Enhancing exposure therapy for anxiety disorders, obsessive-compulsive disorder and post-traumatic stress disorder

Abstract

Translating findings from basic science, several compounds have been identified that may enhance therapeutic outcomes and/or expedite treatment gains when administered alongside exposure-based treatments. Four of these compounds (referred to as cognitive enhancers) have been evaluated in the context of randomized controlled trials for anxiety disorders (e.g., specific phobias, panic disorder, social anxiety disorder), obsessive-compulsive disorder and post-traumatic stress disorder. These cognitive enhancers include d-cycloserine, yohimbine hydrochloride, glucocorticoids and cortisol and brain-derived neurotrophic factor. There is consistent evidence that cognitive enhancers can enhance therapeutic outcomes and/or expedite treatment gains across anxiety disorders, obsessive-compulsive disorder and post-traumatic stress disorder. Emerging evidence has highlighted the importance of within-session fear habituation and between-session fear learning, which can either enhance fear extinction or reconsolidate of fear responses. Although findings from these trials are promising, there are several considerations that warrant further evaluation prior to widespread use of cognitive enhancers in exposure-based treatments. Consistent trial design and large sample sizes are important in future studies of cognitive enhancers.

Keywords::

• brain-derived neurotrophic factor
• cognitive behavioral therapy
• cortisol
• d-cycloserine
• exposure therapy
• yohimbine
• glucocorticoids

Financial & competing interests disclosure

Support for this article comes in part from the National Institute of Mental Health (NIMH) of the National Institutes of Health under award R01MH093381. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health. JF McGuire receives funding from the NIMH. AB Lewin has served as a consultant for ProPhase, Inc. He has received grant support from International Obsessive Compulsive Disorder Foundation; National Alliance for Research on Schizophrenia and Depression; University of South Florida Research Foundation, Inc. He receives textbook honorarium from Springer publishers. He has received travel support from University of South Florida Research Foundation, Inc., Rogers Memorial Hospital, and NIMH. EA Storch has received grant funding in the last 2 years from the NIH, Centers for Disease Control, Agency for Healthcare Research and Quality, National Alliance for Research on Schizophrenia and Affective Disorders, International OCD Foundation, Tourette Syndrome Association and Janssen Pharmaceuticals. He receives textbook honorarium from Springer Publishers, American Psychological Association and Lawrence Erlbaum. Dr. Storch has been an educational consultant and receives salary support from Rogers Memorial Hospital. He is a consultant for ProPhase, Inc. and CroNos, Inc., and is on the Speaker’s Bureau and Scientific Advisory Board for the International OCD Foundation. He receives research support from the All Children’s Hospital Guild Endowed Chair. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Cognitive enhancers are compounds that influence signaling pathways involved in brain regions (e.g., amygdala, hippocampus, prefrontal cortex) associated with fear learning to enhance the neurological circuitry of fear extinction.

• Cognitive enhancers can address several of the challenges confronting exposure-based treatments such as improving therapeutic outcomes, expediting treatment gains to reduce attrition and reducing treatment duration to increase the availability of treatment providers.

• Although several cognitive enhancers have been evaluated, only d-cycloserine (DCS), yohimbine hydrochloride (YHCL), glucocorticoids and cortisol (G-CORT) and brain derived neurotrophic factor (BDNF) have been evaluated in the context of randomized controlled trials (RCTs) for anxiety disorders, obsessive-compulsive disorder and post-traumatic stress disorder (PTSD).

• Across the 22 RCTs of DCS, small-to-moderate improvements in therapeutic outcomes and expedited treatment gains have been observed. Although findings are generally positive, questions remain about the additive benefit of DCS in trials with longer durations.

• Across three RCTs, YHCL has demonstrated preliminary evidence of enhancing therapeutic outcomes and expediting treatment gains, with benefits being more evident at follow-up assessments.

• Across three RCTs, G-CORT has demonstrated a consistent benefit for enhancing therapeutic outcomes, with no examination of expedited treatment gains.

• Across three RCTs, BDNF biomarkers have been associated with improved therapeutic outcomes, with no examination of expedited treatment gains.

• Collectively for DCS and YHCL, within-session fear habituation and between-session fear learning have been associated with improved therapeutic outcomes. This highlights the fear enhancing properties of these compounds, as well as the importance of monitoring these constructs within emerging treatment protocols.

• Future research is needed to expand the limited evidence for YHCL, G-CORT and BDNF, as well as develop empirically-supported guidelines to monitor within- and between-session therapeutic components to enhance fear extinction (rather than reconsolidate existing fear memories).