Resting-state functional connectivity in anxiety disorders: a multicenter fMRI study.

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

Lack of evidence for predictive utility from resting state fMRI data for individual exposure-based cognitive behavioral therapy outcomes: A machine learning study in two large multi-site samples in anxiety disorders.

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.

Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits.

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.

Sexual Dysfunctions in Women with Posttraumatic Stress Disorder Following Childhood Sexual Abuse: Prevalence Rates According to DSM-5 and Clinical Correlates.

Many women with posttraumatic stress disorder (PTSD) after child sexual abuse (CSA) suffer from sexual problems. However, little is known about the frequency of female sexual dysfunctions (FSD) as defined by DSM-5 among women with PTSD due to CSA. Furthermore, factors related to FSD in this patient population are understudied. To assess prevalence rates and clinical correlates of FSD according to DSM-5 criteria in women with PTSD after CSA, a structured clinical interview for sexual dysfunctions according to DSM-5 criteria was administered in a sample of 137 women with PTSD after CSA. Participants also completed measures for PTSD, depression symptoms, and borderline personality disorder symptoms. The association between FSD, severity of abuse, PTSD-, depression-, borderline symptom severity, and age was examined. In a second step, the association between FSD and PTSD-clusters was assessed. Diagnostic criteria of female sexual interest/arousal disorder (FSIAD) were met by 2.6% of women in our sample. 5.2% met criteria of female orgasmic disorder (FOD), and 11.8% those of genito-pelvic pain/penetration disorder (GPPPD). PTSD symptom severity predicted number of fulfilled criteria of FSIAD and FOD, the cluster "negative alterations in cognition and mood," was associated with more fulfilled criteria in FSIAD and FOD. The majority of women reported sexual problems, but diagnostic criteria of FSD were met by only a small number of participants. PTSD symptoms, especially the cluster "negative alterations in cognition and mood," seem to be related to female sexual functioning after CSA.

Effect of acute and long-term exercise on leptin levels in depressed outpatients.

BACKGROUND: Depression is a leading cause of disability worldwide and a significant contributor to the global burden of disease. Altered leptin levels are known to be associated with depressive symptoms, however discrepancies in the results of increased or decreased levels exist. Due to various limitations associated with commonly used antidepressant drugs, alternatives such as exercise therapy are gaining more importance. Therefore, the current study investigates whether depressed patients have higher leptin levels compared to healthy controls and if exercise is efficient to reduce these levels. METHODS: Leptin levels of 105 participants with major depressive disorder (MDD; 45.7% female, age mean ± SEM: 39.1 ± 1.0) and 34 healthy controls (HC; 61.8% female, age mean ± SEM: 36.0 ± 2.0) were measured before and after a bicycle ergometer test. Additionally, the MDD group was separated into three groups: two endurance exercise intervention groups (EX) differing in their intensities, and a waiting list control group (WL). Leptin levels were measured pre and post a 12-week exercise intervention or the waiting period. RESULTS: Baseline data showed no significant differences in leptin levels between the MDD and HC groups. As expected, correlation analyses displayed significant relations between leptin levels and body weight (HC: r = 0.474, p = 0.005; MDD: r = 0.198, p = 0.043) and even more with body fat content (HC: r = 0.755, p < 0.001; MDD: r = 0.675, p < 0.001). The acute effect of the bicycle ergometer test and the 12-week training intervention showed no significant changes in circulating leptin levels. CONCLUSION: Leptin levels were not altered in patients with major depression compared to healthy controls and exercise, both the acute response and after 12 weeks of endurance training, had no effect on the change in leptin levels. TRIAL REGISTRATION: The study was registered at the German register for clinical studies (DRKS) and the International Clinical Trials Registry Platform of the World Health Organization https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00008869 on 28/07/2015.

Impact of new country, discrimination, and acculturation-related factors on depression and anxiety among ex-Soviet Jewish migrants: data from a population-based cross-national comparison study.

Migration, displacement, and flight are major worldwide phenomena and typically pose challenges to mental health. Therefore, migrants' mental health, and the factors which may predict it, have become an important research subject. The present population-based cross-national comparison study explores symptoms of depression, anxiety, and somatization, as well as quality-of-life in samples of ex-Soviet Jewish migrants settling in three new countries: Germany, Austria and Israel, as well as in a sample of non-migrant ex-Soviet Jews in their country of origin, Russia. In the current study, we investigate the relationship of perceived xenophobiа and antisemitism, acculturation attitudes, ethnic and national identity, as well as affiliation with Jewish religion and culture to the psychological well-being of these migrants. Furthermore, we consider xenophobic and antisemitic attitudes as well as the acculturation orientation of the new countries' societies, assessed in the native control samples. Our data suggest that attitudes of the new country's society matter for the mental health of this migrant group. We conclude that the level of distress among ex-Soviet Jewish migrants seems to depend, among other factors, on the characteristics of the new country and/or specific interactions of the migrant population with the society they are settling in.

Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression.

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

Efficacy of temporally intensified exposure for anxiety disorders: A multicenter randomized clinical trial.

BACKGROUND: The need to optimize exposure treatments for anxiety disorders may be addressed by temporally intensified exposure sessions. Effects on symptom reduction and public health benefits should be examined across different anxiety disorders with comorbid conditions. METHODS: This multicenter randomized controlled trial compared two variants of prediction error-based exposure therapy (PeEx) in various anxiety disorders (both 12 sessions + 2 booster sessions, 100 min/session): temporally intensified exposure (PeEx-I) with exposure sessions condensed to 2 weeks (n = 358) and standard nonintensified exposure (PeEx-S) with weekly exposure sessions (n = 368). Primary outcomes were anxiety symptoms (pre, post, and 6-months follow-up). Secondary outcomes were global severity (across sessions), quality of life, disability days, and comorbid depression. RESULTS: Both treatments resulted in substantial improvements at post (PeEx-I: dwithin = 1.50, PeEx-S: dwithin = 1.78) and follow-up (PeEx-I: dwithin = 2.34; PeEx-S: dwithin = 2.03). Both groups showed formally equivalent symptom reduction at post and follow-up. However, time until response during treatment was 32% shorter in PeEx-I (median = 68 days) than PeEx-S (108 days; TRPeEx-I = 0.68). Interestingly, drop-out rates were lower during intensified exposure. PeEx-I was also superior in reducing disability days and improving quality of life at follow-up without increasing relapse. CONCLUSIONS: Both treatment variants focusing on the transdiagnostic exposure-based violation of threat beliefs were effective in reducing symptom severity and disability in severe anxiety disorders. Temporally intensified exposure resulted in faster treatment response with substantial public health benefits and lower drop-out during the exposure phase, without higher relapse. Clinicians can expect better or at least comparable outcomes when delivering exposure in a temporally intensified manner.

A clinical effectiveness trial comparing ACT and CBT for inpatients with depressive and mixed mental disorders.

AbstractObjective: Meta-analyses show that Acceptance and Commitment Therapy (ACT) is an efficacious treatment for a wide range of mental health problems. However, few studies have examined the effectiveness of ACT in naturalistic inpatient settings and in direct comparison to Cognitive Behavior Therapy (CBT). The aim of this study was to investigate the effectiveness of ACT and CBT with regard to depression, general symptom strain and life satisfaction. Method: 177 inpatients in a psychiatric ward were included in the study and assigned to either ACT or CBT group intervention. All patients were assessed with the SCID-I interview and disorder-specific questionnaires as well as with a satisfaction with life scale. To control for confounding variables, amongst others, treatment integrity was evaluated. Results: Both the ACT and CBT intervention showed a large, statistically significant and stable symptom reduction over six months across all outcomes. Both approaches led to small improvement in life satisfaction. With regards to depressive symptoms, more than half of the patients reliably recovered due to therapy. Conclusion: ACT and CBT were similarly effective in treating patients with depressive and other mental disorders in a routine clinical setting. ACT is a viable alternative to CBT for treating inpatients.

An investigation of genetic variability of DNA methyltransferases DNMT3A and 3B does not provide evidence for a major role in the pathogenesis of panic disorder and dimensional anxiety phenotypes.

While DNA methylation patterns have been studied for a role in the pathogenesis of anxiety disorders, the role of the enzymes establishing DNA methylation-DNA methyltransferases (DNMTs)-has yet to be investigated. In an effort to investigate DNMT genotype-specific effects on dimensional anxiety traits in addition to the categorical phenotype of panic disorder, 506 panic disorder patients and 3112 healthy participants were assessed for anxiety related cognition [Agoraphobic Cognitions Questionnaire (ACQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] as well as pathological worry [Penn State Worry Questionnaire (PSWQ)] and genotyped for five single nucleotide polymorphisms (SNPs) in the DNMT3A (rs11683424, rs1465764, rs1465825) and DNMT3B (rs2424932, rs4911259) genes, which have previously been found associated with clinical and trait-related phenotypes. There was no association with the categorical phenotype panic disorder. However, a significant association was discerned between DNMT3A rs1465764 and PSWQ scores in healthy participants, with the minor allele conveying a protective effect. In addition, a marginally significant association between questionnaire scores (PSWQ, ASI) in healthy participants and DNMT3B rs2424932 was detected, again with the minor allele conveying a protective effect. The present results suggest a possible minor role of DNMT3A and DNMT3B gene variation in conveying resilience towards anxiety disorders. As the observed associations indicated a protective effect of two SNPs particularly with pathological worry, future studies are proposed to explore these variants in generalized anxiety disorder rather than panic disorder.

Does prior traumatization affect the treatment outcome of CBT for panic disorder? The potential role of the MAOA gene and depression symptoms.

Although cognitive behavioral therapy (CBT) is highly effective in the treatment of anxiety disorders, many patients still do not benefit. This study investigates whether a history of traumatic event experience is negatively associated with outcomes of CBT for panic disorder. The moderating role of the monoamine oxidase A (MAOA) gene and depression symptoms as well as the association between trauma history and fear reactivity as a potential mechanism are further analyzed. We conducted a post-hoc analysis of 172 male and 60 female patients with panic disorder treated with CBT in a multi-center study. Treatment outcome was assessed at post-treatment using self-report and clinician rating scales. Fear reactivity before treatment was assessed via heart rate and self-reported anxiety during a behavioral avoidance test. Among females, we did not find any differences in treatment response between traumatized and non-traumatized individuals or any two-way interaction trauma history × MAOA genotype. There was a significant three-way interaction trauma history × MAOA genotype × depression symptoms on all treatment outcomes indicating that in traumatized female patients carrying the low-activity allele, treatment effect sizes decreased with increasing depression symptoms at baseline. No such effects were observed for males. In conclusion, we found no evidence for a differential treatment response in traumatized and non-traumatized individuals. There is preliminary evidence for poorer treatment outcomes in a subgroup of female traumatized individuals carrying the low-active variant of the MAOA gene. These patients also report more symptoms of depression symptomatology and exhibit a dampened fear response before treatment which warrants further investigation.

The importance of sexuality, changes in erectile functioning and its association with self-esteem in men with localized prostate cancer: data from an observational study.

BACKGROUND: Treatment for localized prostate cancer (PCa) can cause long-term changes in erectile functioning. However, data on the importance of sexuality and possible consequences of altered erectile functioning on self-esteem in men with localized PCa are lacking. METHODS: Self-report questionnaires were completed by 292 men with PCa, initially managed with active surveillance (AS) or radical prostatectomy (RP). Independent t-tests were conducted to evaluate group differences. A sequential multiple regression model was fitted to analyze the associations between the importance of sexuality, changes in erectile functioning and impairment of self-esteem. Interaction effects were tested using simple slope analyses. RESULTS: Participants were 70 ± 7.2 years old and 66.5% rated sex as being "rather/very important". The two groups differed markedly in changes in erectile functioning, importance of sexuality and impairment of self-esteem (p < .001), with higher values in RP patients. Regression analysis showed that after adjustment for control variables and importance of sexuality, changes in erectile functioning were still associated with impairment of self-esteem (B = .668, SE = .069, p < .001). The interaction of changes in erectile functioning and importance of sexuality reached significance (B = .318, SE = .062, p < .001). CONCLUSIONS: RP patients report more changes in erectile functioning than AS patients. Moreover, in men with localized PCa, erectile functioning and self-esteem are closely related. Sexuality seems to be important for the majority of these men. Physicians should address the possibility of erectile dysfunction and its potential effects on psychological well-being before the treatment decision.

High-Intensity Interval Training in Panic Disorder Patients: A Pilot Study.

High-intensity interval training (HIIT) may produce strong physiological but also psychological effects within a short period. However, it is questionable if this type of training is applicable and effective in patients with panic disorder (PD) because they are more vulnerable to the adverse effects of exercise. Twelve PD patients performed a 12-day HIIT trial. Every second day, patients performed 10 high-intensive 1-minute intervals at 77% to 95% of their maximum heart rate separated by 1-minute intervals with moderate to low intensity. All patients completed the 12-day training period. PD severity, agoraphobia, depression, general disorder severity, and endurance performance improved substantially with moderate to large effects sizes. Moreover, the increase in endurance performance was correlated with the reduction of depression and agoraphobia. HIIT was well tolerated by patients with PD and may induce rapid and strong therapeutic effects. A randomized controlled clinical trial is needed to verify our findings.

Sexual Functioning After Childhood Abuse: The Influence of Post-Traumatic Stress Disorder and Trauma Exposure.

BACKGROUND: Impairments in sexual functioning and sexual satisfaction are very common in women who have experienced childhood sexual abuse (CSA). A growing body of literature suggests a high prevalence of sexual distress in patients with post-traumatic stress disorder (PTSD). However, the influence of sexual trauma exposure per se and the influence of PTSD symptoms on impairments in sexual functioning remain unclear. AIM: The aim of this study was to investigate the influence of sexual trauma exposure and PTSD on sexual functioning and sexual satisfaction by comparing 3 groups of women. METHODS: Women with PTSD after CSA (N = 32), women with a history of CSA and/or physical abuse but without PTSD (trauma controls [TC]; N = 32), and healthy women (N = 32) were compared with regards to self-reported sexual functioning and sexual satisfaction. Trauma exposure was assessed with the Childhood Trauma Questionnaire, and PTSD was assessed with the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. OUTCOMES: Sexual functioning was assessed with the Sexual Experience and Behavior Questionnaire, and sexual satisfaction was assessed with the questionnaire Resources in Sexuality and Relationship. RESULTS: PTSD patients had significantly lower sexual functioning in some aspects of sexual experience (sexual aversion, sexual pain, and sexual satisfaction) but did not significantly differ in sexual arousal and orgasm from the other 2 groups. TC and healthy women did not significantly differ from each other on the measures of sexual functioning or sexual satisfaction. CLINICAL TRANSLATION: Results suggest that the development of PTSD has a greater impact on sexual functioning than does the experience of a traumatic event. This emphasizes the importance to address possible sexual distress and sexual satisfaction in women with PTSD by administering specific diagnostic instruments and by integrating specific interventions targeting sexual problems into a trauma-specific treatment. CONCLUSIONS: The study is the first comparing PTSD patients and TC with healthy women with regards to sexual functioning. Limitations are selection and size of the samples, the assessment of sexual functioning by self-report measures only, and lack of consideration of other potentially relevant factors influencing sexuality. The findings suggest that the experience of sexual abuse does not necessarily lead to sexual impairment, whereas comparably low levels of sexual functioning seem to be prominent in PTSD patients after CSA. Further research is needed on how to improve treatment for this patient group. Bornefeld-Ettmann P, Steil R, Lieberz KA, et al. Sexual Functioning After Childhood Abuse: The Influence of Post-Traumatic Stress Disorder and Trauma Exposure. J Sex Med 2018;15:529-538.

Effects of Cognitive Behavioral Therapy on Neural Processing of Agoraphobia-Specific Stimuli in Panic Disorder and Agoraphobia.

BACKGROUND: Patients suffering from panic disorder and agoraphobia are significantly impaired in daily life due to anxiety about getting into a situation due to apprehension about experiencing a panic attack, especially if escape may be difficult. Dysfunctional beliefs and behavior can be changed with cognitive behavioral therapy; however, the neurobiological effects of such an intervention on the anticipation and observation of agoraphobia-specific stimuli are unknown. METHODS: We compared changes in neural activation by measuring the blood oxygen level-dependent signal of 51 patients and 51 healthy controls between scans before and those after treatment (group by time interaction) during anticipation and observation of agoraphobia-specific compared to neutral pictures using 3-T fMRI. RESULTS: A significant group by time interaction was observed in the ventral striatum during anticipation and in the right amygdala during observation of agoraphobia-specific pictures; the patients displayed a decrease in ventral striatal activation during anticipation from pre- to posttreatment scans, which correlated with clinical improvement measured with the Mobility Inventory. During observation, the patients displayed decreased activation in the amygdala. These activational changes were not observed in the matched healthy controls. CONCLUSIONS: For the first time, neural effects of cognitive behavioral therapy were shown in patients suffering from panic disorder and agoraphobia using disorder-specific stimuli. The decrease in activation in the ventral striatum indicates that cognitive behavioral therapy modifies anticipatory anxiety and may ameliorate abnormally heightened salience attribution to expected threatening stimuli. The decreased amygdala activation in response to agoraphobia-specific stimuli indicates that cognitive behavioral therapy can alter the basal processing of agoraphobia-specific stimuli in a core region of the fear network.

Neurobiological mechanisms of exercise and psychotherapy in depression: The SPeED study-Rationale, design, and methodological issues.

BACKGROUND/AIMS: Even though cognitive behavioral therapy has become a relatively effective treatment for major depressive disorder and cognitive behavioral therapy-related changes of dysfunctional neural activations were shown in recent studies, remission rates still remain at an insufficient level. Therefore, the implementation of effective augmentation strategies is needed. In recent meta-analyses, exercise therapy (especially endurance exercise) was reported to be an effective intervention in major depressive disorder. Despite these findings, underlying mechanisms of the antidepressant effect of exercise especially in combination with cognitive behavioral therapy have rarely been studied to date and an investigation of its neural underpinnings is lacking. A better understanding of the psychological and neural mechanisms of exercise and cognitive behavioral therapy would be important for developing optimal treatment strategies in depression. The SPeED study (Sport/Exercise Therapy and Psychotherapy-evaluating treatment Effects in Depressive patients) is a randomized controlled trial to investigate underlying physiological, neurobiological, and psychological mechanisms of the augmentation of cognitive behavioral therapy with endurance exercise. It is investigated if a preceding endurance exercise program will enhance the effect of a subsequent cognitive behavioral therapy. METHODS: This study will include 105 patients diagnosed with a mild or moderate depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.). The participants are randomized into one of three groups: a high-intensive or a low-intensive endurance exercise group or a waiting list control group. After the exercise program/waiting period, all patients receive an outpatient cognitive behavioral therapy treatment according to a standardized therapy manual. At four measurement points, major depressive disorder symptoms (Beck Depression Inventory, Hamilton Rating Scale for Depression), (neuro)biological measures (neural activations during working memory, monetary incentive delay task, and emotion regulation, as well as cortisol levels and brain-derived neurotrophic factor), neuropsychological test performance, and questionnaires (psychological needs, self-efficacy, and quality of life) are assessed. RESULTS: In this article, we report the design of the SPeED study and refer to important methodological issues such as including both high- and low-intensity endurance exercise groups to allow the investigation of dose-response effects and physiological components of the therapy effects. CONCLUSION: The main aims of this research project are to study effects of endurance exercise and cognitive behavioral therapy on depressive symptoms and to investigate underlying physiological and neurobiological mechanisms of these effects. Results may provide important implications for the development of effective treatment strategies in major depressive disorder, specifically concerning the augmentation of cognitive behavioral therapy by endurance exercise.

Combining D-cycloserine with appetitive extinction learning modulates amygdala activity during recall.

Appetitive Pavlovian conditioning plays a crucial role in the pathogenesis of drug addiction and conditioned reward cues can trigger craving and relapse even after long phases of abstinence. Promising preclinical work showed that the NMDA-receptor partial agonist D-cycloserine (DCS) facilitates Pavlovian extinction learning of fear and drug cues. Furthermore, DCS-augmented exposure therapy seems to be beneficial in various anxiety disorders, while the supposed working mechanism of DCS during human appetitive or aversive extinction learning is still not confirmed. To test the hypothesis that DCS administration before extinction training improves extinction learning, healthy adults (n=32) underwent conditioning, extinction, and extinction recall on three successive days in a randomized, double-blind, placebo-controlled fMRI design. Monetary wins and losses served as unconditioned stimuli during conditioning to probe appetitive and aversive learning. An oral dose of 50mg of DCS or placebo was administered 1h before extinction training and DCS effects during extinction recall were evaluated on a behavioral and neuronal level. We found attenuated amygdala activation in the DCS compared to the placebo group during recall of the extinguished appetitive cue, along with evidence for enhanced functional amygdala-vmPFC coupling in the DCS group. While the absence of additional physiological measures of conditioned responses during recall in this study prevent the evaluation of a behavioral DCS effect, our neuronal findings are in accordance with recent theories linking successful extinction recall in humans to modulatory top-down influences from the vmPFC that inhibit amygdala activation. Our results should encourage further translational studies concerning the usefulness of DCS to target maladaptive Pavlovian reward associations.

Disorder- and Treatment-Specific Therapeutic Competence Scales for Posttraumatic Stress Disorder Intervention: Development and Psychometric Properties.

Although the assessment of therapeutic competence in psychotherapy research is essential for examining its possible associations with treatment outcomes, it is often neglected due to high costs and a lack of valid instruments. This study aimed to develop two therapeutic competence scales that assess disorder-specific and treatment-specific therapeutic competence, and to examine these scales' psychometric properties along with those of the already established Cognitive Therapy Scale (CTS) in a posttraumatic stress disorder (PTSD) sample. Using an inductive procedure, two rating scales for assessing disorder-specific and treatment-specific competence were constructed. The psychometric properties of these scales and those of the CTS were assessed in a sample of 30 videotaped sessions of eight patients from a multicenter study in which PTSD related to child abuse was treated using cognitive processing therapy. Two raters assessed therapeutic competence in 30 videotaped psychotherapy sessions. Interrater reliability, internal consistency, and content validity were determined. The scales (all items and total scores) demonstrated good to excellent interrater reliability, intraclass correlation coefficients (ICCs) = .67 to .97, and internal consistency, Cronbach's α = .73 to .92. The PTSD experts' ratings confirmed good internal validity. We found statistically significant associations with therapeutic adherence, r = .62 to .85; p < .001; and therapeutic alliance, r = .47, p < .001. These preliminary data imply that the two newly developed competence scales and the CTS can be reliably used to assess different types of therapeutic competence in PTSD samples and may be useful as possible predictors of treatment outcomes.

Adherence Rating Scale for Cognitive Processing Therapy - Cognitive Only: Analysis of Psychometric Properties.

BACKGROUND: The assessment of therapeutic adherence is essential for accurately interpreting treatment outcomes in psychotherapy research. However, such assessments are often neglected. AIMS: To fill this gap, we aimed to develop and test a scale that assessed therapeutic adherence to Cognitive Processing Therapy - Cognitive Only (CPT), which was adapted for a treatment study targeting patients with post-traumatic stress disorder and co-occurring borderline personality symptoms. METHOD: Two independent, trained raters assessed 30 randomly selected treatment sessions involving seven therapists and eight patients who were treated in a multicentre randomized controlled trial. RESULTS: The inter-rater reliability for all items and the total score yielded good to excellent results (intraclass correlation coefficient [ICC] = 0.70 to 1.00). Cronbach's α was .56 for the adherence scale. Regarding content validity, three experts confirmed the relevance and appropriateness of each item. CONCLUSION: The adherence rating scale for the adapted version of CPT is a reliable instrument that can be helpful for interpreting treatment effects, analysing possible relationships between therapeutic adherence and treatment outcomes and teaching therapeutic skills.

EMOTIONAL AVAILABILITY IN MOTHER-CHILD INTERACTION: THE EFFECTS OF MATERNAL DEPRESSION IN REMISSION AND ADDITIONAL HISTORY OF CHILDHOOD ABUSE.

BACKGROUND: The association between maternal depression and adverse outcomes in children is well established. Similar links have been found for maternal childhood abuse. One proposed pathway of risk transmission is reduced maternal emotional availability. Our aim was to investigate whether sensitive parenting is impaired in mothers with depression in remission, and whether among these mothers childhood abuse has an additional impact. METHODS: The mother-child interaction of 188 dyads was assessed during a play situation using the Emotional Availability Scales, which measure the overall affective quality of the interaction: maternal sensitivity, structuring, nonhostility, and nonintrusiveness. Mothers with depression in remission were compared to healthy mothers. Children were between 5 and 12 years old. Group differences and impact of additional childhood abuse were analyzed by one-factorial analyses of covariance and planned contrasts. RESULTS: Mothers with depression in remission showed less emotional availability during mother-child interaction compared to healthy control mothers. Specifically, they were less sensitive and, at trend-level, less structuring and more hostile. Among these mothers, we found an additional effect of severe maternal childhood abuse on maternal sensitivity: Mothers with depression in remission and a history of severe childhood abuse were less sensitive than remitted mothers without childhood abuse. CONCLUSIONS: Our data suggest that depression impacts on maternal emotional availability during remission, which might represent a trait characteristic of depression. Mothers with depression in remission and additional severe childhood abuse were particularly affected. These findings may contribute to the understanding of children's vulnerability to develop a depressive disorder themselves.