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

Background/Aims: Little research effort has so far been dedicated to the analysis of the hypothalamic-pituitary-adrenal axis of aetiologically differing subgroups of patients with panic disorder (PD). The current study aimed at a deeper understanding of the cortisol stress response in cannabis-induced PD (CIPD) patients. Methods: Matched groups of 7 PD patients (mean age ± SD: 32.95 ± 9.04 years), 7 CIPD patients (31.94 ± 8.40 years), and 7 healthy controls (HC) (31.13 ± 8.57 years) were included in the study. The Trier Social Stress Test (TSST) was used for stress induction. Salivary cortisol samples were collected and panic- and depression-related questionnaires were applied. Results: A stress response to the TSST was found in 28.6% of PD patients, in 51.1% of CIPD patients, and in 100% of HC subjects. Statistical analyses revealed a cortisol hyporesponsiveness in PD and CIPD patients. While cortisol values of PD patients and HC participantsdiffered significantly, CIPD patients’ cortisol courses balanced between those of PD patients and HC subjects. Conclusions: Current findings show a distinctive pattern of the stress-induced cortisol reaction in CIPD patients, which is markedly different from the hormonal response in PD patients as well as HC subjects. Previous findings of cortisol hyporesponsiveness in PD patients compared to HC subjects were confirmed.

Objective: To examine the association between separation anxiety disorder (SAD) and mental disorders in a community sample and to evaluate whether separation anxiety is specifically related to panic disorder with and without agoraphobia. Method: The data come from a 4-year, prospective longitudinal study of a representative cohort of adolescents and young adults aged 14–24 years at baseline in Munich, Germany. The present analyses are based on a subsample of the younger cohort that completed baseline and two follow-up investigations (n = 1,090). DSM-IV diagnoses were made using the Munich Composite International Diagnostic Interview. Cox regressions with time-dependent covariates were used to examine whether prior SAD is associated with an increased risk for subsequent mental disorders. Results: Participants meeting DSM-IV criteria for SAD were at an increased risk of developing subsequent panic disorder with agoraphobia (PDAG) (HR = 18.1, 95% CI = 5.6–58.7), specific phobia (HR = 2.7, 95% CI = 1.001–7.6), generalized anxiety disorder (HR = 9.4, 95% CI = 1.8–48.7), obsessive-compulsive disorder (HR = 10.7, 95% CI = 1.7–66.1), bipolar disorder (HR = 7.7, 95% CI = 2.8–20.8), pain disorder (HR = 3.5, 95% CI = 1.3–9.1), and alcohol dependence (HR = 4.7, 95% CI = 1.7–12.4). Increased hazard rates for PDAG (HR = 4.2, 95% CI = 1.4–12.1), bipolar disorder type II (HR = 8.1, 95% CI = 2.3–27.4), pain disorder (HR = 1.9, 95% CI = 1.01–3.5), and alcohol dependence (HR = 2.1, 95% CI = 1.1–4.) were also found for subjects fulfilling subthreshold SAD. Conclusions: Although revealing a strong association between SAD and PDAG, our results argue against a specific SAD-PDAG relationship. PDAG was neither a specific outcome nor a complete mediator variable of SAD.

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.

Background: Subtle and inconsistent differences in hypothalamic-pituitary-adrenal (HPA) axis activity have been reported for patients with panic disorder. While these patients show little or no alterations in basal ACTH and cortisol levels, it has been hypothesized that HPA hyperresponsivity was a trait in panic patients when exposed to novel and uncontrollable stimulation. Methods: Thirty-four patients (23 females, mean age 35 yrs) diagnosed with panic disorder were compared to 34 healthy controls matched for age, gender, smoking status, and use of oral contraceptives. Both groups were exposed twice to a potent laboratory stress protocol, the Trier Social Stress Test (TSST) on consecutive days. Free salivary cortisol levels and heart rate responses were repeatedly measured before and following the TSST. In addition, the cortisol awakening response (CAR) was assessed to further investigate HPA reactivity in PD patients. Results: While the TSST induced similar heart rate stress responses in both groups, cortisol responses were clearly absent in the panic patients with normal responses in the controls (F(1.96, 66) = 20.16; p < 0.001). No differences in basal cortisol levels were observed in the extended baseline period. The same cortisol stress non-response patterns were observed when patients with/without comorbid depression, or with/without psychotropic medication were compared. In contrast to their non-response to the psychosocial stressor, panic patients showed a significant CAR. Conclusion: These findings provide strong evidence to suggest that PD patients present with a striking lack of cortisol responsivity to acute uncontrollable psychosocial stress under laboratory conditions. This unresponsiveness of the HPA axis appears to be rather specific, since a normal CAR in the morning could be documented in these patients. Thus, the present results do not support the hypothesis that PD patients show a trait HPA hyperresponsiveness to novel and uncontrollable stimulation. In contrast, the data provide support for a hyporesponsive HPA axis under emotional stress in PD patients.

Panic Disorder (PD) has been associated with abnormalities in the respiratory system for a long time, and treatment programs aimed at reversing these abnormalities have been developed. Panicogenic effects of biological challenges have been shown to be altered after successful treatment. Furthermore, there is evidence that anxious non-PD patients show similar responses to these challenges and hence may benefit from some kind of breathing training (BT). To test these assumptions, we recruited 45 PD patients, 39 Episodic Anxiety (EA) patients who suffered from subclinical panic attacks, and 20 non-anxious controls (NAC). Patients were randomized to one of two versions of a 4-week therapy with BT, either lower or raise end-tidal pCO2, or a waiting list (WL). Before and after treatment, participants underwent in randomized order a Voluntary Hypoventilation (VHO) test and a Voluntary Hyperventilation (VHT) test in which they were asked to either lower or raise their pCO2 while psychophysiological measures were recorded. Each test consisted of 3 segments: 1 min baseline, 3 min paced breathing, and 8 min recovery. Before treatment, PD and EA patients were more anxious, distressed, tense, and worried than NAC, and felt more dizziness, chest pain, and nausea during the laboratory assessment. However, increases in psychological symptoms or physiological sensations from baseline to the paced breathing segments were not different between groups. The two tests produced similar changes except that anxiety and dizziness increased more during the VHT than VHO. We replicated baseline breathing abnormalities previously reported for PD patients, namely greater respiration rate, tidal volume instability, and number of sighs. However, analyses did not find that patients recovered slower to either challenge. After treatment, both therapies improved on the main outcome measure. Furthermore, BT affected baseline pCO2, resulting in lower levels in the hypocapnic groups and higher levels in the hypercapnic groups without affecting any other measures. We conclude that baseline respiratory abnormalities are specific to PD. However, data suggest that the manipulations might have been too weak to elicit other previously reported group differences. Breathing training was equally effective for the lower and raise BT. Hence, factors unrelated to modifying one’s pCO2 must have accounted for the symptomatic improvement. Breathing training should not be restricted to PD but be applied to all patients suffering from anxiety attacks.

Theoretischer Hintergrund: Die Rolle der Therapeutenbegleitung während Expositionsübungen bei Panikstörung mit Agoraphobie (P/A) ist bislang ungeklärt. Eine kürzlich durchgeführte klinische Studie (MAC-Studie) lieferte Hinweise auf ein günstigeres Behandlungsergebnis bei Therapeutenbegleitung. Fragestellung: Wie lassen sich Effekte therapeutenbegleiteter Exposition (T+) im Vergleich zu Exposition ohne Therapeutenbegleitung (T–) erklären? Methode: Daten von 301 Patienten, die eine expositionsbasierte KVT mit bzw. ohne Therapeutenbegleitung erhalten hatten, wurden analysiert. Untersucht wurden der Einfluss der initialen Störungsschwere, des Sicherheitsverhaltens sowie differenzielle Effekte der Bedingungen auf die Angst vor der Angst. Zusätzlich wurde überprüft, inwieweit die Übungshäufigkeit in den Behandlungsbedingungen variiert und einen Mediator des Behandlungserfolgs darstellt. Ergebnisse: Störungsschwere und Sicherheitsverhalten zeigten keine differenziellen Effekte zwischen den Bedingungen; die T+ Bedingung führte jedoch zu stärkeren Reduktionen der Angst vor der Angst im Angstsensitivitätsindex. Patienten der T+ Bedingung führten häufiger selbständig Expositionsübungen durch, während Patienten in T– im Durchschnitt länger übten. Die Übungshäufigkeit stellte dabei einen Mediator des Behandlungserfolgs dar. Schlussfolgerungen: Günstigere Effekte einer therapeutenbegleiteten Exposition gehen auf stärkere Reduktionen der Angst vor der Angst sowie auf eine höhere Übungshäufigkeit im Selbstmanagement zurück. / Theoretical background: There is a paucity of studies examining the role of therapist guidance during in-vivo exposure for panic disorder with agoraphobia (PD/AG). A recent study (MAC-study) suggested superior effects of therapist-guided exposure compared to programmed practice. Objectives: Examining potential mechanisms of therapist-guided exposure. Methods: Data from 301 patients with PD/AG who received either CBT with therapist guidance during in-vivo exposure (T+), or CBT with programmed exposure practice (T–) were analysed in regard to effects of initial symptom severity, subtle avoidance behaviours, reductions in fear of fear, and frequency of exposure homework. Results: There were no interaction effects between symptom severity or subtle avoidance and outcome. T+ was associated with higher reductions in fear of fear as well as with higher frequency of exposure homework. Frequency of exposure homework mediated the effect of group on outcome. Conclusion: Advantages of therapist-guided exposure as well as frequency of self-exposure might be attributed to higher reductions in fear of fear.

Although functional magnetic resonance imaging (fMRI) has gained increasing importance in investigating neural substrates of anxiety disorders, less is known about the stress eliciting properties of the scanner environment itself. The aim of the study was to investigate feasibility, self-reported distress and anxiety management strategies during an fMRI experiment in a comprehensive sample of patients with panic disorder and agoraphobia (PD/AG). Within the national research network PANIC-NET, n = 89 patients and n = 90 controls participated in a multicenter fMRI study. Subjects completed a retrospective questionnaire on self-reported distress, including a habituation profile and exploratory questions about helpful strategies. Drop-out rates and fMRI quality parameters were employed as markers of study feasibility. Different anxiety measures were used to identify patients particularly vulnerable to increased scanner anxiety and impaired data quality. Three (3.5%) patients terminated the session prematurely. While drop-out rates were comparable for patients and controls, data quality was moderately impaired in patients. Distress was significantly elevated in patients compared to controls; claustrophobic anxiety was furthermore associated with pronounced distress and lower fMRI data quality in patients. Patients reported helpful strategies, including motivational factors and cognitive coping strategies. The feasibility of large-scale fMRI studies on PD/AG patients could be proved. Study designs should nevertheless acknowledge that the MRI setting may enhance stress reactions. Future studies are needed to investigate the relationship between self-reported distress and fMRI data in patient groups that are subject to neuroimaging research.

Background: Learning by conditioning is a key ability of animals and humans for acquiring novel behavior necessary for survival in a changing environment. Aberrant conditioning has been considered a crucial factor in the etiology and maintenance of panic disorder with agoraphobia (PD/A). Cognitive-behavioral therapy (CBT) is an effective treatment for PD/A. However, the neural mechanisms underlying the effects of CBT on conditioning processes in PD/A are unknown. Methods: In a randomized, controlled, multicenter clinical trial in medication-free patients with PD/A who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before and after CBT. Quality-controlled fMRI data from 42 patients and 42 healthy subjects were obtained. Results: After CBT, patients compared to control subjects revealed reduced activation for the conditioned response (CS+ > CS–) in the left inferior frontal gyrus (IFG). This activation reduction was correlated with reduction in agoraphobic symptoms from t1 to t2. Patients compared to control subjects also demonstrated increased connectivity between the IFG and regions of the “fear network” (amygdalae, insulae, anterior cingulate cortex) across time. Conclusions: This study demonstrates the link between cerebral correlates of cognitive (IFG) and emotional (“fear network”) processing during symptom improvement across time in PD/A. Further research along this line has promising potential to support the development and further optimization of targeted treatments.