Eye movement desensitization and reprocessing (EMDR) therapy or supportive counseling prior to exposure therapy in patients with panic disorder: study protocol for a multicenter randomized controlled trial (IMPROVE).

BACKGROUND: Exposure-based therapy is the treatment of choice for anxiety disorders, but many patients do not benefit sufficiently from it. Distressing images of threat related to the future or past may maintain the anxiety symptomatology or impede exposure therapy. An intervention that targets threat-related imagery is eye movement desensitization and reprocessing (EMDR) therapy. The main goal of this multicenter randomized controlled trial is to investigate whether EMDR therapy plus exposure therapy, relative to supportive counseling plus exposure therapy, improves treatment efficacy, tolerability, and adherence in patients with panic disorder. In addition, we will examine potential predictors of optimal treatment allocation, mechanisms of change as well as the long term effects of treatment. Finally, we will assess cost-effectiveness. METHODS: A multicenter randomized controlled trial mixed design will be conducted. Participants will be 50 patients, aged ≥ 18, diagnosed with a panic disorder. They will be randomly assigned to one of two conditions: EMDR therapy (i.e., flashforward strategy) or supportive counseling (each consisting of four weekly sessions of 90 min each) prior to exposure therapy (consisting of eight weekly sessions of 90 min each). Assessments will be made pre-treatment (T1), between-treatments (T2), post-treatment (T3), one month post-treatment (FU1) and six months post-treatment (FU2) by an assessor blind to treatment condition. The primary outcome measure is severity of panic-related symptoms. Secondary outcome measures are: tolerability of exposure therapy (initial avoidance, willingness to start exposure therapy, considered drop-out; no-show and drop-out), related symptomatology (generalized anxiety, depression), and functional impairment. DISCUSSION: The primary goals of this research are to compare the efficacy, tolerability, and adherence of EMDR therapy plus exposure therapy and supportive counseling plus exposure therapy and to identify predictors, moderators, and mediators for treatment success. This multi-center research aims to make a significant contribution to our understanding as to how treatment for patients with anxiety disorders can be optimized, and elucidate who can benefit most from this novel approach. TRIAL REGISTRATION: ISRCTN-ISRCTN29668369: Improving anxiety treatment by modifying emotional memories before real-life exposure. Registered 27 June 2022-retrospectively registered. ISRCTN-ISRCTN29668369.

Modeling the development of panic disorder with interoceptive conditioning.

Panic disorder is characterized by the paroxysmal occurrence and fear of bodily symptoms. In recent years it has been proposed that patients "learn" to fear cardiorespiratory sensations through interoceptive conditioning. This study sought to model the initial stage of this process in healthy volunteers (N=44) using mild cardiac sensations. An additional aim was to explore whether anxiety sensitivity - a known risk factor for panic disorder - modulates such interoceptive learning. Infusions of pentagastrin and saline were used to manipulate the presence versus absence of cardiac sensations, respectively, and served as conditioned stimuli in a differential interoceptive conditioning paradigm. Inhalation of 35% CO2-enriched air served as the panicogenic, unconditioned stimulus (UCS). In half of the participants ("prepared" condition), cardiac sensations caused by pentagastrin were followed by inhalation of CO2-enriched air (penta CS+), whereas the absence of such sensations (saline) was followed by room air (saline CS-). The reversed combination ("unprepared" condition) was used in the other half of the participants. Conditioning effects showed up for self-reported UCS-expectancy, but not for skin conductance and anxiety ratings. Only participants from the prepared group learned to expect the UCS, and differential learning was impaired with higher scores on anxiety sensitivity. Expectancy learning was more easily established towards the presence compared to the absence of cardiac sensations, whereas the reverse effect was observed for safety learning. Modeling impaired discriminatory learning and the moderating effect of anxiety sensitivity provides new insight in the development of panic disorder.

The weight of cognitions in panic: the link between misinterpretations and panic attacks.

In cognitive theory it is hypothesized that panic attacks are provoked by catastrophic misinterpretations of bodily sensations. The aim of the present study was to investigate the ability of associated word pairs referring to catastrophic thinking (e.g. palpitations-heart attack) in producing panic attacks. Patients with PD (n = 20), patients with mixed anxiety disorders (n = 20), and a healthy control group (n = 30) participated in the present study. To enhance ecological validity we first conducted a stimulus validation experiment. Subsequently, nine suitable panic and neutral word pairs were presented in block to the participants. Anxiety levels were assessed before and after the presentation. PD patients were more anxious when reading these word pairs, compared to neutral word pairs. However, none of the participants experienced a panic attack upon reading the word pairs. From the present results it seems that catastrophic thinking is rather related to the anticipatory anxiety for panic attacks, but not necessarily with the occurrence of the panic attacks themselves.

Carbon dioxide inhalation as a human experimental model of panic: the relationship between emotions and cardiovascular physiology.

Inhaling carbon dioxide (CO2)-enriched air induces fear and panic symptoms resembling real-life panic attacks, the hallmark of panic disorder. The present study aimed to describe the emotional and cardiovascular effects evoked by inhaling CO2, taking shortcomings of previous studies into account. Healthy volunteers underwent a double inhalation of 0, 9, 17.5, and 35% CO2, according to a randomized, cross-over design. In addition to fear, discomfort, and panic symptom ratings, blood pressure and heart rate were continuously monitored. Results showed a dose-dependent increase in all self-reports. Systolic and diastolic blood pressure rose with increasing CO2 concentration, whereas heart rate results were less consistent. Diastolic blood pressure and heart rate variation correlated with fear and discomfort. Based on this relationship and the observation that the diastolic blood pressure most accurately mimicked the degree of self-reported emotions, it might serve as a putative biomarker to assess the CO2-reactivity in the future.

The role of "interoceptive" fear conditioning in the development of panic disorder.

More than 20% of the general population experience a panic attack at least once in their lives; however, only a minority goes on to develop panic disorder (PD). Conditioning mechanisms have been proposed to explain this evolution in persons who are susceptible to developing panic disorder upon a "traumatic" panic attack. According to preparedness theory, some cues are more likely to condition than others, namely, those referring to internal, bodily signals of danger. The aim of the present study was to test this theory in a differential conditioning paradigm, making use of scripts referring to different internal, bodily sensations as conditioned stimulus (CS) and inhalation of 35% CO(2) as unconditioned stimulus (UCS). Thirty-three healthy volunteers were assigned to three scripts conditions: "suffocation," "neutral," or "urgency." During acquisition, one of two versions of a particular script was always followed by an inhalation of 35% CO(2) (CS+) and the other by room air (CS-). Acquisition was followed by a test phase, where only inhalations of room air were administered. In line with our hypothesis, only participants in the suffocation condition exhibited a selective conditioning effect. They were more fearful and showed a significantly higher increase in tidal volume than participants in the two control conditions. Results are discussed with relation to interoceptive conditioning, preparedness, and the possible role of tidal volume in PD.

Priming associations between bodily sensations and catastrophic misinterpretations: Specific for panic disorder?

Cognitive models assume that panic disorder is characterised by a tendency to misinterpret benign bodily symptoms (e.g. breathlessness) in a catastrophic fashion (e.g. suffocation). This is a central part of the cognitive model which presents a core focus for treatment. Several studies have supported this hypothesis. These studies have, however, almost always relied on self-report. In addition to susceptibility to biases (e.g. distortions of memory), a limitation of research based on verbal report is its inability to capture the spontaneous/automatic nature that is attributed to these catastrophic interpretations. The present paper reports on two experiments in which a priming procedure was used to test the hypothesis that panic disorder is characterised by spontaneous catastrophic interpretations and whether this effect is 'specific' to panic disorder. In line with predictions from the cognitive model, it was observed in the first experiment that the panic group demonstrated facilitated responses to trials consisting of a 'symptom' prime and a 'catastrophic outcome' target (e.g. breathlessness - suffocate). Similar effects were not observed for an anxious control group and a nonclinical control group, supporting the specificity of this effect. Interestingly, however, significant priming effects were observed for a group of mental health professionals (part of the healthy control group) who had no history of panic disorder. Subsequently, this unexpected observation was explicitly addressed in a second experiment, which confirmed the findings of Experiment 1. Together, these results suggest that associations between mental representations of benign bodily symptoms and catastrophic outcomes might develop as part of professional knowledge and experience, and should not necessarily be viewed as pathogenic. Theoretical and clinical implications are discussed.

A specific attentional bias in panic disorder?

According to cognitive theories, panic patients are assumed to have an attentional bias toward bodily sensations. To date, there is only some indirect evidence of such a bias measured by an emotional Stroop task. Moreover, the content and disorder specificity of this bias is rather unclear. The aim of this study was to investigate the specificity of attentional bias in patients with panic disorder (PD). Patients with PD (n=32), patients with mixed anxiety disorders (n=25), and a healthy control group (n=26) performed an emotional Stroop task with three word types: panic threat, general threat, and neutral. There were no differences on reaction times between the different groups, or on the different word types. Despite the generally accepted existence of attentional biases in anxiety disorders, we found no evidence of a specific attentional bias in patients with PD.

Reality monitoring and metacognitive beliefs related to cognitive confidence in obsessive-compulsive disorder.

The present study investigated general reality monitoring ability, and selective reality monitoring ability for anxiety relevant actions in a group of individuals with obsessive-compulsive disorder (OCD) and a group of non-anxious controls. In addition, reality monitoring confidence was assessed, as well as specific meta-cognitive beliefs related to cognitive confidence (by means of the Meta-Cognitions Questionnaire (MCQ)). No differences were found between both groups in actual reality monitoring ability. Unlike previous studies, the reality monitoring task included actions that were related to the individual concerns of the OCD patients and were ideographically selected. Nevertheless, no differential reality monitoring effect was observed for the anxiety relevant stimuli. Data from the MCQ, however, revealed that OCD patients had less overall confidence in their memory for actions and their reality monitoring ability. Analysis of the confidence ratings of the reality monitoring task showed that this reduced confidence was restricted to the neutral actions. No differences were observed for patients that reported low or high frequencies of checking behaviour. The whole of these data do not support memory deficit models of OCD, but are in line with recent emphasis on the importance of memory confidence and other meta-cognitive beliefs in OCD.