Author's reply

We appreciate the interest Dr Remington Nevin has shown in our article¹ and thank you for giving us the opportunity to respond. Dr Remington Nevin claims that mefloquine exposure is an important confounder that we have failed to control for and that our lack of adjustment for this variable may have invalidated our conclusions. We respectfully disagree.

First, there is no empirical evidence that mefloquine use confounds the association between deployment-related exposures and post-traumatic stress disorder (PTSD), nor that PTSD is a specific side-effect of mefloquine use. Adverse reactions that are reported in the National Institute for Health and Care Excellence guidelines include anxiety, depression, sleep disorders, abnormal dreams, dizziness, headache, vomiting, digestive problems and skin reactions.^2–4 A recent Cochrane review found a low incidence of side-effects among mefloquine users.³ Further, mefloquine users do not report more frequent serious side-effects than more commonly used antimalarials such as atovaquone-proguanil or doxycycline.³

Second, data from the UK's Defence Medical Information Capability Programme indicated that between 1 April 2007 and 31 March 2015, approximately 120 000 UK armed forces personnel were prescribed an antimalarial drug, of which around 17 000 were prescribed mefloquine (14%).⁵ When looking specifically at personnel who deployed to Afghanistan between 1 April 2007 and 31 December 2014, only 536 (0.4%) of the 131 000 of personnel who deployed were prescribed mefloquine. A further 12 908 (10%) were prescribed an unknown malarial prophylaxis. The available data relating to both prescription and use, which is determined by service policy,⁶ suggest that mefloquine is not the first-choice malarial prophylactic for UK armed forces personnel other than in circumstances where resistance to other medication is a factor. Hence, it is highly unlikely that mefloquine was prescribed to this 10%. Therefore, its infrequent use would mean that it cannot account for any substantial proportion of the PTSD identified in our study.

Third, adherence to treatment during deployment varies substantially but is generally found to be low to moderate (range 38–61%), further weakening any potential confounding effect of mefloquine antimalarial medication.^{7, 8} Although we could assess whether UK serving personnel were prescribed malarial prophylaxis as part of the health and well-being cohort study questionnaire, it is impossible to accurately assess through self-report whether personnel were compliant with the treatment regime and which medication was prescribed. Hence, even if prescription data were available, it would be difficult to identify the potentially marginal mental health and well-being impact of mefloquine particularly upon PTSD, as factors such as combat exposure have a direct effect.

Given the low prescription rate of mefloquine compounded with the low rates of adherence, it is implausible that mefloquine could have mimicked the pattern of associations of PTSD we observed with deployment, engagement type, serving status and combat role.