Clinical Trial Compared Different Forms of Exposure and Drug Therapy in Combat Veterans with PTSD

Clinical Trial Compared Different Forms of Exposure and Drug Therapy in Combat Veterans with PTSD

Posted: December 15, 2022
Clinical Trial Compared Different Forms of Exposure and Drug Therapy in Combat Veterans with PTSD

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In a step toward precision medicine, a clinical trial found two forms of exposure therapy enabled combat veterans to significantly reduce PTSD symptoms. Whether or not a subject also experienced depression affected which form of treatment was more effective. Those carrying either of 2 common genetic variations affecting processes that may impact fear extinction also showed evidence of having distinct therapy responses.


After analyzing data compiled in a clinical trial conducted over 7 years with Iraq and Afghanistan combat veterans diagnosed with PTSD, a research team reports progress in efforts to match specific patients with specific forms of therapy.

Efforts like this one to realize the promise of “precision medicine” are fueled by steadily accumulating evidence from research indicating that across psychiatric illnesses, individuals receiving the same diagnosis not only report a variety of symptoms but that these symptoms are likely caused by varying combinations of psycho-biological factors. One urgent question is whether, and if so, how, these factors affect treatment results.

JoAnn Difede, Ph.D., a Professor of Psychology in Psychiatry at Weill Cornell Medicine, led a team that set out to conduct a randomized, placebo-controlled trial testing two forms of exposure therapy in combat vets with PTSD, and to further determine the impact, if any, of adding a drug known to enhance aspects of cognition. Francis S. Lee, M.D., Ph.D., Chair of Psychiatry at Weill Cornell Medicine, was a co-author on the paper. He is a member of BBRF’s Scientific Council, the recipient of a BBRF Independent Investigator grant in 2010, and Young Investigator grants in 2005 and 2002. Five other BBRF grantees were members of the research team.

The team studied military personnel treated between 2011 and 2018 at three sites: Weill Cornell Medical College in New York; a VA Hospital in Long Beach, CA; and Walter Reed Bethesda Naval Medical Center in Maryland. A cohort of 192 patients made up the group that was ultimately analyzed.

The subjects were randomized into groups that received different forms of treatment. Half were assigned to receive a virtual reality exposure therapy (VRE); the other half received prolonged imaginal exposure (PE), another kind of exposure therapy

VRE and PE call for patients to systematically confront their fears in a safe environment, the aim being to habituate to feared stimuli, thus retraining the brain to learn that the multi-sensory cues to fear that were learned during the trauma are now safe, and not signals that the feared event is happening again. In PTSD, people are sometimes triggered by stimuli in their everyday environment that may remind them of their trauma or by reexperiencing their traumatic event in unbidden, often vivid sensory images, dreams and flashbacks; they are unable to extinguish the fears that these stimuli or memories trigger.

The study subjects were further randomized: groups receiving VRE and PE were divided into those who would take a drug, D-cycloserine (DCS), an antibiotic repurposed as a cognitive enhancer, 30 minutes before receiving exposure therapy, and those who would receive a placebo pill instead of active DCS.

DCS is a cognitive-enhancing drug that prior research shows to moderately stimulate NMDA receptors found in abundance in excitatory neurons. This is potentially useful in treating PTSD since fear extinction has been shown in animal studies to be inhibited by drugs that block the NMDA receptor. The hope is that DCS might overcome this blockage and thus enhance patients’ ability to extinguish traumatic fears.

Two types of criteria were at the focus of an effort to analyze subsets of study participants. One was whether or not a subject was also diagnosed with major depressive disorder. The other was whether a subject was a carrier of either of two common genetic variants linked in past research with fear extinction. One of these variants, called BDNF Val66Met, impacts the plasticity of brain cells and circuits and its presence in an individual may impair fear extinction. The other variant, called FAAH C385A, affects production of an enzyme whose activity may enhance fear-extinction learning.

The study’s results were reported in the journal Translational Psychiatry. Perhaps the most important conclusion was that both VRE and PE enabled combat veterans to reduce their PTSD symptom scores, and by almost exactly the same amount (on average, about 20 points on a 136-point symptom severity scale). Both were administered a total of nine times over an average of 16 weeks, in 90-minute sessions. In PE, patients are instructed to close their eyes, imagine the scene of their trauma, and repeatedly recount it—“vividly, aloud, and in the present tense.” In VRE, patients wear virtual reality headgear which exposes them to simulations of common combat scenarios while they recount their own trauma. The simulations are controlled by a therapist via a computer console.

While overall there was no significant statistical difference in therapeutic benefit in the two groups, there was one important exception: participants who also suffered from major depression were helped more by VRE. The reasons are not known, but the team speculates the “immersion” effect of virtual reality might help overcome alterations in reward processing experienced by depressed individuals. The analysis also showed that participants who were not depressed did better, on average, with PE.

Another result of the study was that adding DCS to exposure therapy of either type provided no significant advantage vs. placebo.

A final set of results concerns the question of whether study participants bearing either of the two genetic variants potentially affecting fear memory processing may have shown distinct responses to the various forms of therapy given in the trial. The answer was yes, although with important qualifications. Generally, the number of individuals in the trial who carried either of the mutations was not large enough to support firm conclusions. But provisionally, the team found that those who carried the FAAH genetic variant improved more than non-carriers. As for participants carrying the BDNF variant, their PTSD symptoms seemed to improve more if they were in the subgroup taking DCS prior to exposure therapy.

All of these findings bear further study, the team suggested. They concluded, overall, that their results showed that such factors as comorbid major depression or the presence of certain genetic markers may indeed help guide selection of treatments to optimally help patients with combat-related PTSD. Broader application of this principle is also possible but must be demonstrated in future clinical research.

The research team included: Barbara O. Rothbaum, Ph.D., a 2012 BBRF Distinguished Investigator; Christopher Reist, M.D., a 1996 and 1993 BBRF Young Investigator; Tanja Jovanovic, Ph.D., a 2015 BBRF Independent Investigator and 2010 Young Investigator; Seth D. Norholm, Ph.D., a 2002 BBRF Young Investigator; and Charles E. Glatt, M.D., Ph.D., a 2003 and 2001 BBRF Young Investigator.