Elsevier

Psychoneuroendocrinology

Volume 51, January 2015, Pages 589-597
Psychoneuroendocrinology

Cortisol augmentation of a psychological treatment for warfighters with posttraumatic stress disorder: Randomized trial showing improved treatment retention and outcome

https://doi.org/10.1016/j.psyneuen.2014.08.004Get rights and content

Summary

Background

Prolonged exposure (PE) therapy for post-traumatic stress disorder (PTSD) in military veterans has established efficacy, but is ineffective for a substantial number of patients. PE is also associated with high dropout rates. We hypothesized that hydrocortisone augmentation would enhance symptom improvement and reduce drop-out rates by diminishing the distressing effects of traumatic memories retrieved during imaginal exposure. We also hypothesized that in responders, hydrocortisone augmentation would be more effective in reversing glucocorticoid indices associated with PTSD than placebo augmentation.

Method

Twenty-four veterans were randomized to receive either 30 mg oral hydrocortisone or placebo prior to PE sessions 3–10 in a double-blind protocol. Glucocorticoid receptor sensitivity was assessed in cultured peripheral blood mononuclear cells (PBMC) using the in vitro lysozyme inhibition test and was determined before and after treatment. Intent-to-treat analysis was performed using latent growth curve modeling of treatment effects on change in PTSD severity over time. Veterans who no longer met diagnostic criteria for PTSD at post-treatment were designated as responders.

Results

Veterans randomized to hydrocortisone or placebo augmentation did not differ significantly in clinical severity or glucocorticoid sensitivity at pre-treatment. Hydrocortisone augmentation was associated with greater reduction in total PTSD symptoms compared to placebo, a finding that was explained by significantly greater patient retention in the hydrocortisone augmentation condition. A significant treatment condition by responder status interaction for glucocorticoid sensitivity indicated that responders to hydrocortisone augmentation had the highest pre-treatment glucocorticoid sensitivity (lowest lysozyme IC50-DEX) that diminished over the course of treatment. There was a significant association between decline in glucocorticoid responsiveness and improvement in PTSD symptoms among hydrocortisone recipients.

Conclusions

The results of this pilot study suggest that hydrocortisone augmentation of PE may result in greater retention in treatment and thereby promote PTSD symptom improvement. Further, the results suggest that particularly elevated glucocorticoid responsiveness at pre-treatment may identify veterans likely to respond to PE combined with an intervention that targets glucocorticoid sensitivity. Confirmation of these findings will suggest that pharmacologic interventions that target PTSD-associated glucocorticoid dysregulation may be particularly helpful in promoting a positive clinical response to PTSD psychotherapy.

Introduction

Prolonged exposure (PE) is one of several cognitive behavioral treatments recommended by the U.S. Department of Defense and the Department of Veteran's Affairs for treatment of service members and veterans with PTSD (Ruzek et al., 2012, Susskind et al., 2012). This treatment is theorized to work by extinguishing fear responses to the emotions elicited by traumatic memories, reducing experiential and behavioral avoidance of trauma-related feelings, memories, and reminders, and facilitating new learning to correct cognitive distortions resulting from the traumatic exposure (Foa and Kozak, 1986, Hembree and Foa, 2000, Van Minnen and Foa, 2006).

Despite the efficacy of PE among treatment completers, high drop-out rates have been reported in clinical trials and in clinical practice. This is particularly evident for psychotherapies involving veterans. In randomized, controlled trials of PE in veterans, drop-out rates between 23% and 38% have been reported (Schnurr et al., 2007, Eftekhari et al., 2013, Simmons et al., 2013). Recent published analyses of patient charts found drop-out rates ranging from 27% to 44% (Jeffreys et al., 2013, Tuerk et al., 2011, Goodson et al., 2013) for veterans treated with PE by providers hired and trained as trauma specialists in VA specialized PTSD programs. Treatment drop-out has been theorized as a response to the early recounting of the trauma memory in therapy, which initially exacerbates symptoms, activates avoidance mechanisms, and may lead patients to withdraw from treatment (Schnurr et al., 2007, Leiner et al., 2012). It has therefore been of interest to develop strategies to use in tandem with PE to facilitate treatment gains by either accelerating improvement or increasing tolerability to prevent drop-outs. Some augmentation strategies, such as d-cycloserine, have focused on improving the rate of fear extinction, and have been successful in some reports (Rothbaum et al., 2014; for review, see de Kleine et al., 2013).

Hydrocortisone is a synthetic glucocorticoid with anti-inflammatory effects that is widely used in medical practice. The hypothesis that glucocorticoids might augment the therapeutic effect of PE is based on findings demonstrating that glucocorticoids facilitate extinction learning through their actions in potentiating effects of the glutamatergic N-methyl-d-aspartate (NMDA) receptors in the amygdala (Yang et al., 2005, Yang et al., 2007, Sakurai et al., 2007). Glucocorticoid administration is associated with decreased retrieval of fear memories in animals (Cordero et al., 2002, Roozendaal et al., 2004, Cai et al., 2006, Abrari et al., 2008, Kohda et al., 2007, Tronel and Alberini, 2007). Glucocorticoids also enhance memory consolidation and reconsolidation via interactions with brain noradrenergic systems, and therefore may promote the reframing of memories that forms the basis of posttraumatic recovery (Quirarte et al., 1997, Roozendaal, 2003, Nathan et al., 2004, Roozendaal et al., 2006). Patients receiving high doses of glucocorticoids for the treatment of septic shock were significantly less likely to suffer from traumatic recollections of the event or to develop PTSD (Schelling et al., 2004, Schelling et al., 2006). Subsequent randomized trials confirmed that the effect of glucocorticoids such as hydrocortisone in the prevention of PTSD resulted from decreasing the traumatizing effects of memory (reviewed in de Quervain et al., 2009, Zohar et al., 2011). Further support for hydrocortisone augmentation of PE was provided by two randomized studies in which hydrocortisone was combined with exposure therapies for the treatment of anxiety disorders (Soravia et al., 2006, de Quervain et al., 2011). A case report of two PTSD patients showed results of hydrocortisone in comparison to placebo augmentation of PE for two combat veterans with similar pre-treatment symptom severity; the veteran receiving hydrocortisone showed an acceleration of symptom improvement and lower post-treatment PTSD severity (Yehuda et al., 2010a).

This pilot study was conducted to further examine the feasibility and potential benefit of hydrocortisone compared to placebo augmentation of PE for treatment seeking veterans with PTSD. It was hypothesized that, compared to placebo, hydrocortisone augmentation of PE would yield greater reduction in PTSD symptoms and full remission rates at end of treatment and over a 6 week follow-up interval. We further predicted that veterans showing greater glucocorticoid receptor sensitivity at baseline, as assessed by the lysozyme IC50-DEX, would be most responsive to the enhancing effects of hydrocortisone augmentation. Finally, we hypothesized that responders to hydrocortisone augmentation would show lower glucocorticoid sensitivity following treatment than was evident at pre-treatment, and in comparison to non-responders.

Section snippets

Participants and procedures

This was a randomized, double-blind, placebo-controlled trial that took place at the James J. Peters Bronx Veterans Affairs Medical Center between 2010 and 2013. The study was designed as a pilot investigation to support a larger randomized trial. Veteran outpatients who met the case definition of PTSD according to the Clinician Administered PTSD Scale for DSM-IV (CAPS; Blake et al., 1995) and had a minimum score of 50 were eligible to participate. Focal traumas were all experienced during

Pre-treatment comparison of hydrocortisone and placebo group assignments

Fifty-three veterans were enrolled in the study between March 2010 and May 2013. Six veterans withdrew prior to eligibility assessment, and an additional 11 withdrew prior to randomization. Twelve participants were excluded based on diagnostic evaluation (e.g., bipolar diagnosis, active substance abuse) or determination of insufficient PTSD severity. Twenty-four veterans were therefore randomized and form the subject of this report. No side-effects or untoward, unanticipated drug or therapy

Primary psychological outcomes

This pilot study of hydrocortisone augmentation of PE indicated that veterans randomized to hydrocortisone were more likely to benefit from PE than those randomized to placebo. Effect sizes observed for PE are consistent with other randomized controlled trials (Steenkamp and Litz, 2013). In the present study, the significant effect of hydrocortisone cannot be separated from its effect to increase treatment retention, an effect that is likely linked to the proposed actions of hydrocortisone. A

Trial registration

This trial is registered with the National Institute of Health. The protocol is accessible via clinicaltrials.gov (#NCT01090518).

Conflict of interest statement

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Acknowledgements

This work was supported by a grant from the Lightfighters Trust Foundation (LFT2009-02-1) entitled, ‘Cortisol augmentation of a psychological treatment in warfighters with PTSD.’

Additional support received from a grant from the Department of Defense (DOD W81XWH-10-2-0072) entitled, ‘Improving PTSD outcomes in OIF/OEF returnees: A randomized clinical trial of hydrocortisone augmentation of prolonged exposure therapy.’

The authors would like to thank Eleni Dimoulas, PhD and Vincent Passarelli,

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