TY - JOUR
T1 - Enhancing exposure therapy for posttraumatic stress disorder (PTSD)
T2 - a randomized clinical trial of virtual reality and imaginal exposure with a cognitive enhancer
AU - Difede, Jo Ann
AU - Rothbaum, Barbara O.
AU - Rizzo, Albert A.
AU - Wyka, Katarzyna
AU - Spielman, Lisa
AU - Reist, Christopher
AU - Roy, Michael J.
AU - Jovanovic, Tanja
AU - Norrholm, Seth D.
AU - Cukor, Judith
AU - Olden, Megan
AU - Glatt, Charles E.
AU - Lee, Francis S.
N1 - Funding Information:
This manuscript is dedicated to Andrew C. Leon, PhD who served as the study statistician prior to passing away in 2012. The authors would like to acknowledge the following individuals for their help with the study and/or with the preparation of this manuscript: Talia Abraham; Gerald Todd Adamson, PsyD; Stephanie Alley; Margaret Altemus, MD; Kathryn Breazale Black; Mark Burton; Chien-Yen Chang; Veronika Cerar; Stephanie Christian; Denece Clayborne, RN, MSN; Lillian Cohen; Melissa Constantiner, PhD; Michelle Costanzo, PhD; Christopher Courtney, PhD; Paula Domenici, PhD; Rachel Ende; Deirdre Farrell, MA; Kevin Feeley; Lucy Finkelstein-Fox, PhD; John Frazier; Ariella Friedman; Nikki Frousakis, PhD; Rebecca Furth; Qwynn Galloway-Salazar; Maryrose Gerardi, PhD, Sophia Golden; Mario Grimani; PhD; Robin Gross; Michelle Hammond-Susten, LCSW; Arno Hartholt; Lindsay Hauptman; Elizabeth Hembree, PhD; Krista Highland, PhD; Kevin Holloway, PhD; Julianne Imperato-McGinley, MD; Sakineh “Parvin” Khalaghizadeh, MPH; Yehjean Kim; Patricia Koenen-Woods, PhD; Alexandra J. Kreitman; David Kwok; Wendy Law, PhD; Suzanne Leaman, PhD; Ling Lee; Andrew Leeds; Andrew Leon, PhD; Rachel Lerman; Matt Liewer; Karen Livorense, PhD; Andrew McAleavey, PhD; Brittany Mello, MPA; Chriag Merchant; Jack Mondonedo; Tara Monroe; Moeko Nakada; Nancy Needell, MD; Brad Newman; Mahmood Novin, MD; Annell Ovalles, MPH; Jenny Payne; Jessica Palmer; Nicholas Palmer-Kelley; Melissa Peskin, PhD; Emily Ramdhany; Eric Reese; Hal Rives; Kathy Rosenberg, MBA, MA; Liliane Sar-Graycar; Marya Schulte, PhD; Melanie Simonson; Nicolas Sirianni; Julie Slotnick; Richard Sorrentino, PhD; Rebecca Sosman; Rachel Stewart, PhD; Patricia Taylor; Josh Williams; Claire Wu; Joe Yip; and Joshua Yurtsever. The study was funded by the Department of Defense [W81XWH-10–1–1045]. Research reported in this publication was supported by the National Center for Advancing Translational Science of the National Institute of Health under award number UL1TR002384.
Funding Information:
The authors, with the exception of JD, BOR, AAR, JC and TJ, declare no conflicts of interest. JD has funding from Department of Defense Clinical Trial Grants (No. W81XWH-15-1-0645 and No. W81XWH-18-1-0262) and Weill Cornell Medical College. JD serves as a member of the advisory board at Pear Therapeutics, Inc. BOR has funding from Wounded Warrior Project, Department of Defense Clinical Trial Grant No.W81XWH-10-1-1045, National Institute of Mental Health Grant No. 1R01MH094757-01, and McCormick Foundation. BOR receives royalties from Oxford University Press, Guilford, APPI, and Emory University and received advisory board payments from Genentech, Jazz Pharmaceuticals, Nobilis Therapeutics, Neuronetics, and Aptinyx. BOR owns equity in Virtually Better, Inc. that creates virtual reality products. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. However, The Virtual Iraq software used in this study was created by AAR and his team at ICT, not Virtually Better. AAR serves as a member of the advisory board at Pear Therapeutics, Inc. JC serves as a consultant to Virtually Better, Inc. TJ has support from the National Institutes of Health (R01MH111682, R01MH110364). The authors declare no competing interests.
Funding Information:
This manuscript is dedicated to Andrew C. Leon, PhD who served as the study statistician prior to passing away in 2012. The authors would like to acknowledge the following individuals for their help with the study and/or with the preparation of this manuscript: Talia Abraham; Gerald Todd Adamson, PsyD; Stephanie Alley; Margaret Altemus, MD; Kathryn Breazale Black; Mark Burton; Chien-Yen Chang; Veronika Cerar; Stephanie Christian; Denece Clayborne, RN, MSN; Lillian Cohen; Melissa Constantiner, PhD; Michelle Costanzo, PhD; Christopher Courtney, PhD; Paula Domenici, PhD; Rachel Ende; Deirdre Farrell, MA; Kevin Feeley; Lucy Finkelstein-Fox, PhD; John Frazier; Ariella Friedman; Nikki Frousakis, PhD; Rebecca Furth; Qwynn Galloway-Salazar; Maryrose Gerardi, PhD, Sophia Golden; Mario Grimani; PhD; Robin Gross; Michelle Hammond-Susten, LCSW; Arno Hartholt; Lindsay Hauptman; Elizabeth Hembree, PhD; Krista Highland, PhD; Kevin Holloway, PhD; Julianne Imperato-McGinley, MD; Sakineh “Parvin” Khalaghizadeh, MPH; Yehjean Kim; Patricia Koenen-Woods, PhD; Alexandra J. Kreitman; David Kwok; Wendy Law, PhD; Suzanne Leaman, PhD; Ling Lee; Andrew Leeds; Andrew Leon, PhD; Rachel Lerman; Matt Liewer; Karen Livorense, PhD; Andrew McAleavey, PhD; Brittany Mello, MPA; Chriag Merchant; Jack Mondonedo; Tara Monroe; Moeko Nakada; Nancy Needell, MD; Brad Newman; Mahmood Novin, MD; Annell Ovalles, MPH; Jenny Payne; Jessica Palmer; Nicholas Palmer-Kelley; Melissa Peskin, PhD; Emily Ramdhany; Eric Reese; Hal Rives; Kathy Rosenberg, MBA, MA; Liliane Sar-Graycar; Marya Schulte, PhD; Melanie Simonson; Nicolas Sirianni; Julie Slotnick; Richard Sorrentino, PhD; Rebecca Sosman; Rachel Stewart, PhD; Patricia Taylor; Josh Williams; Claire Wu; Joe Yip; and Joshua Yurtsever. The study was funded by the Department of Defense [W81XWH-10–1–1045]. Research reported in this publication was supported by the National Center for Advancing Translational Science of the National Institute of Health under award number UL1TR002384.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Posttraumatic stress disorder (PTSD) is a significant public health issue. Yet, there are limited treatment options and no data to suggest which treatment will work for whom. We tested the efficacy of virtual reality exposure (VRE) or prolonged imaginal exposure (PE), augmented with D-cycloserine (DCS) for combat-related PTSD. As an exploratory aim, we examined whether brain-derived neurotrophic factor (BDNF) and fatty acid amide hydrolase (FAAH) moderated treatment response. Military personnel with PTSD (n = 192) were recruited into a multisite double-blind randomized controlled trial to receive nine weeks of VRE or PE, with DCS or placebo. Primary outcome was the improvement in symptom severity. Randomization was stratified by comorbid depression (MDD) and site. Participants in both VRE and PE showed similar meaningful clinical improvement with no difference between the treatment groups. A significant interaction (p = 0.45) suggested VRE was more effective for depressed participants (CAPS difference M = 3.51 [95% CI 1.17–5.86], p = 0.004, ES = 0.14) while PE was more effective for nondepressed participants (M = −8.87 [95% CI −11.33 to −6.40], p < 0.001, ES = −0.44). The main effect of DCS vs. placebo was not significant. Augmentation by MDD interaction (p = 0.073) suggested that depressed participants improved more on placebo (M = −8.43 [95% CI −10.98 to −5.88], p < 0.001, ES = −0.42); DCS and placebo were equally effective for nondepressed participants. There was an apparent moderating effect of BDNF Val66Met polymorphism on DCS augmentation (ES = 0.67). Met66 allele carriers improved more on DCS (ES = −0.25). FAAH 385 A carriers improved more than non-carriers (ES = 0.33), particularly those with MDD (ES = 0.62). This study provides a step toward precision therapeutics for PTSD by demonstrating that comorbid MDD and genetic markers may help guide treatment selection. ClinicalTrials.gov Identifier: NCT01352637.
AB - Posttraumatic stress disorder (PTSD) is a significant public health issue. Yet, there are limited treatment options and no data to suggest which treatment will work for whom. We tested the efficacy of virtual reality exposure (VRE) or prolonged imaginal exposure (PE), augmented with D-cycloserine (DCS) for combat-related PTSD. As an exploratory aim, we examined whether brain-derived neurotrophic factor (BDNF) and fatty acid amide hydrolase (FAAH) moderated treatment response. Military personnel with PTSD (n = 192) were recruited into a multisite double-blind randomized controlled trial to receive nine weeks of VRE or PE, with DCS or placebo. Primary outcome was the improvement in symptom severity. Randomization was stratified by comorbid depression (MDD) and site. Participants in both VRE and PE showed similar meaningful clinical improvement with no difference between the treatment groups. A significant interaction (p = 0.45) suggested VRE was more effective for depressed participants (CAPS difference M = 3.51 [95% CI 1.17–5.86], p = 0.004, ES = 0.14) while PE was more effective for nondepressed participants (M = −8.87 [95% CI −11.33 to −6.40], p < 0.001, ES = −0.44). The main effect of DCS vs. placebo was not significant. Augmentation by MDD interaction (p = 0.073) suggested that depressed participants improved more on placebo (M = −8.43 [95% CI −10.98 to −5.88], p < 0.001, ES = −0.42); DCS and placebo were equally effective for nondepressed participants. There was an apparent moderating effect of BDNF Val66Met polymorphism on DCS augmentation (ES = 0.67). Met66 allele carriers improved more on DCS (ES = −0.25). FAAH 385 A carriers improved more than non-carriers (ES = 0.33), particularly those with MDD (ES = 0.62). This study provides a step toward precision therapeutics for PTSD by demonstrating that comorbid MDD and genetic markers may help guide treatment selection. ClinicalTrials.gov Identifier: NCT01352637.
UR - http://www.scopus.com/inward/record.url?scp=85134817628&partnerID=8YFLogxK
U2 - 10.1038/s41398-022-02066-x
DO - 10.1038/s41398-022-02066-x
M3 - Article
C2 - 35896533
AN - SCOPUS:85134817628
SN - 2158-3188
VL - 12
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 299
ER -