There are many unanswered questions regarding the neurobiology of social anxiety disorder. Given our assertion that social anxiety disorder should be conceptualized as a chronic neurodevelopmental illness beginning in childhood, several issues require further inquiry. First, we have no knowledge of studies examining the use of early identification and treatment of social anxiety disorder and its comorbid disorders and childhood precursors. Childhood social anxiety disorder is often comorbid with generalized anxiety disorder or separation anxiety disorder (91), and these comorbid forms of the illness have a greater association with panic disorder (92). Comparisons of laboratory neurobiological and neuroimaging measures of successfully treated patients with early intervention and successfully treated patients who were managed only in adulthood would be of interest, as would analyses of treatment responsivity across comorbid subgroups. Such secondary prevention studies might be the natural extension of longitudinal studies of behaviorally inhibited children.
Second, a better understanding of the developmental neurobiology of the brain regions important in social anxiety, such as the amygdala and striatum, and their interactions with the cortex, ascending monoaminergic systems, and hippocampus, clearly is necessary. Related to this objective neurodevelopmental genetic research, we should attempt to target susceptibility genes for the broad social anxiety phenotype. We have a limited understanding of the interaction between genetic vulnerability and stress exposure in socially anxious individuals. Cross-fostering paradigms in which primates raised under the variable-foraging-demand condition are randomly assigned to the offspring of either socially withdrawn or socially competent mothers might help answer the question of whether stress exposure has a more pernicious effect on genetically susceptible individuals.
Third, MRS imaging can be used to study neurotransmitter systems that have not received extensive attention in social anxiety, such as the glutamatergic system. Preclinical rodent models contend that prefrontal cortical efferents, either directly or by means of thalamic nuclei efferents, use the glutamatergic system as a primary source of neuronal stimulation of the "fear" neurocircuitry, which originates from the central nucleus of the amygdala and bed nucleus of the stria terminalis (93, 94). Stressful situations faced by a person with social anxiety disorder might stimulate glutamate release in hippocampal (38) and other brain regions. In this light, agents that attenuate glutamatergic neurotransmission should reduce anxiety levels, as well as the concomitant biochemical alterations associated with stress. Clinical investigations of glutamatergic antagonists might be warranted, since the SSRIs have been only partially successful in the treatment of this disorder. MRS also allows investigators to explore neurotransmitter interactions in vivo, such as the interaction between serotonin and glutamate, elegantly recently explored by Rosenberg et al. (95) in pediatric OCD.
Finally, an important limitation of our understanding of the neurobiology of social anxiety is the difficulty in discriminating what findings are a response to anxiety or stress and what are true risk factors for the development of anxiety. It is of importance that the clinical neuroendocrinology of social anxiety suggests a fully compensated state in adulthood, in that no peripheral (i.e., HPA axis) pathology is evident. In this light it would be of interest to study patients with a recent onset of social anxiety disorder versus patients with distant onset in order to gauge which neuroendocrine findings persist and which ones change over the course of the illness. Another important contrast would be to study patients with active social anxiety disorder versus patients in remission. A more refined understanding of this compensatory phenomenon might offer valuable insights not only into social anxiety disorder but into other psychiatric disorders with prominent neuroendocrine abnormalities as well.
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