38 Chapter 2 Taken together, the pattern that emerges is that psychopathy is associated with structural and functional brain deviations. Alterations in social approach–avoidance behavior, such as decreased social threat avoidance, are likely associated with reduced prefrontal control over limbic structures. Testosterone plays a role in modulation of prefrontal–amygdala connectivity, and is associated with psychopathic tendencies, a relationship that seems to be modulated by cortisol. Lower oxytocin seems to be related to psychopathy as well. However these findings should be considered with caution, due to small sample sizes and differences in definitions of psychopathy. Clinical implications and future directions The above-described neuroendocrine aspects and effects on social motivational behavior in social anxiety and psychopathy give rise to various directions for future research aiming to provide starting points for the enhancement of interventions into these persistent disorders. It would be of theoretical and clinical interest to test whether hormone administration could benefit the treatment of SAD. Exposure therapy is part of first-line treatment of SAD and aims at fear extinction by repeated or prolonged exposure to feared social situations, which should lead to a reduction in fear and avoidance behavior. Although exposure therapy has proven effective, nonresponse rates in large clinical trials have been 50% or higher (Hofmann & Bögels, 2006), and many patients do not achieve remission. In an attempt to enhance exposure therapy efficacy, research has explored the augmentation effects of pharmacological agents thought to enhance the underlying mechanisms of action (e.g., extinction learning) of exposure therapy, for example using D-cycloserine, yohimbine hydrochloride, glucocorticoids, and cortisol and brain-derived neurotrophic factor. This approach has potential, as was shown by studies featuring a variety of pharmacological agents (e.g., Hofmann, Fang, & Gutner, 2014; McGuire, Lewin, & Storch, 2014). Despite initially promising findings, the working mechanisms are still not entirely clear and studies yield mixed findings. It is possible that these cognitive enhancers do not target the most optimal mechanism for enhancement of exposure therapy, and an alternative approach targeting social motivational mechanisms directly might provide a more effective solution. Considering the alleviating effects of testosterone on actual social avoidance behavior in SAD, and considering that exposure therapy is also aimed at reduction of avoidance behavior, it would be of relevance to test whether single-dose testosterone administration – applied only a few times to enhance efficacy of the first few exposure sessions – can enhance therapy efficacy for SAD. Nevertheless, it should
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