Influence of vulnerability factors in panic disorder severity / Influencia de factores de vulnerabilidad en la gravedad del trastorno de pánico

BACKGROUND: we studied herein the predictive value for panic severity of three well-based vulnerability factors: personality traits (neuroticism and extraversion; NEO-PI-R), anxiety sensitivity (ASI), and perceived control (ACQ-R). METHOD: the sample was composed of 52 participants diagnosed with panic disorder, with or without agoraphobia, according to DSM-IV-TR criteria. RESULTS: our results revealed that the anxiety facet is a better predictor of panic severity than neuroticism. Anxiety sensitivity increases the predictive value for panic severity and, finally, perception of control of emotions is the only perception control subscale that increases the predictive value for panic severity more than the anxiety facet and anxiety sensitivity. CONCLUSIONS: this finding supports the assumption of the importance of taking into account the assessment of the lower order dimensions of the vulnerability factors in the field of psychopathology studies. Furthermore, the predictive value of perception of control of emotions indicates the importance of this specific vulnerability factor in the etiology of panic disorder (with or without agoraphobia) and, thus, shows the necessity to include emotion regulation strategies in the psychological treatments

ANTECEDENTES: en este trabajo se estudia el valor predictivo sobre la gravedad del pánico de tres factores de vulnerabilidad bien establecidos: rasgos de personalidad (neuroticismo y extraversión; NEO-PI-R), sensibilidad a la ansiedad (ASI) y percepción de control (ACQ-R). MÉTODO: la muestra fue de 52 participantes con diagnóstico de trastorno de pánico, con o sin agorafobia, según criterios DSM-IV-TR.RESULTADOS: nuestros resultados revelan que la faceta de ansiedad es mejor predictor de la gravedad del pánico que el neuroticismo. La sensibilidad a la ansiedad aumenta el valor predictivo sobre la gravedad del pánico y, finalmente, la percepción de control de las emociones es la única subescala de la percepción de control que aumenta la capacidad predictiva más allá de la faceta de ansiedad y la sensibilidad a la ansiedad. CONCLUSIONES: estos resultados apoyan el supuesto sobre la importancia de evaluar las dimensiones de orden inferior de los factores de vulnerabilidad en los estudios psicopatológicos. Además, el valor predictivo de la percepción de control de las emociones indica la importancia de este factor específico de vulnerabilidad en la etiología del trastorno de pánico (con o sin agorafobia) lo que muestra la necesidad de incluir estrategias de regulación emocional en los tratamientos psicológicos

Evidence for chronic low-grade systemic inflammation in individuals with agoraphobia from a population-based prospective study.

BACKGROUND: Anxiety disorders have been linked to an increased risk of incident coronary heart disease in which inflammation plays a key pathogenic role. To date, no studies have looked at the association between proinflammatory markers and agoraphobia. METHODS: In a random Swiss population sample of 2890 persons (35-67 years, 53% women), we diagnosed a total of 124 individuals (4.3%) with agoraphobia using a validated semi-structured psychiatric interview. We also assessed socioeconomic status, traditional cardiovascular risk factors (i.e., body mass index, hypertension, blood glucose levels, total cholesterol/high-density lipoprotein-cholesterol ratio), and health behaviors (i.e., smoking, alcohol consumption, and physical activity), and other major psychiatric diseases (other anxiety disorders, major depressive disorder, drug dependence) which were treated as covariates in linear regression models. Circulating levels of inflammatory markers, statistically controlled for the baseline demographic and health-related measures, were determined at a mean follow-up of 5.5 ± 0.4 years (range 4.7 - 8.5). RESULTS: Individuals with agoraphobia had significantly higher follow-up levels of C-reactive protein (p = 0.007) and tumor-necrosis-factor-α (p = 0.042) as well as lower levels of the cardioprotective marker adiponectin (p = 0.032) than their non-agoraphobic counterparts. Follow-up levels of interleukin (IL)-1ß and IL-6 did not significantly differ between the two groups. CONCLUSIONS: Our results suggest an increase in chronic low-grade inflammation in agoraphobia over time. Such a mechanism might link agoraphobia with an increased risk of atherosclerosis and coronary heart disease, and needs to be tested in longitudinal studies.

Does rTMS alter neurocognitive functioning in patients with panic disorder/agoraphobia? An fNIRS-based investigation of prefrontal activation during a cognitive task and its modulation via sham-controlled rTMS.

OBJECTIVES: Neurobiologically, panic disorder (PD) is supposed to be characterised by cerebral hypofrontality. Via functional near-infrared spectroscopy (fNIRS), we investigated whether prefrontal hypoactivity during cognitive tasks in PD-patients compared to healthy controls (HC) could be replicated. As intermittent theta burst stimulation (iTBS) modulates cortical activity, we furthermore investigated its ability to normalise prefrontal activation. METHODS: Forty-four PD-patients, randomised to sham or verum group, received 15 iTBS-sessions above the left dorsolateral prefrontal cortex (DLPFC) in addition to psychoeducation. Before first and after last iTBS-treatment, cortical activity during a verbal fluency task was assessed via fNIRS and compared to the results of 23 HC. RESULTS: At baseline, PD-patients showed hypofrontality including the DLPFC, which differed significantly from activation patterns of HC. However, verum iTBS did not augment prefrontal fNIRS activation. Solely after sham iTBS, a significant increase of measured fNIRS activation in the left inferior frontal gyrus (IFG) during the phonological task was found. CONCLUSION: Our results support findings that PD is characterised by prefrontal hypoactivation during cognitive performance. However, verum iTBS as an "add-on" to psychoeducation did not augment prefrontal activity. Instead we only found increased fNIRS activation in the left IFG after sham iTBS application. Possible reasons including task-related psychophysiological arousal are discussed.

The common traits of the ACC and PFC in anxiety disorders in the DSM-5: meta-analysis of voxel-based morphometry studies.

BACKGROUND: The core domains of social anxiety disorder (SAD), generalized anxiety disorder (GAD), panic disorder (PD) with and without agoraphobia (GA), and specific phobia (SP) are cognitive and physical symptoms that are related to the experience of fear and anxiety. It remains unclear whether these highly comorbid conditions that constitute the anxiety disorder subgroups of the Diagnostic and Statistical Manual for Mental Disorders--Fifth Edition (DSM-5) represent distinct disorders or alternative presentations of a single underlying pathology. METHODS: A systematic search of voxel-based morphometry (VBM) studies of SAD, GAD, PD, GA, and SP was performed with an effect-size signed differential mapping (ES-SDM) meta-analysis to estimate the clusters of significant gray matter differences between patients and controls. RESULTS: Twenty-four studies were eligible for inclusion in the meta-analysis. Reductions in the right anterior cingulate gyrus and the left inferior frontal gyrus gray matter volumes (GMVs) were noted in patients with anxiety disorders when potential confounders, such as comorbid major depressive disorder (MDD), age, and antidepressant use were controlled for. We also demonstrated increased GMVs in the right dorsolateral prefrontal cortex (DLPFC) in comorbid depression-anxiety (CDA), drug-naïve and adult patients. Furthermore, we identified a reduced left middle temporal gyrus and right precentral gyrus in anxiety patients without comorbid MDD. CONCLUSION: Our findings indicate that a reduced volume of the right ventral anterior cingulate gyrus and left inferior frontal gyrus is common in anxiety disorders and is independent of comorbid depression, medication use, and age. This generic effect supports the notion that the four types of anxiety disorders have a clear degree of overlap that may reflect shared etiological mechanisms. The results are consistent with neuroanatomical DLPFC models of physiological responses, such as worry and fear, and the importance of the ventral anterior cingulate (ACC)/medial prefrontal cortex (mPFC) in mediating anxiety symptoms.

Decreased gray matter volume of the medial orbitofrontal cortex in panic disorder with agoraphobia: a preliminary study.

BACKGROUND: Patients with panic disorder with agoraphobia (PDA) have clinical symptoms such as the fear of being outside or of open spaces from which escape would be difficult. Although recent neurobiological studies have suggested that fear conditioning and extinction are associated with PDA, no study has examined the possible structural abnormalities in patients with PDA. METHODS: This preliminary study compares the gray matter volume among patients with PDA, those with panic disorder without agoraphobia (PDW), and healthy controls (HC) using high-resolution 3.0 T magnetic resonance imaging (MRI) with voxel-based morphometry (VBM). RESULTS: Compared with HC, patients with PDA showed decreased gray matter volume in their left medial orbitofrontal gyrus. However, differences were not found in the gray matter volumes of patients with PDW and whole panic disorder compared with HC. CONCLUSIONS: These findings suggest that the phobic avoidance found in patients with PDA arise from abnormalities in the medial orbitofrontal cortex, which plays an important role in fear extinction. Future studies should investigate the neuroanatomical substrates of PDA and distinguish them from those of PDW.

Pituitary volume in patients with panic disorder.

Panic patients have many functional deficiencies in the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have shown changed pituitary gland volume in some psychiatric disorders that have functional deficiencies in the HPA axis. However, to date no study has evaluated the pituitary gland volume in patients with panic disorder (PD). We investigated the pituitary gland volume in patients with PD (n=27) and age- and sex-matched healthy controls (n=27), using 1.5-T magnetic resonance imaging in this study. Analysis showed that patients with PD had significantly smaller pituitary volume compared to healthy subjects. Patients with agoraphobia especially had a significantly smaller pituitary volume than patients without agoraphobia. There was a significant relationship between the pituitary volume and both the severity of symptoms and the illness duration in the patient group. The results show that patients with PD have reduced pituitary volume, which may reflect the functional abnormalities seen in this disorder. These findings may help us better understand the pathology of PD.

A new paradigm (Westphal-Paradigm) to study the neural correlates of panic disorder with agoraphobia.

Agoraphobia (with and without panic disorder) is a highly prevalent and disabling anxiety disorder. Its neural complexity can be characterized by specific cues in fMRI studies. Therefore, we developed a fMRI paradigm with agoraphobia-specific stimuli. Pictures of potential agoraphobic situations were generated. Twenty-six patients, suffering from panic disorder and agoraphobia, and 22 healthy controls rated the pictures with respect to arousal, valence, and agoraphobia-related anxiety. The 96 pictures, which discriminated best between groups were chosen, split into two parallel sets and supplemented with matched neutral pictures from the International Affective Picture System. Reliability, criterion, and construct validity of the picture set were determined in a second sample (44 patients, 28 controls). The resulting event-related "Westphal-Paradigm" with cued and uncued pictures was tested in a fMRI pilot study with 16 patients. Internal consistency of the sets was very high; parallelism was given. Positive correlations of picture ratings with Mobility Inventory and Hamilton anxiety scores support construct validity. FMRI data revealed activations in areas associated with the fear circuit including amygdala, insula, and hippocampal areas. Psychometric properties of the Westphal-Paradigm meet necessary quality requirements for further scientific use. The paradigm reliably produces behavioral and fMRI patterns in response to agoraphobia-specific stimuli. To our knowledge, it is the first fMRI paradigm with these properties. This paradigm can be used to further characterize the functional neuroanatomy of panic disorder and agoraphobia and might be useful to contribute data to the differentiation of panic disorder and agoraphobia as related, but conceptually different clinical disorders.

Current status of brain imaging in anxiety disorders.

PURPOSE OF REVIEW: This study reviews the most recent literature about brain imaging research in anxiety disorders. There is a growing body of evidence that neuroimaging of anxiety disorders contributes to a better understanding of the neurobiology of these disorders, by identifying cerebral modifications occurring previously or subsequent to symptoms of anxiety. A systematic search of the literature (January 1978-July 2008) was performed in MEDLINE using the keywords brain imaging, anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, generalized anxiety disorder, specific phobia, social anxiety disorder, panic disorders and agoraphobia. References cited in all trials were searched iteratively to identify missing studies. Our review focused only on the last year's findings. RECENT FINDINGS: There is a consensus on the crucial role of the amygdala, anterior cingulate cortex and insula in the pathophysiology of anxiety disorders. SUMMARY: Brain imaging research in anxiety disorders has become increasingly important, especially in the last decade, because of the opportunity to validate neurobiological hypotheses for anxiety disorders. Thus, neuroimaging data raise the question of the neurobiological cause of anxiety disorders, opening up new reflections not only on pharmacological treatments but also on the nosology of the anxiety disorders.

Resting brain perfusion in social anxiety disorder: a voxel-wise whole brain comparison with healthy control subjects.

INTRODUCTION: Social anxiety disorder (SAD) is a condition characterised by fears of social interaction and performance situations. SAD may be related to a dysregulation or hyperactivity of cortico-limbic circuitry. This is the first voxel-based whole brain study comparing resting function in SAD to a normal control group. METHODS: Resting perfusion in adult subjects with generalised SAD was compared with healthy adult volunteers using Statistical Parametric Mapping (SPM). In subjects with SAD, correlations were also sought between resting perfusion and clinical severity measured using the total Liebowitz Social Anxiety Scale (LSAS). RESULTS: Twenty-eight subjects with SAD were compared with 19 healthy volunteers. SAD subjects had increased resting perfusion in the frontal cortex and right cerebellum, and decreased perfusion in the pons, left cerebellum, and right precuneus. Total LSAS correlated positively with left frontal cortex resting perfusion, and negatively with right fusiform and right lingual perfusion. CONCLUSION: This study demonstrated increased resting frontal function in social anxiety disorder that is consistent with its hypothesised role in the modulation of excessive limbic activity in anxiety disorders. The correlation of posterior cortical resting function with the severity of SAD symptoms may point to defective perception of self and others.

Linkage genome scan for loci predisposing to panic disorder or agoraphobia.

We conducted a 10 cM linkage genome scan in a set of 20 American pedigrees (153 subjects), ascertained through probands with panic disorder (PD). Several anxiety disorders segregate in these families; they were diagnosed on the basis of Schedule for Affective Disorders and Schizophrenia interview. In this article, we describe results for panic disorder and agoraphobia, which are closely related, common, heritable anxiety disorders. This is the first complete linkage genome scan for agoraphobia and the third for PD. A total of 407 markers (389 autosomal, 18 X chromosome) were genotyped. Multipoint LOD score and NPL analysis were completed using GENEHUNTER2. For PD, two genomic regions meet criteria for suggestive linkage. One of these regions is on chromosome 1 (LOD score = 2.04). This region coincides with a region that generated a LOD score of 1.1 in a previous genome scan by Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109]. The other (LOD score = 2.01) is located on chromosome 11p and occurs at marker CCKBR, one of eight candidate genes examined. For agoraphobia, the most promising potential linkage was on chromosome 3 (NPL score = 2.75; P = 0.005). This was accounted for primarily by a single family that by itself generated an NPL score of 10.01 (P = 0.0039) and a LOD score of 2.10. These results provide initial evidence for a genetic locus on chromosome 3 that contributes to risk for agoraphobia. They also support suggestive linkage to two risk loci for panic disorder. Additional potential loci were identified with lesser statistical support; several of these were consistent with previously reported panic disorder linkage results. Overall, the results presented here suggest that PD and agoraphobia are complex traits that share some, but not all, of their susceptibility loci. Published 2001 Wiley-Liss, Inc.

Cerebral ventricular size in panic disorder.

Computed axial brain tomography was studied in 25 patients with panic disorder. Patients had normal ventricular-brain ratio (VBR) compared to published norms. There was a significant association between VBR and duration of benzodiazepine use.