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Effects of exogenous glucocorticoid on combat-related PTSD symptoms

Alina Surís, PhD, ABPP

VA North Texas Health Care System, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

Carol North, MD, MPE

VA North Texas Health Care System, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

Bryon Adinoff, MD

VA North Texas Health Care System, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

Craig M. Powell, MD, PhD

Department of Psychiatry, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Robert Greene, MD, PhD

VA North Texas Health Care System, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

BACKGROUND: Very few systematic human studies focus on changing the underlying traumatic memory after posttraumatic stress disorder (PTSD) has been established. Evidence from animal and human studies indicates that cortisol can be used to address traumatic memories. This translational pilot study is based on our previous rodent research in which extinction of fear memories was enhanced by glucocorticoids. The current study aims to assess the effectiveness of glucocorticoids in augmenting memory extinction and reducing clinical symptoms in veterans with combat-related PTSD.

METHODS: In a double-blind, placebo-controlled study, veterans with combat-related PTSD were exposed to a memory reactivation task using well established imagery and psychophysiology assessment technique followed by administration of either glucocorticoid or placebo.

RESULTS: One week after glucocorticoid or placebo administration, participants who received the study medication showed significant PTSD-related symptom (cluster C) improvement compared with control participants who received placebo only. However, reduction of symptoms degraded at a 1-month postadministration assessment.

CONCLUSIONS: These findings are consistent with a glucocorticoid-mediated enhancement of extinction to ameliorate PTSD symptoms. The use of traumatic memory reactivation temporally paired with glucocorticoid administration holds potential for developing a viable therapeutic option.

KEYWORDS: posttraumatic stress disorder, glucocorticoids, memory extinction, pharmacotherapy



Posttraumatic stress disorder (PTSD) is a disabling, yet prevalent disorder.1 PTSD is hypothesized to represent the endpoint of negative effects associated with reminders of a traumatic exposure, fueled by memories of the exposure because the event happened in the past. In a 2008 report, the National Academy of Science Institute of Medicine (IOM) concluded that PTSD treatment has not received adequate research attention and found little evidence to support the efficacy of most available treatments.2 The exception, however, was exposure therapy; the IOM referenced a number of studies demonstrating significant therapeutic effects of exposure therapy for PTSD symptoms.3-5

Exposure therapy promotes memory extinction, which involves learning new emotional associations to reminders of a traumatic stimulus rather than forgetting or erasing the original memory.6 Learned conditioned responses can be attenuated by presentation of a conditioned stimulus (a reminder of a trauma exposure) without reinforcement by the unconditioned stimulus (actual trauma exposure).6 The trauma memory is replaced with a new memory involving neutral or less upsetting emotions, which disarticulates previously conditioned negative emotions from subsequent trauma reminders. This extinction process is amenable to pharmaceutical enhancement,7,8 stimulating much interest in potential pharmacologic agents for treating PTSD.

Studies designed to examine pharmacologic enhancement of the memory extinction process have been informed by animal models, and glucocorticoids have been shown to enhance this process in rodents.9,10 Consolidation of fear memories also can be enhanced with corticosterone in animal models.11 Regulation of glucocorticoids—primarily cortisol in humans—is significantly altered in patients with PTSD,12,13 suggesting that disruption in cortisol secretion may underlie the difficulties PTSD patients have with extinguishing trauma memories. Non-experimental research on administration of exogenous glucocorticoids shows promise for cortisol as an intervention for PTSD. For example, several studies of intensive care unit patients by Schelling et al14 found that administration of higher doses of hydrocortisone was coupled with a decreased likelihood of developing PTSD. Indeed 1 small study suggests that chronic daily administration of a glucocorticoid can reduce PTSD symptoms during treatment and effects may persist even after the medication is stopped.15 Continuous steroid use, however, is fraught with adverse side effects. If glucocorticoids exert lasting beneficial effects on memory extinction, then perhaps a focused approach pairing reactivation of traumatic memories to brief glucocorticoid administration could suffice.

When fear memories were previously established in rodents by pairing foot shock to specific contextual cues, our team observed that injection of a single dose of corticosterone following memory reactivation reduced behaviors indicating fear memories previously established through pairing foot shock with specific contextual clues.9 Delivery of small “reminder” shocks that were not strong enough to stimulate new fear memories but sufficient to reawaken the established fear responses reversed the dampening effects of corticosterone on fear responses. Similarly, the passage of time also reduced the dampening effects of a single dose of corticosterone.9 The reversal of the corticosterone effects with these maneuvers indicates that the mechanism by which corticosterone dampens fear response behaviors involves actual augmentation of memory extinction rather than interference with fear memory reconsolidation.16 Based on our previous rodent research, this pilot study aimed to assess the effectiveness of glucocorticoids in augmenting memory extinction and reducing clinical symptoms in veterans with combat-related PTSD. In this double-blind, placebo-controlled study, subjects were exposed to a memory reactivation task followed by either hydrocortisone or placebo.


We obtained Veterans Affairs (VA) Institutional Review Board (IRB) approval before commencing the research. Male veterans diagnosed with PTSD related to combat or combat support were eligible for participation. Women were not included to preclude interference of the menstrual phase with measurement of hypothalamic-pituitary-adrenal axis response. Other exclusion criteria were substance abuse or dependence (except nicotine) within the previous 6 months; current steroid, benzodiazepine, or barbiturate use; psychosis; brain damage; and medical contraindications to steroid administration. Use of psychiatric medications was not exclusionary and any changes or new medications during the study period were monitored. A volunteer sample of 22 male combat veterans was recruited from several mental health programs at a large southwestern VA hospital. All participants provided written informed consent, after which they were randomized to receive an intravenous bolus of glucocorticoid (hydrocortisone sodium succinate, 4 mg/kg) or saline in a double-blind fashion. The dose was selected based on effective doses in our animal studies and discussions with study physicians and a doctor of pharmacy who is a drug information specialist regarding typical and safe human doses that would be equivalent to the most efficacious animal dose. All 4 study physician coauthors and the doctor of pharmacy agreed on the final dose.

Baseline assessment included the Clinician-Administered PTSD Scale for DSM-IV (CAPS) to confirm the PTSD diagnosis,17 Structured Clinical Interview for DSM-IV Axis I Disorders to diagnose lifetime and current psychiatric comorbidity,18 Impact of Event Scale-Revised (IES-R) for the presence and severity of related PTSD symptoms by DSM-IV-TR groupings (re-experience, avoidance/numbing, and arousal) for the past week,19 and Quick Inventory of Depressive Symptomatology (Self-Report) (QIDS-SR) for depression symptoms in the previous week.20 After baseline, participants had 3 return study visits (treatment visit, 1-week posttreatment memory reactivation visit, and 1-month posttreatment assessment visit). Two participants dropped out of the study after the initial assessment, yielding a total of 20 study completers.

During the treatment visit, an IV was inserted in the non-dominant arm and participants rested for 45 minutes before being asked to write a 1-page description of their 2 “worst” combat-related trauma memories and to identify from a list any bodily sensations (eg, sweaty palms, breathing fast, etc.) that they experienced at the time of the trauma. (Based on the material the participants provided, a male research staff member recorded a 30-second script incorporating material from participants’ own trauma descriptions to be played during the 1-week posttreatment assessment visit to activate their combat memories.) Next, participants filled out the IES-R once for each of these 2 traumatic events. Immediately after addressing both traumas, the participants were administered an intravenous bolus of either hydrocortisone or saline and then completed the QIDS-SR. They were then instructed to rest quietly for at least 1 hour while the study nurse observed the participants to make sure they did not experience side effects from the medication.

At the 1-week posttreatment memory reactivation visit, 2 standardized neutral scripts21 were presented to participants along with their 2 personal trauma narratives. These scripts were presented in randomly alternating order. Four physiological measures (heart rate, skin conductance, and corrugator and frontalis muscle electromyogram) were recorded during script presentation. After the imagery procedure was completed, an IES-R for each traumatic event and the QIDS-SR were completed. At the 1-month posttreatment visit, only the IES-R, QIDS-SR, and CAPS were administered.

Average baseline psychophysiologic measure variables were not within the established normal range for 2 participants, leaving 19 participants (9 administered hydrocortisone and 10 administered placebo) with complete information for this study’s data analysis. Findings are summarized and presented as raw numbers, percentages, means, and standard deviations. Comparisons of 2 dichotomous variables were performed using χ2 analysis (substituting Fisher exact tests for expected cell sizes <5). Student’s t-tests were used to compare dichotomous with numerical variables.


Baseline characteristics

The hydrocortisone and saline groups were indistinguishable on demographic variables (age, ethnicity, education, marital status, work status, or service connection status), psychiatric comorbidity, and baseline symptoms on the CAPS (total and cluster B, C, and D scores respectively representing PTSD intrusion, avoidance/numbing, and arousal symptom clusters), IES-R (total and intrusion, avoidance/numbing, and arousal scores), and QIDS-SR. Comorbid lifetime psychiatric disorders were diagnosed in 84% of the participants (major depression in 74%, generalized anxiety disorder in 16%, social phobia in 11%, panic disorder in 11%, and anxiety disorder not otherwise specified in 11%). Regarding past diagnoses of substance abuse/dependence, 10% of participants had a history of alcohol abuse, 40% alcohol dependence, 10% cannabis dependence, 5% amphetamine dependence, and 20% cocaine dependence. Nicotine dependence was not assessed. Five of the study participants were receiving service-connected disability payments from the VA for PTSD.

Treatment visit (pairing of hydrocortisone/saline with traumatic memory activation, 1 week after baseline)

At this visit, no change from baseline was found in IES-R scores, as was expected, reflecting stability of the measurement. The hydrocortisone group did not differ from the saline group in IES-R total and symptom subgroup scores. Curiously, however, compared with the saline group, the hydrocortisone group had a significantly higher QIDS-SR score (mean = 15.7, SD = 4.4 vs mean = 11.3, SD = 3.5; t = 2.38, df = 17, P = .029). No side effects were noted for either the medication or control group.

One-week posttreatment memory reactivation visit

Following memory reactivation 1-week posttreatment, IES-R avoidance/numbing scores were significantly lower for the hydrocortisone group compared with the saline group (worst trauma: mean = 1.9, SD = 0.8 vs mean = 2.7, SD = 0.4, t = 2.58, df = 17, P = .019; next worst trauma: mean = 1.9, SD = 1.0 vs mean = 2.6, SD = 0.6, t = 1.84, df = 17, P = .084; average of the 2 traumas: mean = 1.9, SD = 0.9 vs mean = 2.6, SD = 0.5, t = 2.21, df = 17, P = .041.) See the FIGURE for a graphic presentation of the findings for the worst trauma. IES-R intrusion and arousal scores did not differ between the treatment groups. Between-group differences in total IES-R scores for the worst trauma (cortisol = 52.6, SD = 14.4 vs saline = 63.3, SD = 12.0; t = 1.77, df = 17, P = .094) and second worst trauma (cortisol = 51.9, SD = 15.7 vs saline = 63.6, SD = 12.5; t = 1.81, df = 17, P = .088) fell short of statistical significance. QIDS-SR scores at this visit were not significantly different between treatment groups, as was at baseline.

FIGURE Mean posttraumatic symptom scores by symptom group for worst trauma

*P = .019

One-month posttreatment assessment

One month after the last treatment visit, no significant between-group differences were detectable on any of the total or subscale scores of the IES-R, CAPS, and QIDS-SR.


Previous research has suggested potential benefit of brief glucocorticoid administration for PTSD. First, non-experimental studies have shown that chronic glucocorticoid administration may reduce the likelihood of PTSD in traumatized individuals.14 Second, our earlier experimental research demonstrated that brief glucocorticoid administration reduced freezing behavior in rodents after contextual fear conditioning.9 When taken together, findings from these studies suggested potential therapeutic effects with brief glucocorticoid administration in humans. Successfully applying experimental methods from our rodent experiment to humans with PTSD, this study probed the effects of pairing a single administration of a glucocorticoid with a traumatic memory reactivation task. Consistent with our animal studies, administration of an exogenous glucocorticoid after fear memory reactivation reduced response to trauma reminders as measured by standardized assessment scales in our patients with PTSD. This small pilot study represents the first randomized, double-blind, placebo-controlled clinical trial testing the effects of exogenous glucocorticoids on patients with PTSD.

Specifically, this study demonstrated that pairing traumatic memory activation with a single dose of glucocorticoid resulted in lower cluster C (avoidance/ numbing) symptom scores in the hydrocortisone group compared with the saline group 1 week after treatment. Treatment effects were not observed in cluster B (intrusion) or cluster D (arousal) symptoms, but other studies have demonstrated that the avoidance/numbing symptom cluster is a marker of psychopathology in PTSD,22-24 and reduction of problematic avoidance behaviors is a major therapeutic endpoint of exposure therapies.25 The finding that these effects were not observed 1 month later suggests that the observed effects of a single glucocorticoid dose may be relatively transient.

This study’s strengths are the elements of the experimental design; blinding of assessments using a placebo comparison group; systematized, validated measurement tools and implementation of a standardized procedure for trauma memory reactivation; and simultaneous measurement of psychophysiologic recording methods.

This study has several limitations, which may constrain the study’s observable findings. Perhaps the most serious limitation is the small sample size that constrained statistical power. Although worst-trauma avoidance/numbing symptom scores were significantly lower in the cortisol group than in the control group 1 week posttreatment, the treatment group difference in avoidance/numbing symptom scores specifically for the second worst trauma fell short of statistical significance 1 week posttreatment. The finding that the average of between-group difference on both trauma scores combined was statistically significant suggests that limited statistical power may have obscured potential detection of a real difference. Additionally, the significant difference in avoidance/numbing symptom scores between treatment groups at 1 week posttreatment represents merely a between-group difference and not a measure of change over time from pretreatment to posttreatment. No change scores over time were significantly different between treatment groups even though differences between groups were apparent posttreatment. Lack of findings in the change scores also may reflect limited statistical power due to small sample size. The change values were much smaller in magnitude than the actual scores, reducing the ability to detect differences.

Additionally, this study was limited because it tested only a single administration of a limited dosage of cortisol, a procedure that may not have been powerful enough to produce observable changes in symptom scores over time. Using a higher dose might have produced more measurable and durable effects. Because our animal studies showed that multiple pairings of reactivation and glucocorticoid resulted in larger and longer lasting effects than a single pairing on fear memory,9 it is reasonable to predict that multiple pairings of memory activation with cortisol might further enhance the effects and extend them across all PTSD symptom domains.

Finally, the volunteer sample used for this study may not be representative of veterans in general. The medical and pharmacologic agent exclusion criteria hindered the study’s ability to gather a sample because many potential recruits were not eligible for participation. A substantial number of veterans screened were ineligible because of medical (eg, diabetes or cardiovascular) problems and/or use of psychotropics. Excluding women from the study limits its ability to generalize to populations other than men. Lastly, combat veterans receiving treatment for PTSD may not be representative of other PTSD populations.


Even the short-lived effect on IES-R avoidance/numbing scores after a single pairing of memory reactivation and cortisol in the present study are promising indications that repeated sessions of memory reactivation paired with glucocorticoids could lead to significantly enhanced and prolonged clinical benefits. We conclude that the use of traumatic memory reactivation temporally paired with glucocorticoid administration holds potential for developing a viable therapeutic option for PTSD worthy of future study.

ACKNOWLEDGEMENTS: The authors wish to thank Roger Pittman, MD, for training on the imagery procedure and Scott Orr, PhD, for consultation on psychophysiology data interpretation. We also recognize Lisa Thoman, Broc Sanchez, and Sharon Marcus for their dedication and contributions to data gathering.

DISCLOSURES: This manuscript was supported by a grant to Dr. Surís from NARSAD. Dr. Surís also receives grant support from the US Department of Veterans Affairs (VA), Dallas VA Research Corporation, the National Institutes of Health (NIH) National Center for Research Resources, Blue Gator Foundation, and the American Psychiatric Association. Dr. North receives grant funding from the National Institute of Diabetes and Digestive and Kidney Disease, National Institute of Mental Health (NIMH), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), University of Texas Southwestern Medical Center, the American Psychiatric Association, and the Orthopedic Trauma Association, the VA, is a consultant to the University of Oklahoma Health Sciences Center, and is a speaker for Washington University School of Medicine in St. Louis, MO. Dr. Adinoff receives funding from the VA, NIAAA, and NIH/National Institute on Drug Abuse. Dr. Powell receives funding from NIMH, the National Alliance for Autism Research-Autism Speaks, and the NIH National Center for Research Resources. Dr. Greene receives funding from the VA and NIH.


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CORRESPONDENCE: Alina Surís, PhD, ABPP, VA North Texas Health Care System, Mental Health 116A, 4500 S. Lancaster Road, Dallas, TX 75216 USA, E-MAIL