While researching a recent article about the FDA's decision to include a black box warning on the labeling of the antimalarial drug mefloquine cautioning about neurologic and psychiatric adverse complications, I came across a strange story in the journal Tropical Medicine and International Health.



The article chronicled the use of mefloquine among "many, if not all" of the detainees being held at Guantanamo Bay, Cuba. It was written by Remington L. Nevin, who had been a U.S. Army preventive medicine specialist and who is considered an authority on antimalarial toxicity. He explained that the Department of Defense released documents in 2007 in response to a Freedom of Information Act request about the policy of mefloquine use among detainees -- with information that he considered disturbing.



Mefloquine was developed by the military at the Walter Reed Army Institute of Research in the 1970s, which was a time of increasing resistance to chloroquine. It showed efficacy as treatment for illness caused by the blood-stage schizonts but not for the liver-stage schizonts and hypnozoites or the blood-stage gametocytes that are more commonly causes of infection.



Early use also suggested the possibility of central nervous system and behavioral disturbances, but the FDA approved the drug as prophylaxis and it was quickly adopted by the military, given in weekly doses of 250 mg.



But the drug gradually fell out of favor among travelers and military personnel, and the proprietary formulation Lariam was withdrawn from the U.S. market in 2009. Generic formulations remain available, however.



In his article, Nevin explains the rationale for several approaches to the use of antimalarials, including "mass drug administration," in which everyone in a specified region is given the drug, "intermittent preventive treatment," which targets treatment to individuals considered to be at particular risk, and empiric treatment, where patients from endemic areas with symptoms such as fever are presumed to have malaria and are treated.



None of those scenarios applied to Guantanamo, according to Nevin, where the treatment was given in one 750 mg dose followed by a second 500 mg dose 12 hours later. In particular, the empiric approach can't explain the treatment policy, because this is usually associated with cost constraints or difficulties in diagnosis.



"Neither was a factor at Guantanamo. All detainees had regular access to medical care and received a comprehensive medical evaluation upon arrival, which included assessment of vital signs and thick and thin-smear microscopic testing for malaria," Nevin stated.



An additional factor that would weigh against presumptive treatment was the specific recommendation by the CDC against this approach for individuals originating in places other than sub-Saharan Africa, while most of the Guantanamo detainees were from countries such as Pakistand and Afghanistan.



Moreover, the CDC has recommended a combination of atovaquone and proguanil (Malarone) as being better tolerated.



Further factors, Nevin pointed out, were that, at the time mefloquine was being given to the detainees, careful mosquito surveillance was underway in the area. Also, a decade earlier, when 14,000 Haitian refugees were temporarily housed at Guantanamo, no mass administration of antimalarials was undertaken.



So what was the reason for the routine use of mefloquine -- an agent with documented adverse events including depression, hallucinations, confusion, paranoia, and anxiety, and linked to 22 deaths and five suicides -- in Guantanamo?



Nevin wrote:

"One possibility is that the use of mefloquine was simply erroneously directed by senior U.S. military medical officials overly confident of the drug's safety and unfamiliar with its appropriate use ... Another possibility, which is deeply troubling to consider, is that the decision to administer the drug was informed and motivated at least in part by knowledge of the drug's adverse neuropsychiatric effects and the presumed plausible deniability of claims of misuse in the context of its seemingly legitimate clinical or public health indication.



"Further formal investigation may yet reveal the precise rationale and motivation for the use of mefloquine among Guantanamo detainees. As the actions of junior medical personnel assigned to Guantanamo come under increased ethical and legal scrutiny, the actions of senior medical leaders involved in formulating and overseeing detainee mefloquine policy must bear comparable examination."

