Although investigators have examined the psychological and neurobiological mechanisms that underlie Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD), most researchers have assessed these disorders separately. Over 50 percent of people diagnosed with a psychological disorder, however, have additional comorbid disorders . Depression is likely to co-occur with forms of anxiety and, in particular, with social anxiety . Indeed, individuals with comorbid depression/social anxiety (MDD/SAD) have poorer behavioral (e.g. strengthened negative cognitive biases)  and life (e.g. likelihood of suicide attempt)  outcomes than do people with either diagnosis alone.
These deleterious consequences of comorbid depression and social anxiety underscore the importance of elucidating the neural mechanisms that underlie this comorbidity. After decades of research, investigators now have formulated neural models of depression  and of social anxiety (e.g.,)  based on patterns of neural activation that have been found in these disorders. For example, in response to emotional stimuli, depressed participants exhibit abnormal increases in amygdala  and subgenual anterior cingulate cortex activity,  and an abnormal lack of dorsolateral prefrontal cortex activity . In response to emotional stimuli, participants with social anxiety exhibit hyperactivity in the amygdala (similar to depressed participants),  as well as hyperactivity in the rostral anterior cingulate cortex  and insula . These neural models, however, are based on findings of studies conducted with pure, non-comorbid forms of these disorders. We know much less about the neural functioning of individuals with comorbid depression/social anxiety – whether comorbid individuals exhibit neural responses that are more similar to the responses of people with one disorder or the other, an additive combination of the disorder-specific responses, or an intermediate blend of the disorder-specific responses.
Recent studies highlight the utility of examining the neural functioning of individuals with comorbid disorders. For example, Andreescu et al.  found that older participants with diagnosed major depression and high scores on a self-report measure of anxiety exhibited greater activation than did depressed participants with low anxiety scores in the dorsal anterior cingulate cortex in a cognitive interference task. More recently, Etkin and Schatzberg  examined the neural functioning of patients diagnosed with depression and/or Generalized Anxiety Disorder while they performed an emotional conflict task and found that, whereas activation deficits in the ventral cingulate and amygdala were shared by all patient groups, activation in the lateral prefrontal cortex was unique to the non-comorbid depression group. These findings demonstrate that examining individuals with comorbid disorders can distinguish patterns of neural functioning that are common to both disorders from those that are unique to each disorder. In the present study, we both extend these findings of studies assessing other comorbid disorders to examine the neural mechanisms that underlie the comorbidity of depression and social anxiety, and advance research on neural functioning in comorbid disorders by examining the temporal dynamics of whole-brain responses to stress.
Given the importance of stress in the etiology and maintenance of both depression  and anxiety,  it is likely that examining the neural correlates of the stress response will prove critical in understanding neural aspects of comorbidity. For example, Young and colleagues found that individuals with comorbid depression and anxiety (including, but not limited to social anxiety) exhibited greater hypothalamic-pituitary-adrenal (HPA) axis responses to social stress than did individuals diagnosed with either depression or anxiety alone . One potentially illustrative difference between anxious and depressed persons is the timing of their responses to stress. Anxious people are characterized by a vigilance-avoidance attentional bias in which they both engage with and disengage from threat-related stimuli relatively quickly [17–19] (although there is mixed evidence for the avoidance from threat-related stimuli in social anxiety) , which may be one mechanism underlying their enhanced responses during the anticipation of stressors . In contrast, depressed individuals are characterized by high levels of rumination about past negative emotional stimuli, [21, 22] which may underlie their more sustained responses to stress .
Recently, investigators have used social evaluative threat tasks to assess temporal aspects of the neural response to stress in humans. Social evaluative threat tasks induce robust changes in both hypothalamic-pituitary-adrenal axis activity  and peripheral nervous system activity . Investigators have demonstrated that the association between social threat and these stress-induced physiological responses is mediated by the rostral medial frontal cortex . This medial frontal region exhibits activation early in the stressor as well as sustained activation throughout the duration of the stressor [26, 27]. Although this may represent a normal response profile to stress, the finding that the medial frontal cortex is involved in both the initial generation and subsequent maintenance of the stress response highlights this region as a possible site for activation patterns hypothesized to characterize both social anxiety and depression. Whereas the hyper-vigilance to threat in socially anxious people may affect medial frontal cortex activation early in the stressor, the sustained responses to threat in depressed people may influence medial frontal cortex activation late in the stressor.
In the current study, we examined the magnitude and timing of neural responses to social stress in participants diagnosed as having pure depression, pure social anxiety, comorbid depression/social anxiety, or as never having had any Axis-I disorder. We hypothesized that relative to participants without social anxiety, participants diagnosed with social anxiety will exhibit greater changes in medial frontal cortex activation from baseline to early in the stressor (i.e., during instructions or early speech preparation) and less activation late in the stressor (i.e., during late speech preparation or recovery). Alternatively, relative to participants without depression, participants diagnosed with depression will exhibit greater responses in the medial frontal cortex later in the stressor. Finally, it is not clear whether the effects of comorbidity are additive or interactive. We hypothesized that if comorbidity is the additive combination of depression and social anxiety, then comorbid participants should exhibit medial frontal cortex responses both early and late in the stressor.