The enhancing effects of testosterone in exposure treatment for social anxiety disorder: a randomized proof-of-concept trial

Moniek H M Hutschemaekers,Rianne A De Kleine,Karin Roelofs,Mirjam Kampman,Gert-Jan Hendriks

doi:10.1038/s41398-021-01556-8

Moniek H M Hutschemaekers, Rianne A De Kleine + Show 3 more

Open Access

https://doi.org/10.1038/s41398-021-01556-8

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Abstract

Individuals with a social anxiety disorder (SAD) show hypofunctioning of the hypothalamus–pituitary-gonadal (HPG) axis, which is linked to social fear and avoidance behavior. As testosterone administration has been shown to facilitate social-approach behavior in this population, it may enhance the effectiveness of exposure treatment. In this proof-of-concept study, we performed a randomized clinical assay in which 55 women diagnosed with SAD received two exposure therapy sessions. Session 1 was supplemented with either testosterone (0.50 mg) or placebo. Next, transfer effects of testosterone augmentation on within-session subjective fear responses and SAD symptom severity were assessed during a second, unenhanced exposure session (session 2) and at a 1-month follow-up, respectively. The participants having received testosterone showed a more reactive fear pattern, with higher peaks and steeper reductions in fear levels in session 2. Post-hoc exploration of moderating effects of endogenous testosterone levels, revealed that this pattern was specific for women with high basal testosterone, both in the augmented and in the transfer session. In contrast, the participants with low endogenous testosterone showed reduced peak fear levels throughout session 1, again with transfer to the unenhanced session. Testosterone did not significantly affect self-reported anxiety. The effects of testosterone supplementation on fear levels show transfer to non-enhanced exposure, with effects being modulated by endogenous testosterone. These first preliminary results indicate that testosterone may act on important fear mechanisms during exposure, providing the empirical groundwork for further exploration of multi-session testosterone-enhanced exposure treatment for SAD.

Highlights

With a lifetime prevalence of 13% and long-term disability, social anxiety disorder (SAD) is the most common and burdensome of all anxiety disorders [1,2,3]
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
We focused exclusively on women because the pharmacodynamics of the currently used testosterone administration methods have as yet been established in women only [42]

Summary

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 [1,2,3]. Persistent avoidance is the main factor hindering the 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 [4, 5]. 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 [10,11,12,13,14,15]. The results are encouraging, no pharmacological enhancer has been tested that directly acts on acute withinsession social-approach behavior, essential for effective exposure

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