Neuropsychiatric Outcomes After Mefloquine Exposure Among U.S. Military Service Members

Abstract

Abstract. Mefloquine was widely prescribed to U.S. military service members until 2009 when use was limited to personnel with contraindications to doxycycline and no contraindications to mefloquine. The need to estimate the occurrence of neuropsychiatric outcomes (NPOs) in service members prescribed mefloquine warranted a comprehensive evaluation of this issue. Active component service members filling a prescription for mefloquine, doxycycline, or atovaquone/proguanil (A/P) between January 1, 2008 and June 30, 2013, were included in the analysis. The risk of developing incident NPOs and the risk of subsequent NPOs among subjects with a history of the condition were assessed. A total of 367,840 individuals were evaluated (36,538 received mefloquine, 318,421 received doxycycline, and 12,881 received A/P). Among deployed individuals prescribed mefloquine, an increased risk of incident anxiety was seen when compared with doxycycline recipients (incidence rate ratio [IRR] = 1.12 [1.01-1.24]). Among nondeployed mefloquine recipients, an increased risk of posttraumatic stress disorder (PTSD) was seen when compared with A/P recipients (IRR = 1.83 [1. 07-3.14]). An increased risk of tinnitus was seen for both deployed and nondeployed mefloquine recipients compared with A/P recipients (IRR = 1.81 [1.18-2.79]), 1.51 (1.13-2.03), respectively). Six percent of the mefloquine cohort had an NPO in the year before receiving mefloquine. When comparing individuals with a prior neuropsychiatric history to those without, the ratio of relative risks for adjustment disorder, anxiety, insomnia, and PTSD were higher (not statistically significant) for mefloquine compared with doxycycline. These findings emphasize the continued need for physicians prescribing mefloquine to conduct contraindication screening.

Associations between Use of Antimalarial Medications and Health among U.S. Veterans of the Wars in Iraq and Afghanistan

“…The highest prevalence of thoughts of death or self-harm among the deployed was reported by the mefloquine group. Other anecdotal reports and research indicated that neuropsychiatric side effects of mefloquine are a risk, 3,[25][26][27][28][29][30][31][32]40,[43][44][45][46]56 but more so for those with prior MH issues, 29,33,34 first-time users, 31 and women 1,27,31,33,[57][58][59] that is probably because of their lower CI = confidence interval; PTSD = post-traumatic stress disorder; SF-12 = twelve-item short form. * Adjusted odds ratios (95% CI); (-) = interaction.…”

“…Except for reports of four or more antimalarials used, all combinations of mefloquine use were examined (reports of mefloquine and other antimalarials) because of its possible association with neuropsychiatric symptoms. [25][26][27][28][29][30][31][32]40,[43][44][45][46] Antimalarial drug status was based on the survey questions described previously and defined on three levels: whether an antimalarial drug was taken but not specified ("unknown" type), one or more specific drugs were taken ("known" type), or no drugs were taken. Antimalarial drug use was specified as either used or not used.…”

“…24 Mefloquine use has been linked to reports of acute neuropsychiatric side effects in both civilian and military populations, [25][26][27][28][29][30][31][32] particularly in those with a history of psychiatric disorders. 29,33,34 The package insert for mefloquine advises against prescribing it to individuals with a psychiatric disorder or a history of seizures because of product safety concerns based on case reports and clinical studies. This has led to the addition by the manufacturer of a U.S. Food and Drug Administration black-box package warning in 2013 that addresses acute neuropsychiatric effects and the possibility of persistent or permanent neurologic health outcomes.…”

Malaria-Associated Mortality in the Australian Defence Force during the Twentieth Century

“…Large studies have strongly indicated the safety of malaria chemoprophylaxis but serious neuropsychiatric adverse events exist and have taken on a greatly magnified role from extensive coverage on the internet. 22 Achieving excellent malaria prophylaxis operations during the recent Ebola epidemic in west Africa was both the result of convincing the soldiers of the reality of the risk as well as finding a medication they were willing to use. 23 Although continuing to seek better forms of malaria treatment and prophylaxis, such practical solutions provide the way to protect soldiers currently in high endemicity areas.…”

Misclassification and Bias in Military Studies of Mefloquine

“…1 Although not accounting for multiple hypothesis testing, the authors’ finding in subgroup analysis of a significantly increased risk of posttraumatic stress disorder (PTSD) with use of mefloquine is intriguing and calls for further investigation.…”