Neurobiological mechanisms of social anxiety disorder

OBJECTIVE: The authors critically surveyed several preclinical and clinical neurobiological models of social anxiety disorder. METHOD: The authors reviewed the recent literature regarding three animal models of particular relevance to social anxiety. They then examined the recent literature concerning clinical neurobiological aspects of social anxiety disorder, including the developmental neurobiology of anxiety, the genetics of fear and social anxiety, and challenge and imaging studies. RESULTS: The available animal models are useful paradigms for understanding the features of social subordination stress, attachment behavior, and environmental rearing, but they incompletely account for the known neurobiology of human social anxiety disorder. The clinical neurobiology literature surveyed implicates specific neurotransmitter system abnormalities, most notably of the dopamine system, but largely ignores neurodevelopmental processes and the functional interactions between neurotransmitters. Both heritable factors and environmental stress factors appear to be responsible for the onset of social anxiety disorder. CONCLUSIONS: Social anxiety disorder should be conceptualized as a chronic neurodevelopmental illness that might represent a fully compensated state in adulthood. Future investigations from this perspective are discussed.     

Management of anxiety and panic attacks in immediate care facilities

The records of all patients entering the Emergency Department of a large general hospital and an adjacent walk-in medical clinic were reviewed for a 4-week period. Information was gathered on the assessment and treatment of patients given a final diagnosis of anxiety or panic disorder. The majority of patients receiving these diagnoses in both settings presented with physical complaints. In the Emergency Department, where psychiatric consultation services were available, psychiatric appointments were arranged for 80% of patients with anxiety as an entrance complaint and none of those with physical entrance complaints.     

Effect of alprazolam and diazepam on anxiety and panic attacks in panic disorder: a controlled study

Forty-eight patients currently experiencing panic attacks were randomly assigned to double-blind treatment with alprazolam, diazepam, or placebo. Efficacy was assessed using the Hamilton Rating Scale for Anxiety and a panic attack frequency rating scale. Results indicate that the two active treatments appeared equally effective in reducing both the frequency of panic attacks and the severity of generalized anxiety when compared with placebo. Overall, these data support the use of benzodiazepines in the treatment of panic disorder.     

Behavioral biochemical and neuroendocrine concomitants of lactate-induced panic anxiety

In a single-blind study using sodium lactate infusions to provoke panic attacks, 11 of 15 patients with panic disorder panicked with lactate. None of the 15 control subjects panicked during lactate administration. Before receiving lactate, higher preinfusion anxiety levels were present in the patient group as compared to controls. Preinfusion Acute Panic Inventory (API) scores were significantly higher in patients who panicked compared to nonpanicking patients. In addition, patients who panicked during lactate infusion showed a higher mean plasma MHPG level at baseline. During lactate infusion, however, no increase in plasma MHPG was seen in patients who panicked, nor in nonpanickers and controls. Several other biochemical and hormonal variables were measured. No single biochemical or neuroendocrine variable was found to correlate with lactate-induced panic attacks. It is argued that the baseline arousal level of patients with panic disorder may be increased, which renders these patients more vulnerable to panic attacks.     

The cardiac anxiety syndrome — a subtype of panic attacks

Summary Cardiac anxiety syndrome and the diagnosis of cardiac neurosis respectively are characterized by panic attacks. Panic attacks are the core syndrome of a validated anxiety disorder (panic disorder). The purpose of this study was to investigate if the cardiac anxiety syndrome represents a separate disorder or if it is only a subtype of panic attacks.In a sample of 122 patients with panic attacks, all patients with a cardiac anxiety syndrome were selected (n = 31). Furthermore, parallel to this group—matched in the variables age and sex—a second group of patients with no cardiac anxiety syndrome was selected. There were no significant differences in course; in clinical phenomenology, patients with a cardiac anxiety syndrome were only distinguished by a greater intensity of somatization and phobic avoidance from patients with no cardiac anxiety syndrome. These results confirm the hypothesis that the cardiac anxiety syndrome is a subtype of panic attacks and does not represent a separate disorder.     

Community correlates of outcomes in subjects with panic attacks.

The purpose of this study was to document the association between community factors and mental health outcomes in subjects with panic attacks. Randomly selected adults from 18 census tracts were screened for the presence of panic attacks. A structured interview was used to assess health care utilization, psychiatric morbidity, quality of life, and sense of control over panic. Community measures were obtained from census data. Regression analyses found that each community measure was associated with at least one outcome even when adjusted for individual socioeconomic status and barriers to access. Research concerning mental health outcomes in subjects with panic attacks should include community-level data.     

Mouse defensive behaviors: pharmacological and behavioral assays for anxiety and panic

The natural defensive behaviors of laboratory mice have been evaluated in both seminatural and highly structured situations; and characterized in terms of eliciting stimuli, response to pharmacological agents, behavior patterns, and outcome or effect on the social and physical environment. The defense patterns of laboratory mice and rats are generally similar, but mice show risk assessment on initial exposure to highly threatening stimuli while rats do not, while rats display alarm vocalizations, missing in mice. Quantitative differences in freezing and flight for laboratory mice and rats appear to largely reflect domestication effects, with wild mice and rats more similar to each other. This nexus of detailed within-species and comparative data on defense patterns makes it possible to reliably elicit specific defenses in mice or rats in an experimental context, providing well-validated assays of the natural defensive behaviors themselves, as opposed to 'models' of defense.The mouse--rat comparisons indicate considerable cross-species generality for these defense patterns, as does a scattered but considerable literature on other mammalian species, generally involving field studies and typically focusing on those aspects of defensive behavior that are visible at a distance, such as vigilance, or flight. Although potential homologies between normal mouse and human defense systems should ideally involve all four pattern components (stimulus, organismic factors, response characteristics, outcome), predictive validity in terms of response to drugs active against specific defensive psychopathology is the most extensively investigated of these. Flight, as measured in the Mouse Defense Test Battery shows a consistently appropriate response to panicolytic, panicogenic, and panic-neutral drugs, while some other predictive 'panic models' (dPAG-stimulation; DMH-inhibition; possibly conditioned suppression of drinking paradigms) also elicit and (indirectly) measure behaviors potentially related to flight. Models unrelated to flight (e.g. ultrasonic vocalization to conditioned stimuli); or for which flight elements may a relatively minor contributor to the behavior measured (Elevated T-maze) are less predictive of panicolytic or panicogenic action. These findings indicate that natural defensive behaviors provide a well-characterized pattern for analysis of effects of genetic or other physiological manipulations in the mouse, and may also serve as a model for analysis of defense-related human psychopathology.     

Situational panic attacks. Behavioral, physiologic, and biochemical characterization

To investigate the pathophysiology of nonpharmacologically induced panic attacks, 18 drug-free agoraphobic patients and 13 matched healthy subjects underwent structured exposure to phobic situations. Heart rate, blood pressure, and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG), cortisol, growth hormone, and prolactin levels were measured before, during, and after exposure. Fifteen patients experienced situational panic attacks during exposure. Panicking patients displayed significantly greater increases in heart rate but not blood pressure or plasma free MHPG or cortisol in comparison with the healthy subjects. Growth hormone and prolactin responses tended to be smaller in the patients. If brain noradrenergic hyperactivity occurs during situational panic attacks, it may be too brief or too restricted in regional localization to affect MHPG levels in plasma. Chronically recurrent attacks may cause an adaptation of neuroendocrine mechanisms activated by anxiety or stress.     

Psychopathological description of hyperventilation-induced panic attacks: a comparison with spontaneous panic attacks

Our aim was to describe the clinical features of hyperventilation-induced panic attacks (HPA) in panic disorder patients - DSM-IV - and to compare them with their spontaneous panic attacks and with spontaneous panic attacks in panic disorder (PD) patients not sensible to the hyperventilation challenge test. We reexamined 88 previously studied PD patients when they were submitted to a hyperventilation challenge test. They were induced to hyperventilate (30 breaths/min) for 4 min and anxiety scales were applied before and after the test. A total of 51.1% (n = 45) PD patients had a panic attack after hyperventilating - HPA (chi(2) = 13.11, d.f. = 1, p = 0.017). The clinical symptoms of the most severe panic attack were recorded by the HPA patient and by the PD patients not sensible to this test (non-HPA; n = 43, 48.9%) in a diary during a 1-week period and then compared. The HPA group had more respiratory symptoms (chi(2) = 15.26, d.f. = 1, p < 0.001), fulfilling the criteria for the respiratory PD subtype (75.6%), the disorder started later (Mann-Whitney, p < 0.001), had a higher familial prevalence of PD (chi(2) = 19.45, d.f. = 1, p = 0.036), and had more previous depressive episodes (chi(2) = 18.74, d.f. = 1, p < 0.001). The HPA group had similar symptomatology in spontaneous attacks and HPA. The HPA group may be regarded as a subgroup of the respiratory panic disorder subtype with diagnostic and therapeutic implications.     

Failure of glucagon-like peptide-1 to induce panic attacks or anxiety in patients with panic disorder

The insulin secretogogue glucagon like peptide-1 (GLP-1), as well as agents which enhance GLP-1 signaling, are being studied as potential treatments for diabetes. Pre-clinical evidence suggests that these agents may have neuropsychiatric side effects; however, there have been no investigations or reports of these effects in humans. We evaluated possible anxiogenic and panicogenic properties of GLP-1 in 9 healthy subjects (age 47 ± 8 years) and 7 patients with panic disorder (age 38 ± 17 years) using a single-blinded intravenous GLP-1 challenge (2 pmol/kg/min over 60 min). We assessed the occurrence of panic attacks during and after GLP-1 infusion and the emergence of anxiety or panic symptoms using the Acute Panic Inventory (API). No patient or healthy subject experienced any panic attacks at any point during this study. Moreover, there were no significant changes in API scores following the infusion in either group. These data suggest that in humans, intraveneously administered GLP-1 does not appear to have anxiogenic or panicogenic properties, even in patients at highest risk for such reactions.     

Hyperventilation and panic attacks

The role of hyperventilation in the aetiology of panic attacks is still unclear. This paper briefly reviews the role of hyperventilation and abnormal respiration to panic attacks and examines the experimental evidence. Evidence has been found that physiological variables such as paCO2 and pH are involved in the aetiology of panic attacks and panic disorder but the extent and the nature of the involvement of cognitive variables is undetermined. Based on current evidence, there is a need to integrate cognitive variables with the physiological framework proposed by the hyperventilation theory. Until clear experimental evidence is produced about the relationships between cognitive and physiological factors, the applicability of hyperventilation in the aetiology and treatment of panic attacks remains in question.     

Hypoglycemia and panic attacks

Many patients with panic disorder believe hypoglycemia causes their symptoms. Of 10 patients with panic disorder given sodium lactate to induce panic, none had evidence of low blood sugar levels when they began to experience anxiety symptoms.     

Hyperventilation and panic attacks

The symptoms of hyperventilation syndrome and panic disorder are very similar. A questionnaire was used to assess the incidence of panic disorder in 274 patients; 35% of the patients with hyperventilation and only 5% of the non-hyperventilating patients showed panic disorder. The authors conclude that hyperventilation plays an important role in panic disorder and in generalized anxiety disorder.