FOUR AUTHORS REPLY

FOUR AUTHORS REPLY In response to our article (1), Nevin asserts that mefloquine exposure is an important confounder in the association between combat-related traumatic events and trajectories of posttraumatic stress disorder (PTSD) and that our lack of control for this potential exposure invalidates our findings (2). We respectfully disagree with both assertions. Nevin’s arguments for the invalidity of our study are misleading for several reasons: 1) to our knowledge, there is no empirical evidence that mefloquine confounds the association between combat-related traumatic events and PTSD; 2) both combat-exposed cases and controls were deployed in support of Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF), and recommendation for antimalarials are not expected to substantially differ by subsequent combat exposure; 3) compliance with antimalarial chemoprophylaxis is low, further weakening any plausible connection between combat exposure and antimalarial medication; and 4) our study used a data-driven approach to describe trajectories of PTSD among service members deployed with and without combat exposure, and these trajectories have proved robust even when covariates have been considered in the model. A previous study used the same approach and also saw no difference in trajectories of PTSD with and without covariates in the models (3). We consider these points in further detail below. To date, there is no empirical evidence indicating that mefloquine confounds the association between combat-related traumatic events and PTSD. Nevin’s response to our article discussed reports with no empirical evidence and only suggestions of possible confounding (4, 5) and also incorrectly reported that a previous study found a 183% increased risk of subsequent PTSD in non–combat-deployed personnel (6). This was not the finding of the study; rather, the study found an increased risk of PTSD in nondeployed service members and found no effect among deployed service members, where drug exposure should not vary with subsequent combat exposure. Nevin further neglects to mention that these findings applied only when comparing mefloquine to atovaquone/proguanil, which is infrequently prescribed. Last, Nevin neglects to mention that the same study found that mefloquine reduced the risk of PTSD compared with doxycycline (odds ratio = 0.69, 95% confidence interval: 0.52, 0.91) among nondeployed service members. Although we disagree with the assertion that higher PTSD symptoms are due to mefloquine exposure rather than combat-related trauma, it is difficult to assess mefloquine exposure because of the low adherence to antimalarial chemoprophylaxis. Previous studies of service members deployed to Afghanistan found that compliance with antimalarial chemoprophylaxis was very low, ranging from 38% to 61% (7). Although the Millennium Cohort Study can assess whether a service member was prescribed a medication, it is implausible to ascertain whether the service member was compliant with the treatment. Thus even with prescription information, it would be difficult to ascertain the impact that mefloquine might have on psychological health in deployed environments. In addition, our study used an unsupervised, latent modeling approach to describe trajectories of PTSD that emerged in our data. These models described the trajectories of PTSD symptoms that occurred over the course of a decade among service members with a single deployment and further stratified by combat-related trauma. Our study, and several previous studies that identified trajectories in the same cohort population (3), did examine covariates that may have influenced trajectory membership. Invariably, one of the strongest effects is combat exposure, and its effects persist regardless of which or how many covariates are included. Thus, it is highly unlikely that mefloquine—even if its use could have been accurately assessed—would have significantly altered our results. Acknowledgments I am a military service member (or employee of the US Government). This work was prepared as part of my official duties. Title 17, USC, §105 provides the “Copyright protection under this title is not available for any work of the United States Government.” Title 17, USC, §101 defines a US Government work as work prepared by a military service member or employee of the US Government as part of that person’s official duties. The views expressed in this response are those of the authors and do not necessarily reflect the official policy or position of the Department of the Army, Department of the Navy, Department of the Air Force, Department of Veterans Affairs, Department of Defense, or the US Government. Approved for public release; distribution unlimited. Conflict of interest: none declared. References 1 Donoho CJ , Bonanno GA , Porter B , et al. . A decade of war: prospective trajectories of posttraumatic stress disorder symptoms among deployed US military personnel and the influence of combat exposure . Am J Epidemiol . 2017 ; 186 ( 12 ): 1310 – 1318 . Google Scholar CrossRef Search ADS PubMed 2 Nevin R . Re: “A decade of war: prospective trajectories of posttraumatic stress disorder symptoms among deployed US military personnel and the influence of combat exposure” . Am J Epidemiol . 2018 ; 187 ( 7 ): 1573 – 1574 . 3 Bonanno GA , Mancini AD , Horton JL , et al. . Trajectories of trauma symptoms and resilience in deployed US military service members: prospective cohort study . Br J Psychiatry . 2012 ; 200 ( 4 ): 317 – 323 . Google Scholar CrossRef Search ADS PubMed 4 Magill A , Cersovsky S , DeFraites R . Special considerations for US military deployments. In: Brunette GW , ed. CDC Health Information for International Travel: The Yellow Book 2012 . New York, NY : Oxford University Press ; 2012 : 561 – 565 . 5 Livezey J , Oliver T , Cantilena L . Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine . Drug Saf Case Rep . 2016 ; 3 : 7 . Google Scholar CrossRef Search ADS PubMed 6 Eick-Cost AA , Hu Z , Rohrbeck P , et al. . Neuropsychiatric outcomes after mefloquine exposure among US military service members . Am J Trop Med Hyg . 2017 ; 96 ( 1 ): 159 – 166 . Google Scholar CrossRef Search ADS PubMed 7 Brisson M , Brisson P . Compliance with antimalaria chemoprophylaxis in a combat zone . Am J Trop Med Hyg . 2012 ; 86 ( 4 ): 587 – 590 . Google Scholar CrossRef Search ADS PubMed Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Epidemiology Oxford University Press

FOUR AUTHORS REPLY

American Journal of Epidemiology , Volume Advance Article (7) – May 4, 2018

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Publisher
Oxford University Press
Copyright
Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2018.
ISSN
0002-9262
eISSN
1476-6256
D.O.I.
10.1093/aje/kwy074
Publisher site
See Article on Publisher Site

Abstract

In response to our article (1), Nevin asserts that mefloquine exposure is an important confounder in the association between combat-related traumatic events and trajectories of posttraumatic stress disorder (PTSD) and that our lack of control for this potential exposure invalidates our findings (2). We respectfully disagree with both assertions. Nevin’s arguments for the invalidity of our study are misleading for several reasons: 1) to our knowledge, there is no empirical evidence that mefloquine confounds the association between combat-related traumatic events and PTSD; 2) both combat-exposed cases and controls were deployed in support of Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF), and recommendation for antimalarials are not expected to substantially differ by subsequent combat exposure; 3) compliance with antimalarial chemoprophylaxis is low, further weakening any plausible connection between combat exposure and antimalarial medication; and 4) our study used a data-driven approach to describe trajectories of PTSD among service members deployed with and without combat exposure, and these trajectories have proved robust even when covariates have been considered in the model. A previous study used the same approach and also saw no difference in trajectories of PTSD with and without covariates in the models (3). We consider these points in further detail below. To date, there is no empirical evidence indicating that mefloquine confounds the association between combat-related traumatic events and PTSD. Nevin’s response to our article discussed reports with no empirical evidence and only suggestions of possible confounding (4, 5) and also incorrectly reported that a previous study found a 183% increased risk of subsequent PTSD in non–combat-deployed personnel (6). This was not the finding of the study; rather, the study found an increased risk of PTSD in nondeployed service members and found no effect among deployed service members, where drug exposure should not vary with subsequent combat exposure. Nevin further neglects to mention that these findings applied only when comparing mefloquine to atovaquone/proguanil, which is infrequently prescribed. Last, Nevin neglects to mention that the same study found that mefloquine reduced the risk of PTSD compared with doxycycline (odds ratio = 0.69, 95% confidence interval: 0.52, 0.91) among nondeployed service members. Although we disagree with the assertion that higher PTSD symptoms are due to mefloquine exposure rather than combat-related trauma, it is difficult to assess mefloquine exposure because of the low adherence to antimalarial chemoprophylaxis. Previous studies of service members deployed to Afghanistan found that compliance with antimalarial chemoprophylaxis was very low, ranging from 38% to 61% (7). Although the Millennium Cohort Study can assess whether a service member was prescribed a medication, it is implausible to ascertain whether the service member was compliant with the treatment. Thus even with prescription information, it would be difficult to ascertain the impact that mefloquine might have on psychological health in deployed environments. In addition, our study used an unsupervised, latent modeling approach to describe trajectories of PTSD that emerged in our data. These models described the trajectories of PTSD symptoms that occurred over the course of a decade among service members with a single deployment and further stratified by combat-related trauma. Our study, and several previous studies that identified trajectories in the same cohort population (3), did examine covariates that may have influenced trajectory membership. Invariably, one of the strongest effects is combat exposure, and its effects persist regardless of which or how many covariates are included. Thus, it is highly unlikely that mefloquine—even if its use could have been accurately assessed—would have significantly altered our results. Acknowledgments I am a military service member (or employee of the US Government). This work was prepared as part of my official duties. Title 17, USC, §105 provides the “Copyright protection under this title is not available for any work of the United States Government.” Title 17, USC, §101 defines a US Government work as work prepared by a military service member or employee of the US Government as part of that person’s official duties. The views expressed in this response are those of the authors and do not necessarily reflect the official policy or position of the Department of the Army, Department of the Navy, Department of the Air Force, Department of Veterans Affairs, Department of Defense, or the US Government. Approved for public release; distribution unlimited. Conflict of interest: none declared. References 1 Donoho CJ , Bonanno GA , Porter B , et al. . A decade of war: prospective trajectories of posttraumatic stress disorder symptoms among deployed US military personnel and the influence of combat exposure . Am J Epidemiol . 2017 ; 186 ( 12 ): 1310 – 1318 . Google Scholar CrossRef Search ADS PubMed 2 Nevin R . Re: “A decade of war: prospective trajectories of posttraumatic stress disorder symptoms among deployed US military personnel and the influence of combat exposure” . Am J Epidemiol . 2018 ; 187 ( 7 ): 1573 – 1574 . 3 Bonanno GA , Mancini AD , Horton JL , et al. . Trajectories of trauma symptoms and resilience in deployed US military service members: prospective cohort study . Br J Psychiatry . 2012 ; 200 ( 4 ): 317 – 323 . Google Scholar CrossRef Search ADS PubMed 4 Magill A , Cersovsky S , DeFraites R . Special considerations for US military deployments. In: Brunette GW , ed. CDC Health Information for International Travel: The Yellow Book 2012 . New York, NY : Oxford University Press ; 2012 : 561 – 565 . 5 Livezey J , Oliver T , Cantilena L . Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine . Drug Saf Case Rep . 2016 ; 3 : 7 . Google Scholar CrossRef Search ADS PubMed 6 Eick-Cost AA , Hu Z , Rohrbeck P , et al. . Neuropsychiatric outcomes after mefloquine exposure among US military service members . Am J Trop Med Hyg . 2017 ; 96 ( 1 ): 159 – 166 . Google Scholar CrossRef Search ADS PubMed 7 Brisson M , Brisson P . Compliance with antimalaria chemoprophylaxis in a combat zone . Am J Trop Med Hyg . 2012 ; 86 ( 4 ): 587 – 590 . Google Scholar CrossRef Search ADS PubMed Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Journal

American Journal of EpidemiologyOxford University Press

Published: May 4, 2018

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