RE: “A DECADE OF WAR: PROSPECTIVE TRAJECTORIES OF POSTTRAUMATIC STRESS DISORDER SYMPTOMS AMONG DEPLOYED US MILITARY PERSONNEL AND THE INFLUENCE OF COMBAT EXPOSURE”

RE: “A DECADE OF WAR: PROSPECTIVE TRAJECTORIES OF POSTTRAUMATIC STRESS DISORDER SYMPTOMS AMONG... In their recent work, Donoho et al. (1) used latent growth mixture modeling to examine trajectories of posttraumatic stress disorder (PTSD) symptoms in relation to combat exposures among deployed US military personnel who participated in the Millennium Cohort Study (MCS) from 2001 to 2011. I am concerned that these authors have failed to measure and control for an important confounder in their analysis. Participants in the MCS who deployed to Iraq and Afghanistan and comprised the authors’ study population were at risk of exposure to mefloquine, a drug widely used during the period by the US military for malaria prophylaxis. Exposure to mefloquine may cause adverse neuropsychiatric effects that can mimic certain symptoms of PTSD (2). A recent meta-analysis found that among those exposed to mefloquine prophylaxis, symptoms of anxiety were reported in 6%, insomnia in 13%, and abnormal dreams in 14% (3)—the latter described in one military study as “often terrifying nightmares with technicolor clarity...vividly remembered days later” (4, p. 260). Although these symptoms were previously thought to resolve with discontinuation of the drug, international drug regulators now warn that adverse neuropsychiatric effects from mefloquine can be persistent (5). In one study, 21% of those reporting nightmares with use of mefloquine reported this symptom persisting for 3 years or longer (6). Military authors writing for the US Centers for Disease Control and Prevention have noted that mefloquine use may “confound the diagnosis and management” of PTSD (7, p. 563). Researchers at Donoho’s institution, the Walter Reed Army Institute of Research, where mefloquine was developed, have warned that “the significant overlap in symptoms associated with mefloquine toxicity and PTSD obscures the distinction between these diagnoses” (8, p. 4). Because many clinicians do not screen for prior symptomatic mefloquine exposure when conducting psychiatric evaluations (9), there is a risk that chronic adverse effects from the drug could be misattributed to PTSD in research studies. Symptomatic exposure to mefloquine among MCS participants may be correlated with combat exposure. A recent study found that mefloquine exposure among US military personnel, as determined by electronic prescription records, varies directly with combat exposure and with several covariates, including military service and pay grade, that predict combat exposure among MCS participants (10). Symptomatic exposure to mefloquine also creates a separate causal pathway that could predict the PTSD symptoms assessed by the PTSD Checklist–Civilian Version (PCL-C). Unmeasured symptomatic mefloquine exposure may therefore serve as a potentially critical confounder between combat exposure status and the PTSD symptom trajectories subject to mixture modeling in the authors’ analysis. This potential confounding may consequently limit the validity of inference on the authors’ results. In their discussion, the authors note that “a crucial question for future research is...what factors may have increased PTSD symptoms among the relatively small proportion of soldiers who deployed but did not experience combat exposure” (1, pp. 1316–1317). Interestingly, Eick-Cost et al. (10) found that non–combat-deployed personnel with mefloquine exposure had a significant and nearly doubled (183%) risk of subsequent PTSD diagnosis, as compared with those who lacked such exposure (10). Confounding by symptomatic mefloquine exposure has been previously identified as a significant concern in the interpretation of recent military PTSD literature (11, 12). As a result of the significant and potentially fatal threats to validity that may result from such confounding, researchers conducting studies of PTSD among military personnel deployed to combat areas must attempt to measure symptomatic mefloquine exposure among their study participants and to control for its effects in future analyses. Acknowledgments R.L.N. serves as consultant and expert witness in legal cases involving claims of adverse effects from antimalarial drugs, including mefloquine, and also serves as executive director of the Quinism Foundation. 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 RL . Mefloquine and posttraumatic stress disorder. In: Ritchie EC , ed. Textbook of Military Medicine. Forensic and Ethical Issues in Military Behavioral Health . Washington, DC : Borden Institute ; 2015 : 277 – 296 . 3 Tickell-Painter M , Maayan N , Saunders R , et al. . Mefloquine for preventing malaria during travel to endemic areas . Cochrane Database Syst Rev . 2017 ; 10 : CD006491 . Google Scholar PubMed 4 Boudreau E , Schuster B , Sanchez J , et al. . Tolerability of prophylactic Lariam regimens . Trop Med Parasitol . 1993 ; 44 ( 3 ): 257 – 265 . Google Scholar PubMed 5 Nevin RL , Byrd AM . Neuropsychiatric adverse reactions to mefloquine: a systematic comparison of prescribing and patient safety guidance in the US, UK, Ireland, Australia, New Zealand, and Canada . Neurol Ther . 2016 ; 5 ( 1 ): 69 – 83 . Google Scholar CrossRef Search ADS PubMed 6 Ringqvist Å , Bech P , Glenthøj B , et al. . Acute and long-term psychiatric side effects of mefloquine: a follow-up on Danish adverse event reports . Travel Med Infect Dis . 2015 ; 13 ( 1 ): 80 – 88 . Google Scholar CrossRef Search ADS PubMed 7 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 . 8 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 9 Nevin RL . Screening for symptomatic mefloquine exposure among veterans with chronic psychiatric symptoms . Fed Pract . 2017 ; 34 ( 3 ): 12 – 14 . 10 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 11 Nevin RL . Mefloquine exposure may confound associations and limit inference in military studies of posttraumatic stress disorder . Mil Med . 2017 ; 182 ( 11 ): 1757 . Google Scholar CrossRef Search ADS PubMed 12 Nevin RL . Confounding by symptomatic mefloquine exposure in military studies of post-traumatic stress disorder . [published online ahead of print May 16, 2017] Behav Med . (doi: 10.1080/08964289.2017.1330248 ). © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Epidemiology Oxford University Press

RE: “A DECADE OF WAR: PROSPECTIVE TRAJECTORIES OF POSTTRAUMATIC STRESS DISORDER SYMPTOMS AMONG DEPLOYED US MILITARY PERSONNEL AND THE INFLUENCE OF COMBAT EXPOSURE”

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

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Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
ISSN
0002-9262
eISSN
1476-6256
D.O.I.
10.1093/aje/kwy072
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Abstract

In their recent work, Donoho et al. (1) used latent growth mixture modeling to examine trajectories of posttraumatic stress disorder (PTSD) symptoms in relation to combat exposures among deployed US military personnel who participated in the Millennium Cohort Study (MCS) from 2001 to 2011. I am concerned that these authors have failed to measure and control for an important confounder in their analysis. Participants in the MCS who deployed to Iraq and Afghanistan and comprised the authors’ study population were at risk of exposure to mefloquine, a drug widely used during the period by the US military for malaria prophylaxis. Exposure to mefloquine may cause adverse neuropsychiatric effects that can mimic certain symptoms of PTSD (2). A recent meta-analysis found that among those exposed to mefloquine prophylaxis, symptoms of anxiety were reported in 6%, insomnia in 13%, and abnormal dreams in 14% (3)—the latter described in one military study as “often terrifying nightmares with technicolor clarity...vividly remembered days later” (4, p. 260). Although these symptoms were previously thought to resolve with discontinuation of the drug, international drug regulators now warn that adverse neuropsychiatric effects from mefloquine can be persistent (5). In one study, 21% of those reporting nightmares with use of mefloquine reported this symptom persisting for 3 years or longer (6). Military authors writing for the US Centers for Disease Control and Prevention have noted that mefloquine use may “confound the diagnosis and management” of PTSD (7, p. 563). Researchers at Donoho’s institution, the Walter Reed Army Institute of Research, where mefloquine was developed, have warned that “the significant overlap in symptoms associated with mefloquine toxicity and PTSD obscures the distinction between these diagnoses” (8, p. 4). Because many clinicians do not screen for prior symptomatic mefloquine exposure when conducting psychiatric evaluations (9), there is a risk that chronic adverse effects from the drug could be misattributed to PTSD in research studies. Symptomatic exposure to mefloquine among MCS participants may be correlated with combat exposure. A recent study found that mefloquine exposure among US military personnel, as determined by electronic prescription records, varies directly with combat exposure and with several covariates, including military service and pay grade, that predict combat exposure among MCS participants (10). Symptomatic exposure to mefloquine also creates a separate causal pathway that could predict the PTSD symptoms assessed by the PTSD Checklist–Civilian Version (PCL-C). Unmeasured symptomatic mefloquine exposure may therefore serve as a potentially critical confounder between combat exposure status and the PTSD symptom trajectories subject to mixture modeling in the authors’ analysis. This potential confounding may consequently limit the validity of inference on the authors’ results. In their discussion, the authors note that “a crucial question for future research is...what factors may have increased PTSD symptoms among the relatively small proportion of soldiers who deployed but did not experience combat exposure” (1, pp. 1316–1317). Interestingly, Eick-Cost et al. (10) found that non–combat-deployed personnel with mefloquine exposure had a significant and nearly doubled (183%) risk of subsequent PTSD diagnosis, as compared with those who lacked such exposure (10). Confounding by symptomatic mefloquine exposure has been previously identified as a significant concern in the interpretation of recent military PTSD literature (11, 12). As a result of the significant and potentially fatal threats to validity that may result from such confounding, researchers conducting studies of PTSD among military personnel deployed to combat areas must attempt to measure symptomatic mefloquine exposure among their study participants and to control for its effects in future analyses. Acknowledgments R.L.N. serves as consultant and expert witness in legal cases involving claims of adverse effects from antimalarial drugs, including mefloquine, and also serves as executive director of the Quinism Foundation. 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 RL . Mefloquine and posttraumatic stress disorder. In: Ritchie EC , ed. Textbook of Military Medicine. Forensic and Ethical Issues in Military Behavioral Health . Washington, DC : Borden Institute ; 2015 : 277 – 296 . 3 Tickell-Painter M , Maayan N , Saunders R , et al. . Mefloquine for preventing malaria during travel to endemic areas . Cochrane Database Syst Rev . 2017 ; 10 : CD006491 . Google Scholar PubMed 4 Boudreau E , Schuster B , Sanchez J , et al. . Tolerability of prophylactic Lariam regimens . Trop Med Parasitol . 1993 ; 44 ( 3 ): 257 – 265 . Google Scholar PubMed 5 Nevin RL , Byrd AM . Neuropsychiatric adverse reactions to mefloquine: a systematic comparison of prescribing and patient safety guidance in the US, UK, Ireland, Australia, New Zealand, and Canada . Neurol Ther . 2016 ; 5 ( 1 ): 69 – 83 . Google Scholar CrossRef Search ADS PubMed 6 Ringqvist Å , Bech P , Glenthøj B , et al. . Acute and long-term psychiatric side effects of mefloquine: a follow-up on Danish adverse event reports . Travel Med Infect Dis . 2015 ; 13 ( 1 ): 80 – 88 . Google Scholar CrossRef Search ADS PubMed 7 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 . 8 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 9 Nevin RL . Screening for symptomatic mefloquine exposure among veterans with chronic psychiatric symptoms . Fed Pract . 2017 ; 34 ( 3 ): 12 – 14 . 10 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 11 Nevin RL . Mefloquine exposure may confound associations and limit inference in military studies of posttraumatic stress disorder . Mil Med . 2017 ; 182 ( 11 ): 1757 . Google Scholar CrossRef Search ADS PubMed 12 Nevin RL . Confounding by symptomatic mefloquine exposure in military studies of post-traumatic stress disorder . [published online ahead of print May 16, 2017] Behav Med . (doi: 10.1080/08964289.2017.1330248 ). © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

American Journal of EpidemiologyOxford University Press

Published: May 4, 2018

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