The two primary tools for the neurobiologist investigating social anxiety disorder have been pharmacological probes and, more recently, neuroimaging. In examining the clinical neurobiological literature, we attempt to highlight data that replicate preclinical experiments, if possible, although few such studies have been performed.
Challenge studies have shown abnormalities in monoamine (dopamine, norepinephrine) and indoleamine (serotonin) neurotransmission. Of the serotonergic studies, Tancer et al. (10) reported an augmented cortisol response to fenfluramine in patients with social anxiety relative to comparison subjects, a finding similar to that observed in subjects with panic disorder. Hollander et al. (67) reported increased anxiety responses to the serotonergic probe m-CPP, but there were no notable neuroendocrine alterations. In studying dopamine function, Tancer’s group (10) did not find any abnormality of dopaminergic function when using L-dopa as the pharmacological probe (see Appendix 1 for a summary of dopaminergic abnormalities observed in social anxiety disorder [68–72]). Other probes commonly used in studies of panic disorder, such as CO2, lactate, pentagastrin, and epinephrine, generally have produced an intermediate response, between those of patients with panic disorder and comparison subjects, in patients with social anxiety disorder (73, 74). A recent report by Pine et al. (75) revealed a lack of association between CO2 sensitivity and childhood social phobia, which is consistent with studies finding no association between childhood social phobia and adult panic disorder (76). We conclude from these limited studies that there exists an overlapping but distinct neurobiology of social anxiety disorder and panic disorder.
Norepinephrine in Social Phobia
Since autonomic hyperarousal (manifested by flushing, tachycardia, and tremulousness) is a common symptom of patients with panic anxiety and social anxiety in performance situations, understanding autonomic nervous system function in these patients might shed light on the dysfunctional circuitry involved in social anxiety disorder. Stein et al. (77) performed an orthostatic challenge test in patients with social anxiety disorder, panic disorder, and healthy comparison subjects and found that the first group had higher plasma levels of norepinephrine before and after the challenge. This finding was not replicated in a subsequent study comparing subjects with social phobia with normal comparison subjects, and in fact there was a suggestion of impaired parasympathetic (not sympathetic) activity in the group with generalized social anxiety disorder in relation to comparison subjects (78).
Limited data have suggested that the 2 adrenergic antagonist yohimbine increases social anxiety in patients with social anxiety disorder and is associated with increased plasma 3-methoxy-4-hydroxyphenylglycol concentrations (79). In contrast, Papp et al. (80) infused intravenous epinephrine in patients with social anxiety disorder and observed that only one out of 11 patients experienced observable anxiety, which suggests that an increase in plasma epinephrine levels alone is inadequate to cause social anxiety. Notably, Tancer et al. (81) observed a reduced GH response to intravenous, but not oral, clonidine, an 2 adrenergic agonist. The blunted GH response to clonidine is also observed in subjects with panic disorder, major depressive disorder, and generalized anxiety disorder and is thought to possibly reflect reduced postsynaptic adrenergic-2 receptor functioning owing to norepinephrine overactivity. Alternatively, Coplan et al. (16) hypothesized that the blunted GH response to clonidine or other GH secretagogues may reflect an increased central activity of the fear-inducing neuropeptide CRF. In summary, although there are limited data on the role of autonomic nervous system dysfunction in social anxiety, the autonomic hyperarousal observed clinically in some patients bespeaks an underlying dysregulation of the autonomic nervous system.