations (i.e., unspecific pessimistic beliefs) and treatment outcomes, and whether these expectations affect outcomes via the learning rate during exposure therapy that is, the extent to which patients update their fear-related beliefs based on corrective experiences. Since treatment-specific expectations may be more modifiable, clarifying these mechanisms could improve interventions. This study therefore investigated whether treatment-specific expectations and learning rate mediate the effect of generalized negative expectations on treatment outcomes. METHODS:Data from 605 patients with various anxiety disorders undergoing 12 sessions of manualized exposure therapy were analyzed. Generalized negative expectations at baseline (session 0) were hypothesized to predict treatment outcomes (i.e., symptom severity at posttreatment) via expectations about treatment success measured at session 4 and learning rate during exposure. Depression and anxiety at baseline were covariates. Mediation analyses were conducted using the PROCESS macro with bootstrap confidence intervals. RESULTS:Generalized negative expectations predicted poorer treatment outcomes (higher symptom severity), mediated by lower expectations about treatment success (β = 0.0375; 95% CI: 0.0088-0.0730). A sequential mediation via these treatment-specific expectations and learning rate was also significant (β = 0.0059; 95% CI: 0.0008-0.0134), even after accounting for baseline symptom levels (R2 = 0.3375). CONCLUSION:Targeting both generalized and treatment-specific expectations early in treatment may enhance exposure-based learning and improve clinical outcomes in anxiety disorders.

Abstract Executive Functions (EF) control goal-oriented behaviors and are disrupted in patients with psychiatric disorders (PPD). Repeated EF testing in clinical practice and research aims to evaluate disease progression and treatment efficacy. Performance improvements (or “practice effects”) are expected, while deficiencies had been proposed as markers of conversion to dementia. Given the high conversion risk in PPD, understanding the determinants of practice effects is of high relevance. However, the role of genetic predisposition remains unknown. We aim to test the influence of polygenic scores on practice effects across PPD. Data were drawn from the longitudinal deep-phenotyping PsyCourse Study (N = 1,558). Latent factor analysis revealed a common Executive Function factor (cEF), which explained shared variability of 5 different EF tests. We tested the association of polygenic scores for the cEF (PGS-cEF) – based on the largest GWAS on cEF to date (N = 427,037) - with cEF scores improvements in PsyCourse. The PGS for general psychopathology “p-Factor” (PGS-PF) were used as a psychiatric liability comparison. Volunteer adults (> 18 y.o.), with and without diagnoses within the Affective-Psychotic spectrum were recruited across Germany and Austria, followed-up four times at six months intervals. The mean PGS-cEF was lower in patients with psychotic vs. affective disorders (diff: -0.01, 95% CI -0.02 to -0.002) and controls (diff: -0.02, 95% CI -0.03 - -0.006); while the mean PGS-PF was higher in psychotic vs. affective disorders (diff: 0.02, 95% CI 0.01 to 0.04) and controls (diff: 0.03, 95% CI 0.02–0.05). Overall, the PGS-cEF x Visit interaction was associated with the phenotypic latent cEF scores (eta2 = 0.03; p = 1.32e-15), but not with the scores of individual EF tests. There was no PGS-PF x Visit interaction associated with any cognitive score. To the best of our knowledge, this is the first analysis of genetic factors related to EF improvements in PPD. The PGS-cEF, but not the PGS-PF predicted practice effects in cEF scores over 18 months. This prediction was only observable using the latent‑cEF level, and not with the individual scores. Genetic testing and deep phenotyping might hint further information about EF vulnerability in PPD.

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder and phobias) are highly prevalent, often onset early and cause substantial global disability. Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat-response system. Here, we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 out of the 58 associations replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism implicated in ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

Suicide is a significant global public health issue and expected to contribute increasingly to the global burden of disease over the coming decades. Suicide attempts are much more common than completed suicides and represent a major risk factor for and predictor of suicide. Increasing evidence links suicidal behavior to neuroinflammation, i.e., inflammatory processes in the brain. Therefore, in a subsample (n = 155) of the PsyCourse Study we investigated whether the circulating levels of 12 inflammatory proteins from the Olink® Explore 384 Inflammation Panel are associated with suicide attempts. We found significantly higher interleukin (IL)-1β levels in suicide attempters than in non-suicide attempters. Our finding indicates that the IL-1 signaling pathway plays a critical role in suicidal behavior and suggests that targeting this inflammatory pathway may help prevent suicide. This finding needs to be replicated in a larger sample.

Expectancy violation has been proposed as a potential core mechanism of action in psychotherapy, particularly in exposure therapy for anxiety disorders. However, various relevant expectations have been discussed, and empirical studies examining their significance are still scarce. This study aimed to investigate one specific form of expectancy violation, based on Rachman's (1994) match-mismatch model, specifically by comparing expected and experienced fear and examining their relationship to safety behaviour during exposure in vivo in 268 patients meeting DSM-IV criteria for panic disorder with agoraphobia. Participants underwent exposure to a highly controlled manual-based cognitive behaviour therapy in a randomised multicenter psychotherapy study. Participants tended to overpredict fear during exposure. Both expected and experienced fear significantly decreased over the course of repeated exposure exercises, while prediction (in)accuracy (difference between expected and experienced fear) remained stable. The decrease in expected fear over time was a strong predictor of treatment outcomes for the Bodily Sensations Questionnaire (BSQ) and Panic and Agoraphobia Scale (PAS) at post. Even more, the reduction in expected fear was a significant predictor of treatment success across all outcome measures in the follow-up assessment. These findings suggest that violating excessive fear expectancies is not a necessary condition for symptom reduction during exposure therapy.

Alterations in glial cell function and cytokine levels in the central nervous system may be influenced by neuroinflammatory processes, which have a pathogenic role in psychiatric disorders. Variability in genes that encode inflammatory mediators is associated with risk of developing mental disorders. Therefore, by analyzing data from the transdiagnostic PsyCourse Study, we aimed to investigate whether variations in inflammatory mediator genes are associated with current symptom severity.We used cross-sectional data from 1320 individuals with a psychiatric disorder and 466 neurotypical individuals. Outcome variables were the psychopathological data from various rating scales and questionnaires that measured depressive, psychotic, and manic symptoms. Furthermore, from a whole-genome SNP array dataset, we extracted single nucleotide polymorphisms (SNPs) in the loci of genes related to inflammatory mediators, and we performed an association analysis by considering covariates. False discovery rate (FDR) was used to adjust the results for multiple comparisons.A total of 1594 individuals and 1336 SNPs were included in the analyses. The results of regression analysis showed a significant positive association of six SNPs located on the interleukin (IL)-1 receptor type 1 (IL-1R1) gene locus with Altman Self-Rating Mania Scale scores (FDR-adjusted p value < 0.05).Our findings show that genetic variations in IL-1R1 may influence the pathophysiology of psychiatric disorders by affecting brain cytokine profiles associated with manic episodes. IL-1R1 encodes a membrane-bound receptor for IL-1. Several physiological functions, including inflammation, are linked to the IL-1/IL-1R1 signaling pathway. Replication of our findings is warranted.

Micro RNAs (miRNAs) play a crucial role as regulators of various biological processes and have been implicated in the pathogenesis of mental disorders such as schizophrenia and bipolar disorders. In this study, we investigate the expression patterns of miRNAs in the PsyCourse Study (n = 1786), contrasting three broad diagnostic groups: Psychotic (Schizophrenia-spectrum disorders), Affective (Bipolar Disorder I, II and recurrent Depression), and neurotypic healthy individuals. Through comprehensive analyses, including differential miRNA expression, miRNA transcriptome-wide association study (TWAS), and predictive modelling, we identified multiple miRNAs unique to Psychotic and Affective groups as well as shared by both. Furthermore, we performed integrative analysis to identify the target genes of the dysregulated miRNAs and elucidate their potential roles in psychosis. Our findings reveal significant alterations of multiple miRNAs such as miR-584-3p and miR-99b-5p across the studied diagnostic groups, highlighting their role as molecular correlates. Additionally, the miRNA TWAS analysis discovered previously known and novel genetically dysregulated miRNAs confirming the relevance in the etiology of the diagnostic groups. Importantly, novel factors and putative molecular mechanisms underlying these groups were uncovered through the integration of miRNA-target gene interactions. This comprehensive investigation provides valuable insights into the molecular underpinnings of severe mental disorders, shedding light on the complex regulatory networks involving miRNAs.

We investigated whether the brain age gap (BAG)—the difference between chronological age and age estimated from structural MRI scans—is associated with long-term disease course in affective disorders, using a prospective nine-year follow-up design. T1-weighted MRI data were collected at two time points (mean interval = 8.98 ± 2.20 years) from patients with Major Depressive Disorder (MDD; N = 32), Bipolar Disorder (BD; N = 6), and healthy controls (HC; N = 37) across two sites. Using a brain age prediction model trained on a sample of over 10,000 subjects of the German National Cohort (GNC), we estimated individual BAG at baseline and follow-up using gray matter segments derived from MRI images. Employing linear-mixed-effects models, we tested main effects of diagnosis and hospitalizations as well as their interaction with time on BAG. In an exploratory analysis, we tested if BAG at baseline was predictive of hospitalizations during the nine-year follow-up using logistic regression and 10-fold nested cross-validation. MDD patients showed significantly higher BAG compared to HC (2.27 ± 5.68 vs. 1.00 ± 5.12 years, d = –0.23), while BAG in BD patients was descriptively elevated (4.71 ± 5.40 years). In the Münster subsample (N = 52), patients with at least one hospitalization had higher BAG than those without (4.16 ± 5.74 vs. 1.65 ± 5.41 years, d = –0.45). No group-by-time interaction was observed. Higher BAG at baseline predicted hospitalization during follow-up (p = 0.035), although cross-validated prediction accuracy (64.3%) did not reach significance (p = 0.071). BAG remained stable over time and was not influenced by future recurrence, supporting its role as a potential trait-like marker of vulnerability to illness recurrence. While exploratory, these findings suggest that BAG may capture individual risk for future hospitalization in affective disorders.

BACKGROUND:Exposure-based CBT is highly effective in treating patients with panic disorder and agoraphobia; however, access to such treatments is often limited. Smartphone-based self-management apps offer a promising low-threshold treatment alternative to face-to-face therapy. Although such health apps have shown to be effective in reducing anxiety symptoms, comparisons to active treatments are still scarce. Therefore, this study compared the effectiveness of a self-help app to an established face-to-face CBT intervention for panic and agoraphobia. METHOD:The present study conducts a post hoc comparison of two independent RCTs examining participants with panic disorder and/or agoraphobia. Interventions in both studies were based on the same CBT manual. Study 1 (n = 138) included face-to-face CBT; Study 2 addressed the effects of a digital self-help intervention (n = 57). Main outcomes comprised symptoms of both panic disorder and agoraphobia, depressive symptoms and agoraphobic avoidance. Data were analysed using linear mixed models in intent-to-treat and completer data sets. RESULTS:Linear mixed models showed that face-to-face treatment was superior to app treatment in reducing panic and agoraphobic symptoms (R2 = 0.32), depressive symptoms (R2 = 0.24) and agoraphobic avoidance (R2 = 0.12 and 0.15). Dropout rates did not differ significantly, and both interventions demonstrated high levels of adherence. DISCUSSION:Although a smartphone-based CBT intervention was effective in reducing symptoms of panic and agoraphobia, its efficacy was significantly below the effects of the same intervention delivered in face-to-face format. Thus, digital interventions might be most suitable within a stepped-care approach or to bridge waiting times for psychotherapy.

Responses to exposure therapy vary across individuals, emphasizing the need for a deeper understanding of its underlying mechanisms. This study examined two key processes during exposure that serve as readouts of different clinical rationales: (1) within-session fear reduction (measured as the decline from peak to end fear within an exposure exercise) and (2) threat expectancy processes (assessed via expectancy violation, expectancy change, and learning rate). Data from 516 patients with anxiety disorders who completed at least 10 exposure exercises in a clinical trial were analyzed. Results showed that expectancy measures and fear reduction were only weakly correlated within exposure exercises. While no significant differences were found in their time courses, both readouts independently predicted treatment success. Specifically, a higher learning rate and greater relative fear reduction were associated with better outcomes. These findings highlight the clinical relevance of monitoring fear reduction and expectancy-related readouts as indicators of two distinct exposure rationales - the fear reduction rationale and the threat expectancy rationale. Although it remains unclear whether they reflect separate mechanisms of change or different aspects of a shared mechanism, addressing both rationales may help optimize and personalize exposure therapy.

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.

Background: Polygenic scores (PGSs) hold the potential to identify patients who respond favorably to specific psychiatric treatments. However, their biological interpretation remains unclear. In this study, we developed pathway-specific PGSs (PSPGSs) for lithium response and assessed their association with clinical lithium response in patients with bipolar disorder. Methods: Using sets of genes involved in pathways affected by lithium, we developed 9 PSPGSs and evaluated their associations with lithium response in the International Consortium on Lithium Genetics (ConLi+Gen) (N = 2367), with validation in combined PsyCourse (Pathomechanisms and Signatures in the Longitudinal Course of Psychosis) (N = 105) and BipoLife (N = 102) cohorts. The association between each PSPGS and lithium response—defined both as a continuous ALDA score and a categorical outcome (good vs. poor responses)—was evaluated using regression models, with adjustment for confounders. The cutoff for a significant association was p < .05 after multiple testing correction. Results: The PGSs for acetylcholine, GABA (gamma-aminobutyric acid), and mitochondria were associated with response to lithium in both categorical and continuous outcomes. However, the PGSs for calcium channel, circadian rhythm, and GSK (glycogen synthase kinase) were associated only with the continuous outcome. Each score explained 0.29% to 1.91% of the variance in the categorical and 0.30% to 1.54% of the variance in the continuous outcomes. A multivariate model combining PSPGSs that showed significant associations in the univariate analysis (combined PSPGS) increased the percentage of variance explained (R2) to 3.71% and 3.18% for the categorical and continuous outcomes, respectively. Associations for PGSs for GABA and circadian rhythm were replicated. Patients with the highest genetic loading (10th decile) for acetylcholine variants were 3.03 times more likely (95% CI, 1.95 to 4.69) to show a good lithium response (categorical outcome) than patients with the lowest genetic loading (1st decile). Conclusions: PSPGSs achieved predictive performance comparable to the conventional genome-wide PGSs, with the added advantage of biological interpretability using a smaller list of genetic variants.

INTRODUCTION:Achieving sustainable success in the treatment of anxiety disorders remains a central objective in mental health care. Although research has demonstrated the short-term efficacy of psychotherapy, evidence regarding long-term sustainability is limited. This study examined treatment outcomes 5 years after prediction-error-based exposure therapy. METHODS:For 355 patients (616 eligible; 58% follow-up rate), newly collected follow-up data on anxiety symptoms and psychosocial functioning were compared to pretreatment, posttreatment, and 6-month follow-up data from a multicenter clinical trial characterized by high treatment fidelity. RESULTS:Improvements in anxiety symptoms and psychosocial functioning that were evident at posttreatment and 6-month follow-up were largely preserved after 5 years. No significant differences emerged between randomized groups of temporally intensified and non-intensified exposure. From 6 months to 5 years, overall remission rates remained stable, with the majority of patients exhibiting no reliable change in symptom severity. Reliable relapse occurred in 4.9% and reliable new remission in 6.5%. Most patients (63.4%) did not seek additional treatment. Among those who did, depression (64.2%) and anxiety (60.5%) were the most frequently cited reasons, although only a minority (6.0%) sought further treatment exclusively for anxiety. Additional treatment during the follow-up period was associated with higher symptom severity throughout assessments. CONCLUSION:These findings highlight the sustainability and long-term public health benefits of exposure-based CBT for anxiety disorders. Most patients do not need additional treatments for mental disorders even 5 years after treatment. Nevertheless, further efforts are needed to optimize interventions for those patients who do not achieve remission or experience relapse.

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 8416 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 symptoms and affect. Higher positive emotions independently predicted better treatment outcome beyond learning indicators, and partially mediated the association between learning indicators and treatment outcome. These findings indicate that positive emotions are partly associated with successful learning during exposure but seem to have a unique contribution to overall treatment success, underlining the need to strengthen positive emotions via different possible means.