How mood is affected by environment and upsetting events: The moderating role of psychological flexibility.

OBJECTIVE: Patients suffering from psychological disorders report decreased quality of life and low mood. The relationship of these symptoms to daily upsetting events or environments, and in the context of active coping mechanisms is poorly understood. The present study thus investigates the association between mood, psychological flexibility, upsetting events, and environment in the daily life of outpatients. METHOD: We investigated 80 outpatients at the beginning of treatment, using event sampling methodology (ESM). Patients' mood, occurrence of upsetting events, current environment, and psychological flexibility were sampled six times per day during a one-week intensive longitudinal examination. Data were analyzed using linear mixed models (LMMs). RESULTS: Participants reported worse mood the more upsetting events they experienced. Further, participants reported better mood when in private environments (e.g., with friends), and worse mood when at the hospital, compared to being at home. Higher levels of psychological flexibility, however, were associated with better mood, irrespective of the occurrence of upsetting events or current environment. CONCLUSION: Results suggest that mood is positively associated with psychological flexibility, not despite, but especially during the dynamic and context-specific challenges of daily life. Psychological flexibility may thus potentially act as a buffer against distress-provoking situations as patients go about their daily lives. TRIAL REGISTRATION: ISRCTN.org identifier: ISRCTN11209732.

Psychotherapy for Chronic In- and Outpatients with Common Mental Disorders: The "Choose Change" Effectiveness Trial.

INTRODUCTION: Treatment non-response occurs regularly, but psychotherapy is seldom examined for such patients. Existing studies targeted single diagnoses, were relatively small, and paid little attention to treatment under real-world conditions. OBJECTIVE: The Choose Change trial tested whether psychotherapy was effective in treating chronic patients with treatment non-response in a transdiagnostic sample of common mental disorders across two variants of treatment delivery (inpatient and outpatient). METHODS: The controlled nonrandomized effectiveness trial was conducted between May 2016 and May 2021. The study took place in two psychiatric clinics with N = 200 patients (n = 108 inpatients and n = 92 outpatients). Treatment variants were integrated inpatient care versus outpatient care based on acceptance and commitment therapy (ACT) for approximately 12 weeks. Therapists delivered individualized and non-manualized ACT. Main outcome measures were symptoms (Brief Symptom Checklist [BSCL]); well-being (Mental Health Continuum-Short Form [MHC-SF]), and functioning (WHO Disability Assessment Schedule [WHO-DAS]). RESULTS: Both inpatients and outpatients showed decreases in symptomatology (i.e., BSCL: d = 0.68) and increases in well-being and functioning (MHC-SF: d = 0.60 and WHO-DAS: d = 0.70), with more improvement in the inpatients during treatment. Both groups maintained gains 1 year following treatment, and the groups did not significantly differ from each other at this timepoint. Psychological flexibility moderated impact of stress on outcomes. CONCLUSIONS: Psychotherapy as practiced under routine conditions is effective for a sample of patients with common mental disorders, a long history of treatment experience and burden of disease, in both inpatient and outpatient settings. TRIAL REGISTRATION: This study was registered in the ISRCTN registry on May 20, 2016, with the registration number ISRCTN11209732.

Predictors of changing patterns of adherence to containment measures during the early stage of COVID-19 pandemic: an international longitudinal study.

BACKGROUND: Identifying common factors that affect public adherence to COVID-19 containment measures can directly inform the development of official public health communication strategies. The present international longitudinal study aimed to examine whether prosociality, together with other theoretically derived motivating factors (self-efficacy, perceived susceptibility and severity of COVID-19, perceived social support) predict the change in adherence to COVID-19 containment strategies. METHOD: In wave 1 of data collection, adults from eight geographical regions completed online surveys beginning in April 2020, and wave 2 began in June and ended in September 2020. Hypothesized predictors included prosociality, self-efficacy in following COVID-19 containment measures, perceived susceptibility to COVID-19, perceived severity of COVID-19 and perceived social support. Baseline covariates included age, sex, history of COVID-19 infection and geographical regions. Participants who reported adhering to specific containment measures, including physical distancing, avoidance of non-essential travel and hand hygiene, were classified as adherence. The dependent variable was the category of adherence, which was constructed based on changes in adherence across the survey period and included four categories: non-adherence, less adherence, greater adherence and sustained adherence (which was designated as the reference category). RESULTS: In total, 2189 adult participants (82% female, 57.2% aged 31-59 years) from East Asia (217 [9.7%]), West Asia (246 [11.2%]), North and South America (131 [6.0%]), Northern Europe (600 [27.4%]), Western Europe (322 [14.7%]), Southern Europe (433 [19.8%]), Eastern Europe (148 [6.8%]) and other regions (96 [4.4%]) were analyzed. Adjusted multinomial logistic regression analyses showed that prosociality, self-efficacy, perceived susceptibility and severity of COVID-19 were significant factors affecting adherence. Participants with greater self-efficacy at wave 1 were less likely to become non-adherence at wave 2 by 26% (adjusted odds ratio [aOR], 0.74; 95% CI, 0.71 to 0.77; P < .001), while those with greater prosociality at wave 1 were less likely to become less adherence at wave 2 by 23% (aOR, 0.77; 95% CI, 0.75 to 0.79; P = .04). CONCLUSIONS: This study provides evidence that in addition to emphasizing the potential severity of COVID-19 and the potential susceptibility to contact with the virus, fostering self-efficacy in following containment strategies and prosociality appears to be a viable public health education or communication strategy to combat COVID-19.

The role of psychological flexibility in the relationships between burnout, job satisfaction, and mental health among nurses in combatting COVID-19: A two-region survey.

BACKGROUND: A growing body of evidence suggests that the COVID-19 pandemic is adversely impacting the mental health and well-being of frontline nurses worldwide. It is therefore important to understand how such impact can be mitigated, including by studying psychological capacities that could help the nurses regulate and minimize the impact. AIM: To examine the role of psychological flexibility in mitigating the adverse impacts of burnout and low job satisfaction on mental health problems (i.e., anxiety, depression, and stress) and well-being among the frontline nurses in Hong Kong and Switzerland during the COVID-19 pandemic. DESIGN: Cross-sectional, two-region survey study. METHOD: Four hundred fifty-two nurses from Hong Kong (n = 158) and Switzerland (n = 294) completed an online survey. An adjusted structured equation model was used to examine the interrelationship of the constructs. RESULTS: Psychological flexibility was found to partially mediate the effects of job satisfaction on mental well-being (ß = 0.32, 95% CI [0.19, 0.57], p = 0.001) and mental health problems (ß = -0.79, 95% CI [-1.57, -0.44], p = 0.001), respectively. Similarly, this partial mediation was found in the effects of burnout on mental well-being (ß = -0.35, 95% CI [-0.89, -0.15], p = 0.002) and mental health problems (ß = 0.89, 95% CI [0.48, 3.65], p = 0.001). CONCLUSION: Psychological flexibility could be a crucial psychological resilience factor against the adverse impact of nurses' burnout on their mental health problems and well-being during COVID-19. CLINICAL RELEVANCE: Organizational measures should focus on fostering psychological flexibility in nurses through highly accessible, brief psychotherapeutic interventions, such as Acceptance and Commitment Therapy, to reduce the impact on mental health.

How Response Styles Moderate the Relationship between Daily Stress and Social Interactions in Depression, Social Phobia, and Controls.

INTRODUCTION: Stress and social isolation are potent predictors of negative health outcomes and are impacted in mood and anxiety disorders. Difficulties in social interactions have been particularly noted in people diagnosed with major depression disorder (MDD) and social phobia (SP). It remains poorly understood, however, how these variables interact on a moment-to-moment basis and which variables moderate this relationship. Psychological flexibility, or the ability to be open to experiences while maintaining engagement in valued activities, may help moderate the relationship between stress and social interaction. OBJECTIVE: This study examined these variables in participants diagnosed with MDD and SP and compared them to a control group. METHODS: Participants were diagnosed with a mental disorder (n = 118 MDD; n = 47 SP) or were in the control group consisting of participants without MDD or SP (n = 119). Using the event sampling methodology (ESM), participants were queried six times per day for 7 days about stress, social interactions, and emotional response (rigid vs. flexible). RESULTS: Higher current stress levels were related to more social interactions. This relationship was even stronger in situations when response flexibility was increased, especially in the clinical groups. CONCLUSIONS: Data suggest that a healthy psychological process (flexible emotional responding) buffers the relationship between stress and social interactions. We discuss how these variables interact and whether these patterns may paradoxically contribute to the maintenance of psychopathology.

The spatiotemporal movement of patients in and out of a psychiatric hospital: an observational GPS study.

BACKGROUND: Movement is a basic component of health. Little is known about the spatiotemporal movement of patients with mental disorders. The aim of this study was to determine how spatiotemporal movement of patients related to their symptoms and wellbeing. METHOD: A total of 106 patients (inpatients (n = 69) and outpatients (n = 37)) treated for a wide range of mental disorders (transdiagnostic sample) carried a GPS-enabled smartphone for one week at the beginning of treatment. Algorithms were applied to establish spatiotemporal clusters and subsequently related to known characteristics of these groups (i.e., at the hospital, at home). Symptomatology, Wellbeing, and Psychological flexibility were also assessed. RESULTS: Spatiotemporal patterns of inpatients and outpatients showed differences consistent with predictions (e.g., outpatients showed higher active areas). These patterns were largely unassociated with symptoms (except for agoraphobic symptoms). Greater movement and variety of movement were more predictive of wellbeing, however, in both inpatients and outpatients. CONCLUSION: Measuring spatiotemporal patterns is feasible, predictive of wellbeing, and may be a marker of patient functioning. Ethical issues of collecting GPS data are discussed.

Can psychological flexibility and prosociality mitigate illness perceptions toward COVID-19 on mental health? A cross-sectional study among Hong Kong adults.

BACKGROUND: The negative impact of COVID-19 pandemic on public mental health can be persistent and substantial over a long period of time, but little is known regarding what psychological factors or processes can buffer such impact. The present study aimed to examine the mediating roles of coping, psychological flexibility and prosociality in the impacts of perceived illness threats toward COVID-19 on mental health. METHOD: Five-hundred and fourteen Hong Kong citizens (18 years or above) completed an online survey to measure illness perceptions toward COVID-19, coping, psychological flexibility, prosociality, and mental health, together with their socio-demographic variables. Structural equation modelling was used to explore the explanatory model that was the best-fit to illustrate the relationships between these constructs. RESULTS: Serial mediation structural equation model showed that only psychological flexibility (unstandardised beta coefficient, ß = - 0.12, 95% CI [- 0.20, - 0.02], p = 0.031) and prosociality (unstandardised ß = 0.04, 95% CI [0.01, 0.08], p = 0.001) fully mediated the relationship between illness perceptions toward COVID-19 and mental health. In addition, psychological flexibility exerted a direct effect on prosociality (standardised ß = 0.22, 95% CI [0.12, 0.32], p < 0.001). This best-fit model explained 62% of the variance of mental health. CONCLUSIONS: Fostering psychological flexibility and prosocial behaviour may play significant roles in mitigating the adverse effects of COVID-19 and its perceived threats on public mental health.

The effect of anticipatory stress and openness and engagement on subsequently perceived sleep quality-An Experience Sampling Method study.

High stress levels can influence sleep quality negatively. If this also applies to anticipatory stress is poorly documented, however. Across insomnia severity levels, this study examined participants' evening levels of (a) anticipatory stress and (b) their skills hypothesized to downregulate the impact of stress, namely openness to internal experiences and continuous engagement in meaningful activities (openness and engagement) and their association with the quality of the subsequent night's sleep. The moderating role of insomnia severity was also tested. We used a quasi-experimental longitudinal design with Experience Sampling Method using smartphones over the course of 1 week (3,976 assessments; 93.2% of prompted queries). Participants recorded their sleep quality, anticipatory stress, and openness and engagement within their daily context. Participants included in the study were diagnosed with major depressive disorder (n = 118), social phobia (n = 47) or belonged to the control group (n = 119). Both anticipatory stress and openness and engagement predicted subsequent sleep quality. Diagnostic group was associated with overall sleep quality, but did not interact with the predictors. These findings were invariant across levels of self-reported insomnia severity. Furthermore, openness and engagement and anticipatory stress did not interact in their effect on sleep quality. The results suggest that both stress reduction and increased openness and engagement are associated with improved subjective sleep quality on a day to day basis, regardless of insomnia severity. Targeting these variables may help improve sleep quality. Future research should disentangle the effects of openness and engagement on anticipatory stress.

An Avatar-Led Intervention Promotes Smoking Cessation in Young Adults: A Pilot Randomized Clinical Trial.

BACKGROUND: Smoking remains a global concern, especially for young adults. There is a dearth of smoking cessation programs for this population, who seldom seek help or are motivated to quit. PURPOSE: This pilot study assessed the effectiveness of a digital avatar-led Acceptance and Commitment Therapy (ACT) smoking cessation program (Flexiquit) for young adult smokers at all levels of motivation to quit. METHODS: Smokers with no particular interest in quitting smoking (65.45% reported being in pre-contemplation or contemplation stages of change) were recruited from three universities (105 smoking ≥ 1 cigarette per day during the past 30 days, 68 females). Those who completed questionnaires online (N = 84; M = 22.44 years, SD = 2.61, range 18-28 years old) were randomized to either a six-session avatar-led intervention (Flexiquit; N = 49) or a wait-list control (N = 35). Primary outcomes included cessation status (7-day point prevalence) and number of cigarettes smoked per day; secondary outcomes were nicotine dependence, intention-to-quit smoking and self-efficacy, assessed at pre- and post-intervention, and only for Flexiquit at 6-month follow-up. RESULTS: In intention-to-treat analysis more participants (OR = 3.10, 95% CI = 0.92-10.41) in the treatment group (28.57%) versus the control group (11.43%) reported quitting smoking; however, the difference was not statistically significant (p = .067). There were statistically significant decreases in average number of cigarettes, nicotine dependence and increases in self-efficacy, and intention-to-quit smoking compared to controls. Treatment gains in the Flexiquit group were maintained through the 6-month follow-up. CONCLUSIONS: An avatar-led digitized smoking cessation intervention based on ACT could increase the odds of quitting smoking. Findings suggest that a digitized program designed to engage young adults in smoking cessation may result in quitting smoking and has a high applicability potential especially among the hard-to-reach population of young adults. QUESTION: Can an avatar-led digitized Acceptance and Commitment Therapy (ACT) smoking cessation intervention result in quitting smoking and increasing intention to quit among young smokers at various levels of motivation to quit, compared to a wait-list control group? FINDINGS: In this pilot randomized clinical trial that included 84 smokers, 28.57% in the treatment condition versus 11.43% in the wait-list control group were abstinent at post (intention-to-treat [ITT] analysis). An avatar-led digitized ACT smoking cessation intervention results in high quitting smoking rates and has a high applicability potential especially among the hard-to-reach population of young adult smokers.

Specific traumatic events elevate the risk of a suicide attempt in a 10-year longitudinal community study on adolescents and young adults.

Traumatic events (TEs) have been associated with suicide attempts (SAs). However, the empirical status of some TEs is inconclusive. This also concerns community adolescents and young adults, known to be a high-risk group for SAs. We examined associations between (a) a range of prior TEs (physical attack, rape/sexual abuse, serious accident, and witnessing somebody else experiencing a TE) and a subsequent SA, and (b) the number of prior TEs and an SA, and (c) we estimated attributable proportions of SAs, in relation to each TE. Over a 10-year period, the Early Developmental Stages of Psychopathology (EDSP) study prospectively assessed community members, aged 14-24 years at baseline. Starting with 3021 subjects, each individual was assessed up to four times. Assessment was based on the Munich-Composite International Diagnostic Interview. Temporal associations were estimated using the Cox model with time-dependent covariates. Attributable proportions were based on the results of the Cox models. All four TEs elevated the risk for a subsequent SA, adjusting for confounders. Highest risk was found for the combined TE rape/sexual abuse. Results showed that 56-90% of SAs could be attributed to TEs in the exposed group; on the population level, attributable proportions ranged between 6.9% and 23.5%. Different TEs have been shown to elevate the risk of an SA in a young community sample. Our results suggest that both health professionals and health policy decision-makers consider specific TEs and the number of prior TEs as risk factors for SAs.

"Choose change": design and methods of an acceptance and commitment therapy effectiveness trial for transdiagnostic treatment-resistant patients.

BACKGROUND: Acceptance and Commitment Therapy (ACT) has been successfully established in hundreds of efficacy trials. It is less understood, however, how ACT works in real-world settings. Furthermore, little is known about how contextual variables such as treatment setting (inpatient vs. outpatient), social network and environment of the patient impact outcome. METHODS: This paper describes the methods of the Choose Change study that compares transdiagnostic inpatients (n = 85) and outpatients (n = 85) with varying degrees of treatment experience and treatment success (i.e., no previous treatment vs. previous remission vs. treatment-resistant). Patients received ACT during an intensive treatment phase lasting approximately twelve treatment sessions, and were accompanied up to twelve months following intensive treatment. Main outcomes include symptoms, functioning, and well-being. Multiple levels of data are investigated, including treatment context, weekly assessments, a behavioral approach test, multiple follow-up phases, and ambulatory assessment using Event Sampling Methodology, to examine patients' daily context. DISCUSSION: We aim to investigate antecedents, consequences, and inherent processes that contribute to the maintenance or fluctuations of psychological disorders and the efficacy of ACT treatment. Furthermore, this study intends to increase understanding of how accurately participants can report on their own experiences, in order to expand our knowledge of how to probe for such information in the future. The results of Choose Change will provide basic clinical theory and clinical care with important and meaningful insights into the effectiveness of ACT, trans diagnostically, in in- and outpatients, and in a naturalistic setting. TRIAL REGISTRATION: This study was retrospectively registered in the ISRCTN Registry (registration number ISRCTN11209732 ) on May 20th 2016.

General or specific? The memory-experience gap for individuals diagnosed with a major depressive disorder or a social phobia diagnosis, and individuals without such diagnoses.

Psychological treatment and assessment necessarily rely on patients' recall. Yet several empirical studies have documented a gap between memory and real-life experience (i.e., memory-experience gap; MeG). We investigated and compared the MeG of sadness, social anxiety, happiness, and physical activity for participants diagnosed with a major depressive disorder (MDD), a social phobia (SP), and participants without such diagnoses (CG). The study included 118 participants diagnosed with a MDD, 47 with a SP, and 119 CG. Using event-sampling methods (ESM), participants were asked via smartphone to report their experiences throughout a week and then to recall those again retrospectively at the end of the study week. Results indicate significant differences in the MeG with respect to the experience that was salient to them (e.g., MDD group - sadness; SP group - social anxiety; CG group - happiness). Furthermore, all groups showed a MeG for physical activity and, the results indicate significant group differences in the magnitude of the MeGs. This study demonstrated the presence of a MeG in individuals in a MDD, SP, and CG group and in positive and negative affective experiences. Differential patterns across the samples contribute to a better understanding of this gap and its implications.

Psychoneuroendocrine evaluation of an acceptance and commitment based stress management training.

BACKGROUND AND OBJECTIVES: Acceptance and Commitment Therapy (ACT), a behavioral therapy that targets psychological flexibility (PF), has been shown to be efficacious across a wide range of problems, including chronic work-related stress and perceived stress. ACT's effect on the multiple levels of the acute stress response (i.e., subjective and biological) is less well understood. The aim of the current study was to test whether ACT, by working toward PF, would reduce both the endocrine and subjective evaluations of participants' acute stress response. METHODS: Participants (n = 35) were randomized to an ACT condition or waitlist (WL). Participants in the ACT condition received a two-day ACT workshop on how to flexibly deal with stress. All participants completed a standardized laboratory stress test. RESULTS: The ACT and WL groups did not differ on main comparisons of the endocrine response (i.e., cortisol) or subjective evaluation. Baseline levels of PF moderated some outcomes. Avoidant participants had a stronger endocrine stress reaction if they received the ACT intervention. LIMITATIONS: The control condition was a WL and not an active intervention comparison. CONCLUSIONS: ACT is not useful in reducing the acute stress response and may even be iatrogenic, at least during tasks with little real-world impact for their personal values. Clinical or methodological significance of this article: This was one of the first studies to investigate the impact of an ACT intervention on biological parameters. The short-term intervention did not attenuate acute endocrine stress levels or subjective stress appraisals. Future studies should investigate which interventions and under which conditions attenuate acute and long-term stress responses.

Mental disorders and the risk for the subsequent first suicide attempt: results of a community study on adolescents and young adults.

Adolescents and young adults represent the high-risk group for first onset of both DSM-IV mental disorders and lifetime suicide attempt (SA). Yet few studies have evaluated the temporal association of prior mental disorders and subsequent first SA in a young community sample. We examined (a) such associations using a broad range of specific DSM-IV mental disorders, (b) the risk of experiencing the outcome due to prior comorbidity, and (c) the proportion of SAs that could be attributed to prior disorders. During a 10-year prospective study, data were gathered from 3021 community subjects, 14-24 years of age at baseline. DSM-IV disorders and SA were assessed with the Munich-Composite International Diagnostic Interview. Cox models with time-dependent covariates were used to estimate the temporal associations of prior mental disorders with subsequent first SA. Most prior mental disorders showed elevated risk for subsequent first SA. Highest risks were associated with posttraumatic stress disorder (PTSD), dysthymia, and nicotine dependence. Comorbidity elevated the risk for subsequent first SA, and the more disorders a subject had, the higher the risk for first SA. More than 90% of SAs in the exposed group could be attributed to PTSD, and over 30% of SAs in the total sample could be attributed to specific phobia. Several DSM-IV disorders increase the risk for first SA in adolescents and young adults. Several promising early intervention targets were observed, e.g., specific phobia, nicotine dependence, dysthymia, and whether a young person is burdened with comorbid mental disorders.

IMPACT OF SPECIFIC PHOBIA ON THE RISK OF ONSET OF MENTAL DISORDERS: A 10-YEAR PROSPECTIVE-LONGITUDINAL COMMUNITY STUDY OF ADOLESCENTS AND YOUNG ADULTS.

BACKGROUND: The role of specific phobia as a potentially important psychopathological precursor condition to more severe mental disorders is understudied. We examined the prospective-longitudinal association of early childhood/adolescent phobia with subsequent mental disorders and the proportion of outcome disease incidence attributable to specific phobia simultaneously for a broad range of disorders. METHODS: N = 2210 14- to 24-year-old community subjects were followed up for 10 years. DSM-IV-specific phobia as exposure and a broad range of DSM-IV mental disorders as outcomes were assessed with the DSM-IV/M-CIDI. Logistic regressions, adjusting for confounders, were used to estimate the associations of specific phobia with the subsequent onset of outcome disorders. RESULTS: Baseline specific phobia predicted the subsequent first onset of anxiety disorders [panic disorder: risk ratio (RR) = 4.38, 95% confidence interval (2.34, 8.21); generalized anxiety disorder: RR = 4.10 (2.19, 7.69); posttraumatic stress disorder: RR = 2.15 (1.13, 4.10); obsessive-compulsive disorder: RR = 3.79 (1.63, 8.82)], affective disorders [major depression: RR = 1.54 (1.16, 2.03); bipolar disorder: RR = 2.20 (1.10, 4.41); dysthymia: RR = 2.75 (1.48, 5.11)], pain disorder: RR = 1.52 (1.14, 2.02), and eating disorders: RR = 2.27 (1.14, 4.51). Population attributable fractions (PAFs; i.e., proportion of outcome disease incidence in the total population attributable to specific phobia) were highest for panic disorder (PAF = 33.93), generalized anxiety disorder (PAF = 32.3), and obsessive-compulsive disorders (PAF = 30.2). CONCLUSION: This study provides strong evidence that specific phobia is an early onset disorder predicting the subsequent onset of a range of disorders. Future studies should examine the underlying mechanisms and the potential of using specific phobia as a target for prevention of subsequent psychopathology.

Treating Treatment-Resistant Patients with Panic Disorder and Agoraphobia Using Psychotherapy: A Randomized Controlled Switching Trial.

Background: Nonresponsiveness to therapy is generally acknowledged, but only a few studies have tested switching to psychotherapy. This study is one of the first to examine the malleability of treatment-resistant patients using acceptance and commitment therapy (ACT). Methods: This was a randomized controlled trial that included 43 patients diagnosed with primary panic disorder and/or agoraphobia (PD/A) with prior unsuccessful state-of-the-art treatment (mean number of previous sessions = 42.2). Patients were treated with an ACT manual administered by novice therapists and followed up for 6 months. They were randomized to immediate treatment (n = 33) or a 4-week waiting list (n = 10) with delayed treatment (n = 8). Treatment consisted of eight sessions, implemented twice weekly over 4 weeks. Primary outcomes were measured with the Panic and Agoraphobia Scale (PAS), the Clinical Global Impression (CGI), and the Mobility Inventory (MI). Results: At post-treatment, patients who received ACT reported significantly more improvements on the PAS and CGI (d = 0.72 and 0.89, respectively) than those who were on the waiting list, while improvement on the MI (d = 0.50) was nearly significant. Secondary outcomes were consistent with ACT theory. Follow-up assessments indicated a stable and continued improvement after treatment. The dropout rate was low (9%). Conclusions: Despite a clinically challenging sample and brief treatment administered by novice therapists, patients who received ACT reported significantly greater changes in functioning and symptomatology than those on the waiting list, with medium-to-large effect sizes that were maintained for at least 6 months. These proof-of-principle data suggest that ACT is a viable treatment option for treatment-resistant PD/A patients. Further work on switching to psychotherapy for nonresponders is clearly needed. © 2015 S. Karger AG, Basel.

5HTT is associated with the phenotype psychological flexibility: results from a randomized clinical trial.

Adaption to changing environments is evolutionarily advantageous. Studies that link genetic and phenotypic expression of flexible adjustment to one's context are largely lacking. In this study, we tested the importance of psychological flexibility, or goal-related context sensitivity, in an interaction between psychotherapy outcome for panic disorder with agoraphobia (PD/AG) and a genetic polymorphism. Given the established role of the 5HTT-LPR polymorphism in behavioral flexibility, we tested whether this polymorphism (short group vs. long group) impacted therapy response as a function of various endophenotypes (i.e., psychological flexibility, panic, agoraphobic avoidance, and anxiety sensitivity). Patients with PD/AG were recruited from a large multicenter randomized controlled clinical trial on cognitive-behavioral therapy. Pre- to post-treatment changes by 5HTT polymorphism were analyzed. 5HTT polymorphism status differentiated pre- to post-treatment changes in the endophenotype psychological flexibility (effect size difference d = 0.4, p < 0.05), but none of the specific symptom-related endophenotypes consistently for both the intent-to-treat sample (n = 228) and the treatment completers (n = 194). Based on the consistency of these findings with existing theory on behavioral flexibility, the specificity of the results across phenotypes, and the consistency of results across analyses (i.e., completer and intent to treat), we conclude that 5HTT polymorphism and the endophenotype psychological flexibility are important variables for the treatment of PD/AG. The endophenotype psychological flexibility may help bridge genetic and psychological literatures. Despite the limitation of the post hoc nature of these analyses, further study is clearly warranted.

MicroRNA hsa-miR-4717-5p regulates RGS2 and may be a risk factor for anxiety-related traits.

Regulator of G-protein Signaling 2 (RGS2) is a key regulator of G-protein-coupled signaling pathways involved in fear and anxiety. Data from rodent models and genetic analysis of anxiety-related traits and disorders in humans suggest down-regulation of RGS2 expression to be a risk factor for anxiety. Here we investigated, whether genetic variation in microRNAs mediating posttranscriptional down-regulation of RGS2 may be a risk factor for anxiety as well. 75 microRNAs predicted to regulate RGS2 were identified by four bioinformatic algorithms and validated experimentally by luciferase reporter gene assays. Specificity was confirmed for six microRNAs (hsa-miR-1271-5p, hsa-miR-22-3p, hsa-miR-3591-3p, hsa-miR-377-3p, hsa-miR-4717-5p, hsa-miR-96-5p) by disrupting their seed sequence at the 3' untranslated region of RGS2. Hsa-miR-4717-5p showed the most robust effect on RGS2 and regulated two other candidate genes of anxiety disorders (CNR1 and IKBKE) as well. Two SNPs (rs150925, rs161427) within and 1,000 bp upstream of the hostgene of hsa-miR-4717-5p (MIR4717) show a minor allele frequency greater than 0.05. Both were in high linkage disequilibrium (r(2) = 1, D' = 1) and both major (G) alleles showed a trend for association with panic disorder with comorbid agoraphobia in one of two patient/control samples (combined n(patients) = 497). Dimensional anxiety traits, as described by Anxiety Sensitivity Index (ASI) and Agoraphobic Cognitions Questionnaire (ACQ) were significantly higher among carriers of both major (G) alleles in a combined patient/control sample (n(combined) = 831). Taken together, data indicate that MIR4717 regulates human RGS2 and contributes to the genetic risk towards anxiety-related traits.

RGS2 ggenetic variation: association analysis with panic disorder and dimensional as well as intermediate phenotypes of anxiety.

Accumulating evidence from mouse models points to the G protein-coupled receptor RGS2 (regulator of G-protein signaling 2) as a promising candidate gene for anxiety in humans. Recently, RGS2 polymorphisms were found to be associated with various anxiety disorders, e.g., rs4606 with panic disorder (PD), but other findings have been negative or inconsistent concerning the respective risk allele. To further examine the role of RGS2 polymorphisms in the pathogenesis of PD, we genotyped rs4606 and five additional RGS2 tag single nucleotide polymorphisms (SNPs; rs16834831, rs10801153, rs16829458, rs1342809, rs1890397) in two independent PD samples, comprising 531 matched case/control pairs. The functional SNP rs4606 was nominally associated with PD when both samples were combined. The upstream SNP rs10801153 displayed a Bonferroni-resistant significant association with PD in the second and the combined sample (P = 0.006 and P = 0.017). We furthermore investigated the effect of rs10801153 on dimensional anxiety traits, a behavioral avoidance test (BAT), and an index for emotional processing in the respective subsets of the total sample. In line with categorical results, homozygous risk (G) allele carriers displayed higher scores on the Agoraphobic Cognitions Questionnaire (ACQ; P = 0.015) and showed significantly more defensive behavior during fear provoking situations (P = 0.001). Furthermore, significant effects on brain activation in response to angry (P = 0.013), happy (P = 0.042) and neutral faces (P = 0.032) were detected. Taken together, these findings provide further evidence for the potential role of RGS2 as a candidate gene for PD.

Neural correlates of procedural variants in cognitive-behavioral therapy: a randomized, controlled multicenter FMRI study.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective treatment for panic disorder with agoraphobia (PD/AG). It is unknown, how variants of CBT differentially modulate brain networks involved in PD/AG. This study was aimed to evaluate the effects of therapist-guided (T+) versus self-guided (T-) exposure on the neural correlates of fear conditioning in PD/AG. METHOD: In a randomized, controlled multicenter clinical trial in medication-free patients with PD/AG who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before (t1) and after CBT (t2). Quality-controlled fMRI data from 42 patients and 42 healthy subjects (HS) were obtained. Patients were randomized to two variants of CBT (T+, n = 22, and T-, n = 20). RESULTS: The interaction of diagnosis (PD/AG, HS), treatment group (T+, T-), time point (t1, t2) and stimulus type (conditioned stimulus: yes, no) revealed activation in the left hippocampus and the occipitotemporal cortex. The T+ group demonstrated increased activation of the hippocampus at t2 (t2 > t1), which was positively correlated with treatment outcome, and a decreased connectivity between the left inferior frontal gyrus and the left hippocampus across time (t1 > t2). CONCLUSION: After T+ exposure, contingency-encoding processes related to the posterior hippocampus are augmented and more decoupled from processes of the left inferior frontal gyrus, previously shown to be dysfunctionally activated in PD/AG. Linking single procedural variants to neural substrates offers the potential to inform about the optimization of targeted psychotherapeutic interventions.