Le trouble panique avec agoraphobie (TPA) et le trouble d'anxiété sociale (TAS) sont les deux troubles anxieux (TA) dont la prévalence est la plus forte. Ces troubles ont un impact considérable sur le fonctionnement social, la qualité de vie, l'apparition de troubles comorbides, les relations avec les proches et peuvent conduire à des coûts économiques et sociaux excessifs. De plus, les personnes qui en souffrent présentent des difficultés importantes d'accès au traitement. Malgré l'existence de traitements qui ont démontré leur efficacité, ces personnes peuvent attendre longtemps avant de consulter. Plusieurs obstacles sont à l'origine de ce problème d'accessibilité aux soins spécialisés. Ainsi, il importe de pouvoir identifier les obstacles ainsi que les facteurs qui influencent la recherche de soins chez cette population. L'identification de ces variables s'avère primordiale et permettra de développer des stratégies permettant un meilleurs accès aux soins en santé mentale. L'étude du fardeau chez les proches, du soutien social ainsi que de leurs besoins spécifiques quant aux services désirés permettra aussi de mieux connaître l'impact de ces troubles. Le chapitre I est une introduction générale qui fait l'état des connaissances dans le domaine des difficultés d'accès aux traitements cliniques pour les personnes souffrant de TA. Ce chapitre présente également des stratégies qui viendraient pallier aux problèmes d'accessibilité, principalement l'utilisation du Web et le recours aux pairs-aidants (PA). Le chapitre II constitue un article empirique qui porte sur les besoins de soin non-comblés et les obstacles au traitement chez une population de personnes ayant reçu un diagnostic de TPA, de TAS ou les deux. Le chapitre III présente les résultats d'un article qui examine l'impact des difficultés des personnes souffrant de troubles émotionnels sur leurs proches, le soutien social donné ainsi que les besoins de services. Le chapitre IV comprend un dernier article qui évalue le niveau de préparation des participants ayant complété une formation de PA pour l'accompagnement de personnes souffrant de TPA et de TAS. Finalement, le chapitre V présente une discussion générale et une analyse critique des résultats obtenus dans les articles en tenant compte des considérations méthodologiques, des pistes de recherches futures et des implications cliniques. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Trouble panique avec agoraphobie, trouble d'anxiété sociale, obstacles, accessibilité, soins spécialisés, internet, proches, pairs-aidants, formation

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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.

Background: Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients. Method: The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls. Results: Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation. Conclusions: The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.

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: 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 disorderspecific 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.

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.

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.