Blunted growth hormone response to clonidine in patients with generalized anxiety disorder

Patients with panic disorder or depression have abnormal responses to the alpha 2-adrenergic receptor partial agonist clonidine. Evidence linking anxiety to noradrenergic dysfunction and the presence of anxiety symptoms in both depression and panic suggest that abnormal responses to clonidine in these disorders could be due to the anxiety symptoms. To explore a possible link between "nonspecific" anxiety symptoms and abnormal responses to clonidine, patients with DSM-III-defined generalized anxiety disorder were given intravenous infusions of clonidine hydrochloride. Responses of plasma growth hormone, 3-methoxy-4-hydroxyphenylglycol, heart rate, blood pressure, and psychological states were determined in 11 patients with generalized anxiety disorder and 14 healthy subjects. Clonidine produced significantly smaller growth hormone responses in patients than in healthy controls. The two groups did not differ in 3-methoxy-4-hydroxyphenylglycol, heart rate, blood pressure, or psychological responses to clonidine. These results are compared with data from similar studies on patients with panic disorder and depression. The blunting of the growth hormone response to clonidine in all three disorders could be due to the presence of generalized anxiety symptoms. Subsensitivity of postsynaptic alpha 2-adrenoreceptors may be present in all three disorders; however, there are alternative interpretations of growth hormone blunting in response to clonidine. Blunting was observed in DSM-III-defined generalized anxiety disorder, whether or not the DSM-III-R criterion of excessive worry was also present.     

Neural response to eye contact and paroxetine treatment in generalized social anxiety disorder

Generalized social anxiety disorder (GSAD) is characterized by excessive fears of scrutiny and negative evaluation, but neural circuitry related to scrutiny in GSAD has been little studied. In this study, 16 unmedicated adults with GSAD and 16 matched healthy comparison (HC) participants underwent functional magnetic resonance imaging to assess neural response to viewed images of faces simulating movement into eye contact versus away from eye contact. GSAD patients were then treated for 8 weeks with paroxetine, and 15 patients were re-imaged. At baseline, GSAD patients had elevated neural response to eye contact in parahippocampal cortex, inferior parietal lobule, supramarginal gyrus, posterior cingulate and middle occipital cortex. During paroxetine treatment, symptomatic improvement was associated with decreased neural response to eye contact in regions including inferior and middle frontal gyri, anterior cingulate, posterior cingulate, precuneus and inferior parietal lobule. Both the magnitude of GSAD symptom reduction with paroxetine treatment and the baseline comparison of GSAD vs. HCs were associated with neural processing of eye contact in distributed networks that included regions involved in self-referential processing. These findings demonstrate that eye contact in GSAD engages neurocircuitry consistent with the heightened self-conscious emotional states known to characterize GSAD patients during scrutiny.     

Emotional response patterns during social threat in individuals with generalized social anxiety disorder and non-anxious controls

Patterns of synchrony in repeated measures of heart rate, skin conductance levels, negative affect, and positive affect were investigated in patients with social anxiety disorder and non-anxious controls during a speech task. Despite expected low levels of absolute concordance between measures of affect and arousal overall, results revealed clearly defined and specific patterns of emotional response coherence that distinguished between the two groups and depended on the types of measures used. Specifically, findings demonstrated that (a) for both patients and controls, increased heart rate was significantly synchronized with increased negative affect, with patients showing overall stronger levels of synchrony between these two measures than controls; (b) for controls only, increased heart rate was significantly synchronized with increased positive affect; and (c) for patients only, increased skin conductance was significantly synchronized with both increased negative affect and decreased positive affect. These findings are discussed in relation to current conceptualizations of the construct of emotion as well as directions for future research and potential implications for clinical practice.     

Defensive startle response to emotional social cues in social anxiety

Potentiation of fear-related defense behaviours coordinated by the amygdala in response to environmental threat characterizes several anxiety disorders. We compared eye-blink startle responses to startle probes delivered during the presentation of emotional and neutral social cues in high and low generalized social anxiety. Socially anxious individuals exhibited larger startle responses to emotional (positive and negative) relative to neutral social cues, compared to non-anxious individuals.     

Amygdala hypersensitivity in response to emotional faces in Tourette's patients

Abstract

Objectives. Tourette's syndrome is characterised by motor and vocal tics as well as a high level of impulsivity and emotional dysregulation. Neuroimaging studies point to structural changes of the basal ganglia, prefrontal cortex and parts of the limbic system. However, there is no link between behavioural symptoms and the structural changes in the amygdala. One aspect of daily social interaction is the perception of emotional facial expressions, closely linked to amgydala function. Methods. We therefore investigated via fMRI the implicit discrimination of six emotional facial expressions in 19 adult Tourette's patients. Results. In comparison to healthy control group, Tourette's patients showed significantly higher amygdala activation, especially pronounced for fearful, angry and neutral expressions. The BOLD-activity of the left amygdala correlated negatively with the personality trait extraversion. Conclusions. We will discuss these findings as a result of either deficient frontal inhibition due to structural changes or a desynchronization in the interaction of the cortico-striato-thalamo-cortical network within structures of the limbic system. Our data show an altered pattern of implicit emotion discrimination and emphasize the need to consider motor and non-motor symptoms in Tourette's syndrome in the choice of both behavioural and pharmacological treatment.     

Tryptophan depletion affects the autonomic stress response in generalized social anxiety disorder

In generalized social anxiety disorder (gSAD), serotonergic dysfunctions are found, as well as abnormalities of the autonomic nervous system (ANS) in basal conditions and of the hypothalamic pituitary adrenal (HPA) axis in response to psychological challenges. These findings raise the question whether these phenomena are interrelated.Therefore we designed a study in which two groups with nine pair wise age and gender matched gSAD patients (total of 10 men and 8 women), who were successfully treated with a selective serotonin reuptake inhibitor (SSRI), underwent a tryptophan depletion challenge (TD) or a placebo condition. A TD procedure temporarily decreases serotonergic neurotransmission. In order to activate the stress system the TD/placebo challenge was combined with a public speaking task. We assessed ANS responses, as measured with the promising new marker salivary alpha-amylase (sAA), and HPA-axis responses, as measured with salivary cortisol.The most important result was that the TD group showed a significant larger sAA response to the public speaking task as compared to the placebo group, reflecting hyperresponsivity of the ANS in this group, whereas no differences were seen in cortisol responses. This suggests that in gSAD there is a vulnerability of the ANS more than the HPA-axis.     

Attentional bias for emotional faces in children with generalized anxiety disorder

ObjectiveTo examine attentional bias for angry and happy faces in 7- to 12-year-old children with generalized anxiety disorder (GAD; n = 23) and nonanxious controls (n = 25).MethodChildren completed a visual probe task in which pairs of face stimuli were displayed for 500 milliseconds and were replaced by a visual probe in the spatial location of one of the faces.ResultsSeverely anxious children with GAD showed an attentional bias toward both angry and happy faces. Children with GAD with a milder level of anxiety and nonanxious controls did not show an attentional bias toward emotional faces. Moreover, within the GAD group, attentional bias for angry faces was associated with increased anxiety severity and the presence of social phobia.ConclusionsBiased attention toward threat as a function of increased severity in pediatric GAD may reflect differing threat appraisal processes or emotion regulation strategies.     

Delays in referral of patients with social phobia, panic disorder and generalized anxiety disorder attending a specialist anxiety clinic

Individuals with anxiety disorders experience substantial delays in obtaining treatment, but little is known about whether people with specific anxiety subcategories are differentially affected. The present study used a modified Encounter Form to examine the cause and length of delays in reaching primary care and specialist services amongst patients with panic disorder (PD/PD-Ag), social phobia (SP), and generalized anxiety disorder (GAD). Participants were 142 consecutive patients attending a specialist anxiety clinic in South Western Sydney. On average, participants with SP took much longer to consult a primary health care provider. Primary care assessments of those with SP often failed to detect anxiety as the key problem, and subsequently, those with SP reported longer delays in reaching specialist care (>9 years). It is not possible to extrapolate the findings to all individuals with SP, as the study was based on specialist service attenders. Nevertheless, the data supports previous findings in suggesting that SP may not be well-recognized as a disorder needing treatment, either by the patient or the primary health care provider. Appropriate educational programs seem warranted to ensure appropriate treatment for this condition.     

Clinical similarity and biological diversity in the response to alprazolam in patients with panic disorder and generalized anxiety disorder

Thirty-six patients with panic disorder (PD) and 35 patients with generalized anxiety disorder (GAD) participated in an open alprazolam treatment phase that preceded controlled withdrawal from alprazolam. Clinical ratings, blood pressure and heart rate were obtained along with plasma measurements of Cortisol, ACTH, growth hormone and catecholamines. A similar clinical response profile was evident in both groups with rapid onset of improvement within the first week. The two diagnostic groups differed in their biological response to alprazolam. PD patients had a significant reduction in blood pressure, plasma Cortisol and a trend toward significant reduction in plasma epinephrine, which were not seen in the GAD patients. GAD patients showed a significant reduction in plasma norepinephrine. These findings provide further evidence that PD and GAD are biologically distinct syndromes.     

Amygdala response in patients with acute PTSD to masked and unmasked emotional facial expressions

OBJECTIVE: This study used functional magnetic resonance imaging to investigate amygdala response in patients with acute posttraumatic stress disorder (PTSD) to emotional expressions. METHOD: Thirteen medication-free individuals with acute PTSD and no axis I psychiatric comorbidity were scanned while viewing pictures of fearful or happy faces, presented above or below consciousness, with backward masking. RESULTS: There was a significant positive correlation between the severity of PTSD and the difference in amygdala responses between masked fearful and happy faces and a corresponding negative correlation for the difference between unmasked fearful and happy faces. CONCLUSIONS: These findings suggest that functional abnormalities in brain responses to emotional stimuli observed in chronic PTSD are already apparent in its acute phase.     

Noradrenergic function in generalized anxiety disorder: effects of yohimbine in healthy subjects and patients with generalized anxiety disorder

There is extensive preclinical and clinical support for the hypothesis that hyperactivity of noradrenergic neuronal systems is related to the pathophysiology of some forms of human anxiety. In the present investigation, the behavioral, biochemical, and cardiovascular responses to the alpha 2-adrenergic receptor antagonist, yohimbine, was determined in 20 patients with generalized anxiety disorder (GAD) and 20 healthy subjects. The responses to yohimbine were generally similar in the two groups except there was a trend for the yohimbine-induced increase in plasma 3-methoxy-4-hydroxyphenylglycol to be less in the GAD patients. These findings contrast with previous studies of the effects of yohimbine in panic disorder patients and, thereby, support a neurobiological distinction between these two disorders.     

Emotion regulation deficits in generalized anxiety disorder, social anxiety disorder, and their co-occurrence

Preliminary evidence supports the role of emotion-related deficits in generalized anxiety disorder (GAD), including heightened emotional intensity, poor understanding of emotion, negative cognitive reactivity to emotions, and maladaptive emotion management. However, questions remain concerning the specificity of these emotion-related deficits compared to highly comorbid conditions such as social anxiety disorder (SAD). In the current study, 113 undergraduate students were administered measures of GAD, SAD, and emotion-related factors in order to clarify relationships among these variables. In univariate analyses, presence of SAD did not significantly impact the association between GAD and the emotion-related measures. Further, a discriminant function analysis revealed that emotional intensity and impaired regulation strategies provided the greatest discrimination between groups and best predicted a diagnosis of GAD (regardless of SAD comorbidity). Although their discriminatory ability was weaker, poor emotional understanding best predicted a diagnosis of SAD (regardless of GAD comorbidity), and non-acceptance of emotions best predicted comorbid GAD and SAD.     

Impact of gastrointestinal symptom severity on response to venlafaxine extended-release in patients with generalized anxiety disorder

BACKGROUND: This retrospective analysis evaluated the prevalence and severity of pre-treatment gastrointestinal (GI) symptoms in patients with generalized anxiety disorder (GAD), the impact of these GI symptoms on the efficacy and tolerability of venlafaxine extended-release (XR), and the effect of treatment on prestudy GI symptoms. METHOD: Data from 1932 nondepressed GAD patients were pooled from 5 randomized, double-blind, placebo-controlled studies of venlafaxine XR clinically conducted between May 1995 and December 1997. The GI symptom severity at baseline was estimated from item 11 on the Hamilton Rating Scale for Anxiety (HAM-A). Patients with a GI symptom severity score < or = 2 (moderate or less) and those with a GI symptom severity score > 2 (severe/very severe) were compared for baseline characteristics and short-term (8-week) and long-term (24-week) outcomes. RESULTS: At baseline, for all randomized patients with a HAM-A item 11 score, GI symptoms were rated moderate or lower in 82.8% of patients (GI-low) and severe/very severe in 17.2% (GI-high). The GI-high subgroup was statistically significantly (p < .05) younger, had a longer duration of GAD, and had higher mean HAM-A total scores than the GI-low subgroup. Compared with placebo, venlafaxine XR significantly reduced HAM-A total and psychic anxiety factor scores, regardless of baseline GI symptom severity. The incidence of adverse events, particularly nausea, was higher for the GI-high versus GI-low subgroup. CONCLUSION: Baseline severity of GI symptoms correlated with overall severity of GAD but had no impact on treatment outcome with venlafaxine XR. These data do not support the hypothesis that high baseline GI symptom severity has a negative effect on treatment with venlafaxine XR in GAD patients.     

Neuroactive steroid levels in patients with generalized anxiety disorder

Serum levels of allopregnanolone, pregnenolone sulfate, and dehydroepiandrosterone sulfate were measured in 8 male patients with generalized anxiety disorder (GAD) and 8 healthy control subjects. Results suggest that patients with GAD have significantly lower levels of pregnenolone sulfate than control subjects.     

Psychiatric comorbidity in Greek patients with generalized anxiety disorder

From a total sample of 1,448 psychiatric outpatients, 81 (5.6%) received a diagnosis of generalized anxiety disorder (GAD) according to DSM-III-R criteria. Fifty-three (65%) of them had another Axis I diagnosis, while this percentage increased to 78% (63/81) when lifetime psychiatric diagnoses were recorded. The most frequent comorbid diagnoses were panic disorder, dysthymia, major depression and social phobia. Forty-three (53%) of the GAD patients met the criteria for personality disorder. They manifested obsessive-compulsive, avoidant personality and personalities of cluster C in general significantly more frequently than the rest of the total sample. The presence of a personality disorder was related to a significantly higher score on almost all the Minnesota Multiphasic Personality Inventory clinical and research scales, to a worse level of functioning and to an earlier age of onset of GAD. The results of the present study (1) support previous findings of high rates of comorbidity of clinical syndromes in GAD, (2) indicate that GAD co-occurs frequently with cluster C personality disorders, mainly avoidant and obsessive-compulsive, and (3) that the presence of a concomitant personality disorder is related to severer psychopathology and to a worse level of functioning. Copyright Copyright 1999 S. Karger AG, Basel