Psychiatric Side Effects of Mefloquine: Applications to Forensic Psychiatry
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REGULAR ARTICLE Psychiatric Side Effects of Mefloquine: Applications to Forensic Psychiatry Elspeth Cameron Ritchie, MD, MPH, Jerald Block, MD, and Remington Lee Nevin, MD, MPH Mefloquine (previously marketed in the United States as Lariam®) is an antimalarial medication with potent psychotropic potential. Severe psychiatric side effects due to mefloquine intoxication are well documented, including anxiety, panic attacks, paranoia, persecutory delusions, dissociative psychosis, and anterograde amnesia. Exposure to the drug has been associated with acts of violence and suicide. In this article, we discuss the history of mefloquine use and describe plausible mechanisms of its psychotropic action. Mefloquine intoxication has not yet been successfully advanced in legal proceedings as a defense or as a mitigating factor, but it appears likely that it eventually will be. Considerations for the application of claims of mefloquine intoxication in forensic settings are discussed. J Am Acad Psychiatry Law 41:224–35, 2013 Mefloquine is a 4-quinolinemethanol antimalarial The company pursued regulatory approval and mar- first synthesized in the early 1970s1 by researchers keted the drug to civilian travelers in the United affiliated with the United States military’s Walter States under the trade name Lariam® after its initial Reed Army Institute of Research (WRAIR).2 The Food and Drug Administration (FDA) licensure in drug’s development was the culmination of a 10-year 1989.5 Owing to its efficacy, presumed safety, and drug discovery effort, during which time more than convenient dose schedule that facilitated prophylac- 300,000 compounds were screened for their antima- tic use, mefloquine was soon identified as the drug of 2 larial properties. Of a handful of compounds active choice6,7 for use by U.S. travelers to areas of chloro- against chloroquine-resistant strains of Plasmodium quine-resistant malaria at a dose of one 250-mg tab- falciparum malaria that demonstrated seemingly fa- 8,9 2 let weekly. vorable toxicity profiles, mefloquine (initially Early prelicensure studies on mefloquine were known as WR 142490) was selected for further de- 2,10 3 conducted predominantly among male prisoners, velopment and testing in humans. military personnel,5,11,12 and subjects in third-world To secure the drug’s commercial manufacture and countries.11,13,14 Although vertigo and nausea were its continued availability, intellectual property rights commonly reported in these early trials, in the ab- and research related to mefloquine were transferred 4 sence of sensitive and unbiased prospective report- at no cost to F. Hoffman-La Roche Ltd. (Roche). ing15 the drug was considered to be largely free of the Dr. Ritchie is Chief Medical Officer, Department of Mental Health, severe psychiatric side effects that had characterized District of Columbia Department of Health, Washington, DC. Dr. the related antimalarial compounds chloroquine16,17 Block is Medical Director, Department of Rural Mental Health, Port- 18,19 land Veterans Affairs Medical Center, Portland, OR. Dr. Nevin is a and quinacrine. doctoral student in the Department of Mental Health, Johns Hopkins The purported safety of mefloquine was so well Bloomberg School of Public Health, Baltimore, Maryland. The views expressed are those of the authors alone and do not necessarily reflect established that when reports of severe psychiatric the views of the District of Columbia Department of Mental Health, side effects, including amnesia, confusion and psy- the Department of Veterans Affairs, or the U.S. Government. Ad- dress correspondence to: Elspeth Cameron Ritchie, MD, MPH, chosis, first emerged in the literature following the 609 H Street NE, Room 325, Washington, DC 20002. E-mail: drug’s early European licensure,20–23 these symp- [email protected]. toms were frequently dismissed as coincidental24 or Disclosures of financial or other potential conflicts of interest: Dr. were later attributed by influential authors to the Nevin has served as paid and pro bono consultant to attorneys repre- senting litigants advancing claims of harm from exposure to meflo- stresses of overseas travel, recreational drug use, or 25–27 quine. pre-existing or latent mental illness. Despite 224 The Journal of the American Academy of Psychiatry and the Law Ritchie, Block, and Nevin continued reports in the literature of severe psychi- and thus forensic psychiatrists may be called to com- atric side effects following the drug’s U.S. licensure, ment on the drug’s effects. In this review, the psychi- it was only in 2001, after the drug had been in wide- atric side effects of mefloquine and the putative spread use for over 15 years and the first formal pathophysiology of these effects are discussed, and blinded and controlled prospective studies were con- specific forensic concerns are considered. This infor- ducted in a representative civilian population,28,29 mation is anticipated to be useful when forensic psy- that mefloquine’s potent psychotropic capability be- chiatrists are asked to consult on cases involving mil- came more widely appreciated. Results of these and itary personnel and veterans, civilian travelers, and subsequent trials have since demonstrated that the employees on overseas assignment who claim legal incidence of specific neuropsychiatric symptoms implications from their exposure to the drug. including nightmares, anxiety, and psychosis dur- ing prophylactic use are each at least 100 times Psychiatric Side Effects 28,30,31 more common than has been previously According to the current U.S. mefloquine package 32–35 reported. insert,70 psychiatric symptoms associated with pro- 31,36,37 More recent reports of suicide and suicidal phylactic mefloquine use include abnormal dreams, 38–47 ideation, and studies linking the drug to acts of anxiety, paranoia, agitation, confusion, memory im- 48 violence have raised additional safety con- pairment, and hallucinations. Despite over 20 years 49,50 cerns. As public awareness of the potential dan- of licensed use, the underlying pathophysiology of 51–54 gers of mefloquine have grown, and civil litiga- these side effects has been poorly understood.71 Re- 55,56 tion related to the drug has increased, cent insights37,40,72 suggest that these side effects re- mefloquine has lost significant market share in the sult directly from the accumulation of the drug 57 United States in favor of safer and better tolerated within and acting on specific targets in the brain. In 28 antimalarial medications. Today, mefloquine is no this section, the putative pathophysiology of meflo- longer considered the drug of choice, either in ther- quine intoxication is described in further detail fol- apy or in chemoprophylaxis of malaria.58 Roche re- lowing a discussion of its typical clinical cently withdrew Lariam® from the U.S. market, al- presentation. though generic forms remain widely available.59 Use of mefloquine had previously been encour- Clinical Presentation aged among United States overseas diplomatic staff60 Case reports suggest that mefloquine intoxication and Peace Corps volunteers.8,25 Mandatory use of may begin with a variable prodrome which may pres- the drug was also broadly directed among deployed ent with personality change,40 unease,40 anxi- U.S. military service members.61,62 Recently, grow- ety,73–75 phobias,76,77 and a sense of impending ing awareness of the drug’s inappropriate prescrib- doom and restlessness.76 These prodromal symp- ing33,34,63 to service members with mental health toms may progress to outright para- contraindications,39,62,64 including those with a his- noia,38,46,73,74,78–81 delusions,46,47,78,81 magical tory of posttraumatic stress disorder and traumatic thinking,79 persecutory mania,73,78,81–83 restless- brain injury,34,63 and poor documentation of its pre- ness,84 aggression,22 and panic attacks.44,85,86 Con- scribing64 has significantly diminished the utility of fusion38,39,87–91 and symptoms of depres- mefloquine in deployed settings.65 As a result, today, sion38,39,44,47,92 have also been reported. Such mefloquine is considered the drug of last resort by symptoms have been reported after only a single U.S. military policy,66,67 to be used only when doxy- 250-mg tablet40,93–96 and may progress in severity cycline and the combination drug atovaquone/ with subsequent doses.40,96 proguanil (Malarone) cannot be used.58,65,68,69 Since the drug’s initial licensing in 1989,97 the Because the drug is associated with an increased U.S. mefloquine package insert has warned that “if risk of violence48 and psychiatric symptoms, users of signs of unexplained anxiety, depression, restlessness, mefloquine may be likely to be encountered in the or confusion are noticed, these may be considered civil or criminal legal systems. Current or past users prodromal to a more serious event.” The package of the drug may claim that exposure has caused phys- insert further cautions that should these prodromal ical or mental injury. The psychiatric effects of the symptoms occur, “[i]n these cases, the drug must be drug may be featured in future forensic evaluations, discontinued.” Volume 41, Number 2, 2013 225 Psychiatric Side Effects of Mefloquine Many, but not all,96 users of mefloquine will cor- cide, suicide attempt,41 and parasuicidal behavior40 rectly discontinue use of the drug at the onset of the associated with the use of mefloquine. unsettling prodromal symptoms of intoxication.28 An additional distinguishing feature reported with However, those with a