Mefloquine (previously marketed in the United States as Lariam [F Hoffmann-LaRoche Ltd, Basel, Switzerland]) is a neurotoxic quinoline-derivative originally developed by the US military for treatment and prophylaxis of malaria. Originally the US military’s preferred antimalarial drug, mefloquine has been widely used during overseas operations, but recently lost favor because of its association with severe neuropsychiatric side effects. These side effects are now the subject of a “black box” warning, which must appear on the US product label, accompanied by advisories that psychiatric side effects may last years after dosing, and that neurological side effects may be permanent. Recent insights suggest that neuropsychiatric side effects may be considered to be symptomatic of a potentially life-threatening intoxication syndrome (or toxidrome) common to other members of the quinoline class.
Although the drug was originally thought to have few psychiatric effects, symptoms of mefloquine intoxication are now known to affect a majority of users when the drug is administered at treatment doses of 1,250 mg, and at least a sizeable minority when administered at prophylactic doses of 250 mg weekly. Lariam package inserts now warn that “very common” psychiatric symptoms (including abnormal dreams and insomnia) may affect greater than 10% of prophylactic users, and “common” psychiatric symptoms (including anxiety and depression) may affect 1% to 10% of prophylactic users.6,7 Earlier product inserts emphasized that should certain “prodromal” symptoms develop, including anxiety, depression, restlessness, or confusion, the drug must be discontinued to avoid a “more serious event,” which is likely a euphemism for fulminant intoxication and neurotoxicity. Today’s Lariam product information expands on this guidance to add nightmares to the list of “prodromal” symptoms and caution that any “change in mental state” is reason to immediately discontinue the medication.
Many of the symptoms of the mefloquine toxidrome, including vivid nightmares, personality and affective change, disordered sleep, irritability, anger, difficulties with concentration, dissociation and amnesia, may mimic prior Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria B-D, as well as DSM-5 criteria B-E for posttraumatic stress disorder (PTSD), and may last long after discontinuation of dosing. According to a publication by the Centers for Disease Control and Prevention, these symptoms “may confound the diagnosis and management of posttraumatic stress disorder.” As mefloquine has been commonly prescribed to military personnel during combat deployments, risk of intoxication may therefore have frequently coexisted with pervasive exposure to DSM-IV and DSM-5 criterion A stressors, particularly confounding the PTSD diagnosis in military and veteran populations exposed to the drug.
In this chapter, the history of mefloquine’s development and its use within the US military are reviewed, and then the clinical features of the mefloquine toxidrome are described with its chronic effects. The chapter then highlights how specific psychiatric symptoms caused by mefloquine may readily confound PTSD diagnostic criteria, particularly those of DSM-IV, which unlike DSM-5 did not specify a diagnostic exclusion for symptoms resulting from a medication’s effects. This review ends with a discussion of applications of this information to forensic psychiatry and presents a representative case study illustrating challenges in the diagnosis of mefloquine intoxication among military personnel.
R. L. Nevin, Mefloquine and post-traumatic stress disorder, in Elspeth C. Ritchie (ed.), Forensic and Ethical Issues in Military Behavioural Health, Borden Institute, Surgeon General U.S. Army, Falls Church, 2014.