Improving Exposure Therapy: Rationale and Design of an International Consortium.

The Exposure Therapy Consortium (ETC) was established to advance the science and practice of exposure therapy. To encourage participation from researchers and clinicians, this article describes the organizational structure and activities of the ETC. Initial research working group experiences and a proof-of-principle study underscore the potential of team science and larger-scale collaborative research in this area. Clinical working groups have begun to identify opportunities to enhance access to helpful resources for implementing exposure therapy effectively. This article discusses directions for expanding the consortium's activities and its impact on a global scale.

DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment.

Epigenetic alterations are regarded as a potential mechanism mediating the effects of environmental risk factors on vulnerability for a range of mental health problems. Recent studies have addressed the question whether DNA methylation patterns predict the outcome of psychological interventions and whether treatment effects might be associated with changes of DNA methylation. We assessed phobic fear symptoms, treatment-relevant traits and treatment response in 308 adults free of psychotropic medication - highly fearful of either spiders, blood-injury-injections, dental-treatments or heights - all subjected to highly standardized exposure-based one-session fear treatment. DNA methylation level of the promotor region of the serotonin transporter gene (SLC6A4) was assessed in either saliva samples (spider and dental treatment fear cohorts) or oral mucosa (BII, heights) to check whether possible effects are independent of the surrogate tissue examined. Moreover, in order to examine possible DNA methylation by genotype effects, patients were assessed for genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR). DNA methylation levels were neither associated with pre-treatment fear levels, treatment relevant traits or treatment outcome data even when allelic variation of the 5HTTLPR was considered. Overall DNA methylation levels were higher in saliva samples compared to buccal samples. In saliva samples there was a small pre- to post-treatment increase in DNA methylation, which, however, was also not associated with the investigated phenotypes. We conclude that DNA methylation of SLC6A4 is no suitable biomarker for response efficacy to highly standardized one-session exposure-based fear treatments.

CBT-Intervention for panic disorder in primary care: 5 years follow-up of a cRCT during the Covid-19 pandemic.

A practice team-based exercise programme with elements of cognitive behavioural therapy (CBT) and case management for patients with panic disorder with or without agoraphobia in primary care showed significant positive effects. Here, we analyse the long-term effects (>5 years) of this intervention in the stressful context of the Covid-19 pandemic. All participants of the original PARADIES cluster randomized controlled trial (cRCT; 2012-2016) were invited to participate in a follow-up during the Covid-19 pandemic. Clinical outcomes were anxiety symptoms, number and severity of panic attacks, agoraphobic avoidance behaviour, Covid-specific anxiety symptom severity, depression, and patient assessment of chronic illness care. Data were analysed cross-sectionally for group differences (intervention, control) and longitudinally (T0: baseline, T1: 6 months and TCorona: >60 months). Of the original 419 participants, 100 participated in the 60 months follow-up (October 2020-May 2021). In the cross-sectional analysis, the anxiety symptom severity in the intervention group was lower than in the control group (p = .011, Cohen's d = .517). In the longitudinal analysis, both groups showed an increase of anxiety and depression symptoms compared to pre-pandemic level. The intervention may have had a lasting impact regarding anxiety severity despite the challenging context of the Covid-19 pandemic. However, we cannot say to what extend the intervention still played a role in participants' lives; other factors may also have helped with coping. The increase of anxiety and depression symptoms in both groups over time could be attributed to external circumstances.

Demonstration of a 'leapfrog' randomized controlled trial as a method to accelerate the development and optimization of psychological interventions.

BACKGROUND: The scale of the global mental health burden indicates the inadequacy not only of current treatment options, but also the pace of the standard treatment development process. The 'leapfrog' trial design is a newly-developed simple Bayesian adaptive trial design with potential to accelerate treatment development. A first leapfrog trial was conducted to provide a demonstration and test feasibility, applying the method to a low-intensity internet-delivered intervention targeting anhedonia. METHODS: At the start of this online, single-blind leapfrog trial, participants self-reporting depression were randomized to an initial control arm comprising four weeks of weekly questionnaires, or one of two versions of a four-week cognitive training intervention, imagery cognitive bias modification (imagery CBM). Intervention arms were compared to control on an ongoing basis via sequential Bayesian analyses, based on a primary outcome of anhedonia at post-intervention. Results were used to eliminate and replace arms, or to promote them to become the control condition based on pre-specified Bayes factor and sample size thresholds. Two further intervention arms (variants of imagery CBM) were added into the trial as it progressed. RESULTS: N = 188 participants were randomized across the five trial arms. The leapfrog methodology was successfully implemented to identify a 'winning' version of the imagery CBM, i.e. the version most successful in reducing anhedonia, following sequential elimination of the other arms. CONCLUSIONS: The study demonstrates feasibility of the leapfrog design and provides a foundation for its adoption as a method to accelerate treatment development in mental health. Registration: clinicaltrials.gov, NCT04791137.

Calibrating your own fears: Feasibility of a remote fear conditioning paradigm with semi-subjective stimulus calibration and differences in fear learning.

Fear conditioning studies have occurred mostly in the laboratory, but recently researchers have started to adapt fear conditioning procedures for remote application. Standardization of aversive stimulus material not causing unnecessarily strong discomfort remains an issue especially relevant to research without experimental supervision. The present study introduces a novel semi-subjective method to calibrate aversive sounds in a remotely conducted fear conditioning paradigm. To demonstrate feasibility and proof of concept, 165 participants completed the paradigm, calibrating the loudness of an aversive sound without the guidance of an experimental instructor. This study also aimed to replicate existing findings of participant groups that differed in their early CS-UCS contingency awareness. Participants were classified as Accurate (UCS more likely after the CS+ than CS-), Poor (UCS more likely after the CS- than CS+, or UCS unlikely after either CS), and Threat Biased (UCS equally likely after the CS+ and CS-). Results indicated both the feasibility and efficacy of the paradigm, with participants showing typical patterns of fear learning. Threat Biased participants showed significantly higher uncertainty towards safety signals. There were no differences between the groups in terms of personality traits, thus questioning whether these attributes mediate differences in fear learning and the emergence of anxiety disorders. Using semi-subjective sound calibration appears to be functional, and future studies may consider implementing the new method when remotely administering fear conditioning paradigms.

Fear conditioning and extinction learning in the mood and anxiety disorders spectrum - Associations with the outcome of cognitive behavior therapy.

In the current study, we test for the specificity of deficits in fear acquisition and extinction for the anxiety disorders spectrum. We compared fear acquisition and fear extinction learning between a group of patients with either an anxiety disorder (n = 93) or depression (n = 103) attending for treatment in our outpatient center and a sample of healthy control participants (n = 60). To assess the specificity of the predictive validity of extinction learning and safety learning for the outcome of exposure-based treatments, patients additionally underwent disorder-specific cognitive behavior therapy (CBT). We found only very little evidence for differences in safety or extinction learning between healthy controls and patients with anxiety-disorders or depression using both a group-based categorical analytic approach, as well as a trans-diagnostic, dimensional analytic approach. On the contrary, for anxiety patients only, more favorable extinction learning and more favorable safety learning was associated with more favorable treatment outcome. In sum, this specific prediction of treatment outcome in anxiety patients confirms and extends current theoretical models of exposure-based treatments for anxiety disorders, but does not support the notion of general extinction learning deficits in the anxiety disorders spectrum.

Genes in treatment: Polygenic risk scores for different psychopathologies, neuroticism, educational attainment and IQ and the outcome of two different exposure-based fear treatments.

OBJECTIVES: Evidence for a genetic influence on psychological treatment outcome so far has been inconsistent, likely due to the focus on candidate genes and the heterogeneity of the disorders treated. Using polygenic risk scores (PRS) in homogenous patient samples may increase the chance of detecting genetic influences. METHODS: A sample of 342 phobic patients treated either for clinically relevant dental fear (n = 189) or other (mixed) phobic fears (n = 153) underwent highly standardised exposure-based CBT. A brief five-session format was used to treat dental fear, whereas longer multi-session treatments were used with the mixed-fear cohort. PRS were calculated based on large genetic studies of Neuroticism, Educational Attainment (EA), Intelligence, and four psychopathology domains. We compared PRS of post-treatment and follow-up remitters and non-remitters and regressed PRS on fear reduction percentages. RESULTS: In the dental fear cohort, EA PRS were associated with treatment outcomes, i.e. drop-out, short- and long-term remission state, fear reduction, and attendance of subsequent dental appointments. In the mixed fear treatment cohort, no gene effects were observable. CONCLUSIONS: Results indicate the importance of EA-related traits for outcomes following brief, but not long, standardised exposure-based CBT. Such use of PRS may help inform selection and tailoring of treatments.

High place phenomenon: prevalence and clinical correlates in two German samples.

BACKGROUND: The high place phenomenon, that is, a sudden urge to jump when in a high place, is an experience known to many people, that has rarely been studied. The present study aimed to assess the prevalence of the high place phenomenon in a non-clinical and a clinical German sample. Furthermore, clinical correlates of the experience were assessed. METHODS: The study sample comprised 276 participants (67% female; Mage = 32.08, SDage = 10.73) who took part in an online assessment and 94 patients (73.4% female; Mage = 49.26, SDage = 13.32) suffering from clinically relevant fear of flying. Participants filled out questionnaires on experiences with the high place phenomenon, depression, anxiety, suicide ideation and anxiety sensitivity. RESULTS: The high place phenomenon was known to nearly 60% of the online sample and to 45% of the patient sample. Suicide ideation as well as anxiety sensitivity were positively associated with experiences with the high place phenomenon in the online sample. Depression, anxiety and suicide ideation were unrelated to experiences with the phenomenon in the patient sample. CONCLUSION: The high place phenomenon is commonly reported by (lifetime/current) suicide ideators. However, it is also a common experience in individuals who have never suffered from suicide ideation. It is therefore cautioned not to interpret such experiences as an expression of a hidden death wish.

Affective Styles in Panic Disorder and Specific Phobia: Changes Through Cognitive Behavior Therapy and Prediction of Remission.

Affective styles appear to be relevant to the development of psychopathology, especially anxiety disorders. The aim of the current study was to investigate changes in affective styles in patients with panic disorder and specific phobia, as a result of undergoing cognitive-behavioral therapy, and to identify a possible link between certain affective styles and remission. The sample consisted of outpatients (N = 101) suffering from panic disorder, specific phobia, or agoraphobia who completed the Affective Style Questionnaire (ASQ) before and after therapy, as well as at a 6-month follow-up assessment. Multivariate analyses of variance were conducted to test for changes due to therapy. Logistic regression analyses were calculated to test for the impact of affective styles on remission from anxiety disorders, and hierarchical regression analyses were calculated to examine the association between changes in affective styles and symptom reduction. Results indicated significant increases on the ASQ subscales adjusting and tolerating after therapy. Concealing did not decrease significantly after therapy. In addition, higher scores on adjusting significantly predicted remission from anxiety disorders. Finally, we found a significant association between increases on the adjusting scale and the reduction of anxiety symptoms.

A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders.

Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (rg ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h2SNP) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h2SNP could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.

DNA methylation of FKBP5 and response to exposure-based psychological therapy.

Differential DNA methylation of the hypothalamic-pituitary-adrenal axis related gene FKBP5 has recently been shown to be associated with varying response to environmental influences and may play a role in how well people respond to psychological treatments. Participants (n = 111) received exposure-based cognitive behavioural therapy (CBT) for agoraphobia with or without panic disorder, or specific phobias. Percentage DNA methylation levels were measured for the promoter region and intron 7 of FKBP5. The association between percentage reduction in clinical severity and change in DNA methylation was tested using linear mixed models. The effect of genotype (rs1360780) was tested by the inclusion of an interaction term. The association between change in DNA methylation and FKBP5 expression was examined. Change in percentage DNA methylation at one CpG site of intron 7 was associated with percentage reduction in severity (ß = -4.26, p = 3.90 × 10-4 ), where a decrease in DNA methylation was associated with greater response to therapy. An interaction was detected between rs1360780 and changes in DNA methylation in the promoter region of FKBP5 on treatment outcome (p = .045) but did not survive correction for multiple testing. Changes in DNA methylation were not associated with FKBP5 expression. Decreasing DNA methylation at one CpG site of intron 7 of FKBP5 was strongly associated with decreasing anxiety severity following exposure-based CBT. In addition, there was suggestive evidence that allele-specific methylation at the promoter region may also be associated with treatment response. The results of this study add to the growing literature demonstrating the role of biological processes such as DNA methylation in response to environmental influences.

High frequency heart rate variability: Evidence for a transdiagnostic association with suicide ideation.

Low levels of high frequency heart rate variability (HF-HRV) have been shown to be associated with suicidal ideation and behavior in students and depressed patients. The goal of the present study was to examine associations between suicide ideation and resting HF-HRV as well as HF-HRV reactivity in a diagnostically heterogeneous sample of adult outpatients with or without concurrent suicide ideation. Participants were N = 85 outpatients (67.1% female; age: M = 38.8, SD = 13.72). HF-HRV reactivity was assessed using a sad film induction method. Associations between resting HF-HRV, HF-HRV reactivity and suicide ideation were analyzed using linear regression modeling - controlling for depression, anxiety and stress. HF-HRV reactivity towards the sad film, but not low resting HF-HRV baseline, was predictive of higher scores on suicidal ideation within the whole sample. In women, lower resting as well as perturbed HF-HRV reactivity was associated with higher scores on suicidal ideation. Results suggest that suicide ideators have a reduced capacity to regulate their response to stress.

Predictors of remission from panic disorder, agoraphobia and specific phobia in outpatients receiving exposure therapy: The importance of positive mental health.

Positive mental health has been shown to predict remission from anxiety disorders in community samples. However, it is unclear, whether positive mental health is also predictive of symptom severity and remission from anxiety disorders in patients receiving exposure therapy. A total of 130 adult outpatients suffering from panic disorder, agoraphobia, or specific phobia received manualized exposure-therapy. Positive mental health was considered as a predictor of symptom severity and remission at the post-treatment assessment and at the follow-up assessment six months after treatment termination - controlling for depression, anxiety, anxiety cognitions, bodily sensations, number of treatment sessions, age and gender. Pre-treatment positive mental health was the only predictor of post-treatment symptom severity and remission status. Post-treatment positive mental health and avoidance behavior predicted symptom severity and remission status at the follow-up assessment. In conclusion, the current study highlights the importance of positive mental health in understanding remission from anxiety disorders.

Lifestyle choices and mental health: a longitudinal survey with German and Chinese students.

BACKGROUND: A healthy lifestyle can be beneficial for one's mental health. Thus, identifying healthy lifestyle choices that promote psychological well-being and reduce mental problems is useful to prevent mental disorders. The aim of this longitudinal study was to evaluate the predictive values of a broad range of lifestyle choices for positive mental health (PMH) and mental health problems (MHP) in German and Chinese students. METHOD: Data were assessed at baseline and at 1-year follow-up. Samples included 2991 German (Mage = 21.69, SD = 4.07) and 12,405 Chinese (Mage = 20.59, SD = 1.58) university students. Lifestyle choices were body mass index, frequency of physical and mental activities, frequency of alcohol consumption, smoking, vegetarian diet, and social rhythm irregularity. PMH and MHP were measured with the Positive Mental Health Scale and a 21-item version of the Depression Anxiety and Stress Scale. The predictive values of lifestyle choices for PMH and MHP at baseline and follow-up were assessed with single-group and multi-group path analyses. RESULTS: Better mental health (higher PMH and fewer MHP) at baseline was predicted by a lower body mass index, a higher frequency of physical and mental activities, non-smoking, a non-vegetarian diet, and a more regular social rhythm. When controlling for baseline mental health, age, and gender, physical activity was a positive predictor of PMH, smoking was a positive predictor of MHP, and a more irregular social rhythm was a positive predictor of PMH and a negative predictor of MHP at follow-up. The good fit of a multi-group model indicated that most lifestyle choices predict mental health comparably across samples. Some country-specific effects emerged: frequency of alcohol consumption, for example, predicted better mental health in German and poorer mental health in Chinese students. CONCLUSIONS: Our findings underline the importance of healthy lifestyle choices for improved psychological well-being and fewer mental health difficulties. Effects of lifestyle on mental health are comparable in German and Chinese students. Some healthy lifestyle choices (i.e., more frequent physical activity, non-smoking, regular social rhythm) are related to improvements in mental health over a 1-year period.

The Return of Fear: Variation of the Serotonin Transporter Gene Predicts Outcome of a Highly Standardized Exposure-Based One-Session Fear Treatment.

BACKGROUND: Methodological problems of existing research, such as the application of unstandardized treatments in heterogeneous samples, has hampered clear conclusions about the extent and direction to which allelic variation of the serotonin transporter gene-linked polymorphic region (5- HTTLPR) is associated with a differential response to psychological treatment. The present study aimed to investigate the effects of the 5-HTTLPR genotype on treatment outcome under highly standardized environmental conditions. METHODS: We treated 222 medication-free adults highly fearful of spiders, dental surgeries or blood, injuries and injections with a highly standardized exposure-based 1-session treatment and genotyped them for the 5-HTTLPR. Participants' subjective fear was assessed before, immediately after treatment and at 7 months of follow-up. RESULTS: There were no differences between 5-HTTLPR genotypes in treatment outcome effects at the immediate posttreatment assessment. However, we observed a highly significant genotype × treatment effect (p = 0.004) at the 7-month follow-up. Fear levels of homozygous S allele carriers differed from those heterozygous (p = 0.026) and homozygous (p = 0.012) for the L allele. Compared to posttreatment assessment, LL allele carriers exhibited a further fear decrease at the follow-up assessment. In contrast, SS allele carriers displayed a strong return of fear. CONCLUSIONS: Results suggest that genetic variation of the serotonin transporter is associated with differential stability of inhibitory learning processes, potentially reflecting heightened susceptibility for context-related processes that facilitate a return of fear in S allele carriers. If replicated, results suggest the 5-HTTLPR might represent a biomarker for the long-term outcome of brief exposure-based fear treatments and might inform genotype-based selection of psychotherapeutic interventions.

The influence of frontal alpha-asymmetry on the processing of approach- and withdrawal-related stimuli-A multichannel psychophysiology study.

The approach-withdrawal model of hemispheric activation suggests that left frontal cortical areas mediate approach, while right frontal cortical areas mediate withdrawal motivation. Within this framework, the present study investigates the association of frontal cortical asymmetry with attentional and emotional responses toward approach- and withdrawal-related emotional stimuli. Resting frontal asymmetry was measured from 43 students before they passively viewed negative, neutral, and positive emotional pictures. The startle reflex, skin conductance response, and subjective ratings of valence and arousal were assessed to quantify emotional responding, while attention was assessed with ERPs. We also assessed frontal asymmetry in response to the pictures. Results indicated that relatively stronger right frontal cortical activation was associated with increased N1 amplitudes and more negative subjective emotional evaluation of all stimuli. Furthermore, enhanced right frontal asymmetry (state and trait) was associated with diminished emotional modulation of the late positive potential. In contrast, no association of frontal asymmetry with defensive reflex physiology or activation of sympathetic nervous system activity was found. The current data suggest dissociable influence of resting frontal brain asymmetry on attentional and physiological processing of withdrawal- and approach-related stimuli. That is, asymmetrical frontal cortical brain activation might not modulate approach-/withdrawal-related motor responses and sympathetic arousal directly, but instead enhances allocation of attentional resources to subjectively significant stimuli. The results are discussed in terms of their potential importance for emotion perception in anxiety disorders and their contribution to the understanding of frontal asymmetry.

Separate and combined effects of genetic variants and pre-treatment whole blood gene expression on response to exposure-based cognitive behavioural therapy for anxiety disorders.

OBJECTIVES: Exposure-based cognitive behavioural therapy (eCBT) is an effective treatment for anxiety disorders. Response varies between individuals. Gene expression integrates genetic and environmental influences. We analysed the effect of gene expression and genetic markers separately and together on treatment response. METHODS: Adult participants (n ≤ 181) diagnosed with panic disorder or a specific phobia underwent eCBT as part of standard care. Percentage decrease in the Clinical Global Impression severity rating was assessed across treatment, and between baseline and a 6-month follow-up. Associations with treatment response were assessed using expression data from 3,233 probes, and expression profiles clustered in a data- and literature-driven manner. A total of 3,343,497 genetic variants were used to predict treatment response alone and combined in polygenic risk scores. Genotype and expression data were combined in expression quantitative trait loci (eQTL) analyses. RESULTS: Expression levels were not associated with either treatment phenotype in any analysis. A total of 1,492 eQTLs were identified with q < 0.05, but interactions between genetic variants and treatment response did not affect expression levels significantly. Genetic variants did not significantly predict treatment response alone or in polygenic risk scores. CONCLUSIONS: We assessed gene expression alone and alongside genetic variants. No associations with treatment outcome were identified. Future studies require larger sample sizes to discover associations.

Modality of fear cues affects acoustic startle potentiation but not heart-rate response in patients with dental phobia.

The acoustic startle response (SR) has consistently been shown to be enhanced by fear-arousing cross-modal background stimuli in phobics. Intra-modal fear-potentiation of acoustic SR was rarely investigated and generated inconsistent results. The present study compared the acoustic SR to phobia-related sounds with that to phobia-related pictures in 104 dental phobic patients and 22 controls. Acoustic background stimuli were dental treatment noises and birdsong and visual stimuli were dental treatment and neutral control pictures. Background stimuli were presented for 4 s, randomly followed by the administration of the startle stimulus. In addition to SR, heart-rate (HR) was recorded throughout the trials. Irrespective of their content, background pictures elicited greater SR than noises in both groups with a trend for phobic participants to show startle potentiation to phobia-related pictures but not noises. Unlike controls, phobics showed HR acceleration to both dental pictures and noises. HR acceleration of the phobia group was significantly positively correlated with SR in the noise condition only. The acoustic SR to phobia-related noises is likely to be inhibited by prolonged sensorimotor gating.

Mental retrieval of treatment context in dental phobia.

BACKGROUND: The effect of mental retrieval of an exposure session was investigated during a follow-up examination in dental phobia patients. METHOD: The exposure session took place at the psychology unit and the follow-up a week later at the dental clinic prior to dental treatment while patients were seated in the dental chair. During exposure, individuals with dental phobia (N = 72) were shown a video of a dental appointment, after which they were instructed to imagine themselves receiving dental treatment. During follow-up half of the participants received instructions to mentally retrieve the exposure session and the other half were asked to recall everyday activities. Before and after exposure treatment, and after mental retrieval, participants were shown three dental instruments while heart rate (HR) and avoidance and subjective units of discomfort (SUD) were recorded. RESULTS: Questionnaires of phobic anxiety administered before and after treatment indicated significant improvement. Mental retrieval of treatment was moderately superior to the control condition with regard to avoidance. Over 80% of patients underwent the subsequent dental treatment session. Those not adhering showed initially more dysfunctional cognitions and more desire for control. CONCLUSION: There is some evidence that retrieval of treatment context may have a moderately beneficial effect on avoidance.