Agoraphobia and panic attacks complicated by primary aldosteronism improved by treatment with eplerenone: a case report.

BACKGROUND: Primary aldosteronism (PA) is an adrenal gland disease, that induces increased secretion of the mineralocorticoid, aldosterone, resulting in symptoms such as hypertension. This study reports a patient with agoraphobia and panic attacks, associated with PA. This patient's psychiatric symptoms improved after treatment with eplerenone, a mineralocorticoid receptor antagonist. CASE PRESENTATION: The patient was a 40-year-old female with agoraphobia, which refers to the irrational fear of situations that may cause anxiety, and panic attacks characterized by profuse sweating, palpitations, and generalized weakness. She was diagnosed with hypertension from PA. Subsequently, she received treatment with eplerenone, which improved her agoraphobia and panic attacks. CONCLUSIONS: There have been no previous reports on PA associated with agoraphobia and panic attacks that improved with pharmacotherapy. Patients with agoraphobia and panic attacks should be evaluated for PA. In patients with PA, pharmacotherapy with eplerenone should be considered.

Altered Low Frequency Heart Rate Variability Associated with Agoraphobia in Panic Disorder: A Retrospective Study.

PURPOSE: This study aimed to compare the clinical features of panic disorder (PD) with comorbid agoraphobia to those of PD alone. We focused on autonomic nervous system (ANS) alterations reflected in heart rate variability (HRV) and executive function deficits reflected in the Stroop test. MATERIALS AND METHODS: We retrospectively compared psychometric features, Stroop test results, and resting-state HRV across three groups: a subclinical group with anxiety attack history, a PD group without agoraphobia, and a PD group with agoraphobia. The subclinical group included 10 male and 34 female, the PD without agoraphobia group included 17 male and 19 female, and the PD with agoraphobia group included 11 male and 18 female. RESULTS: The PD with agoraphobia group had higher Symptom Checklist-95 scores than the other groups. Both PD groups had longer reaction times in the Stroop test than the subclinical group. There were no significant differences in HRV parameters between the PD groups with and without agoraphobia. Compared with the subclinical group, the PD with agoraphobia group showed significantly lower values of the natural logarithm of low-frequency HRV. CONCLUSION: Our results do not support that executive function deficits and ANS alterations are more pronounced with comorbid agoraphobia among PD groups. However, PD with agoraphobia patients showed more complex and severe clinical symptoms in their self-reports. Compared with the subclinical group, PD patients with agoraphobia showed specific features in the natural logarithm of low-frequency HRV. Our findings suggest that agoraphobia comorbidity should be considered when evaluating or treating patients with PD.

Agoraphobic avoidance in patients with psychosis: Severity and response to automated VR therapy in a secondary analysis of a randomised controlled clinical trial.

BACKGROUND: The social withdrawal of many patients with psychosis can be conceptualised as agoraphobic avoidance due to a range of long-standing fears. We hypothesised that greater severity of agoraphobic avoidance is associated with higher levels of psychiatric symptoms and lower levels of quality of life. We also hypothesised that patients with severe agoraphobic avoidance would experience a range of benefits from an automated virtual reality (VR) therapy that allows them to practise everyday anxiety-provoking situations in simulated environments. METHODS: 345 patients with psychosis in a randomised controlled trial were categorised into average, moderate, high, and severe avoidance groups using the Oxford Agoraphobic Avoidance Scale. Associations of agoraphobia severity with symptom and functioning variables, and response over six months to brief automated VR therapy (gameChange), were tested. RESULTS: Greater severity of agoraphobic avoidance was associated with higher levels of persecutory ideation, auditory hallucinations, depression, hopelessness, and threat cognitions, and lower levels of meaningful activity, quality of life, and perceptions of recovery. Patients with severe agoraphobia showed the greatest benefits with gameChange VR therapy, with significant improvements at end of treatment in agoraphobic avoidance, agoraphobic distress, ideas of reference, persecutory ideation, paranoia worries, recovering quality of life, and perceived recovery, but no significant improvements in depression, suicidal ideation, or health-related quality of life. CONCLUSIONS: Patients with psychosis with severe agoraphobic avoidance, such as being unable to leave the home, have high clinical need. Automated VR therapy can deliver clinical improvement in agoraphobia for these patients, leading to a number of wider benefits.

Cortisol response under low intensity exercise during cognitive-behavioral therapy is associated with therapeutic outcome in panic disorder-an exploratory study.

OBJECTIVES: Patients with Panic Disorder (PD) show an abnormal stress-induced functioning of the Hypothalamic-Pituitary-adrenal (HPA)-axis. Different protocols for stress induction are of rather low relevance for the psychotherapeutic treatment. In practice, interoceptive exposure is often realized as Low Intensity Exercise (LIE), as compared to an incremental cycle exercise test to exhaustion. Currently, it is not known, whether LIE displays an effective interoceptive stressor 1.) leading to a significant anxiety induction; 2.) a comparable HPA- and Sympathetic-Adreno-Medullar (SAM)-axis response in both patients and healthy controls; 3.) stress responses under LIE are associated with treatment outcomes. PATIENTS AND METHODS: N = 20 patients with PD and n = 20 healthy controls were exposed to ten minutes of LIE on an exercise bike. LIE was applied as part of the interoceptive exposure, during an intensive Cognitive-Behavioral Therapy (CBT) in a day clinic. Heart rate was monitored and salivary cortisol samples collected. Before and after the LIE, state anxiety/ arousal were assessed. In order to evaluate psychopathology, the Panic and Agoraphobia Scale, Mobility Inventory, Agoraphobic Cognitions Questionnaire and Body Sensations Questionnaire were applied, before (T1) and after five weeks (T2) of an intensive CBT. RESULTS: LIE led to a significant and similar heart rate increase in both groups. Cortisol decreased over time in both groups, especially in male patients. A higher psychopathology before, and after CBT, was associated with a significantly lower cortisol response under LIE. CONCLUSIONS: In the present study, LIE led to a divergent stress response: while there was a significant heart rate increase, cortisol decreased over time, particularly in male patients. A lower reactivity of the HPA-axis seems to be associated with a lower treatment outcome, which may affect extinction based learning. The findings suggest, that interoceptive stimuli should be designed carefully in order to be potent stressors.

Patient characteristics and changes in anxiety symptoms in patients with panic disorder: Post-hoc analysis of the PARADIES cluster randomised trial.

Anxiety disorders are among the most common mental health problems in primary care. The PARADIES (Patient Activation foR Anxiety DIsordErS) intervention combined elements of cognitive behavioural therapy with case management and has demonstrated efficacy. Our aim was to explore patient characteristics, which may influence the course of anxiety symptoms over a 12 months period. Multiple linear regression was used to quantify associations of baseline characteristics (demographics, clinical parameters, medication use) with changes in anxiety symptoms as measured by the Beck anxiety inventory. Treatment modalities (e.g. adherence to appointment schedules) were considered as confounders. We examined univariate associations between dependent and independent variables before considering all independent variables in a multivariate final model. To find the best model to explain BAI score changes, we performed step-wise selection of independent variables based on Akaike information criteria. We tested for interaction terms between treatment allocation (intervention vs control) and independent variables using the multivariate model. We repeated these analyses in control vs intervention groups separately. From the original trial (N = 419), 236 patients (56.3%) were included. In the multivariate model, receiving the intervention (p<0.001), higher anxiety symptom severity (p<0.001) and longer illness duration at baseline (p = 0.033) were significantly associated with changes in anxiety symptom severity to the better while depression severity at baseline (p<0.001) was significantly associated with changes in anxiety symptoms to the worse. In stratified analyses, the control group showed significant associations between depression symptom severity and illness duration with anxiety symptom changes while baseline severity of anxiety symptoms remained significantly associated with anxiety symptom changes in both groups. A brief primary-care-based exposure training combined with case management is effective in a broad range of patients with panic disorder with/without agoraphobia, including those with longer illness duration and co-existing symptoms of depression at baseline.

Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial.

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid- and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (ß = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (ß = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens.

Self-guided digital treatment with virtual reality for panic disorder and agoraphobia: a study protocol for a randomized controlled trial.

BACKGROUND: Cognitive behavioral therapy is the first-line treatment for patients with panic disorder (PD) and agoraphobia (AG). Yet, many patients remain untreated due to limited treatment resources. Digital self-guided short-term treatment applications may help to overcome this issue. While some therapeutic applications are already supported by health insurance companies, data on their efficacy is limited. The current study investigates the effect of self-guided digital treatment comprising psychoeducation and virtual reality exposure therapy (VRET). METHODS: Thirty patients diagnosed with PD, AG, or panic disorder with agoraphobia (PDA) will be randomly assigned to either the experimental group (EG) or the control group (CG). Participants of both groups will undergo baseline diagnostics in the first two sessions. The subsequent treatment for the EG consists of a self-guided 6-week phase of application-based psychoeducation, one therapy session preparing for the VRET, and 4 weeks of application-based self-guided VRET. To control for the potential effects of the therapy session with the therapist, the CG will receive relaxation and stress-reduction training instead. All patients will then undergo a closing session which terminates with the post-assessment (~ 10 weeks after baseline assessment) and a follow-up assessment 6 weeks following the closing session. Symptom severity (primary outcome) will be assessed at baseline, interim, post-treatment, and follow-up. Additionally, remission status (secondary outcome) will be obtained at follow-up. Both measures will be compared between the groups. DISCUSSION: The current study aims at providing insights into the efficacy of short-term treatment applications including psychoeducation and self-guided VRET. If successful, this approach might be a feasible and promising way to ease the burden of PD, AG, and PDA on the public health system and contribute to a faster access to treatment. TRIAL REGISTRATION: ISRCTN ISRCTN10661970 . Prospectively registered on 17 January 2022.

Comparative efficacy and acceptability of psychotherapies for panic disorder with or without agoraphobia: systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: Psychotherapies are the treatment of choice for panic disorder, but which should be considered as first-line treatment is yet to be substantiated by evidence. AIMS: To examine the most effective and accepted psychotherapy for the acute phase of panic disorder with or without agoraphobia via a network meta-analysis. METHOD: We conducted a systematic review and network meta-analysis of randomised controlled trials (RCTs) to examine the most effective and accepted psychotherapy for the acute phase of panic disorder. We searched MEDLINE, Embase, PsycInfo and CENTRAL, from inception to 1 Jan 2021 for RCTs. Cochrane and PRISMA guidelines were used. Pairwise and network meta-analyses were conducted using a random-effects model. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The protocol was published in a peer-reviewed journal and in PROSPERO (CRD42020206258). RESULTS: We included 136 RCTs in the systematic review. Taking into consideration efficacy (7352 participants), acceptability (6862 participants) and the CINeMA confidence in evidence appraisal, the best interventions in comparison with treatment as usual (TAU) were cognitive-behavioural therapy (CBT) (for efficacy: standardised mean differences s.m.d. = -0.67, 95% CI -0.95 to -0.39; CINeMA: moderate; for acceptability: relative risk RR = 1.21, 95% CI -0.94 to 1.56; CINeMA: moderate) and short-term psychodynamic therapy (for efficacy: s.m.d. = -0.61, 95% CI -1.15 to -0.07; CINeMA: low; for acceptability: RR = 0.92, 95% CI 0.54-1.54; CINeMA: moderate). After removing RCTs at high risk of bias only CBT remained more efficacious than TAU. CONCLUSIONS: CBT and short-term psychodynamic therapy are reasonable first-line choices. Studies with high risk of bias tend to inflate the overall efficacy of treatments. Results from this systematic review and network meta-analysis should inform clinicians and guidelines.

[Agoraphobia with panic disorder combined with depression]. / Simptomokompleks agorafobii s panicheskim rasstroistvom, komorbidnyi s depressiei.

OBJECTIVE: The aim of the study was to investigate the course of agoraphobia with panic disorder combined with the major depressive disorder to establish positive and negative prevalence predictors. MATERIAL AND METHODS: The sample consisted of 49 women. The average age was 41.5±9.9 years. All patients (n=49; 100%) had symptoms of agoraphobia with panic disorder (F40.01) (n=49; 100%) and recurrent depressive disorder with mild (F33.01) (n=33; 67.3%) or moderate (F33.11) (n=16; 32.7%) severity. The duration of the disease by the time of inclusion in the study was from 2 to 5 years. Clinical-psychopathological, clinical-follow-up, clinical-dynamic, and statistical methods were used. RESULTS AND CONCLUSION: Two types of agoraphobia prevalence with panic disorder were identified. Type I is a relatively favorable one with complete remissions of phobic anxiety and affective disorders (n=29; 59.2%). Type II is an unfavorable one with constant phobic anxiety symptoms (n=20; 40.8%). The predictive factors of the unfavorable type of agoraphobia with panic disorder (APD) combined with depression were psychogenic situations, astheno-vegetative disorders at the onset of APD, gastrointestinal symptoms, senestopathy, fear of going crazy, or loss of control in the structure of a panic attack (PA), morning PA, vertebral artery syndrome, diseases of the gastrointestinal tract, panic attacks with provocation, depression with hysteroform symptoms in pre-manifest period APD, the age at the time of the debut APD, professional status, occupational psychogenic, family microclimate, health problems, endocrine system diseases, severe agoraphobia.

A longitudinal study of personality traits, anxiety, and depressive disorders in young adults.

BACKGROUND: How personality traits, anxiety, and depressive disorders relate longitudinally has implications for etiologic research and prevention. We sought to determine how neuroticism and extraversion relate to first-onset anxiety and depressive disorders in young adults. DESIGN: An inception cohort of 489 university freshmen was followed for 6 years. METHOD: Participants self-reported personality traits using the Eysenck Personality Questionnaire. Anxiety and depressive disorders were assessed using the Diagnostic Interview Schedule. RESULTS: Baseline neuroticism predicted first-onset panic disorder, agoraphobia, generalized anxiety disorder (GAD), and major depressive disorder (MDD), while introversion predicted first-onset agoraphobia (moderate-large effects). Participants who developed panic disorder, agoraphobia, GAD, or MDD had increases in neuroticism if the disorder was current at follow-up (moderate-large effects). Participants who developed MDD but were in remission by follow-up had a moderate increase in neuroticism. CONCLUSIONS: High neuroticism in young adulthood is either a true risk factor, or marker of risk, for first-onset anxiety and depressive disorders, as is low extraversion for agoraphobia. The current data suggest large neuroticism "state" effects for panic disorder, agoraphobia, and MDD, and moderate "scar" effects from MDD. Though many clinicians and researchers regard personality traits simply as "vulnerability" factors, longitudinal analyses suggest additional complexity.

Clinical implications of agoraphobia in patients with panic disorder.

Agoraphobia is frequently accompanied by panic disorder and causes considerable suffering. The aim of this study was to compare clinical features and treatment courses between patients with and without agoraphobia in panic disorder.In this retrospective study, 87 patients with panic disorder were divided into two groups depending on the presence of agoraphobia: patients with agoraphobia (PDA, n = 41) and patients without agoraphobia (PD, n = 46). Agoraphobia subscale score of the Albany Panic and Phobia Questionnaire was used to identify correlations between agoraphobia and panic and affective symptoms.The PDA group showed more severe panic and affective symptoms than the PD group. Patients with PDA were more likely to be younger at the age of onset, take benzodiazepines for longer durations, and be treated with antipsychotics augmentation. Agoraphobia subscale was associated with panic symptoms, depression, anxiety, and the duration of benzodiazepines use.The findings suggest that patients with PDA experienced more severe panic symptoms, more profound psychiatric comorbidity, and worse illness progression than those with PD.

Stepped-care versus treatment as usual in panic disorder: A randomized controlled trial.

Stepped-care (SC) models for anxiety disorders are implemented on a large scale and are assumed to be as effective for the greater majority of patients as more intensive treatment schemes. To compare the outcomes of SC and international guideline-based treatment (Treatment as Usual: TAU) for panic disorder, a total of 128 patients were randomized to either SC or TAU (ratio 2: 1, respectively) using a computer generated algorithm. They were treated in four mental health care centres in the Netherlands after therapists had been trained in SC by a senior expert therapist. SC comprised 10-week guided self-help (pen-and-paper version) followed, if indicated, by 13-week manualized face-to-face cognitive behavioural therapy (CBT), with medication- if prescribed- kept constant. TAU consisted of 23-week regular face-to-face CBT (RCBT) with medication -when prescribed- also kept constant. The means of the attended sessions in the SC condition was 5.9 (SD = 4.8) for ITT and 9.6 (SD = 9.6) for the RCBT condition. The difference in the number of attended sessions between the conditions was significant (t(126) = -3.87, p < .001). Remission rates between treatment conditions did not differ significantly (SC: 44.5%; RCBT: 53.3%) and symptom reduction was similar. Stepping up SC treatment to face-to-face CBT showed a minimal additional effect. Importantly, drop-out rates differed significantly for the two conditions (SC: 48.2%; RCBT: 26.7%). SC was effective in the treatment of panic disorder in terms of symptom reduction and remission rate, but dropout rates were twice as high as those seen in RCBT, with the second phase of SC not substantially improving treatment response. However, SC required significantly less therapist contact time compared to RCBT, and more research is needed to explore predictors of success for guided self-help interventions to allow treatment intensity to be tailored to patients' needs and preferences.

The Impact of Personality Pathology on Treatment Outcome in Late-life Panic Disorder.

BACKGROUND: Comorbid personality disorders are assumed to negatively interfere with the treatment outcome of affective disorders. Data on late-life panic disorder remain unknown. We examined the association of personality pathology and treatment outcome related to age and treatment modality. METHODS: An observational study on the effectiveness of cognitive-behavioral therapy (CBT) for panic disorder with agoraphobia among patients 18 to 74 years of age and randomized controlled comparison of paroxetine and CBT in older patients (60 y of age or older) were performed. The diagnosis of panic disorder was confirmed by the Anxiety Disorder Interview Schedule-Revised (ADIS-IV) and personality features were assessed with the Personality Diagnostic Questionnaire. The impact of personality features on either agoraphobic cognitions (Agoraphobic Cognitions Questionnaire) or avoidance behavior (Mobility Inventory Avoidance Scale) was examined by multiple linear regression analyses adjusted for sex, level of education, duration of illness, comorbid psychopathology, and baseline severity. The interaction between personality and age was examined among those treated with CBT (n=90); the interaction between personality and treatment modality was examined among the older subgroup (n=34). RESULTS: Cluster B personality pathology (evaluated on the basis of either Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria depending on the date of assessment) was negatively associated with outcomes of CBT in both younger and older adults with panic disorder and agoraphobia. Older adults with a higher number of features of any personality pathology or cluster A pathology had worse treatment outcomes when treated with paroxetine compared with CBT. CONCLUSIONS: Cluster B pathology had a detrimental effect on CBT treatment outcome for panic disorder in both age groups. In late-life panic disorder with comorbid personality pathology, CBT may be preferred over treatment with paroxetine.

Role of Benzodiazepines in Anxiety Disorders.

This chapter reviews the role of benzodiazepines (BZs) in the treatment of anxiety disorders, specifically panic disorder with or without agoraphobia, generalized anxiety disorder, and social anxiety disorder (social phobia). BZs pharmacology, classification, efficacy, adverse effects, withdrawal symptoms, possible dependence, and abuse; their positioning among pharmacological treatment; and guidance on how to use them are discussed.

Internet-delivered cognitive behavioral therapy for panic disorder with or without agoraphobia: a systematic review and meta-analysis.

The current systematic review and meta-analysis examined the efficacy and effectiveness of internet-delivered cognitive behavioral therapy (iCBT) on panic disorder and agoraphobia symptom severity. Twenty-seven studies were identified. Results from nine randomised controlled trials (RCTs) showed that iCBT outperformed waiting list and information controls for panic (g = 1.22) and agoraphobia (g = .91) symptoms, but the quality of RCTs varied and heterogeneity was high. Results from three RCTs suggested iCBT may have similar outcomes to face-to-face CBT in reducing panic and agoraphobia symptoms. Within-group effect sizes between baseline and post-treatment were large for panic (n = 29, g = 1.16) and medium for agoraphobia symptom severity (n = 18, g = .73). Subgroup analyses of within-group pre/post treatment effect sizes showed larger within-group effect sizes for efficacy studies (n = 15) compared to effectiveness studies (n = 14) for panic severity (g = 1.38 vs. g = .98) but not agoraphobia severity. There was no impact of program length, inclusion or arousal reduction techniques, or degree of clinician support. Within-group effects of iCBT suggest the reduction in panic and agoraphobia symptom severity is maintained at 3-6 month follow-up (n = 12).

Cognitive behavioral therapy for postpartum panic disorder: a case series.

BACKGROUND: Clinical anxiety is common during the perinatal period, and anxiety symptoms often persist after childbirth. Ten to 30 % of perinatal women are diagnosed with panic disorder (PD)-far more than the 1.5-3% rate among the general population. Although cognitive behavioral therapy (CBT) has been determined to be an effective treatment for PD, few studies have been conducted on CBT effectiveness in treating postpartum PD and, to the best of the knowledge of the present authors, no research has been conducted on postpartum PD among Japanese women. In this manuscript, we report on our administration of CBT to three postpartum patients with PD, detailing the improvement in their symptoms. CASE PRESENTATION: All patients in this study were married, in their thirties, and diagnosed using the Mini-International Neuropsychiatric Interview as having PD with agoraphobia. The Panic Disorder Severity Scale (PDSS) was used to evaluate patients' panic symptoms and their severity. All patients received a total of 16 weekly 50-min sessions of CBT, and all completed the treatment. All patients were exceedingly preoccupied with the perception that a "mother must protect her child," which reinforced the fear that "the continuation of their perinatal symptoms would prevent them from rearing their children". After treatment, all participants' panic symptoms were found to have decreased according to the PDSS, and two no longer met clinical criteria: Chihiro's score changed from 13 to 3, Beth's PDSS score at baseline from 22 to 6, and Tammy's score changed from 7 to 1. CONCLUSIONS: CBT provides a therapeutic effect and is a feasible method for treating postpartum PD. It is important that therapists prescribe tasks that patients can perform collaboratively with their children.

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.