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Objective Previous studies have found evidence of an attentional bias for trauma-related stimuli in posttraumatic stress disorder (PTSD) using eye-tracking (ET) technlogy. However, it is unclear whether findings for PTSD after traumatic events in adulthood can be transferred to PTSD after interpersonal trauma in childhood. The latter is often accompanied by more complex symptom features, including, for example, affective dysregulation and has not yet been studied using ET. The aim of this study was to explore which components of attention are biased in adult victims of childhood trauma with PTSD compared to those without PTSD. Method Female participants with (n = 27) or without (n = 27) PTSD who had experienced interpersonal violence in childhood or adolescence watched different trauma-related stimuli (Experiment 1: words, Experiment 2: facial expressions). We analyzed whether trauma-related stimuli were primarily detected (vigilance bias) and/or dwelled on longer (maintenance bias) compared to stimuli of other emotional qualities. Results For trauma-related words, there was evidence of a maintenance bias but not of a vigilance bias. For trauma-related facial expressions, there was no evidence of any bias. Conclusions At present, an attentional bias to trauma-related stimuli cannot be considered as robust in PTSD following trauma in childhood compared to that of PTSD following trauma in adulthood. The findings are discussed with respect to difficulties attributing effects specifically to PTSD in this highly comorbid though understudied population. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

About half of individuals seeking treatment for borderline personality disorder (BPD) present with co-occurring posttraumatic stress disorder (PTSD). However, therapies that have been proven efficacious for simultaneously treating the full spectrum of core symptoms in patients with a dual diagnosis of BPD + PTSD are lacking.This is a subgroup analysis from a randomized controlled trial (registration number DRKS00005578) which compared the efficacy of two treatment programs, dialectical behavior therapy for PTSD (DBT-PTSD) versus cognitive processing therapy (CPT). Specifically, the present analysis was carried out in 93 women with a dual diagnosis of BPD + PTSD (Diagnostic and Statistical Manual for Mental Disorders; DSM-5). Outcome evaluations included the Clinician-Administered PTSD Scale, the Borderline Symptom List, and validated scales assessing dissociation, depression, and global functioning. The primary analysis was based on the intent-to-treat population, using mixed models.Both PTSD and BPD symptoms significantly decreased in both treatment groups. For PTSD symptoms, pre-post effect sizes were d = 1.20, 95% confidence interval (CI): [0.80-1.58] in the DBT-PTSD group and d = 0.90, 95% CI: [0.57-1.22] in the CPT group; for BPD symptoms, they were d = 1.17, 95% CI: [0.77-1.55], and d = 0.50, 95% CI: [0.20-0.79], respectively. Between-group comparisons significantly favored DBT-PTSD for improvement in symptoms of PTSD, BPD, and dissociation. Between-group differences regarding depression and global functioning were not significant.Both DBT-PTSD and CPT emerged as promising treatment options for simultaneously addressing the full spectrum of core symptoms in patients diagnosed with BPD + PTSD. Differential efficacy was in favor of DBT-PTSD as participants randomized to the DBT-PTSD arm improved more with respect to both their BPD and PTSD symptoms. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Study Objectives Subjective reports of sleep impairments are common in individuals with posttraumatic stress disorder (PTSD), but objective assessments of sleep have yielded mixed results. Methods We investigated sleep via actigraphy and e-diary on 6 consecutive nights in a group of 117 women with PTSD after childhood abuse (CA; PTSD group), a group of 31 mentally healthy women with a history of CA (healthy trauma controls, HTC group) and a group of 36 nontraumatized mentally healthy women (healthy controls, HC group). Results The PTSD group reported lower sleep quality, more nights with nightmares, and shorter sleep duration than both HTC and HC. Actigraphic measures showed more and longer sleep interruptions in the PTSD group compared to HTC and HC, but no difference in sleep duration. While the PTSD group underestimated their sleep duration, both HTC and HC overestimated their sleep duration. HTC did not differ from HC regarding sleep impairments. Conclusions Sleep in women with PTSD after CA seems to be more fragmented but not shorter compared to sleep patterns of mentally healthy control subjects. The results suggest a stronger effect of PTSD psychopathology on sleep compared to the effect of trauma per se. Subset of Data from Clinical Trial Treating Psychosocial and Neural Consequences of Childhood Interpersonal Violence in Adults (RELEASE), https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00000000, German Clinical Trials registration number: DRKS00005578

Patients with anxiety disorders have a lower heart rate variability (HRV) than healthy controls. Low HRV is associated with cardiovascular disease and dysfunction of the autonomic nervous system (ANS). The aim of the present study was to investigate if HRV in patients with agoraphobia with or without panic disorder can be influenced by cognitive behavioral therapy (CBT). 73 patients with agoraphobia with or without panic disorder were included in the study. Heart rate (HR) and HRV were recorded at rest before and after CBT and during in-vivo exposure. No changes in HR and HRV were observed throughout therapy. During in-vivo exposure HRV increased significantly and HR exhibited a tendency to decrease. Despite clinical improvement of anxiety symptoms, ANS activity at rest did not seem to be influenced by CBT. However, during in-vivo exposure, HRV changed significantly, indicating a higher parasympathetic activity at the end of exposure.

Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.

Theoretically, panic disorder and agoraphobia pathology can be conceptualized as a cascade of dynamically changing defensive responses to threat cues from inside the body. Guided by this trans-diagnostic model we tested the interaction between defensive activation and vagal control as a marker of prefrontal inhibition of subcortical defensive activation. We investigated ultra-short-term changes of vagally controlled high frequency heart rate variability (HRV) during a standardized threat challenge (entrapment) in n = 232 patients with panic disorder and agoraphobia, and its interaction with various indices of defensive activation. We found a strong inverse relationship between HRV and heart rate during threat, which was stronger at the beginning of exposure. Patients with a strong increase in heart rate showed a deactivation of prefrontal vagal control while patients showing less heart rate acceleration showed an increase in vagal control. Moreover, vagal control collapsed in case of imminent threat, i.e., when body symptoms increase and seem to get out of control. In these cases of defensive action patients either fled from the situation or experienced a panic attack. Active avoidance, panic attacks, and increased sympathetic arousal are associated with an inability to maintain vagal control over the heart suggesting that teaching such regulation strategies during exposure treatment might be helpful to keep prefrontal control, particularly during the transition zone from post-encounter to circa strike defense. Trial Registration Number: ISRCTN80046034. German Federal Ministry of Education and Research Universität Greifswald (1032)

The use of d-cycloserine (DCS) to augment exposure based therapy for anxiety disorders has shown mixed, although overall positive effects. Aim of the present study was to examine post-exposure administration of DCS in patients with agoraphobia with or without panic disorder. 73 patients with agoraphobia (with or without panic disorder) were treated with 12 sessions of cognitive behavioral therapy (CBT) including 3 exposures. Following successful exposure patients were given double blind either placebo or 50 mg of DCS. Primary outcome criterion was change in the Panic and Agoraphobia Scale (PAS) between CBT session t1, t4 (+∼2 months), t10 (+∼3 months) und t11 (+∼4 months). During the course of CBT the patients' symptomatology decreased significantly as measured by primary and secondary outcome criteria, however, without an additional benefit for DCS treated patients. Exploratory sub-group analyses for severely ill patients and patients with high anxiety and strong habituation during exposure showed that DCS administration was associated with increased improvement during the 1-month follow-up period (t10 - t11) with medium to large effect sizes (range in effect size η2p from .06 to .25). Our study results are consistent with recent research on DCS, indicating a beneficial augmentative effect for sub-groups of anxiety patients. The lack of an overall DCS effect for the whole patient sample might be explained by a dual mechanism in fear conditioning and extinction with different cognitive processes being involved during exposure depending on the degree of anxiety experienced by the patient.

Victimized women are thought to have impairments in identifying risk and to have dysfunctional reactions to threatening situations, which increase the risk for revictimization. To investigate possible deficits in revictimized women, we used a method examining women's perceptions of an implicit facial cue of aggressiveness – the facial Width-to-Height Ratio (fWHR). We tested whether revictimized women show impairments in detecting aggressiveness in male faces by neglecting cues of fWHR and choosing a smaller preferred distance to men. Fifty-two revictimized PTSD patients and 52 healthy controls provided ratings of aggressiveness and attractiveness for 65 photographed men and chose their preferred distance towards 11 pictured men. Multiple regression analyses indicated that revictimized women do not show impairments in perceiving and reacting to cues of aggression accurately. Hierarchical linear models, however, indicated that revictimized women rated all men as less aggressive. Revictimized women with histories of intimate partner violence (IPV) rated men with larger fWHRs and higher values of actual aggression to be more attractive than did revictimized women without IPV histories. A reduced appraisal of threat signals as threatening and an attraction to wider-faced and more aggressive men might increase the risk for revictimization.

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.

Background For the next edition of the International Statistical Classification of Diseases (ICD-11) it is proposed to include prolonged grief disorder as a new diagnosis. The diagnosis describes persistent intensive and disabling grief reactions to bereavement (WHO, 2016b). The aim of the present survey was to determine the extent to which the diagnosis is accepted by practitioners in the healthcare and psychosocial field. Methods A total of 2088 German-speaking professionals in the fields of psychotherapy, psychology, counselling, medicine and palliative care completed the online survey. Results 42.4% of the participants felt that the advantages of including the diagnosis outweigh the disadvantages, 32.9% came to the conclusion that there are more disadvantages. The remaining 24.7% stated that advantages and disadvantages are balanced. The proposed classification as separate diagnosis was supported by 24.8%, while 60.0% preferred alternatives (e.g. as subtype of adjustment disorder). Furthermore, a time criterion of at least 12 months was voted for considerably more frequently (49.2%) than the proposed 6 months (11.3%). Objections were predominantly expressed with regard to pathologization of normal grief and to the difficulty of adequate crosscultural application of the diagnosis. Limitations Results are limited to predominantly German health-care professionals. The items did not undergo psychometric analyses. Conclusions The disagreement about the diagnosis found in specialist literature is also reflected in the responses by the participants. The present results provide stimulation for future questions and validation studies carried out as part of the ICD revision.

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.

The availability of large-scale datasets and sophisticated machine learning tools enables developing models that predict treatment outcomes for individual patients. However, few studies used routinely available sociodemographic and clinical data for this task, and many previous investigations used highly selected samples. This study aimed to investigate cognitive behavioral therapy (CBT) outcomes in a large, naturalistic and longitudinal dataset. Routine data from a university-based outpatient center with n = 2.147 patients was analyzed. Only baseline data including sociodemographics, symptom measures and functional impairment ratings was used for prediction. Different competing classification and regression models were compared to each other; the best models were then applied to previously unseen validation data. Applied on the validation set, the best performing classification model for remission achieved a balanced accuracy of 59% (p 0.001) and the best performing regression model for dimensional change achieved r = 0.27 (p 0.001). Age, sex, functional impairment, symptom severity, and axis II comorbidity were among the most important features. Predictor performances significantly exceeded chance level but were far from clinical utility. Neither applying more sophisticated approaches nor restricting the sample to homogeneous subgroups resulted in considerable performance gains. Adding hypotheses-based, more specific clinical constructs and deep (e.g. neurobiological) to digital phenotypes may increase prediction performance.

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.

Physiological mechanisms of an anti-depressive effect of physical exercise in major depressive disorder (MDD) seem to involve alterations in brain-derived neurotrophic factor (BDNF) level. However, previous studies which investigated this effect in a single bout of exercise, did not control for confounding peripheral factors that contribute to BDNF-alterations. Therefore, the underlying cause of exercise-induced BDNF-changes remains unclear. The current study aims to investigate serum BDNF (sBDNF)-changes due to a single-bout of graded aerobic exercise in a group of 30 outpatients with MDD, suggesting a more precise analysis method by taking plasma volume shift and number of platelets into account. Results show that exercise-induced increases in sBDNF remain significant (p .001) when adjusting for plasma volume shift and controlling for number of platelets. The interaction of sBDNF change and number of platelets was also significant (p = .001) indicating larger sBDNF-increase in participants with smaller number of platelets. Thus, findings of this study suggest an involvement of peripheral as well as additional - possibly brain-derived - mechanisms explaining exercise-related BDNF release in MDD. For future studies in the field of exercise-related BDNF research, the importance of controlling for peripheral parameters is emphasized.

IMPORTANCE: Childhood abuse significantly increases the risk of developing posttraumatic stress disorder (PTSD), often accompanied by symptoms of borderline personality disorder (BPD) and other co-occurring mental disorders. Despite the high prevalence, systematic evaluations of evidence-based treatments for PTSD after childhood abuse are sparse. OBJECTIVE: To compare the efficacy of dialectical behavior therapy for PTSD (DBT-PTSD), a new, specifically designed, phase-based treatment program, against that of cognitive processing therapy (CPT), one of the best empirically supported treatments for PTSD. DESIGN, SETTING, AND PARTICIPANTS: From January 2014 to October 2016, women who sought treatment were included in a multicenter randomized clinical trial with blinded outcome assessments at 3 German university outpatient clinics. The participants were prospectively observed for 15 months. Women with childhood abuse–associated PTSD who additionally met 3 or more DSM-5 criteria for BPD, including affective instability, were included. Data analysis took place from October 2018 to December 2019. INTERVENTIONS: Participants received equal dosages and frequencies of DBT-PTSD or CPT, up to 45 individual sessions within 1 year and 3 additional sessions during the following 3 months. MAIN OUTCOMES AND MEASURES: The predefined primary outcome was the course of the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) score from randomization to month 15. Intent-to-treat analyses based on dimensional CAPS-5 scores were complemented by categorical outcome measures assessing symptomatic remission, reliable improvement, and reliable recovery. RESULTS: Of 955 consecutive individuals assessed for eligibility, 193 were randomized (DBT-PTSD, 98; CPT, 95; mean [SD] age, 36.3 [11.1] years) and included in the intent-to-treat analyses. Analysis revealed significantly improved CAPS-5 scores in both groups (effect sizes: DBT-PTSD: d, 1.35; CPT: d, 0.98) and a small but statistically significant superiority of DBT-PTSD (group difference: 4.82 [95% CI, 0.67-8.96]; P = .02; d, 0.33). Compared with the CPT group, participants in the DBT-PTSD group were less likely to drop out early (37 [39.0%] vs 25 [25.5%]; P = .046) and had higher rates of symptomatic remission (35 [40.7%] vs 52 [58.4%]; P = .02), reliable improvement (53 [55.8%] vs 73 [74.5%]; P = .006), and reliable recovery (34 [38.6%] vs 52 [57.1%]; P = .01). CONCLUSIONS AND RELEVANCE: These findings support the efficacy of DBT-PTSD and CPT in the treatment of women with childhood abuse–associated complex PTSD. Results pertaining to the primary outcomes favored DBT-PTSD. The study shows that even severe childhood abuse–associated PTSD with emotion dysregulation can be treated efficaciously. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00005578

Background The association between maternal depression and adverse emotional and behavioral outcomes in children is well established. One associated factor might be altered affect recognition which may be transmitted transgenerationally. Individuals with history of depression show biased recognition of sadness. Our aim was to investigate parallels in maternal and children's affect recognition with remitted depressed mothers. Methods 60 Mother–child dyads completed an affect recognition morphing task. We examined two groups of remitted depressed mothers, with and without history of physical or sexual abuse, and a group of healthy mothers without history of physical or sexual abuse. Children were between 5 and 12 years old. Results Across groups, mothers identified happy faces fastest. Mothers with remitted depression showed a higher accuracy and response bias for sadness. We found corresponding results in their children. Maternal and children's bias and accuracy for sadness were positively correlated. Effects of remitted depression were found independent of maternal history of physical or sexual abuse. Limitations Our sample size was relatively small and further longitudinal research is needed to investigate how maternal and children's affect recognition are associated with behavioral and emotional outcomes in the long term. Conclusions Our data suggest a negative processing bias in mothers with remitted depression which might represent both the perpetuation of and vulnerability to depression. Children of remitted depressed mothers appear to be exposed to this processing bias outside acute depressive episodes. This may promote the development of a corresponding processing bias in the children and could make children of depressed mothers more vulnerable to depressive disorders themselves.

Exposure therapy is considered an effective treatment strategy for phobic anxiety, however, it is rarely applied in clinical practice. The under-usage might be due to various factors of which heightened stress levels not only in patients but also in therapists are presumed to be of particular relevance. The present study aimed to investigate whether different forms of exposure might lead to varying physiological and psychological stress responses in therapists and phobic patients. 25 patients with specific phobia underwent individual cognitive behavioural therapy, performed by 25 psychotherapist trainees, applying exposure sessions in graduated form or the flooding technique. Patients and therapists provided subjective evaluations of stress and five saliva samples for analysis of salivary cortisol and alpha-amylase either during two graduated exposure sessions or during one flooding session, while a regular therapy session served as control condition. Therapists displayed heightened salivary alpha-amylase release during exposure of the flooding, but not the graduated, type. Patients showed elevated salivary cortisol during flooding exposure numerically, however, not on a statistically significant level. Therapists reported more pronounced subjective stress during flooding compared to graduated exposure. Elevated stress levels should be addressed in clinical training in order to improve application of exposure in routine practice.

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.

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.

Exposure-based Cognitive Behavioral Therapy (eb-CBT) represents the most evidence-based psychotherapeutic approach in anxiety disorders. However, its efficacy may be limited by a delay in onset of action and a substantial number of patients does not respond sufficiently to treatment. In this context, aerobic exercise was found to be effective in reducing clinical anxiety as well as to improve (elements of) disorder-specific CBT in some mental disorders. We therefore investigated the effect of aerobic exercise supplementary to an eb-CBT in panic disorder and agoraphobia (PD/AG). 77 patients with PD/AG performed a 30 min treadmill task with moderate or low intensity (70% or 30% of the maximal oxygen uptake [VO2max]) prior to five exposure sessions within a standardized seven-week CBT. At baseline, after completing the treatment period (post) and six month after post (follow-up), several measures of (un)specific psychopathology (Hamilton Anxiety Rating Scale [Ham-A], Mobility Inventory [MI], Panic and Agoraphobia Scale [PAS], Agoraphobic Cognitions Questionnaire [ACQ], Body Sensations Questionnaire [BSQ]) were established to assess for clinical changes. All patients experienced a significant improvement of symptoms from baseline to post (for all measures p < .001) but repeated-measures analyses of variance found a trend towards a significant time x group interaction in the Ham-A in favor for the moderate intense exercise group (f[1, 74] = 4.15, p = .045, alpha = .025). This trend, however, disappeared at follow-up since the low-intense exercise group further improved significantly in Ham-A after post. Our findings therefore might point to an accelerating effect of moderate-intense exercise within an exposure-based CBT for AG/PD.

This work is part of the German multicenter trial ‘Mechanisms of Action in CBT (MAC)’. The MAC study is funded by the German Federal Ministry of Education and Research (BMBF; project no. 01GV0615) as part of the BMBF Psychotherapy Research Funding Initiative. The study was further supported by the DFG (Grant RE1632/5-1 and KFO 125 to AR; SFB TRR 58 Z02 to JD, PP and AR; C02 to JD and KD; DE357/4-1 to JD, AR, JR and AH; RTG 1256 to AR, JD and PP; IZKF-Würzburg Z-6 to HW). Corticotropin releasing hormone (CRH) is a major regulator of the hypothalamicpituitary-adrenal (HPA) axis. Binding to its receptor CRHR1 triggers the downstream release of cortisol, a hormone needed for regulation of stress responses. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here, we aimed to evaluate CRHR1 as a candidate molecule in panic disorder (PD). Allelic variation throughout the CRHR1 gene was captured by 9 selected single nucleotide polymorphisms (SNPs); these were genotyped in 531 matched case/control pairs (discovery sample (n=239); replication sample (n=292)). Four SNPs were found to be associated with PD, in at least one sub-sample. The minor alleles of rs17689918 and rs17689966 were found to significantly increase risk for PD in females of the discovery, the replication and the combined sample, both withstanding correction for multiple testing (prs17689918=1.3*10-4; prs17689966=0.042). Expressional analysis demonstrated that both minor alleles of rs17689918 and rs17689966 significantly decreased CRHR1 mRNA in the forebrain and amygdala. Bioinformatical analysis revealed a high proportion of differential neuro-relevant transcription factor binding possibly underlying expression changes. When investigating the neural correlates underlying this association, risk allele carriers of rs17689918 and rs17689966 showed aberrant differential conditioning and safety signal processing arguing for predominant generalization of fear and hence anxious apprehension. Furthermore, the minor risk (A) allele of rs17689918 led to less flight behavior during fear provoking situations, but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus, reduced CRHR1 expression driven by CRHR1 risk allele leads to a phenotype characterized by a fear bias and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder. Postprint

In the present study, we explored possible alterations in the default mode network (DMN) and its functional connectivity in 41 schizophrenia patients and 42 age-matched healthy controls. Schizophrenia patients displayed reduced activation in the ventromedial prefrontal cortex, left superior temporal gyrus including auditory cortex and temporal pole. Psychophysiological interaction analysis revealed reduced connectivity between left superior temporal gyrus including auditory cortex and the left temporal pole in schizophrenia patients compared to healthy subjects.

Patient satisfaction with psychiatric treatment has emerged as an important factor with respect to the quality of health care.Patient satisfaction using the Zurich Satisfaction Questionnaire (ZUF-8) as well as symptom severity (measured with the Hamilton Depression Scale [HRSD], Brief Psychiatric Rating Scale and Clinical Global Impression Scale) was assessed at admission and discharge of inpatient treatment in patients with a major depressive episode (MDD, N = 217) and schizophrenia (N = 75). Differences between the two diagnostic groups (using T-tests) and correlations of patient satisfaction with different social and treatment variables were calculated (Pearson product-moment correlation).The mean score of patient satisfaction was 26.8 points (ZUF-8; range 8-32 points), without differences between MDD and schizophrenia (t = 0.45, p = 0.78). Patients with MDD and personality disorder showed lower satisfaction than patients with MDD without personality disorder (t = 2.31, p = 0.03). Patient satisfaction correlated negatively with severity of depressive symptoms at discharge (HRSD: r = - 0.38; p0.01) and number of comorbidities (r = - 0.42; p0.01) in MDD. Number of prescribed drugs correlated negatively with patient satisfaction in both groups (depression: r = - 0.28, p = 0.02; schizophrenia: r = - 0.24; p = 0.03).Patient satisfaction was high without differences between MDD and schizophrenia. Severity of disease and comorbidites in MDD and number of prescribed drugs in both groups were related with reduced patient satisfaction.

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.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.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.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.

Background Maternal sensitive behavior depends on recognizing one’s own child’s affective states. The present study investigated distinct and overlapping neural responses of mothers to sad and happy facial expressions of their own child (in comparison to facial expressions of an unfamiliar child). Methods We used functional MRI to measure dissociable and overlapping activation patterns in 27 healthy mothers in response to happy, neutral and sad facial expressions of their own school-aged child and a gender- and age-matched unfamiliar child. To investigate differential activation to sad compared to happy faces of one’s own child, we used interaction contrasts. During the scan, mothers had to indicate the affect of the presented face. After scanning, they were asked to rate the perceived emotional arousal and valence levels for each face using a 7-point Likert-scale (adapted SAM version). Results While viewing their own child’s sad faces, mothers showed activation in the amygdala and anterior cingulate cortex whereas happy facial expressions of the own child elicited activation in the hippocampus. Conjoint activation in response to one’s own child happy and sad expressions was found in the insula and the superior temporal gyrus. Conclusions Maternal brain activations differed depending on the child’s affective state. Sad faces of the own child activated areas commonly associated with a threat detection network, whereas happy faces activated reward related brain areas. Overlapping activation was found in empathy related networks. These distinct neural activation patterns might facilitate sensitive maternal behavior.

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.

Societal cost-of-illness in a German sample of patients with borderline personality disorder (BPD) was calculated for 12 months prior to an outpatient Dialectical Behavior Therapy (DBT) program, during a year of DBT in routine outpatient care and during a follow-up year. We retrospectively assessed resource consumption and productivity loss by means of a structured interview. Direct costs were calculated as opportunity costs and indirect costs were calculated according to the Human Capital Approach. All costs were expressed in Euros for the year 2010. Total mean annual BPD-related societal cost-of-illness was €28026 (SD = €33081) during pre-treatment, €18758 (SD = €19450) during the DBT treatment year for the 47 DBT treatment completers, and €14750 (SD = €18592) during the follow-up year for the 33 patients who participated in the final assessment. Cost savings were mainly due to marked reductions in inpatient treatment costs, while indirect costs barely decreased. In conclusion, our findings provide evidence that the treatment of BPD patients with an outpatient DBT program is associated with substantial overall cost savings. Already during the DBT treatment year, these savings clearly exceed the additional treatment costs of DBT and are further extended during the follow-up year. Correspondingly, outpatient DBT has the potential to be a cost-effective treatment for BPD patients. Efforts promoting its implementation in routine care should be undertaken.

Health-related quality of life (HRQoL) is important for long-term social functioning. It is considerably reduced in patients with depression. We studied the impact of HRQoL on treatment outcome in patients with unipolar depression. Furthermore, we analysed factors associated with HRQoL in inpatients with unipolar depression. One hundred and eighty patients suffering from major depressive disorder were evaluated during their inpatient treatment by assessing admission and discharge depression severity and their HRQoL, using the Medical Outcomes Study 12-item Short Form (SF-12). Baseline and treatment variables associated with HRQoL were examined by regression analysis. Primary outcome measures were the Hamilton Rating Scale and the Beck Depression Inventory. HRQoL improved significantly during inpatient treatment. Lower HRQoL outcomes were strongly associated with higher age, somatic comorbidities, a recurrent depressive disorder and stronger depressive symptoms at admission. Additionally, patients with a complex treatment situation (high number of medications, antidepressant switch) showed stronger impairment of HRQoL. Personality disorders and additional psychotherapy did not predict HRQoL. The inpatient treatment resulted in an increase of the SF-12 scores, although to a lower extent than depressive symptoms. Several factors negatively influence HRQoL, such as the presence of somatic and axis I psychiatric comorbiditites and a recurrent or severe depressive episode. Targeting somatic comorbidities in patients with unipolar depression seem to play an important role for HRQoL.

Background: In healthy individuals, voluntary modification of self-relevance has proven effective in regulating subjective emotional experience as well as physiologic responses evoked by emotive stimuli. As social anxiety disorder (SAD) is characterized by both altered emotional and self-related processing, we tested if emotion regulation through self-focused reappraisal is effective in individuals with SAD.Methods: While undergoing 3 T functional magnetic resonance imaging, individuals with SAD and matched healthy controls either passively viewed neutral and aversive pictures or actively increased or decreased their negative emotional experience through the modification of selfrelevance or personal distance to aversive pictures. Participants rated all pictures with regard to the intensity of elicited emotions and self-relatedness.Results: We included 21 individuals with SAD and 23 controls in our study. Individuals with SAD reported significantly stronger emotional intensity across conditions and showed a nonsignificant tendency to judge pictures as more self-related than controls. Compared with controls, individuals with SAD showed an overactivation in bilateral temporoparietal regions and in the posterior midcingulate cortex during the passive viewing of aversive compared with neutral pictures. During instructed emotion regulation, activation patterns normalized and no significant group differences were detected.Limitations: As no positive pictures were presented, results might be limited to the regu lation of negative emotion.Conclusion: During passive viewing of aversive images, individuals with SAD showed evidence of neural hyperreactivity that may be interpreted as increased bodily self-consciousness and heightened perspective-taking. During voluntary increase and decrease of negative emotional intensity, group differences disappeared, suggesting self-focused reappraisal as a successful emotion regulation strategy for individuals with SAD.

Shame has been described as a central emotion in narcissistic personality disorder (NPD). However, there is a dearth of empirical data on shame in NPD. Patients with NPD (N=28), non-clinical controls (N=34) and individuals with borderline personality disorder (BPD, N=31) completed self-report measures of state shame, shame-proneness, and guilt-proneness. Furthermore, the Implicit Association Test (IAT) was included as a measure of implicit shame, assessing implicit shame-self associations relative to anxiety-self associations. Participants with NPD reported higher levels of explicit shame than non-clinical controls, but lower levels than patients with BPD. Levels of guilt-proneness did not differ among the three study groups. The implicit shame-self associations (relative to anxiety-self associations) were significantly stronger among patients with NPD compared to nonclinical controls and BPD patients. Our findings indicate that shame is a prominent feature of NPD. Implications for diagnosis and treatment are discussed.

This study examines the relationship of personality disorders (PDs) with the outcome of an inpatient treatment for depression. One hundred sixty-eight inpatients with unipolar depression (41% with PD according to SCID-II) were assessed at admission, discharge, and 1-year follow-up. Patients without as well as with PD showed a significant and comparable intake-to-discharge symptom reduction in all inventories. At posttreatment, patients with PD scored higher in self-report measures of symptom severity (Brief Symptom Inventory, Beck Depression Inventory) than patients without PD, due to their higher symptom levels at intake. However, there was no difference in clinician-rated therapy outcome (Hamilton Rating Scale for Depression [17-item version], Global Assessment of Functioning Scale, Clinical Global Impression Scale) between both patient groups at discharge. At 1-year follow-up, patients without PD maintained their treatment outcome, whereas patients with PD showed a slight increase in symptom severity, compared to discharge. The results suggest that a difference in acute treatment outcome between depressed patients with and without PD may be found using self-ratings but not expert ratings of symptom severity. Furthermore, the importance of subsequent outpatient treatment that takes into account the special needs of depressed patients with comorbid PD is highlighted.

Background: Anxious depression (AD) is common in patients with unipolar depression. It remains unclear if they have a higher level of depressive symptoms, a higher risk of non-response, a poorer prognosis and a higher relapse rate compared to non-anxious depressed (non-AD) patients. Methods: 168 patients took part in all three measurement points: (1) intake, (2) discharge and (3) follow-up. Patients fulfilled the criteria for anxious depression if they had a baseline score 4 7o n the anxiety/ somatisation factor of the Hamilton Rating Scale for Depression (HRSD). Patients with AD and non-AD were compared regarding symptom reduction from intake to discharge as well as from discharge to one year after discharge. Primary outcome measure was the HRSD. Results: The prevalence of AD was considerably high (81%). At intake, patients with AD had a significant higher score in the modified HRSD (M¼20.6774.12 vs. M¼14.3575.06). Both patient groups showed a significant and comparable intake-to-discharge symptom reduction in all inventories. Remission rates at discharge did not differ between AD and non-AD patients. At 1-year follow-up, AD patients showed a similar symptom severity compared to non-AD patients. Conclusion: Symptoms of anxiety are common in depressive disorders are associated with higher depressive symptoms at the beginning of treatment. Acute and longer-term treatment outcome of AD patients was comparable to that of non-AD patients. Limitations: Limitations of this study are the naturalistic design, treatment was not standardized and comorbid anxiety disorders were not assed using a structured interview.

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.

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.

Contains fulltext : 177350.pdf (Publisher’s version ) (Closed access) The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 x 10-8; rs191260602, P=3.9 x 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 x 10-4) and rs7688285 (P=7.6 x 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

OBJECTIVE: Cognitive-behavioral therapy (CBT) is a first-line treatment for panic disorder with agoraphobia (PD/AG). Nevertheless, an understanding of its mechanisms and particularly the role of therapist-guided exposure is lacking. This study was aimed to evaluate whether therapist-guided exposure in situ is associated with more pervasive and long-lasting effects than therapist-prescribed exposure in situ. METHOD: A multicenter randomized controlled trial, in which 369 PD/AG patients were treated and followed up for 6 months. Patients were randomized to 2 manual-based variants of CBT (T+/T-) or a wait-list control group (WL; n = 68) and were treated twice weekly for 12 sessions. CBT variants were identical in content, structure, and length, except for implementation of exposure in situ: In the T+ variant (n = 163), therapists planned and supervised exposure in situ exercises outside the therapy room; in the T- group (n = 138), therapists planned and discussed patients' in situ exposure exercises but did not accompany them. Primary outcome measures were (a) Hamilton Anxiety Scale, (b) Clinical Global Impression, (c) number of panic attacks, and (d) agoraphobic avoidance (Mobility Inventory). RESULTS: For T+ and T- compared with WL, all outcome measures improved significantly with large effect sizes from baseline to post (range = -0.5 to -2.5) and from post to follow-up (range = -0.02 to -1.0). T+ improved more than T- on the Clinical Global Impression and Mobility Inventory at post and follow-up and had greater reduction in panic attacks during the follow-up period. Reduction in agoraphobic avoidance accelerated after exposure was introduced. A dose-response relation was found for Time × Frequency of Exposure and reduction in agoraphobic avoidance. CONCLUSIONS: Therapist-guided exposure is more effective for agoraphobic avoidance, overall functioning, and panic attacks in the follow-up period than is CBT without therapist-guided exposure. Therapist-guided exposure promotes additional therapeutic improvement--possibly mediated by increased physical engagement in feared situations--beyond the effects of a CBT treatment in which exposure is simply instructed.

Cognitive behavioral therapy (CBT) is efficacious for panic disorder with agoraphobia (PD/A). Nevertheless, the active ingredients of treatment and the mechanisms through which CBT achieves its effects remain largely unknown. The mechanisms of action in CBT (MAC) study was established to investigate these questions in 369 patients diagnosed with PD/A. The MAC study utilized a multi-center, randomized controlled design, with two active treatment conditions in which the administration of exposure was varied, and a wait-list control group. The special feature of MAC is the way in which imbedded experimental, psychophysiological, and neurobiological paradigms were included to elucidate therapeutic and psychopathological processes. This paper describes the aims and goals of the MAC study and the methods utilized to achieve them. All aspects of the research design (e.g., assessments, treatment, experimental procedures) were implemented so as to facilitate the detection of active therapeutic components, and the mediators and moderators of therapeutic change. To this end, clinical, behavioral, physiological, experimental, and genetic data were collected and will be integrated.

Objective Nonsuicidal deliberate self-harm and factitious disorders have been proposed as subtypes within the autodestructive behavior spectrum, basically differing in the issue of concealment. Aims are to determine Axis I diagnoses and psychopathologic correlates of open self-harmers and patients diagnosed with factitious disorders. Methods One hundred ninety-four psychosomatic medicine inpatients participated. Assessment included the structured World Health Organization Composite International Diagnostic Interview (computerized version) and self-report questionnaires for anxiety, depression, perceived stress, and personal coping resources. Results Thirty-seven patients identified with self-destructive behavior were matched with 37 patients without such behavior. Overt self-harmers (n = 18) were more frequently diagnosed with anxiety, depressive, substance abuse/dependence, or eating disorders and reported more stress than factitious disorder patients (n = 19) or those without self-destructive behavior. Patients with factitious disorder exhibited lower Axis I comorbidity and less psychopathology than patients without self-harm behavior. Conclusions Regarding psychopathologic assessment, contrary to open self-harmers, factitious disorder patients appear strikingly inconspicuous.

Participants with generalized social phobia (GSP) with (n=36) and without (n=19) avoidant personality disorder (AVPD) were compared via contrasts of group means and classification analysis on purported core features of AVPD. GSP-AVPD participants proved to be more severely impaired or distressed on some group contrasts. Cluster analysis identified two groups in the sample, with group membership significantly correlated to AVPD diagnosis. However, almost all significant findings were nullified when severity of social phobia was statistically controlled. Thus, at least where participants with social phobia are concerned, it seems most parsimonious to consider AVPD a severe form of GSP rather than a separate diagnostic category.

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.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.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.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.

Introduction: Cognitive behavioural therapy (CBT) and pharmacological treatment with selective serotonin or serotonin-noradrenalin reuptake inhibitors (SSRI/SSNRI) are regarded as efficacious treatments for panic disorder with agoraphobia (PD/AG). However, little is known about treatment-specific effects on symptoms and neurofunctional correlates. Experimental procedures: We used a comparative design with PD/AG patients receiving either two types of CBT (therapist-guided (n=29) or non-guided exposure (n=22)) or pharmacological treatment (SSRI/SSNRI; n=28) as well as a wait-list control group (WL; n=15) to investigate differential treatment effects in general aspects of fear and depression (Hamilton Anxiety Rating Scale HAM-A and Beck Depression Inventory BDI), disorder-specific symptoms (Mobility Inventory MI, Panic and Agoraphobia Scale subscale panic attacks PAS-panic, Anxiety Sensitivity Index ASI, rating of agoraphobic stimuli) and neurofunctional substrates during symptom provocation (Westphal-Paradigm) using functional magnetic resonance imaging (fMRI). Comparisons of neural activation patterns also included healthy controls (n=29). Results: Both treatments led to a significantly greater reduction in panic attacks, depression and general anxiety than the WL group. The CBT groups, in particular, the therapist-guided arm, had a significantly greater decrease in avoidance, fear of phobic situations and anxiety symptoms and reduction in bilateral amygdala activation while the processing of agoraphobia-related pictures compared to the SSRI/SSNRI and WL groups. Discussion: This study demonstrates that therapist-guided CBT leads to a more pronounced short-term impact on agoraphobic psychopathology and supports the assumption of the amygdala as a central structure in a complex fear processing system as well as the amygdala׳s involvement in the fear system׳s sensitivity to treatment.

Background.Previous studies of the dimensional structure of panic attack symptoms have mostly identified a respiratory and a vestibular/mixed somatic dimension. Evidence for additional dimensions such as a cardiac dimension and the allocation of several of the panic attack symptom criteria is less consistent. Clarifying the dimensional structure of the panic attack symptoms should help to specify the relationship of potential risk factors like anxiety sensitivity and fear of suffocation to the experience of panic attacks and the development of panic disorder.Method.In an outpatient multicentre study 350 panic patients with agoraphobia rated the intensity of each of the ten DSM-IV bodily symptoms during a typical panic attack. The factor structure of these data was investigated with nonlinear confirmatory factor analysis (CFA). The identified bodily symptom dimensions were related to panic cognitions, anxiety sensitivity and fear of suffocation by means of nonlinear structural equation modelling (SEM).Results.CFA indicated a respiratory, a vestibular/mixed somatic and a cardiac dimension of the bodily symptom criteria. These three factors were differentially associated with specific panic cognitions, different anxiety sensitivity facets and suffocation fear.Conclusions.Taking into account the dimensional structure of panic attack symptoms may help to increase the specificity of the associations between the experience of panic attack symptoms and various panic related constructs.

Exposure‐based psychological interventions currently represent the empirically best established first line form of cognitive‐behavioural therapy for all types of anxiety disorders. Although shown to be highly effective in both randomized clinical and other studies, there are important deficits: (1) the core mechanisms of action are still under debate, (2) it is not known whether such treatments work equally well in all forms of anxiety disorders, including comorbid diagnoses like depression, (3) it is not known whether an intensified treatment with more frequent sessions in a shorter period of time provides better outcome than distributed sessions over longer time intervals. This paper reports the methods and design of a large‐scale multicentre randomized clinical trial (RCT) involving up to 700 patients designed to answer these questions. Based on substantial advances in basic research we regard extinction as the putative core candidate model to explain the mechanism of action of exposure‐based treatments. The RCT is flanked by four add‐on projects that apply experimental neurophysiological and psychophysiological, (epi)genetic and ecological momentary assessment methods to examine extinction and its potential moderators. Beyond the focus on extinction we also involve stakeholders and routine psychotherapists in preparation for more effective dissemination into clinical practice.

In cognitive behavioural therapy of phobic anxiety, in vivo exposure is considered as an effective treatment strategy. Apparently, it involves the experience of stress and anxiety in patients. Given the therapist's role during exposure sessions, it is conceivable that the performance is also accompanied with the experience of stress in therapists, especially when unversed in conducting psychotherapy. Studies confirmed that cognitive behavioural therapists tend to avoid therapist-guided in vivo exposure. The objective of this study was the simultaneous investigation of therapist's and patient's stress response during in vivo exposure. Therefore, 23 agoraphobic patients and their 23 treating therapists in training provided five saliva samples during an in vivo exposure and five samples during an ordinary therapy session. Before and during exposure session, subjective evaluations of stress and anxiety were assessed. Results suggested that therapists reported similar levels of perceived stress as patients before exposure. Both groups displayed significantly elevated salivary cortisol (sC) levels during exposure compared to the control session and a trend for alterations in salivary alpha-amylase (sAA) activity was found. Therapists reached peak concentrations of sC before start of the intervention followed by a decline during exposure, while patients displayed peak levels of cortisol secretion after 60 min of exposure. In vivo exposure seems to be a demanding intervention not only for the patient, but also for therapists in training. However, it was also demonstrated that physiological and subjective stress rather decrease during the intervention and that both groups rated exposure to be substantially successful. Based on the presented results, another potential factor contributing to the under-usage of exposure treatment is conceivable and needs to be addressed in future research.

Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12 sessions of manualized cognitive-behavioural therapy (CBT) and were genotyped for HTR1A rs6295. In four subsamples of this multicentre trial, exposure behaviour (n = 185), defensive reactivity measured using a behavioural avoidance test (BAT; before CBT: n = 245; after CBT: n = 171) and functional magnetic resonance imaging (fMRI) data during fear conditioning were acquired before and after CBT (n = 39). HTR1A risk genotype (GG) carriers more often escaped during the BAT before treatment. Exploratory fMRI results suggest increased activation of the amygdala in response to threat as well as safety cues before and after treatment in GG carriers. Furthermore, GG carriers demonstrated reduced effects of CBT on differential conditioning in regions including the bilateral insulae and the anterior cingulate cortex. Finally, risk genotype carriers demonstrated reduced self-initiated exposure behaviour to aversive situations. This study demonstrates the effect of HTR1A variation on defensive behaviour, amygdala activity, CBT-induced neural plasticity and normalization of defence behaviour in PD/AG. Our results, therefore, translate evidence from animal studies to humans and suggest a central role for HTR1A in differentiating subgroups of patients with anxiety disorders.

The monitoring and regulation of one's own physiological reactions and cardioregulatory abnormalities are central to the aetiology and maintenance of social anxiety disorder (SAD). We therefore explored the neural correspondences of these heart rate alterations. 21 patients with SAD and 21 matched healthy controls (HCs) underwent 3T-fMRI scanning. Simultaneously, high-frequency heart rate variability (HF-HRV) was acquired during a short-term resting period and an implicit emotional face-matching task. Compared to HCs, patients with SAD reported increased self-focused attention while being less accurate in estimating their heartbeats. Physiologically, they showed less HF-HRV at rest and during task. Across groups, HF-HRV at rest correlated positively with activation in visual face-processing areas. The right caudate nucleus showed an interaction of group and cardioregulation: Activation in this region was positively correlated in patients with SAD but negatively in HCs. We conclude that cardioregulation is altered in SAD on the subjective, physiological, and brain level.

Cognitive-behavioral therapy (CBT) aims to help patients establish new behaviors that will be maintained and adapted to the demands of new situations. The long-term outcomes are therefore crucial in testing the durability of CBT. A two-year follow-up assessment was undertaken on a subsample of n = 146 PD/AG patients from a multicenter randomized controlled trial. Treatment consisted of two variations of CBT: exposure in situ in the presence of the therapist (T+) or on their own following therapist preparation (T-). Both variations of CBT had high response rates and, overall, maintained the level of symptomatology observed at post-treatment with high levels of clinical significance. Effect sizes 24 months following treatment were somewhat lower than at the 6-month follow up. Once patients reached responder status, they generally tended to remain responders at subsequent assessments. Differences were observed for patients that obtained additional treatment during the follow-up period. Expert opinion and subjective appraisal of treatment outcome differed. No robust baseline predictors of 2-year outcome were observed. Most patients maintain clinically meaningful changes two years following treatment across multiple outcome measures. Approximately 1/3 of patients continued to experience meaningful residual problems.

Non-response to an antidepressant monotherapy in unipolar depression is quite common. Therefore strategies for subsequent treatment steps are necessary. However, there is a lack of direct comparisons of these different strategies. In this naturalistic study we compared the outcome to different strategies after failure of the primary antidepressant treatment. Failure of primary antidepressant monotherapy occurred in 135 patients. 98 of these patients have been administered 4 treatment strategies of the physicians’ choice: lithium augmentation (Li-Augm), switching to another antidepressant (AD-Switch), combination of 2 antidepressants (AD-Comb) or augmentation with second generation antipsychotic (SGA-Augm). Primary outcome measure was the 17-item Hamilton rating scale for depression (HRSD). Patients who received Li-Augm or augmentation with SGAs showed significantly greater improvement in HRSD and BDI compared to patients with antidepressant switch or antidepressant combination. Remission rates for Li-Augm and SGA-Augm were 89.3% and 86.2% compared to 40.7% for AD-Switch and 42.9% for AD-Comb. Changing to another pharmacological class (Li-Augm or augmentation with SGAs) showed better treatment results than sticking to the class of antidepressants (AD-Switch and AD-Comb) after primary failure in response to antidepressant monotherapy in unipolar depression. The lack of randomization and absence of a non-response definition are design flaws. Controlled studies are required to confirm the findings of this trial.

This naturalistic study is a contribution to randomized controlled trials which reflect only a very limited part of patients of the clinical practice and the relevance of guideline recommended treatment.Adhering to quality assurance and development of treatment guidelines, 224 patients were evaluated for the effectiveness of inpatient treatment of unipolar depressive disorders by assessing admission and discharge depression scores, response and remission rates. Furthermore patients who were treated according to current guidelines (duration of treatment, dosage of antidepressants, combination of medication and psychotherapy) were compared to patients who did not meet those criteria. Primary outcome measure was the 17-item Hamilton Rating Scale for Depression (HAMD). Secondary outcome measures included Beck Depression Inventary (BDI).Mean HAMD-17 total score decreased from 28.9 to 8.0. Effect sizes d were similar to other naturalistic studies (d(HAMD) = 2.9; d(BDI) = 1.4); 84.4% of the patients could reach complete or partial response criteria for the HAMD-17. Patients treated according to guidelines could reach remission in 73% of cases (HAMD) vs. 59.6% remission rate for non-guideline patients.This trial shows high remission rates in inpatient treatment of depression compared to similar effectiveness studies. Guideline according treatment might be superior to other treatment strategies.

Background The learning perspective of panic disorder distinguishes between acute panic and anxious apprehension as distinct emotional states. Following animal models, these clinical entities reflect different stages of defensive reactivity depending upon the imminence of interoceptive or exteroceptive threat cues. The current study tested this model by investigating the dynamics of defensive reactivity in a large group of patients with panic disorder and agoraphobia (PD/AG). Methods Three hundred forty-five PD/AG patients participated in a standardized behavioral avoidance test (being entrapped in a small, dark chamber for 10 minutes). Defense reactivity was assessed measuring avoidance and escape behavior, self-reports of anxiety and panic symptoms, autonomic arousal (heart rate and skin conductance), and potentiation of the startle reflex before and during exposure of the behavioral avoidance test. Results Panic disorder and agoraphobia patients differed substantially in their defensive reactivity. While 31.6% of the patients showed strong anxious apprehension during this task (as indexed by increased reports of anxiety, elevated physiological arousal, and startle potentiation), 20.9% of the patients escaped from the test chamber. Active escape was initiated at the peak of the autonomic surge accompanied by an inhibition of the startle response as predicted by the animal model. These physiological responses resembled the pattern observed during the 34 reported panic attacks. Conclusions We found evidence that defensive reactivity in PD/AG patients is dynamically organized ranging from anxious apprehension to panic with increasing proximity of interoceptive threat. These data support the learning perspective of panic disorder.