Serotonin, periaqueductal gray matter and panic disorder

This article reviews experimental evidence and theoretical constructs that implicate serotonin (5-HT) modulation of defensive behavior within the midbrain periaqueductal gray matter(PAG) in panic disorder. Results obtained with conflict tests in experimental animals indicate that 5-HT enhances anxiety, whereas results with aversive stimulation of the dorsal PAG point to an anxiolytic role of 5-HT. To solve this contradiction, it has been suggested that the emotional states determined by the two paradigms are different. Conflict tests would generate anticipatory anxiety, whereas PAG stimulation would produce fear as evoked by proximal threat. Clinically, the former would be related to generalized anxiety while the latter to panic disorder. Thus, 5-HT is supposed to facilitate anxiety, but to inhibit panic. This hypothesis has been tested in the animal model of anxiety and panic named the elevated T-maze and in two procedures of human experimental anxiety applied to healthy volunteers or panic patients. Overall, the obtained results have shown that drugs that enhance 5-HT action increase different indexes of anxiety, but decrease indexes of panic. Drugs that impair 5-HT action had the opposite effects. Thus, so far the predictions derived from the above hypothesis have been fulfilled. The main clinical implications are that a 5-HT deficit in the PAG may participate in the pathophysiology of panic disorder and that an enhancement of 5-HT in the same region mediates the anti-panic action of antidepressant drugs.     

Serotonin, the periaqueductal gray and panic

This article reviews experimental evidence and theoretical constructs that implicate serotonin (5-HT) modulation of defensive behavior within the midbrain periaqueductal gray in panic disorder (PD). Evidence with conflict tests in experimental animals indicates that 5-HT enhances anxiety, whereas results with aversive stimulation of the dorsal periaqueductal gray point to an anxiolytic role of 5-HT. To solve this contradiction, it has been suggested that the emotional states determined by the two types of animal model are different. Conflict tests would generate conditioned anxiety, whereas periaqueductal gray stimulation would produce unconditioned fear, as evoked by proximal threat. Clinically, the former would be related to generalized anxiety while the latter to PD. Thus, 5-HT is supposed to facilitate anxiety, but to inhibit panic. This hypothesis has been tested in the animal model of anxiety and panic named the elevated T-maze, in two procedures of human experimental anxiety applied to healthy volunteers or panic patients, and in CO2-induced panic attacks. Overall, the obtained results have shown that drugs that enhance 5-HT function increase different indexes of anxiety, but decrease indexes of panic. Drugs that impair 5-HT function have the opposite effects. Thus, so far the predictions derived from the above hypothesis have been fulfilled.     

Anxiety sensitivity: a missing piece to the agoraphobia-without-panic puzzle

This article reviews the controversy surrounding the diagnosis of agoraphobia without panic attacks and proposes a key role for anxiety sensitivity in explaining agoraphobic avoidance among those who have never experienced panic. Although rare in clinical samples, agoraphobia without panic is commonly observed in population-based surveys, including more recent studies in which misclassification bias is addressed. Differential treatment seeking may partially explain these discrepant findings; however, it remains unclear why agoraphobic avoidance develops in the absence of panic. Because anxiety sensitivity is a dispositional analogue of panic, it is proposed that high anxiety sensitivity is a risk factor for agoraphobic avoidance in the absence of frank panic attacks. Preliminary evidence to support this contention is reviewed.     

Diagnostic aspects of anxiety disorders]

A concise review is presented of epidemiological, family- and genetic studies in anxiety disorders. Special emphasis is given to recent developments in the classification of anxiety disorders. The literature in which a more central role of panic attacks is suggested, is critically reviewed. Based upon the studies reviewed it is questionable whether the diagnosis agoraphobia without panic attacks is justified.     

Panic attack frequency and vulnerability to anxiogenic challenge studies

Intravenous lactate infusion and 60 mg oral fenfluramine challenges were administered to 26 patients with panic disorder (PD) and 12 age- and sex-matched control subjects. PD patients had significantly greater anxiety responses to either challenge than controls. When a panic attack frequency index scale of 1-4 was used, PD patients with more recent and more frequent spontaneous panic attacks scored higher on either challenge. There was a significant correlation between increasing panic attack frequency and greater anxiogenic responses to lactate and fenfluramine. Nine of 12 patients (75%) with high attack frequency (defined as having one or more panic attacks per week) reacted positively to both challenges in contrast to 0 of 14 PD patients with low frequency (less than or equal to 1 attack/month). The findings suggest that the current heightened anticipatory state of the patient (influenced by recent spontaneous panic attacks) rather than putative underlying trait factors predominates in the evocation of experimentally induced anxiety reactions. Future studies must consider the frequency of recent spontaneous panic attacks in the evaluation of anxiogenic reactivity to provocative stimuli.     

Severe threat in the genesis of panic disorder

The hypothesis that panic disorder is a separate biological disease has attracted a great deal of controversy in recent years. One of the cornerstones of this theory is that panic attacks arise spontaneously, suggesting that the illness is generated by an autonomous physiological process. A number of cases are reported that illustrate Beck's theory that cognitive factors are central to the genesis of acute anxiety. Evidence for a developmental/cognitive theory of anxiety is discussed, and it is concluded that a purely biological model for panic disorder is inadequate.     

Nocturnal panic

The phenomenon of nocturnal panic was examined by comparing individuals with panic disorder who reported the experience of nocturnal panic (N = 37) with those who did not (N = 56). Variables that were assessed included frequency and intensity of daytime panic attacks, generalized anxiety, and responses to a standardized physiological assessment. In addition, the most recent nocturnal panic was rated on measures of intensity, duration, and circumstances. Nocturnal panic occurred in individuals who were equally avoidant and distressed as individuals who did not experience nocturnal panic. However, nocturnal panickers experienced daytime panics and general somatic sensations more frequently than other panickers. The similarity of nocturnal panic to sleep apnea, dream-induced anxiety attacks, and night terrors is discussed. The nature of nocturnal panic is described within the context of an explanatory model that combines behavioral and physical factors.     

Avoidance-oriented coping as a predictor of panic-related distress: a test using biological challenge

The present experimental psychopathology study sought to investigate the extent to which pre-experimental levels of avoidance-oriented coping predict anxious and fearful responding during acute physical stress, relative to other theoretically relevant variables. Participants included 80 individuals with no known history of psychological or physical health problems. Dependent measures include self-reported anxiety, DSM-IV panic symptoms, and physiological indices of heart rate and skin conductance. Consistent with our hypotheses, the tendency to engage in avoidance-oriented coping predicted increased physical panic symptoms and self-reported anxiety elicited by biological challenge, relative to specific anxiety sensitivity (AS) dimensions. These findings are discussed in terms of how specific types of coping are associated with prototypical indices of panic distress, with implications for forwarding future work on emotional regulation in panic disorder.     

Should art be integrated into cognitive behavioral therapy for anxiety disorders?

Although cognitive behavioral therapy (CBT) is the preferred treatment method for anxiety disorders, it is underutilized and has been critiqued for being too verbal or abstract. Due to the role of imagery in maintaining anxiety disorders, art may be a useful addition to CBT for anxiety disorders. Art was incorporated into a brief CBT model in two quantitative case studies: Case 1 for panic disorder with agoraphobia (PDA) and Case 2 for generalized anxiety disorder (GAD). The A-B, single-subject experimental design included a two-week baseline period and a seven-week intervention period in both cases. The participant with PDA recorded her symptoms of PDA and her level of general anxiety throughout the baseline and intervention periods using a panic diary, whereas the participant with GAD recorded her level of general anxiety. In Case 1 for PDA, the intervention resulted in statistically significant reductions in panic frequency and some features of panic anxiety and agoraphobia. In Case 2 for GAD, the decrease in general anxiety was marginally significant.     

Do panic patients process unconditioned fear vs. conditioned anxiety differently than normal subjects?

Panic patients were evaluated with two models of experimental anxiety that are believed to generate distinct emotional states: (1) a stimulated public speaking test (SPS), a presumed indicator of unconditioned fear, and (2) conditioning of skin conductance responses (CSCR) to a tone associated with an aversive white noise, an index of conditioned anxiety. Subjective states were evaluated through the visual analogue mood scale (VAMS) and a bodily symptoms scale (BSS). In the SPS test, panic patients showed higher baseline levels of VAMS-measured anxiety than controls. Unlike controls, panic patients failed to show increased anxiety before and during speech. Although baseline levels of arousal were similar in both groups, VAMS mental sedation decreased in controls, but not in panic patients during the SPS. Panic patients showed more discontent than controls throughout the whole experimental session. They also scored higher than controls on several items of the BSS. In the CSCR test, panic patients showed more spontaneous fluctuations of skin conductance than controls. Nevertheless, conditioning of skin conductance responses to the tone was similar in both groups. Therefore, panic patients seemed to process unconditioned fear abnormally.     

Neurobiology of panic disorder: from animal models to brain neuroimaging

Evidence from animal models of anxiety has led to the hypothesis that serotonin enhances inhibitory avoidance (related to anxiety) in the forebrain, but inhibits one-way escape (panic) in the midbrain periaqueductal gray (PAG). Stressing the difference between these emotions, neuroendocrinological results indicate that the hypothalamic-pituitary-adrenal axis is activated by anticipatory anxiety, but not by panic attack nor by electrical stimulation of the rat PAG. Functional neuroimaging has shown activation of the insula and upper brain stem (including PAG), as well as deactivation of the anterior cingulated cortex (ACC) during experimental panic attacks. Voxel-based morphometric analysis of brain magnetic resonance images has shown a grey matter volume increase in the insula and upper brain stem, and a decrease in the ACC of panic patients at rest, as compared to healthy controls. The insula and the ACC detect interoceptive stimuli, which are overestimated by panic patients. It is suggested that these brain areas and the PAG are involved in the pathophysiology of panic disorder.     

Nonclinical panic attacks in late adolescence prevalence and associated psychopathology

This study investigated the prevalence of nonclinical panic attacks and associated psychopathology in 576 older adolescents. Nonclinical panic attacks are defined as panic occurring in individuals not seeking treatment. In this study, recent panickers (those reporting at least one nonclinical panic attack in the past month) comprised 12.2% of the sample. Nonpanickers and past panickers comprised 71.4 and 16.5% of the sample, respectively. Recent panickers evidenced significantly higher levels of trait anxiety, state anxiety, and depression, with a trend toward higher levels of anxiety sensitivity and internal negative attributions. This group also reported lower life experiences ratings suggesting higher levels of negative life stress. Finally, 46 recent panickers were administered a structured diagnostic interview, and 31 received a clinical diagnosis. The most common diagnoses were generalized anxiety disorder, social phobia, and specific phobia. Comorbidity rates were high in this sample: 24 of the 31 who received a diagnosis were comorbid with at least one other disorder. Implications of these findings for assessment and treatment are discussed.     

Anxiety and salivary cortisol in symptomatic and nonsymptomatic panic patients and healthy volunteers performing simulated public speaking

Anxiety and salivary cortisol were measured in subjects performing simulated public speaking (SPS), a procedure that has been neurobiologically related to panic disorder. The subjects were divided into three groups: 18 symptomatic panic patients, 16 nonsymptomatic, drug-treated panic patients, and 17 healthy controls. In the experimental session, subjective anxiety (Visual Analogue Mood Scale) and the total score of the Bodily Symptom Scale (BSS) were higher in symptomatic patients than in controls, with nonsymptomatic patients in between. Measures of cortisol taken at home showed that the level was higher at 9:00 h than at 23:00 h in every group, indicating a normal circadian regulation of the hypothalamic-pituitary-adrenal (HPA) axis in panic patients. Also in every group, the level of cortisol was high at the beginning of the experimental session and decreased after 70 min. This fall parallels the decrease in anxiety and BSS ratings, and appears to reflect habituation of initial, anticipatory anxiety. Preparation and performance of speech raised anxiety and BSS scores to the initial levels, but failed to increase cortisol measured over 60 min, starting at the end of the speech. Therefore, SPS does not seem to activate the HPA axis, as reported in panic attacks.     

Effects of heart-rate feedback on estimated cardiovascular fitness in patients with panic disorder

Psychological parameters that are believed to affect estimations of cardiovascular fitness were examined in patients with panic disorder and nonclinical controls. Fifty-four participants [panic disorder patients (n = 27) and age- and sex-matched nonclinical controls (n = 27)] completed a cycle ergometer test and were compared on the basis of estimated VO2 max. Participants were randomly assigned to experimental conditions in which they received heart-rate feedback or no feedback during the test. Patients with panic disorder exhibited lower VO2 max and decreased exercise tolerance (i.e., were more likely to discontinue the test) than nonclinical controls. Furthermore, individuals with high anxiety sensitivity (i.e., a fear of autonomic arousal), but not a panic disorder diagnosis per se, achieved significantly lower VO2 max when provided with heart-rate feedback. Moreover, diagnostic status interacted with levels of anxiety sensitivity to predict VO2 max. Patients with panic disorder display poorer cardiovascular fitness after controlling for anxiety and other factors that underestimate performance during fitness testing.     

Anxiety sensitivity as a predictor of the development of panic symptoms,panic attacks,and panic disorder: a prospective study

The purpose of the study was to examine how anxiety sensitivity (AS) acts as a dispositional factor in the development of panic symptoms, panic attacks, and panic disorder. Between 1986 and 1988, data were collected from 505 undergraduates at an urban university. At Time 1, measures used were the ASI to assess AS, the trait scale of the State-Trait Anxiety Inventory (STAI-T) to measure trait anxiety, and self-report questionnaires to measure personal and family history of panic and anxiety symptoms. During the Spring of 1999, 178 of these subjects were re-contacted, and information was gathered on subjects' subsequent development of panic symptoms, panic attacks, panic disorder, and trait anxiety (STAI-T). The ASI was the strongest predictor of the development of panic symptoms and panic attacks. After controlling for trait anxiety, the ASI was not predictive of the development of panic disorder.     

Cross-cultural variations in the prevalence and presentation of anxiety disorders

Considerable cross-cultural variation exists in the prevalence and presentation of the anxiety disorders as defined by the fourth edition of the Diagnostic and Statistical Manual. Researchers debate whether this variation represents cultural differences in the phenomenology of universal disorders or the existence of unique culturally constructed disorders. This article reviews recent literature on the prevalence and presentation of five anxiety disorders: generalized anxiety disorder, social anxiety disorder, panic disorder, specific phobia and post-traumatic stress disorder, both across countries and within the USA. This article indicates that certain anxiety disorders (e.g., generalized anxiety disorder and panic disorder) may vary greatly in rate across cultural groups. It indicates that the clinical presentation of anxiety disorders, with respect to symptom presentation and the interpretation of symptoms, varies across cultures. A difference in catastrophic cognitions about anxiety symptoms across cultures is hypothesized to be a key aspect of cross-cultural variation in the anxiety disorders. Future research directions are suggested.     

Prevention of Anxiety Disorders

Research into the prevention of anxiety has increased dramatically in the past few years. Prevention programs have been directed at broad, nonspecific anxiety and at more specific anxiety types, such as panic disorder and post-traumatic stress disorder. Prevention of anxiety is still a relatively new field, but there has been a recent surge of literature reporting on different prevention programs. Universal prevention trials have shown modest but promising results, and school-based programs offered to all students also help to reduce stigmatization and common barriers to accessing treatment (eg, time, location, and cost). In contrast, targeted programs tend to show somewhat larger effects but rely on identification of relevant populations. Specific programs for the prevention of panic disorder and post-traumatic stress disorder have also demonstrated some preliminary success. This paper reviews the recent studies of prevention of anxiety and discusses several key issues, specifically (1) identification of at-risk participants for prevention programs, (2) motivation for participation, (3) optimal age for intervention, and (4) who should deliver the program.     

Is anxiety hereditary?

Familial aggregation of anxiety disorders has repeatedly been reported: the estimated risk among the first degree relatives is of 15% to 18% compared to 3% in control groups. The most recent studies are focused on more homogeneous clinical subgroups. Thus, among agoraphobics first degree relatives, the risk is elevated not only for agoraphobia but also for panic attacks and other phobias. In families of panic attacks, the risk of panic attacks in the first degree relatives is specifically elevated. Thanks to the extremely fast development of genetic linkage and molecular genetics, progress is expected in the field of genetics and psychiatry. Linkage methods applied to anxiety disorders are discussed.     

Marijuana sensitivity and panic anxiety

The authors explore the relationship between marijuana smoking and panic anxiety by examining the effects of marijuana smoking on patients with panic anxiety compared with marijuana's effects on both patient and nonpatient controls. Patients with panic anxiety were found to be particularly likely to experience increased anxiety while smoking marijuana. The majority of panic anxiety patients spontaneously stopped using marijuana because of increased anxiety; continued marijuana smoking in these individuals was found to be infrequent. The results suggest that current marijuana use is atypical of panic anxiety patients.