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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)

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

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.

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.

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.

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

Posttraumatic stress disorder (PTSD) after childhood abuse (CA) is often related to severe co-occurring psychopathology, such as symptoms of borderline personality disorder (BPD). The ICD-11 has included Complex PTSD as a new diagnosis, which is defined by PTSD symptoms plus disturbances in emotion regulation, self-concept, and interpersonal relationships. Unfortunately, the empirical database on psychosocial treatments for survivors of CA is quite limited. Furthermore, the few existing studies often have either excluded subjects with self-harm behaviour and suicidal ideation — which is common behaviour in subjects suffering from Complex PTSD. Thus, researchers are still trying to identify efficacious treatment programmes for this group of patients. We have designed DBT-PTSD to meet the specific needs of patients with Complex PTSD. The treatment programme is based on the rules and principles of dialectical behavioural therapy (DBT), and adds interventions derived from cognitive behavioural therapy, acceptance and commitment therapy and compassion-focused therapy. DBT-PTSD can be provided as a comprehensive residential programme or as an outpatient programme. The effects of the residential programme were evaluated in a randomised controlled trial. Data revealed significant reduction of posttraumatic symptoms, with large between-group effect sizes when compared to a treatment-as-usual wait list condition (Cohen’s d = 1.5). The first aim of this project on hand is to evaluate the efficacy of the outpatient DBT-PTSD programme. The second aim is to identify the major therapeutic variables mediating treatment efficacy. The third aim is to study neural mechanisms and treatment sensitivity of two frequent sequelae of PTSD after CA: intrusions and dissociation. To address these questions, we include female patients who experienced CA and who fulfil DSM-5 criteria for PTSD plus borderline features, including criteria for severe emotion dysregulation. The study is funded by the German Federal Ministry of Education and Research, and started in 2014. Participants are randomised to outpatient psychotherapy with either DBT-PTSD or Cognitive Processing Therapy. Formal power analysis revealed a minimum of 180 patients to be recruited. The primary outcome is the change on the Clinician-Administered PTSD Scale for DSM-5. The expected results will be a major step forward in establishing empirically supported psychological treatments for survivors of CA suffering from Complex PTSD. German Clinical Trials Register: registration number DRKS00005578 , date of registration 19 December 2013.

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.

Psychooncological interventions are an integral component of the treatment of breast cancer patients in certified breast cancer centers. Effective multidisciplinary care requires excellent communication among the team members, including written communication. The study explores how written communication can be implemented in a multidisciplinary team treating cancer patients.A computerized form to enter psychooncological findings into a software designed for the documentation of the diagnostics and therapy of patients with breast cancer was developed.The psychooncological module includes the sectionsThe psychooncological module facilitates the combination of oncological and psychooncological documentation. It can give structured psychooncological information to the physicians. However, the development of the module has to be continued.Psychoonkologische Versorgung ist ein integraler Bestandteil der Behandlung in einem zertifizierten Brustzentrum. Erfolgreiche multidisziplinäre Versorgung erfordert ausgezeichnete Kommunikation zwischen den Teammitgliedern, insbesondere auch schriftliche Kommunikation. Die Studie stellt dar, wie ein schriftlicher Austausch in einem multidisziplinären Team umgesetzt werden kann.Für das im Brustzentrum der Charité eingesetzte Dokumentationssystem wurde ein Formular zur Eingabe psychoonkologischer Befunde entwickelt.Das Psychoonkologie-Modul ist gegliedert in die KategorienDas vorgestellte computergestützte Psychoonkologie-Modul ermöglicht eine Verbindung zwischen onkologischer und psychoonkologischer Dokumentation. Es kann strukturierte Informationen an die behandelnden Ärzte vermitteln, muss jedoch in einigen Punkten überarbeitet werden.

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

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.

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.

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.

BackgroundPanic disorder with agoraphobia is characterized by panic attacks and anxiety in situations where escape might be difficult. However, neuroimaging studies specifically focusing on agoraphobia are rare. Here we used functional magnetic resonance imaging (fMRI) with disorder-specific stimuli to investigate the neural substrates of agoraphobia.MethodWe compared the neural activations of 72 patients suffering from panic disorder with agoraphobia with 72 matched healthy control subjects in a 3-T fMRI study. To isolate agoraphobia-specific alterations we tested the effects of the anticipation and perception of an agoraphobia-specific stimulus set. During fMRI, 48 agoraphobia-specific and 48 neutral pictures were randomly presented with and without anticipatory stimulus indicating the content of the subsequent pictures (Westphal paradigm).ResultsDuring the anticipation of agoraphobia-specific pictures, stronger activations were found in the bilateral ventral striatum and left insula in patients compared with controls. There were no group differences during the perception phase of agoraphobia-specific pictures.ConclusionsThis study revealed stronger region-specific activations in patients suffering from panic disorder with agoraphobia in anticipation of agoraphobia-specific stimuli. Patients seem to process these stimuli more intensively based on individual salience. Hyperactivation of the ventral striatum and insula when anticipating agoraphobia-specific situations might be a central neurofunctional correlate of agoraphobia. Knowledge about the neural correlates of anticipatory and perceptual processes regarding agoraphobic situations will help to optimize and evaluate treatments, such as exposure therapy, in patients with panic disorder and agoraphobia.

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.

Hintergrund: Bislang liegen in Deutschland keine Befunde über die krankheitsbedingten Kosten von Patienten mit einer Borderline Persönlichkeitsstörung (BPS) aus der gesellschaftlichen Perspektive vor. Fragestellung: Wie hoch sind die jährlichen Krankheitskosten pro BPS-Patient? In welchen Bereichen entstehen die höchsten Kosten? Methodik: Auf der Grundlage aktueller gesundheitsökonomischer Empfehlungen wurden die krankheitsbedingten Kosten von N = 55 BPS-Patienten in Berlin für den Zeitraum von 12 Monaten vor Beginn einer ambulanten Psychotherapie aus der gesellschaftlichen Perspektive mit einem Interview erhoben und berechnet. Ergebnisse: Die Krankheitskosten in den 12 Monaten vor der Therapie betrugen insgesamt € 26.882 (SD = € 32.275) pro BPS-Patient. € 17.976 (SD = € 23.867) davon waren direkte Kosten, € 8.906 (SD = € 15.518) wurden für indirekte Kosten berechnet. Die höchsten Kosten entstanden durch stationäre und teilstationäre Aufenthalte (M = € 13.121; SD = € 19.808) sowie durch krankheitsbedingte Erwerbsunfähigkeit (M = € 7.020; SD = € 15.099). Schlussfolgerungen: Die BPS geht mit hohen gesellschaftlichen Kosten einher, die weitaus höher sind als die durch viele andere psychische und somatische Erkrankungen bedingten Kosten.

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.

Childhood interpersonal violence is a major risk factor for developing Posttraumatic Stress Disorder (PTSD), other axis-I disorders or Borderline Personality Disorder (BPD). Individuals with a history of childhood sexual abuse (CSA) and childhood physical abuse (CPA) who meet the criteria of any axis-I disorder usually also exhibit general psychopathologic symptoms and impairments in quality of life and sexuality. The present study investigates whether women with a history of potentially traumatic CSA/CPA without any axis-I disorder or BPD show subthreshold symptoms of PTSD-specific and general psychopathology and impairments in global functioning, quality of life, and sexuality. Data were obtained from N = 92 female participants: n = 31 participants with a history of potentially traumatic CSA/CPA (defined as fulfilling PTSD criterion A) without any axis-I disorder or BPD; n = 31 participants with PTSD related to CSA/CPA; and n = 30 healthy controls without any traumatic experiences. All three groups were matched for age and education. Those with a history of CSA/CPA with and without PTSD were further matched with regard to severity of physical and sexual abuse. While women with a history of potentially traumatic CSA/CPA without axis-I disorder or BPD clearly differed from the PTSD-group in the collected measures, they did not differ from healthy controls (e.g., GAF:87, BSI:0.3, BDI-II:4.5). They showed neither PTSD-specific nor general subthreshold symptoms nor any measurable restrictions in quality of life or sexual satisfaction. Women with a history of potentially traumatic childhood interpersonal violence without axis-I disorder or BPD show a high level of functioning and a low level of pathological impairment that are comparable to the level of healthy controls. Further studies are needed to identify what helped these women survive these potentially traumatic experiences without developing any mental disorders. German Clinical Trials Registration ID: DRKS00006095 . Registered 21 May 2014.

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.

BACKGROUND: Patients with a narcissistic personality disorder (NPD) do not often consult a psychotherapist or psychiatrist because of their NPD, but rather, because of co-occurring psychiatric disorders, or higher general symptom stress. Until now there is no actual data about rates of co-occurrence disorders and general symptom stress. OBJECTIVE: Which axis I and axis II disorders occur typically in NPD in comparison to patients with a borderline personality disorder (BPD)? How are general symptom stress and depressive symptoms related? METHODS: Prevalence of co-occurring disorders (Structured Clinical Interview for DSM-IV for Axis I and Axis II) and general symptom stress (SCL-90-R) and depression (BDI) were investigated in 62 patients with a NPD, 62 patients with a BPD and 59 patients with a double diagnosis NPD/BPD. RESULTS: Affective disorders (64.5%) and substance use disorders (35.5%) were the most comorbid psychiatric disorders in patients with NPD. Substance use disorders (p

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.

Journalists frequently report on disasters. There is a growing evidence that they are subsequently at higher risk of post-traumatic and depressive symptoms. We conducted an internet-based study with 61 journalists who had covered the tsunami disaster in December 2004 from the affected region. The extent of trauma exposure, symptoms and social variables were assessed. About 8 months after the event, indications of post-traumatic stress disorder were found in 6.6 per cent of the sample. Post-traumatic and depressive symptoms were related to the extent of traumatic exposure and to several social variables, most importantly, a low degree of social acknowledgment by supervisor and colleagues. Copyright © 2007 John Wiley & Sons, Ltd.

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.

Background Dialectical behavior therapy (DBT) has been proven to be an efficacious treatment for borderline personality disorder (BPD) in several randomized controlled trials (RCTs). However, generalizability of this outcome to the routine health care (effectiveness) has rarely been investigated to date. The aim of this study is to examine the effectiveness of DBT for BPD under the routine health care situation in Germany. Methods The study has a longitudinal design over a course of four years with six assessment points. In this paper, results for the first year of treatment are reported. Outcome was assessed at four times throughout an initial phase (of up to five therapy-sessions) and an additional 12 months of therapy. Overall, n =78 patients started the study, 47 patients completed one year of treatment. Dependent variables were number and duration of inpatient treatment stays, number of suicide attempts and non-suicidal self-injury, severity of borderline symptoms, depression, level of dissociation, and general psychopathology. Results Patients significantly improved regarding self-injurious behaviors, number of inpatient hospital stays, severity of borderline symptoms and psychopathology. At the end of the first treatment year, 77% of the patients no longer met criteria for BPD diagnosis. Fewer therapy discontinuations by patients were observed when therapists participated in consultation teams. Conclusions Under routine mental health care conditions in Germany, outpatient DBT leads to positive results comparable to those reported in other effectiveness studies and in randomized controlled trials.

The purpose of the study was to examine affect balance in dyads of patients and their relatives and its relationship to behaviour therapy outcome for agoraphobia and panic. Thirty-five agoraphobic outpatients and their relatives participated in the study. On the basis of a 10-min videotaped discussion between the patients and their partners, coded with Kategoriensystem fur Partnerschaftliche Interaktion (KPI; Hahlweg et al., 1984), dyads were classified as affect balanced or unbalanced. Affect-balanced dyads were those who demonstrated a preponderance of positive over negative and neutral behaviours for both people in the interaction. Compared to patients in unbalanced families, patients from balanced families were more likely to benefit from treatment on agoraphobic avoidance, although not on panic frequency, at both post-test and a naturalistic 6-month follow-up. Copyright © 2002 John Wiley & Sons, Ltd.

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 impact of concurrent Axis I and Axis II disorder diagnoses on the efficacy of psychotherapy in a clinical setting for panic disorder with agoraphobia was studied in a sample of 51 agoraphobic outpatients. Diagnoses were based on the Structured Clinical Interview for DSM-III-R. The effects of secondary major depression, dysthymia, generalized anxiety disorder, and avoidant personality disorder were examined via multiple regression analyses. Major depression was associated with less improvement on phobic behavior at 6-month follow-up, whereas dysthymia and avoidant personality disorder predicted less reduction in the frequency of panic attacks at posttest and follow-up, respectively. There was little evidence that generalized anxiety was associated with poorer outcome in this sample. Limitations to the internal validity of the study include uncontrolled use of medication and naturalistic treatment during the follow-up period.

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.

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.

Agoraphobia (with and without panic disorder) is a highly prevalent and disabling anxiety disorder. Its neural complexity can be characterized by specific cues in fMRI studies. Therefore, we developed a fMRI paradigm with agoraphobia-specific stimuli. Pictures of potential agoraphobic situations were generated. Twenty-six patients, suffering from panic disorder and agoraphobia, and 22 healthy controls rated the pictures with respect to arousal, valence, and agoraphobia-related anxiety. The 96 pictures, which discriminated best between groups were chosen, split into two parallel sets and supplemented with matched neutral pictures from the International Affective Picture System. Reliability, criterion, and construct validity of the picture set were determined in a second sample (44 patients, 28 controls). The resulting event-related “Westphal-Paradigm” with cued and uncued pictures was tested in a fMRI pilot study with 16 patients. Internal consistency of the sets was very high; parallelism was given. Positive correlations of picture ratings with Mobility Inventory and Hamilton anxiety scores support construct validity. FMRI data revealed activations in areas associated with the fear circuit including amygdala, insula, and hippocampal areas. Psychometric properties of the Westphal-Paradigm meet necessary quality requirements for further scientific use. The paradigm reliably produces behavioral and fMRI patterns in response to agoraphobia-specific stimuli. To our knowledge, it is the first fMRI paradigm with these properties. This paradigm can be used to further characterize the functional neuroanatomy of panic disorder and agoraphobia and might be useful to contribute data to the differentiation of panic disorder and agoraphobia as related, but conceptually different clinical disorders.

The study's objective was to empirically assess cognitive and emotional empathy in patients with narcissistic personality disorder (NPD). To date, "lack of empathy" is a core feature of NPD solely based on clinical observation. The study's method was that forty-seven patients with NPD, 53 healthy controls, and 27 clinical controls with borderline personality disorder (BPD) were included in the study. Emotional and cognitive empathy were assessed with traditional questionnaire measures, the newly developed Multifaceted Empathy Test (MET), and the Movie for the Assessment of Social Cognition (MASC). The study's results were that individuals with NPD displayed significant impairments in emotional empathy on the MET. Furthermore, relative to BPD patients and healthy controls, NPD patients did not show deficits in cognitive empathy on the MET or MASC. Crucially, this empathic profile of NPD is not captured by the Structured Clinical Interview for DSM-IV for Axis II Disorders (SCID-II). The study's conclusions were that while NPD involves deficits in emotional empathy, cognitive empathy seems grossly unaffected.