Background: The military has a critical need for a highly portable, easily administered intervention that can attenuate acute symptoms and prevent longer-term mental health consequences following critical incidents. Objective: This project, PTSD Prevention Using Oral Hydrocortisone in the Immediate Aftermath of Trauma (Principal Investigator: Rachel Yehuda), proposes to test a one-time prophylactic pharmacologic intervention – administration of oral hydrocortisone (HCORT) – for the prevention of post-traumatic stress disorder (PTSD) and related mental health disturbances. HCORT is a synthetic glucocorticoid similar to the body’s own cortisol and has numerous clinical uses as an anti-inflammatory agent. In response to acute stress, ample cortisol levels are critical to activating, and then containing, systems mobilized as part of the fight-or-flight response. There is evidence that people with lower cortisol levels at the time of trauma exposure are at elevated risk for PTSD.Hypothesis: A single administration of HCORT within 6 hours after trauma will facilitate cortisol-induced suppression of adrenaline that might otherwise lead to the “over-consolidation” of traumatic memories and lead to quicker and greater recovery. A quicker recovery will be defined as: (1) an accelerated decline in the presence and severity of trauma-related distress, impairment, and PTSD symptoms across 7 months in those treated with HCORT vs. placebo, (2) less PTSD at endpoint, and (3) higher scores on resilience-related measures. Biological markers associated with prediction of recovery and response to HCORT will be assessed. There are sound pilot data supporting hypotheses from two prior trials performed by the investigators.Specific Aims: (1) To determine whether early intervention with a single oral dose of HCORT, compared to placebo, will reduce the risk of PTSD in trauma survivors displaying distress in the emergency department (ED). (2) To evaluate whether HCORT alters the trajectory of a range of mental health symptoms (e.g., anxiety, depression, dissociation, disrupted sleep). (3) To determine whether acute hormonal and related molecular responses to trauma predict the development of PTSD (in the placebo condition) or its prevention by HCORT. (4) To assess biological measures over time in those receiving HCORT vs. placebo to establish whether biological changes associated with resilience have occurred.Study Design: This is a two-site double-blind, randomized, placebo-controlled trial in which trauma victims receive a single oral dose of HCORT or placebo within the first 6 hours following trauma. The intervention will occur in the ED and participants will be subsequently assessed at 2, 6, 12, and 42 weeks. Two hundred twenty recently traumatized patients presenting to the ED in two large hospitals serving a diverse population of civilians (Mount Sinai Hospital in New York City) and civilians and military personnel (Chaim Sheba Medical Center Tel Hashomer, Israel) will be recruited to yield 130 study completers. The collection of biological measures at each time point will allow verification of mechanism of action of the HCORT intervention. Patients will be approached while awaiting treatment in the ED. After obtaining written, informed consent, research staff will conduct a brief evaluation to assess eligibility and obtain a pre-treatment baseline. Participants will be randomized to HCORT or placebo within an hour of the evaluation. After ingestion of HCORT or placebo, blood will be drawn for the baseline biological assessment. Symptoms will be assessed and blood and salivarycortisol samples will be obtained at each subsequent visit. Biological assessments include: plasma cortisol and adrenocorticotrophin hormone, whole blood NR3C1 and FKBP5 gene methylation and expression, salivary circadian rhythm of cortisol, plasma neuropeptide Y, cytokines and immune markers, and sympathetic nervous system activity. The low dose dexamethasone suppression test will be performed at the end of the study period (42 weeks). Samples will be collected for DNA and RNA analyses of molecular pathways associated with recovery, to support a separate proposal, submitted by Dr. Hammamieh at USACEHR.Relevance: The proposed approach, if successful, would lead to an easily administered, highly inexpensive, and portable intervention that does not require evaluation or identification of “risk” or “vulnerability” prior to or after trauma exposure. This resilience-enhancing intervention would be safe for both men and women and could also be administered to people who would not otherwise develop PTSD without harm or consequence.Clinical Impact: This intervention will represent the first evidence-based treatment for the prevention of PTSD in trauma-exposed individuals. If successful, the intervention could dramatically improve patient care by mitigating the impact of trauma and promoting resilience, reducing patient and social burdens in terms of individual suffering, functional impairment, military readiness, unemployment, and healthcare utilization. Findings will also benefit PTSD research through the elaboration of relevant biological mechanisms of action, contributing to knowledge about biomarkers and networks of PTSD risk and resilience and the potential development of new treatments.
|Effective start/end date||1/05/19 → 30/04/23|
- Congressionally Directed Medical Research Programs: $5,999,739.00