67 The enhancing effects of testosterone in exposure treatment for social anxiety disorder Introduction With a lifetime prevalence of 13% and long-term disability, social anxiety disorder (SAD) is the most common and burdensome of all anxiety disorders (Bandelow & Michaelis, 2015; Bruce et al., 2005; Hendriks et al., 2016). Persistent avoidance is the main factor hindering extinction of fear during social situations, which is why reducing avoidance behavior is the core target of exposure therapy, the treatment of choice for SAD (Arnaudova et al., 2017; Clark & Wells, 1995). However, with response rates of 45-55%, the intervention leaves room for improvement (Carpenter et al., 2018; Hofmann & Smits, 2008b; Loerinc et al., 2015; Young et al., 2019). Particularly, augmentation strategies aimed at alleviating social avoidance and promoting social approach have the potential to boost core mechanisms assumed to underlie the effects of exposure in SAD. Previous attempts to enhance the therapy’s efficacy with pharmacological agents (e.g., d-cycloserine (DCS), yohimbine, oxytocin) targeted the process of extinction learning in SAD (Guastella et al., 2009; Guastella, Lovibond, Dadds, Mitchell, & Richardson, 2007; Hofmann et al., 2006; Rodebaugh et al., 2013; Smits et al., 2020; Smits, Rosenfield, Otto, et al., 2013a). Although the results are encouraging, no pharmacological enhancer has been tested that directly acts on acute within-session social approach behavior, essential for effective exposure. Testosterone, the end product of the hypothalamus-pituitary-gonadal (HPG) axis, is important in the regulation of social motivational behavior, including approach and avoidance behavior (Hermans & Van Honk, 2006). In both animal and human studies, low endogenous testosterone has been linked to socially submissive, anxious, and avoidant behaviors (Archer, 2006; Josephs et al., 2006; Sapolsky, 1991), while high basal testosterone is related to social dominance and approach behavior (Maner et al., 2008; Mazur & Booth, 1998). Importantly, in individuals with SAD (Giltay et al., 2012) and other social avoidance-related disorders such as depression (Almeida et al., 2008; Giltay et al., 2012) reduced levels of endogenous testosterone have been found. Moreover, relatively high pre-treatment testosterone concentrations predicted a better outcome of exposure therapy in terms of larger symptom reductions (Hutschemaekers et al., 2020). Additionally, causal studies on the relationship between testosterone and avoidance behavior further confirm the social avoidance-reducing and approach-facilitating properties of testosterone (Enter et al., 2014; Enter, Spinhoven, et al., 2016; Terburg et al., 2016). Testosterone acts on dopaminergic projections from the amygdala to the striatum and its administration was shown to bias amygdala activity towards social threat approach in humans (Hermans et al., 2010; Radke et al., 2015). At a behavioral level, testosterone 4
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