Transfer of exposure therapy effects to a threat context not considered during treatment in patients with panic disorder and agoraphobia: Implications for potential mechanisms of change.

Further developments of exposure-based therapy (EBT) require more knowledge about transfer of treatment to non-trained everyday contexts. However, little is known about transfer effects of EBT. Using a standardized EBT protocol in 275 patients with panic disorder and agoraphobia we investigated the transfer of EBT to a highly standardized context during a Behavioral Avoidance Test (BAT; being entrapped in a small and dark test chamber) and not part of the exposure sessions. Patients of a treatment group underwent the BATs before treatment (t1), after a preparatory treatment phase (t2), and after an agoraphobic exposure phase (t3) and were compared with wait-list control patients, who repeated BAT assessments across the same time period. We found stronger reductions in avoidance behavior, reported fear, and autonomic arousal during the BAT from t1 to t3 in the treatment group patients who were anxious during t1 relative to the anxious but untreated patients. Fear reduction was related to treatment outcome indicating the contribution of transfer effects to successful EBT. Interestingly, reduction varied for different fear response systems suggesting different processes to may be involved in transfer effects. Importantly, final BAT assessment still evoked residual fear in the treatment group as compared to BAT non-anxious control patients, suggesting limited transfer effects - one possible reason for the return of symptoms in new situations.

Vagal control of the heart decreases during increasing imminence of interoceptive threat in patients with panic disorder and agoraphobia.

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.

Therapygenetic effects of 5-HTTLPR on cognitive-behavioral therapy in anxiety disorders: A meta-analysis.

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy.

Association of rs7688285 allelic variation coding for GLRB with fear reactivity and exposure-based therapy in patients with panic disorder and agoraphobia.

The gene coding for glycine receptor ß subunits (GLRB) has been found to be related to panic disorder and agoraphobia (PD/AG) and to be associated with altered insular BOLD activation during fear conditioning, as an intermediate phenotype of defensive system reactivity in healthy subjects. In a multicenter clinical trial on PD/AG patients we investigated in three sub-samples whether GLRB allelic variation (A/G; A-allele identified as «risk¼) in the single nucleotide polymorphism rs7688285 was associated with autonomic (behavioral avoidance test BAT; n = 267 patients) and neural (differential fear conditioning; n = 49 patients, n = 38 controls) measures, and furthermore with responding towards exposure-based cognitive behavioral therapy (CBT, n = 184 patients). An interaction of genotype with current PD/AG diagnosis (PD/AG vs. controls; fMRI data only) and their modification after CBT was tested as well. Exploratory fMRI results prior to CBT, revealed A-allele carriers irrespective of diagnostic status to show overall higher BOLD activation in the hippocampus, motor cortex (MC) and insula. Differential activation in the MC, anterior cingulate cortex (ACC) and insula was found in the interaction genotype X diagnosis. Differential activation in ACC and hippocampus was present in differential fear learning. ACC activation was modified after treatment, while no overall rs7688285 dependent effect on clinical outcomes was found. On the behavioral level, A-allele carriers showed pronounced fear reactivity prior to CBT which partially normalized afterwards. In sum, rs7688285 variation interacts in a complex manner with PD/AG on a functional systems level and might be involved in the development of PD/AG but not in their treatment.

Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes.

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.

Anxious and alert? Hypervigilance in social anxiety disorder.

The vast majority of research on attentional biases to threat focusses on selective attention, even though several cognitive-behavioral models furthermore assume hypervigilance to be important in this regard. Thus, the current study examined hypervigilance in trait and state social anxiety. We analyzed visual scanpath lengths and fixation counts of participants with Social Anxiety Disorder (SAD) (n = 61) and healthy controls (n = 60) in a combined visual search and eye tracking paradigm, including photographs of facial expressions. Half of all participants were randomly assigned to a state anxiety induction. Interaction effects revealed opposed attentional patterns of participants with SAD as compared to healthy controls considering overall visual scanpath lengths (F(1,117) = 5.32, p = 0.023, η2partial = 0.043) and fixation counts (F(1,117) = 5.10, p = 0.026, η2partial = 0.042). Accordingly, participants with SAD showed signs of hypervigilance in the anxiety induction condition. In contrast, there was no main effect of diagnostic group, indicating that individuals with SAD shift their attentional focus to broad scanning behavior only under conditions of threat. Our results add to the small number of existing studies on hypervigilance in SAD and suggest the topic to be promising for future research.

Attentional biases to threat in social anxiety disorder: time to focus our attention elsewhere?

BACKGROUND: Cognitive models propose that attentional biases to threat contribute to the maintenance of social anxiety disorder (SAD). However, the specific characteristics of such biases are still object to debate. OBJECTIVES: The current study aimed to disentangle effects of trait and state social anxiety on attention allocation towards social stimuli. METHODS: Participants with SAD (n = 67) and healthy controls (n = 62) completed three visual search tasks while their eye movements were recorded. Half of the participants in each group were randomly assigned to a state anxiety induction. RESULTS: Contrary to our predictions, neither trait nor state social anxiety was associated with a facilitated attention to or a delayed disengagement from threat. However, participants with SAD did show reduced fixation durations for threatening stimuli, indicating an avoidance of threat. Induction of state anxiety led to an increased distractibility by threat. CONCLUSIONS: We suggest that attention allocation in SAD is characterized by an avoidant rather than a vigilant attentional bias. Accordingly, our results contradict previous results that associate SAD with facilitated attention to threat and existing approaches to modify attentional biases, that aim to decrease attention towards threatening stimuli.

Using Functional Analysis as a Framework to Guide Individualized Treatment for Negative Symptoms.

Although numerous interventions are available for negative symptoms, outcomes have been unsatisfactory with pharmacological and psychological interventions producing changes of only limited clinical significance. Here, we argue that because negative symptoms occur as a complex syndrome caused and maintained by numerous factors that vary between individuals they are unlikely to be treated effectively by the present "one size fits all" approaches. Instead, a well-founded selection of those interventions relevant to each individual is needed to optimize both the efficiency and the efficacy of existing approaches. The concept of functional analysis (FA) can be used to structure existing knowledge so that it can guide individualized treatment planning. FA is based on stimulus-response learning mechanisms taking into account the characteristics of the organism that contribute to the responses, their consequences and the contingency with which consequences are tied to the response. FA can thus be flexibly applied to the level of individual patients to understand the factors causing and maintaining negative symptoms and derive suitable interventions. In this article we will briefly introduce the concept of FA and demonstrate-exemplarily-how known psychological and biological correlates of negative symptoms can be incorporated into its framework. We then outline the framework's implications for individual assessment and treatment. Following the logic of FA, we argue that a detailed assessment is needed to identify the key factors causing or maintaining negative symptoms for each individual patient. Interventions can then be selected according to their likelihood of changing these key factors and need to take interactions between different factors into account. Supplementary case vignettes exemplify the usefulness of functional analysis for individual treatment planning. Finally, we discuss and point to avenues for future research guided by this model.

Post-event processing in social anxiety disorder after real-life social situations - An ambulatory assessment study.

Excessive post-mortem processing after social situations, a core symptom of social anxiety disorder (SAD), is thought to contribute to the perpetuation of social anxiety by consolidating negative self-schemata. Empirical findings on actual mechanisms underlying this so-called Post-Event Processing (PEP) are still scarce. The present study sought to identify variables associated with the experience of PEP after real-life social situations in a sample of 49 individuals diagnosed with SAD. Using an ambulatory assessment approach, individuals were asked to report on each distressing social event experienced during one week. A total of 192 events were captured. Hierarchical linear modeling indicated that next to trait social anxiety, the type of social situation (performance vs. interaction situations), self-focused attention, safety behavior use, and negative affect predicted levels of PEP after social situations. These findings add to the growing literature that emphasizes the importance of situational factors for the experience of PEP, and highlight potential venues to prevent it.

Performance perceptions and self-focused attention predict post-event processing after a real-life social performance situation.

BACKGROUND AND OBJECTIVES: Cognitive approaches to social anxiety suggest that an excessive brooding about one's performance in a social situation (post-event processing; PEP) is involved in the maintenance of anxiety. To date, most studies investigating PEP were conducted in laboratory settings. The present study sought to replicate previous findings on predictors of PEP after a naturalistic social performance situation. METHODS: Sixty-five students, who had to give an evaluated presentation for credits, completed measures of trait social anxiety. Immediately after their presentation, participants rated state anxiety and attentional focus during the presentation, and provided an overall evaluation of their performance. One week after the presentation, they rated PEP during the preceding week, and reappraised their performance. RESULTS: Regression analyses demonstrated that the performance ratings after and self-focused attention during the presentation were unique predictors of PEP over and above the effects of trait and state anxiety. There was no evidence that PEP was associated with a biased recall of individual performance evaluations. CONCLUSIONS: The results support cognitive theories that emphasize the importance of negative self-perceptions in the development of social anxiety and related processes, and underline self-focused attention and self-evaluative processes as important targets during treatment.

The strategy does not matter: Effects of acceptance, reappraisal, and distraction on the course of anticipatory anxiety in social anxiety disorder.

OBJECTIVES: Anticipatory anxiety is a core feature of social anxiety disorder (SAD); however, there is a paucity of data on effective strategies for dealing with this affective state. The present study examined the effects of reappraisal, acceptance, and distraction on the course of anticipatory anxiety. DESIGN: The study used an experimental design, randomly assigning participants to one of three strategy groups. Participants were instructed to employ these strategies during the anticipation of an impromptu speech. METHODS: Participants with SAD (n = 67) and healthy controls (n = 72) were compared with regard to their ability to adopt the prescribed strategies and with regard to the effects of strategy use on self-reported and psychophysiological markers of arousal. RESULTS: SAD participants reported more problems in adopting the assigned strategies than controls, although the time spent with each strategy did not differ by group. In both groups, acceptance was rated as more difficult to adopt than reappraisal and distraction. Subjective ratings of anxiety decreased during the first 10 min of anticipation regardless of diagnostic group or strategy, but anxiety increased again immediately prior to the speech. Psychophysiological parameters were largely unaffected by group or strategy. CONCLUSION: The results question whether there are differential benefits of different emotion regulation (ER) strategies in dealing with anticipatory anxiety. The observed rebound of anxiety prior to the social event calls into doubt the long-term effectiveness of these strategies, at least during the regulation of anticipatory anxiety. PRACTITIONER POINTS: Coping with anticipatory anxiety is an important issue in treating SAD. Compared to healthy controls, individuals diagnosed with SAD experienced more problems in adopting prescribed ER strategies for dealing with anticipatory anxiety. We found no differences between acceptance, reappraisal, and distraction, calling into question that one strategy should be generally recommended by clinicians.

Emotion regulation difficulties in social anxiety disorder and their specific contributions to anxious responding.

OBJECTIVE: Recent theories emphasize the contribution of emotion regulation (ER) difficulties to psychopathology. The present study sought to identify patterns of ER difficulties in social anxiety disorder (SAD) and to test the predictive value of these difficulties for actual anxious responding during the anticipation of a social evaluative task. METHOD: Participants diagnosed with SAD (n = 67) and healthy controls (n = 59) completed self-ratings of ER difficulties (DERS) and depressive symptoms. This was followed by the announcement of an impromptu speech. During the anticipation period, subjective ratings of anxiety and arousal were assessed. RESULTS: Compared to healthy controls, SAD participants reported significantly higher levels of ER difficulties. With the exception of "lack of emotional awareness," these differences remained significant when controlling for depression. ER difficulties also contributed to anxious responding during the stress test; but this held true only for nonclinical participants. CONCLUSION: SAD is characterized by a wide range of ER deficits. However, the associations between ER difficulties and symptoms of anxiety remain poorly understood.

The role of safety behaviors in exposure-based treatment for panic disorder and agoraphobia: associations to symptom severity, treatment course, and outcome.

The potentially detrimental effects of safety behaviors during exposure therapy are still subject to debate. Empirical findings are inconsistent, and few studies have investigated effects of idiosyncratic safety behavior manifestations during exposure or in everyday life. These limitations might be due to a lack of appropriate measures that address individual safety behaviors. We examined psychometric properties and predictive value of the Texas Safety Maneuver Scale (TSMS), a questionnaire specifically targeting safety behaviors in panic disorder and agoraphobia. Effects of safety behavior use, both during everyday life and during therapy, were examined using data from a multicenter RCT of N=268 patients that aimed at evaluating efficacy and mechanisms of action of two variants of an exposure-based therapy. The TSMS total score demonstrated good internal consistency (α=0.89), and it showed significant correlations with selected measures of baseline anxiety and impairment. The proposed factor structure could not be replicated. Frequent safety behavior use at baseline was associated with actual safety behavior during exposure exercises. Pronounced in-situ safety behavior, but not baseline safety behavior was associated to detrimental treatment outcome. The results underline the relevance of a rigorous safety behavior assessment in therapy. The actual relationship between safety behavior use and treatment outcome is yet to determine.

Specificity of homework compliance effects on treatment outcome in CBT: evidence from a controlled trial on panic disorder and agoraphobia.

OBJECTIVES: Although homework assignments are an integral component of cognitive-behavioral therapy (CBT) and relate to positive therapy outcomes, it is unclear whether specific homework types and their completion have specific effects on outcome. METHOD: Data from N = 292 patients (75% female, mean age 36 years) with panic disorder and agoraphobia and treated with standardized CBT were analyzed with homework compliance quality and quantity for different types of homework serving as predictors for different outcome variables. RESULTS: Quality ratings of homework completion were stronger outcome predictors than quantitative compliance ratings. Exposure homework was a better outcome predictor than homework relating to psychoeducation and self-monitoring. CONCLUSION: Different aspects of homework compliance and specific homework types might differentially relate to CBT outcome.

Internet-delivered attention modification training as a treatment for social phobia: a randomized controlled trial.

Attentional biases toward social threat are a well-known phenomenon in social phobia. Recently, computer-delivered trainings have been developed to modify these patterns of attention and thereby reduce anxiety symptoms. Distribution of such attention trainings (ATs) via internet might be a promising approach in overcoming obstacles in health care utilization. However, there is no evidence supporting the effectiveness of internet-based ATs in clinical populations. The current trial examined effects of an internet-based AT on self-report measures, behavioral data and diagnostic status in individuals with social phobia (N = 56). Participants were randomly assigned to either AT using a modified dot probe paradigm or a control condition without attention modification. After training and at a 4-month follow-up, both groups showed small, albeit significant reductions in social anxiety and depression, but there was no evidence for superiority of the AT condition. The present findings question the effectiveness of internet-based ATs in social phobia. Future studies need to investigate effective variants of internet-based ATs before they can be widely applied.

Dynamics of defensive reactivity in patients with panic disorder and agoraphobia: implications for the etiology of panic disorder.

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.

Anticipatory anxiety as a function of panic attacks and panic-related self-efficacy: an ambulatory assessment study in panic disorder.

BACKGROUND: Panic attacks and anticipatory anxiety are considered to be inter-correlated, yet distinctive, features of panic disorder, both contributing to its onset and maintenance as well as to the associated impairment. Given the difficulty to yield ecologically valid data on these fluctuating symptoms the natural course of anticipatory anxiety and its correlates have seldom been addressed with adequate methods. AIMS: The current study aimed at further exploring the natural variance of anticipatory anxiety and its interdependence with panic-related variables. In addition, impact of anxiety sensitivity, and perceived ability to cope with panic on the relation between panic attacks and subsequent anxiety was inspected. METHOD: Based on an Ecological Momentary Assessment approach, 21 patients with panic disorder rated study variables continuously over one week; 549 question sets were completed. RESULTS: Anticipatory anxiety followed a diurnal pattern and was associated with situational and internal variables typically linked to panic experiences. Preceding panic attacks intensified anticipatory anxiety and associated negative emotional states; however, perceived ability to cope attenuated these effects. CONCLUSION: Based on natural observation data, results largely support the importance of cognitive appraisals for anticipatory anxiety, and its interplay with panic attacks as it has been suggested by cognitive theory and recent findings in extinction learning research.

Psychological treatment for panic disorder with agoraphobia: a randomized controlled trial to examine the role of therapist-guided exposure in situ in CBT.

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.

Phenomenological differences between acute and chronic forms of major depression in inpatients.

BACKGROUND: Chronic forms of depression are highly prevalent especially in inpatient settings. Defined only by episode duration greater than 2 years, heterogeneous diagnoses like dysthymic disorder, double depression, major depression and recurrent major depression are included. Chronic depression is considered difficult to treat, although its distinguishing characteristics remain unclear. AIMS: The purpose of the present study was empirically to approach proposed differences between acute and chronic forms of depression. METHODS: 80 psychiatric inpatients positively screened for depression and diagnosed with the Composite International Diagnostic Interview (CIDI), completed a set of questionnaires regarding symptom severity (a simplified version of the Beck Depression Inventory), dysfunctional attitudes (Dysfunctional Attitudes Scale), ruminative response style (Response Styles Questionnaire, Why Ruminate Scale) and interpersonal problems (Inventory of Interpersonal Problems; IIP). RESULTS: 30 patients were diagnosed with chronic forms of depression; 34 patients with acute depression. Patients did not differ regarding symptom severity, ruminative response styles, all but one subscales of the IIP or presence of comorbid post-traumatic stress disorder. However, chronic depression did show higher dysfunctional attitudes than acute depression, and reported higher rates of socially avoidant behavior. CONCLUSIONS: In line with previous findings, acute and chronic forms of depression differed in dysfunctional attitudes, which might actually reflect a distinguishing pattern of chronicity. Chronic depression patients also reported higher socially avoidant behavior, which might be crucial to focus in treatment. Surprisingly, other variables that are assumed to characterize chronic depression could not be confirmed as distinguishing features. Future research should take etiological aspects into account.