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Threats to the validity of studies of post-traumatic stress disorder from unmeasured symptomatic exposure to mefloquine

Published online by Cambridge University Press:  21 March 2019

Remington Nevin
Affiliation:
Executive Director, The Quinism Foundation, USA. Email: rnevin@quinism.org
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Abstract

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Correspondence
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Copyright © The Royal College of Psychiatrists 2019 

I read with interest the recent study by Stevelink and colleaguesReference Stevelink, Jones, Hull, Pernet, MacCrimmon and Goodwin1 that studied the prevalence of various mental health outcomes, including post-traumatic stress disorder (PTSD), among UK military personnel following the conflicts in Iraq and Afghanistan. I am concerned that several of the authors' conclusions may be invalid, owing to a failure to measure and control for an important confounder in their study.

Participants in the authors’ study were at risk of exposure to mefloquine, an antimalarial drug widely used by the UK military during the period, particularly during training missions in Africa and during deployments to Afghanistan. Mefloquine is known to cause psychiatric adverse effects, including nightmares, insomnia, depression and anxiety, which can last years after use. Individuals who experience psychiatric adverse effects during continued use of the drug, a condition known as symptomatic exposure, are at risk of these adverse effects becoming chronic. For example, based on a synthesis of recent data, abnormal dreams and nightmares lasting over 3 years after use of mefloquine may affect over 2% of those exposed to the drug.Reference Nevin2

Various US military authors have cautioned that mefloquine use can ‘confound the diagnosis and management of PTSD’,Reference Magill, Cersovsky, DeFraites and Brunette3 and that given ‘the overlapping symptoms of post-traumatic stress disorder and mefloquine toxicity, it can be challenging to distinguish between the two diagnoses’.Reference Livezey, Oliver and Cantilena4 The importance of identifying past mefloquine exposure is further unscored by the addition of criterion H to the PTSD diagnostic criteria in DSM-5, which requires that the disturbance not be the result of the effects of a medication.Reference Nevin and Ritchie5 As the chronic adverse effects of mefloquine may mimic several symptoms of PTSD, including several symptoms assessed using the 17-item National Centre for PTSD Checklist (PCL-C), the authors use of this instrument without distinguishing which symptoms may have been the result of mefloquine risks the adverse effects of the drug having been misattributed to PTSD.

As mefloquine exposure is correlated with deployment, and as symptomatic mefloquine exposure creates a separate causal pathway for the development of several symptoms assessed by the PCL-C, symptomatic mefloquine exposure serves as a classic epidemiological confounder in the authors’ study.Reference Nevin2

In order to avoid potentially fatal threats to validity that result from such confounding, the authors are encouraged to measure symptomatic mefloquine exposure in future studies and to control for these effects during analysis. Our group has introduced the two-question White River Mefloquine Instrument (WRMI-2)6 for this purpose and encourages the use of this instrument in research and in the clinical evaluation of recent veterans at risk of mefloquine exposure.

Declaration of interest:

R.N has been retained as consultant and expert witness in legal cases involving claims of adverse effects from antimalarial drugs, including mefloquine.

References

1Stevelink, SAM, Jones, M, Hull, L, Pernet, D, MacCrimmon, S, Goodwin, L, et al. Mental health outcomes at the end of the British involvement in the Iraq and Afghanistan conflicts: a cohort study. Br J Psychiatry 2018; 213: 690–7.CrossRefGoogle ScholarPubMed
2Nevin, RL. 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: 1573–4.CrossRefGoogle Scholar
3Magill, A, Cersovsky, S, DeFraites, R. Special considerations for US military deployments. In CDC Health Information for International Travel: The Yellow Book 2012 (ed Brunette, GW): 561–5. Oxford University Press, 2012.Google Scholar
4Livezey, J, Oliver, T, Cantilena, L. Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine. Drug Saf - Case Rep 2016; 3: 7.CrossRefGoogle Scholar
5Nevin, RL. Mefloquine and posttraumatic stress disorder. In Textbook of Military Medicine. Forensic and Ethical Issues in Military Behavioral Health (ed Ritchie, EC): 277–96. Borden Institute, 2015.Google Scholar
6The Quinism Foundation. The Quinism Foundation Partners with the National Centre for Trauma to Screen U.K. Veterans for Symptomatic Mefloquine Exposure. July 30, 2018. Available at: https://quinism.org/press-releases/the-quinism-foundation-partners-with-the-national-centre-for-trauma-to-screen-u-k-veterans-for-symptomatic-mefloquine-exposure.Google Scholar
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