45 Endogenous testosterone levels are predictive of symptom reduction with exposure therapy in social anxiety disorder Introduction Social anxiety disorder (SAD) is one of the most common anxiety disorders, with a lifetime prevalence rate of 13% (Bandelow & Michaelis, 2015). Persistent avoidance behavior in SAD is a major factor that hinders extinction of fear during social situations (Arnaudova et al., 2017; Clark & Wells, 1995). Avoidance behavior is the target of exposure therapy, which, although it is a first-line treatment for the disorder, leaves ample room for improvement (response rates vary between 45-55% and effect sizes are small to moderate Hedges’g 0.48-0.62 - Carpenter et al., 2018; Hofmann and Smits, 2008; Loerinc et al., 2005). Accordingly, studying social avoidance and its biomarkers has the potential to improve outcomes for individuals with SAD and related disorders. Produced by the Hypothalamus-Pituitary-Gonadal (HPG)-axis, testosterone constitutes an important regulator of social motivational behavior in general, including avoidance behavior (Hermans & Van Honk, 2006). The social challenge hypothesis (Wingfield et al., 1990), originally based on testosterone and aggression associations in monogamous birds (Wingfield et al., 2001) and later also established in primates (Muller & Wrangham, 2004) and humans (Bateup et al., 2002; Neave & Wolfson, 2003) is the most predominant theory of testosterone reactivity. It states that testosterone levels rise in preparation to a challenging encounter in which social status may be threatened, thereby initiating approach motivation and reducing fear (Archer, 2006; Bos, Panksepp, et al., 2012). Consistent with this hypothesis, high endogenous testosterone has been associated with social dominance and approach behavior (Maner et al., 2008; Mazur & Booth, 1998), and low testosterone levels have been linked to socially submissive, anxious and avoidant behavior (Archer, 2006; Josephs et al., 2006; Sapolsky, 1991). Importantly, reduced levels of endogenous testosterone have been found in those suffering from SAD (Giltay et al., 2012) and other social avoidance-related disorders such as depression (Almeida et al., 2008; Giltay et al., 2012). The anxiolytic properties of testosterone have been linked to its effect on GABAergic transmission in neural fear circuits (Gutiérrez-García, Contreras, Vásquez-Hernández, Molina-Jiménez, & Jacome-Jacome, 2009; McHenry et al., 2014) whereas the threat-approach facilitating properties have been linked to its effects on the amygdala and striatum (i.e., biasing the amygdala towards threat approach and reward anticipation, Radke et al., 2015 and Hermans et al., 2010, respectively). Relevant to the treatment of SAD, causal studies on the relationship between testosterone and fearful avoidance behavior, further confirm the social motivational aspects of testosterone. For example, administering testosterone to healthy participants prior to threat exposure has been shown to reduce fear, enhance reward sensitivity and promote 3
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