Creamer and colleagues recently investigated the prevalence of nightmares in United States military personnel seen at their center for sleep medicine evaluation and described associations of this and related outcomes with deployment history and with various comorbid psychiatric disorders.1 I am concerned that the authors have failed to measure and control for an important covariate in their analysis, which may have served to confound associations observed in their study.
Mefloquine is a neurotoxic quinoline antimalarial drug that has been widely used for the prevention of malaria during United States military deployments over the past quarter-century.2 Prior exposure to mefloquine may be a cause of several of the outcome variables observed in their analysis, including nightmares and insomnia. A recent meta-analysis finds that when mefloquine is used for malaria prevention, symptoms of anxiety and depression are each reported by 6%, insomnia is reported by 13%, and symptoms of abnormal dreams and nightmares, described in one study as “often terrifying… with technicolor clarity… vividly remembered days later,”3 are reported by 14%.4
Although previously thought to resolve following discontinuation of the drug, international drug regulators now warn that such symptoms may last years after use.5 In a recent study, 21% of those reporting nightmares with use of mefloquine reported these continuing for 3 years or longer.6
Military authors have noted that that “the significant overlap in symptoms associated with mefloquine toxicity and posttraumatic stress disorder (PTSD) obscures the distinction between these diagnoses,”7 and that mefloquine use may “confound the diagnosis and management” of PTSD.8 Consistent with such confounding, a recent study finds that non-combat-deployed personnel with mefloquine exposure had a significant and nearly doubled risk of subsequent PTSD diagnosis, as compared to those who lacked such exposure.9
As mefloquine exposure is correlated with deployment, and as mefloquine exposure provides a separate causal pathway for many outcome variables associated with sleep disorders, unmeasured mefloquine exposure may serve as a potentially critical confounder in studies of sleep disorders among deployed military personnel and veterans. Unmeasured mefloquine exposure has been previously identified as a significant concern in the interpretation of recent military studies of PTSD and emergence delirium.10–12 Owing to the potential for confounding, researchers conducting studies of sleep disorders among veterans should measure prior symptomatic exposure13 and control for its effects in future analysis.
The author has seen and has approved this manuscript. The author has served as consultant and expert witness in legal cases involving claims of adverse effects from antimalarial drugs.
Nevin RL. Measurement of mefloquine exposure in studies of veterans' sleep disorders. J Clin Sleep Med. 2018;14(7):1273–1274.
Creamer JL, Brock MS, Matsangas P, Motamedi V, Mysliwiec V. Nightmares in United States Military personnel with sleep disturbances. J Clin Sleep Med. 2018;14(3):419–426. [PubMed Central][PubMed]
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.
Boudreau E, Schuster B, Sanchez J, et al. Tolerability of prophylactic Lariam regimens. Trop Med Parasitol. 1993;44:257–65. [PubMed]
Tickell-Painter M, Maayan N, Saunders R, Pace C, Sinclair D. Mefloquine for preventing malaria during travel to endemic areas. Cochrane Database Syst Rev. 2017;10:CD006491[PubMed]
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;5:69–83. [PubMed Central][PubMed]
Ringqvist Å, Bech P, Glenthøj B, Petersen E. Acute and long-term psychiatric side effects of mefloquine: a follow-up on Danish adverse event reports. Travel Med Infect Dis. 2015;13:80–88. [PubMed]
Livezey J, Oliver T, Cantilena L. Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine. Drug Saf - Case Reports. 2016;3:7
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.
Eick-Cost AA, Hu Z, Rohrbeck P, Clark LL. Neuropsychiatric outcomes after mefloquine exposure among U.S. military service members. Am J Trop Med Hyg. 2017;96:159–166. [PubMed Central][PubMed]
Nevin RL. Re: McGuire JM. The Incidence of and Risk Factors for Emergence Delirium in U.S. Military Combat Veterans. J PeriAnesthesia Nurs. 2013;28(6):334–335
Nevin RL. Confounding by symptomatic mefloquine exposure in military studies of post-traumatic stress disorder. Behav Med. 2018;44(2):171–172. [PubMed]
Nevin RL. Mefloquine exposure may confound associations and limit inference in military studies of posttraumatic stress disorder. Mil Med. 2017;182:1757[PubMed]
Nevin RL. Screening for symptomatic mefloquine exposure among veterans with chronic psychiatric symptoms. Fed Pract. 2017;34:12–14