The Mefloquine Intoxication Syndrome: A Significant Potential Confounder in the Diagnosis and Management of PTSD and Other Chronic Deployment-Related Neuropsychiatric Disorders

  • Remington Lee NevinEmail author
  • Elspeth Cameron Ritchie


Intoxication with the antimalarial drug mefloquine (previously marketed as Lariam) is a potentially life-threatening condition marked by changes in affect, behavior, cognition, and thought that may be associated with a risk of central nervous system (CNS) neuronal injury as well as chronic neurological and psychiatric sequelae. The acute symptoms of mefloquine intoxication may mimic and be mistaken for a number of acute psychiatric disorders including posttraumatic stress disorder (PTSD). Particularly in deployed settings, this may delay the correct diagnosis of mefloquine intoxication, risking subsequent morbidity. As the subacute and chronic psychiatric and neurologic sequelae of acute mefloquine intoxication may also confound the later diagnosis and management of PTSD, as well as other chronic neuropsychiatric disorders prevalent among deployed cohorts, health-care providers must screen for prior mefloquine exposure and consider the diagnosis of mefloquine intoxication in patients with appropriate history and findings on clinical evaluation.


Mefloquine intoxication syndrome PTSD and mefloquine intoxication syndrome Deployment-related neuropsychiatric disorders Veterans and mefloquine intoxication syndrome 


  1. 1.
    Nevin RL. Mefloquine and posttraumatic stress disorder. In: Ritchie EC, ed. Textbook of military medicine. Forensic and ethical issues in military behavioral health. Washington, DC: Borden Institute; 2015:277–96.Google Scholar
  2. 2.
    Magill A, Cersovsky S, DeFraites R. Special considerations for US military deployments. CDC Yellow Book—Travelers’ Health Chapter 8. (2014). Accessed 8 May 2015.
  3. 3.
    Walter Reed Army Institute of Research. Neurotoxicity associated with mefloquine, an anti-malarial drug: small business technology transfer (STTR) solicitation topic number A06-T034 (Army). (2006). Accessed 8 May 2015.
  4. 4.
    Nevin RL. Idiosyncratic quinoline central nervous system toxicity: historical insights into the chronic neurological sequelae of mefloquine. Int J Parasitol Drugs Drug Resist. 2014;4(2):118–25.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    U.S. Food and Drug Administration. Release P03–52. FDA creates medication guide for Lariam. 2003.Google Scholar
  6. 6.
    Laskas JM. The coward. Gentlem Q. 2004;74:106–112, 159–161.Google Scholar
  7. 7.
    Fleet M. Case dropped against U.S. soldier initially accused of cowardice. (2004). Accessed 8 May 2015.
  8. 8.
    Brant M. War stories: drugging the troops. Newsweek. 2004 Jan 9. Accessed 8 May 2015.Google Scholar
  9. 9.
    Associated Press. Hallucinations linked to drug given to troops. February 14. (2005). Accessed 8 May 2015.
  10. 10.
    Nevin RL. Limbic encephalopathy and central vestibulopathy caused by mefloquine: a case report. Travel Med Infect Dis. 2012;10(3):144–51.PubMedCrossRefGoogle Scholar
  11. 11.
    Clattenburg RN, Donnelly CL. Case study: neuropsychiatric symptoms associated with the antimalarial agent mefloquine. J Am Acad Child Adolesc Psychiatry. 1997;36(11):1606–08. Accessed 8 May 2015.PubMedGoogle Scholar
  12. 12.
    Kukoyi O, Carney CP. Curses, madness, and mefloquine. Psychosomatics. 2003;44(4):339–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Barrett PJ, Emmins PD, Clarke PD, Bradley DJ. Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travellers. BMJ 1996;313(7056):525–8.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Colebunders R. Cured of fear of flying. Travel Med infect Dis. 2011;9(2):82.PubMedCrossRefGoogle Scholar
  15. 15.
    Peterson AL, Seegmiller RA, Schindler LS. Severe neuropsychiatric reaction in a deployed military member after prophylactic mefloquine. Case Rep Psychiatry. 2011;2011:350417.Google Scholar
  16. 16.
    Van Riemsdijk MM, van der Klauw MM, van Heest JA, et al. Neuro-psychiatric effects of antimalarials. Eur J Clin Pharmacol. 1997;52(1):1–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Tran TM, Browning J, Dell ML. Psychosis with paranoid delusions after a therapeutic dose of mefloquine: a case report. Malar J. 2006;5:74.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Schlagenhauf P, Steffen R. Neuropsychiatric events and travel: do antimalarials play a role? J Travel Med. 2000;7(5):225–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Javorsky DJ, Tremont G, Keitner GI, Parmentier AH. Cognitive and neuropsychiatric side effects of mefloquine. J Neuropsychiatry Clin Neurosci. 2001;13(2):302.PubMedCrossRefGoogle Scholar
  20. 20.
    Gascón J, Almeda J, Corominas N, Corachán M. Severe neuropsychiatric reaction following mefloquine use. Med Clin. 1993;101(13):515–6.Google Scholar
  21. 21.
    Tor PC, Lee HY, Tan CH. Mefloquine-induced mania in a 22-year-old Chinese man. Singap Med J. 2006;47(6):549–50.Google Scholar
  22. 22.
    Piening RB, Young SA. Mefloquine-induced psychosis. Ann Emerg Med. 1996;27(6):792–3.PubMedCrossRefGoogle Scholar
  23. 23.
    Eaton L. Adverse reactions. Nurs Times 1996;92(24):16–7.PubMedGoogle Scholar
  24. 24.
    Thapa R, Biswas B. Childhood mefloquine-induced mania and psychosis: a case report. J Child Neurol. 2009;24(8):1008–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Caillon E, Schmitt L, Moron P. Acute depressive symptoms after mefloquine treatment. Am J Psychiatry. 1992;149(5):712.PubMedGoogle Scholar
  26. 26.
    De Gennes C, Colas C, Nollet D, et al. Panic attack after therapeutic administration of mefloquine. Ann Med Interne. 1991;142(8):631.Google Scholar
  27. 27.
    Borruat FX, Nater B, Robyn L, Genton B. Prolonged visual illusions induced by mefloquine (Lariam): a case report. J Travel Med. 2001;8(3):148–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Amraoui A, Burgos V, Alexandre JY. Acute psychosis following mefloquine therapy: a case report. Med Mal Infect. 1998;28:678–9.CrossRefGoogle Scholar
  29. 29.
    Sowunmi A, Adio RA, Oduola AM, Ogundahunsi OA, Salako LA. Acute psychosis after mefloquine. Report of six cases. Trop Geogr Med. 1995;47(4):179–80.PubMedGoogle Scholar
  30. 30.
    Meszaros K, Kasper S. Psychopathological phenomena in long-term follow-up of acute psychosis after preventive mefloquinine (Lariam) administration. Nervenarzt. 1996;67(5):404–6.PubMedGoogle Scholar
  31. 31.
    Brumbaugh M, Price P, Fagan N, Hsieh H. Psychotic mania associated with mefloquine in a bipolar patient. South Med J. 2008;101(5):550–1.PubMedCrossRefGoogle Scholar
  32. 32.
    Lebain P, Juliard C, Davy JP, Dollfus S. Neuropsychiatric symptoms in preventive antimalarial treatment with mefloquine: apropos of 2 cases. Encephale. 2000;26(4):67–70.PubMedGoogle Scholar
  33. 33.
    Croft AM, World MJ. Neuropsychiatric reactions with mefloquine chemoprophylaxis. Lancet. 1996;347(8997):326.PubMedCrossRefGoogle Scholar
  34. 34.
    Folkerts H, Kuhs H. Psychotic episode caused by prevention of malaria with mefloquine. A case report. Nervenarzt. 1992;63(5):300–2.PubMedGoogle Scholar
  35. 35.
    Stuiver PC, Ligthelm RJ, Goud TJ. Acute psychosis after mefloquine. Lancet. 1989;2(8657):282.PubMedCrossRefGoogle Scholar
  36. 36.
    Recasens C, Zittoun C, Féline A. A psychotic episode in a patient coming home from Africa: the possible role of mefloquine. Ann Psychiatry. 1993;8(2):100–3.Google Scholar
  37. 37.
    Hollweg M, Soyka M, Greil W. Mefloquine-induced psychoses—problems in etiologic classification based on 2 case reports. Psychiatr Prax. 1995;22(1):33–6.PubMedGoogle Scholar
  38. 38.
    Even C, Friedman S, Lanouar K. Bipolar disorder after mefloquine treatment. J Psychiatry Neurosci. 2001;26(3):252–3.PubMedCentralPubMedGoogle Scholar
  39. 39.
    Oueriagli Nabih F, Touhami M, Laffinti A, Abilkacem L. Mood disorder after malaria prophylaxis with mefloquine (two case reports). Encephale. 2011;37(5):393–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Perry IC. Malaria prophylaxis. BMJ. 1995;310(6995):1673.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Minei-Rachmilewitz T. Neuropsychiatric side effects of malarial prophylaxis with mefloquine (Lariam). Harefuah. 1999;137(1–2):25–7, 87.PubMedGoogle Scholar
  42. 42.
    Krüger E, Grube M, Hartwich P. Acute paranoid hallucinatory psychosis following mefloquine prophylaxis (Lariam). Psychiatr Prax. 1999;26(5):252–4.PubMedGoogle Scholar
  43. 43.
    McEvoy K, Anton B, Chisolm MS. Depersonalization/derealization disorder after exposure to mefloquine. Psychosomatics. 2014;56(1):98–102.PubMedCrossRefGoogle Scholar
  44. 44.
    Nevin R. Organic depersonalization as a chronic sequela of mefloquine intoxication. Psychosomatics. 2015;56(1):103–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Hennequin C, Bourée P, Bazin N, Bisaro F, Feline A. Severe psychiatric side effects observed during prophylaxis and treatment with mefloquine. Arch Intern Med. 1994;154(20):2360–2.PubMedCrossRefGoogle Scholar
  46. 46.
    Marsepoil T, Petithory J, Faucher JM, Ho P, Viriot E, Benaiche F. Encephalopathy and memory disorders during treatments with mefloquine. Rev Med Interne. 1993;14(8):788–91.PubMedCrossRefGoogle Scholar
  47. 47.
    Carme B, Nevez G, Peguet C, Bories C, Andrejak M. Neuropsychiatric intolerance during mefloquine prophylaxis. 5 case reports. Med Mal Infect. 1996;26:728–9.CrossRefGoogle Scholar
  48. 48.
    Nevin RL. A Memoir of Mefloquine Amnesia: a review of the answer to the riddle is me by David Stuart MacLean. AJOB Neurosci. 2014;5(4):88–91.CrossRefGoogle Scholar
  49. 49.
    Fuller SJ, Naraqi S, Gilessi G. Paranoid psychosis related to mefloquine antimalarial prophylaxis. P N G Med J. 2002;45(3–4):219–21.PubMedGoogle Scholar
  50. 50.
    Vuurman EF, Muntjewerff ND, Uiterwijk MM, et al. Effects of mefloquine alone and with alcohol on psychomotor and driving performance. Eur J Clin Pharmacol. 1996;50(6):475–82.PubMedCrossRefGoogle Scholar
  51. 51.
    Speich R, Haller A. Central anticholinergic syndrome with the antimalarial drug mefloquine. New Engl J Med. 1994;331(1):57–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Gobbi F, Rossanese A, Buonfrate D, Angheben A, Postiglione C, Bisoffi Z. Epilepsy triggered by mefloquine in an adult traveler to Uganda. World J Clin Cases. 2014;2(1):12–5.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    World Health Organization. Central nervous system reactions related to the antimalarial drug, mefloquine. WHO/MAL/89/1054; 1989:1–20.Google Scholar
  54. 54.
    Ritchie EC, Block J, Nevin RL. Psychiatric side effects of mefloquine: applications to forensic psychiatry. J Am Acad Psychiatry Law. 2013;41:224–35.PubMedGoogle Scholar
  55. 55.
    Ringqvist A, Bech P, Glenthøj B, Petersen E. Acute and long-term psychiatric side effects of mefloquine: a follow-up on Danish adverse event reports. Travel Med Infect Dis. 2015;13(1):80–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Mawson A. Mefloquine use, psychosis, and violence: a retinoid toxicity hypothesis. Med Sci Monit. 2013;19:579–83.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Croft AM, Herxheimer A. Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement? BMC Public Health. 2002;2:6.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Nevin RL. Mefloquine neurotoxicity and gap junction blockade: critical insights in drug repositioning. Neurotoxicology. 2011;32(6):986–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Hood JE, Jenkins JW, Milatovic D, Rongzhu L, Aschner M. Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons. Neurotoxicology. 2010;31(5):518–23.PubMedCrossRefGoogle Scholar
  60. 60.
    Dow GS, Hudson TH, Vahey M, Koenig ML. The acute neurotoxicity of mefloquine may be mediated through a disruption of calcium homeostasis and ER function in vitro. Malar J. 2003;2:14.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Milatovic D, Jenkins JW, Hood JE, Yu Y, Rongzhu L, Aschner M. Mefloquine neurotoxicity is mediated by non-receptor tyrosine kinase. Neurotoxicology. 2011;32(5):578–85.PubMedCrossRefGoogle Scholar
  62. 62.
    Dow GS, Milner E, Bathurst I, et al. Central nervous system exposure of next generation quinoline methanols is reduced relative to mefloquine after intravenous dosing in mice. Malar J. 2011;10:150.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Dow G, Bauman R, Caridha D, et al. Mefloquine induces dose-related neurological effects in a rat model. Antimicrob Agents Chemother. 2006;50(3):1045–53.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Nevin RL. Neuropharmacokinetic heterogeneity of mefloquine in the treatment of progressive multifocal leukoencephalopathy. Intern Med. 2012;51(16):2257–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Barraud de Lagerie S, Comets E, Gautrand C, et al. Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice. Br J Pharmacol. 2004;141(7):1214–22.PubMedCrossRefGoogle Scholar
  66. 66.
    Jones R, Kunsman G, Levine B, Smith M, Stahl C. Mefloquine distribution in postmortem cases. Forensic Sci Int. 1994;68(1):29–32.PubMedCrossRefGoogle Scholar
  67. 67.
    Pham YT, Nosten F, Farinotti R, White NJ, Gimenez F. Cerebral uptake of mefloquine enantiomers in fatal cerebral malaria. Int J Clin Pharmacol Ther. 1999;37(1):58–61.PubMedGoogle Scholar
  68. 68.
    Hessén-Söderman A, Bergenius J, Palme I, Bergqvist Y, Hellgren U. Mefloquine prophylaxis and hearing, postural control, and vestibular functions. J Travel Med. 1995;2(2):66–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Jaspers CA, Hopperus Buma AP, van Thiel PP, van Hulst RA, Kager PA. Tolerance of mefloquine chemoprophylaxis in Dutch military personnel. Am J Trop Med Hyg. 1996;55(2):230–4.PubMedGoogle Scholar
  70. 70.
    Schwartz E, Potasman I, Rotenberg M, Almog S, Sadetzki S. Serious adverse events of mefloquine in relation to blood level and gender. Am J Trop Med Hyg. 2001;65(3):189–92.PubMedGoogle Scholar
  71. 71.
    Rozman RS, Molek NA, Koby R. The absorption, distribution, and excretion in mice of the antimalarial mefloquine, erythro-2,8-bis(trifluoromethyl)-alpha-(2-piperidyl)-4-quinolinemethanol hydrochloride. Drug Metab Dispos. 1978;6(6):654–8.PubMedGoogle Scholar
  72. 72.
    Mu JY, Israili ZH, Dayton PG. Studies of the disposition and metabolism of mefloquine HCl (WR 142,490), a quinolinemethanol antimalarial, in the rat. Limited studies with an analog, WR 30,090. Drug Metab Dispos. 1975;3(3):198–210.PubMedGoogle Scholar
  73. 73.
    Chung H, Jimmerson VR, Rozman RS, Sanders JE. Disposition of the diastereoisomer of mefloquine in mice. Pharmacology. 1982;24(5):267–74.PubMedCrossRefGoogle Scholar
  74. 74.
    Baudry S, Pham YT, Baune B, et al. Stereoselective passage of mefloquine through the blood-brain barrier in the rat. J Pharm Pharmacol. 1997;49(11):1086–90.PubMedCrossRefGoogle Scholar
  75. 75.
    Schwartz DE, Weber W, Richard-Lenoble D, Gentilini M. Kinetic studies of mefloquine and of one of its metabolites, Ro 21–5104, in the dog and in man. Acta Trop. 1980;37(3):238–42.PubMedGoogle Scholar
  76. 76.
    Burmester JK, Sedova M, Shapero MH, Mansfield E. DMET microarray technology for pharmacogenomics-based personalized medicine. Method Mol Biol. 2010;632(1):99–124.CrossRefGoogle Scholar
  77. 77.
    Aarnoudse ALHJ, van Schaik RHN, Dieleman J, et al. MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine. Clin Pharmacol Ther. 2006;80(4):367–74.PubMedCrossRefGoogle Scholar
  78. 78.
    Zaigraykina N, Potasman I. Polymorphism at the MDR1 locus as a cause of mefloquine-induced psychosis. Harefuah. 2010;149(9):583–4, 620, 619.PubMedGoogle Scholar
  79. 79.
    Van Essen TA, van der Giessen RS, Koekkoek SKE, et al. Anti-malaria drug mefloquine induces motor learning deficits in humans. Front Neurosci. 2010;4:191.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Ries S. Cerebral spasm during malaria prophylaxis with mefloquine. Dtsch Med Wochenschr. 1993;118(51–52):1911–2.PubMedGoogle Scholar
  81. 81.
    Loken AC, Haymaker W. Pamaquine poisoning in man, with a clinicopathologic study of one case. Am J Trop Med Hyg. 1949;29(3):341–52.PubMedGoogle Scholar
  82. 82.
    Potasman I, Juven Y, Weller B, Schwartz E. Does mefloquine prophylaxis affect electroencephalographic patterns? Am J Med 2002;112(2):147–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Bernard J, Le Camus J, Sarrouy J, et al. Toxic encephalopathy caused by mefloquine? Presse Med. 1987;16(33):1654–5.PubMedGoogle Scholar
  84. 84.
    Rønn AM, Bygbjerg IC. Acute brain syndrome after mefloquine treatment. Ugeskr Laeger. 1994;156(41):6044–5.PubMedGoogle Scholar
  85. 85.
    Lapras J, Vighetto A, Trillet M, Garin JP. Transient disorders of memory after a malaria attack. Caused by mefloquine? Presse Med. 1989;18(15):776.PubMedGoogle Scholar
  86. 86.
    World Health Organization. Neurotoxicity risk assessment for human health: principles and approaches. Environmental health criteria series, No. 223. World Health Organization. 2001.Google Scholar
  87. 87.
    Ohbuchi T, Yokoyama T, Saito T, et al. Possible contribution of pannexin channel to ATP-induced currents in vitro in vasopressin neurons isolated from the rat supraoptic nucleus. Brain Res. 2011;1394:71–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Rubertone MV, Brundage JF. The Defense Medical Surveillance System and the Department of Defense Serum Repository: glimpses of the future of public health surveillance. Am J Pub Health. 2002;92(12):1900–4.CrossRefGoogle Scholar
  89. 89.
    Hohl CM, Karpov A, Reddekopp L, Stausberg J. ICD-10 codes used to identify adverse drug events in administrative data: a systematic review. J Am Med Inform Assoc. 2014;21:547–57.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    American Psychiatric Association. Trauma- and stressor-related disorders. Diagnostic and statistical manual of mental disorders. 5th edn. Washington, DC: American Psychiatric Association; 2013.Google Scholar
  91. 91.
    Boudreau E, Schuster B, Sanchez J, et al. Tolerability of prophylactic Lariam regimens. Trop Med Parasitol. 1993;44(3):257–65.PubMedGoogle Scholar
  92. 92.
    Nevin RL, Pietrusiak PP, Caci JB. Prevalence of contraindications to mefloquine use among USA military personnel deployed to Afghanistan. Malar J. 2008;7:30.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Wooltorton E. Mefloquine: contraindicated in patients with mood, psychotic or seizure disorders. CMAJ. 2002;167(10):1147.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Hoffman-La Roche F. Dear Pharmacist Letter. September. (2002). Accessed 8 May 2015.
  95. 95.
    Nevin RL. Mefloquine prescriptions in the presence of contraindications: prevalence among US military personnel deployed to Afghanistan, 2007. Pharmacoepidemiol Drug Saf. 2010;19(2):206–10.PubMedCrossRefGoogle Scholar
  96. 96.
    Lobel HO. Adverse health events and malaria prophylaxis. Healthwise (A newsletter for peace corps medical officers worldwide). 1996;5(2):1, 3–4.Google Scholar
  97. 97.
    Schlagenhauf P, Lobel H, Steffen R, et al. Tolerance of mefloquine by SwissAir trainee pilots. Am J Trop Med Hyg. 1997;56(2):235–40.PubMedGoogle Scholar
  98. 98.
    Schlagenhauf P. Mefloquine for malaria chemoprophylaxis 1992–1998: a review. J Travel Med. 1999;6(2):122–33.PubMedCrossRefGoogle Scholar
  99. 99.
    Schlagenhauf P. Mefloquine, methodologies, and the media. J Travel Med. 1996;3(4):197–9.PubMedCrossRefGoogle Scholar
  100. 100.
    Hoffman-La Roche F. Lariam patient monitoring card. France. August 7, 2013.Google Scholar
  101. 101.
    Hoffman-La Roche F. Lariam Guide to Healthcare Professionals. Ireland. July, 2013.Google Scholar
  102. 102.
    Hoffman-La Roche F. Lariam Dear Doctor Letter. Ireland. July, 2013.Google Scholar
  103. 103.
    U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA approves label changes for antimalarial drug mefloquine hydrochloride due to risk of serious psychiatric and nerve side effects. July 29. (2013). Accessed 8 May 2015.
  104. 104.
    Hoffman-La Roche F. Lariam Product Insert. Ireland, July 2013.Google Scholar
  105. 105.
    Overbosch D, Schilthuis H, Bienzle U, et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. Clin Infect Dis. 2001;33(7):1015–21.PubMedCrossRefGoogle Scholar
  106. 106.
    U.S. Army Office of the Surgeon General. Memorandum. Subject: Updated Guidance on the Use of Mefloquine for Malaria Prophylaxis. February 2. (2009).
  107. 107.
    Stürchler D, Handschin J, Kaiser D, et al. Neuropsychiatric side effects of mefloquine. New Engl J Med. 1990;322(24):1752–3.PubMedGoogle Scholar
  108. 108.
    Levin A. FDA warning highlights mefloquine’s mental health risks. Psychiatr News. 2013;48(18):1.Google Scholar
  109. 109.
    Whitman TJ, Coyne PE, Magill AJ, et al. An outbreak of Plasmodium falciparum malaria in U.S. Marines deployed to Liberia. Am J Trop Med Hyg. 2010;83(2):258–65.PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Woodson J. Memorandum. Subject: Notification for Healthcare Providers of Mefloquine Box Warning. August 12, 2013.Google Scholar
  111. 111.
    Woodson J. HA Policy Memorandum 13–02: Guidance on Medications for Prophylaxis of Malaria. April 15. (2013). Accessed 8 May 2015.
  112. 112.
    Grupp D, Rauber A, Fröscher W. Neuropsychiatric disturbances after malaria prophylaxis with mefloquine. Aktuelle Neurol. 1994;21:134–6.CrossRefGoogle Scholar
  113. 113.
    Sowunmi A. Acute psychosis after mefloquine: a case report. East Afr Med J. 1994;71(12):818–9.PubMedGoogle Scholar
  114. 114.
    Maxwell NM, Nevin RL, Stahl S, et al. Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy. Clin Case Rep. 2015;3(6):379–387.Google Scholar
  115. 115.
    De Leon J, Susce MT, Pan R-M, Fairchild M, Koch WH, Wedlund PJ. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005;66(1):15–27.PubMedCrossRefGoogle Scholar
  116. 116.
    Yoo H-D, Lee S-N, Kang H-A, Cho H-Y, Lee I-K, Lee Y-B. Influence of ABCB1 genetic polymorphisms on the pharmacokinetics of risperidone in healthy subjects with CYP2D6*10/*10. Br J Pharmacol. 2011;164(2b):433–43.PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    Jauch R, Griesser E, Oesterhelt G. Metabolism of Ro 21-5998 (mefloquine) in the rat. Arzneimittelforschung. 1980;30(1):60–7.PubMedGoogle Scholar
  118. 118.
    Ridtitid W, Wongnawa M, Mahatthanatrakul W, Chaipol P, Sunbhanich M. Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. J Pharm Pharmacol. 2000;52(10):1265–9.PubMedCrossRefGoogle Scholar
  119. 119.
    De Lagerie SB, Fernandez C, German-Fattal M, Gantier J-C, Gimenez F, Farinotti R. Impact of cerebral malaria on brain distribution of mefloquine. Drug Metab Lett. 2009;3(1):15–7.PubMedCrossRefGoogle Scholar
  120. 120.
    Bauer B, Yang X, Hartz AMS, et al. In vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation. Mol Pharmacol. 2006;70(4):1212–9.PubMedCrossRefGoogle Scholar
  121. 121.
    Henry M, Alibert S, Rogier C, Barbe J, Pradines B. Inhibition of efflux of quinolines as new therapeutic strategy in malaria. Curr Top Med Chem. 2008;8(7):563–78.PubMedCrossRefGoogle Scholar
  122. 122.
    Linnet K, Ejsing TB. A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Focus on psychotropic drugs. Eur Neuropsychopharmacol. 2008;18(3):157–69.PubMedCrossRefGoogle Scholar
  123. 123.
    O’Brien FE, Dinan TG, Griffin BT, Cryan JF. Interactions between antidepressants and P-glycoprotein at the blood-brain barrier: clinical significance of in vitro and in vivo findings. Br J Pharmacol. 2012;165(2):289–312.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Skarke C, Jarrar M, Schmidt H, et al. Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics. 2003;13(11):651–60.PubMedCrossRefGoogle Scholar
  125. 125.
    Khaliq Y, Gallicano K, Tisdale C, Carignan G, Cooper C, McCarthy A. Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers. Br J Clin Pharmacol. 2001;51(6):591–600.PubMedCentralPubMedCrossRefGoogle Scholar
  126. 126.
    Ridtitid W, Wongnawa M, Mahatthanatrakul W, Raungsri N, Sunbhanich M. Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers. J Clin Pharm Ther. 2005;30(3):285–90.PubMedCrossRefGoogle Scholar
  127. 127.
    Rijpma SR, van den Heuvel JJ, van der Velden M, Sauerwein RW, Russel FG, Koenderink JB. Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity. Malar J. 2014;13(1):359.PubMedCentralPubMedCrossRefGoogle Scholar
  128. 128.
    Kerb R, Fux R, Mörike K, et al. Pharmacogenetics of antimalarial drugs: effect on metabolism and transport. Lancet Infect Dis. 2009;9(12):760–74.PubMedCrossRefGoogle Scholar
  129. 129.
    McArdle JJ, Sellin LC, Coakley KM, et al. Mefloquine inhibits cholinesterases at the mouse neuromuscular junction. Neuropharmacology. 2005;49(8):1132–9.PubMedCrossRefGoogle Scholar
  130. 130.
    Summers WK, Allen RE, Pitts FN. Does physostigmine reverse quinidine delirium? West J Med. 1981;135(5):411–41.PubMedCentralPubMedGoogle Scholar
  131. 131.
    Alam A, Puri NV. Inefficacy of antipsychotics in treatment of delirium and agitation in two cases of Bickerstaff brainstem encephalitis. J Neuropsychiatry Clin Neurosci. 2014;26(2):176–8.PubMedCrossRefGoogle Scholar
  132. 132.
    Bourgeois JA, Koike AK, Simmons JE, Telles S, Eggleston C. Adjunctive valproic acid for delirium and/or agitation on a consultation-liaison service: a report of six cases. J Neuropsychiatry Clin Neurosci. 2005;17(2):232–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Lai JS, Zhao C, Warsh JJ, Li PP. Cytoprotection by lithium and valproate varies between cell types and cellular stresses. Eur J Pharmacol. 2006;539(1–2):18–26.PubMedCrossRefGoogle Scholar
  134. 134.
    Monti B, Gatta V, Piretti F, Raffaelli SS, Virgili M, Contestabile A. Valproic acid is neuroprotective in the rotenone rat model of Parkinson’s disease: involvement of alpha-synuclein. Neurotox Res. 2010;17(2):130–41.PubMedCrossRefGoogle Scholar
  135. 135.
    Burke BM. Mefloquine. Lancet. 1993;341(8860):1605–6.PubMedCrossRefGoogle Scholar
  136. 136.
    Prescrire International. Medication-induced violence towards others. Prescrire Int. 2014;23(150):153–5.Google Scholar
  137. 137.
    Moore TJ, Glenmullen J, Furberg CD. Prescription drugs associated with reports of violence towards others. PLoS ONE. 2010;5(12):e15337.PubMedCentralPubMedCrossRefGoogle Scholar
  138. 138.
    Scrip. Roche’s Lariam linked to a suicide in UK. Scrip 1998;(2331):23.Google Scholar
  139. 139.
    Jousset N, Rougé-Maillart C, Turcant A, Guilleux M, Le Bouil A, Tracqui A. Suicide by skull stab wounds: a case of drug-induced psychosis. Am J Forensic Med Pathol. 2010;31(4):378–81.PubMedCrossRefGoogle Scholar
  140. 140.
    Pharmaceutical Journal. BNF updates “suicide” warnings for mefloquine. Pharm J. 2013;291:620.Google Scholar
  141. 141.
    Prescrire International. Mefloquine: persistent vestibular disorders. Prescrire Int. 2014;23(150):157.Google Scholar
  142. 142.
    Lobel HO, Coyne PE, Rosenthal PJ. Drug overdoses with antimalarial agents: prescribing and dispensing errors. JAMA. 1998;280(17):1483.PubMedCrossRefGoogle Scholar
  143. 143.
    Ismail T, Mauerhofer E, Slomianka L. The hippocampal region of rats and mice after a single i.p. dose of clioquinol: loss of synaptic zinc, cell death and c-Fos induction. Neuroscience. 2008;157(3):697–707.PubMedCrossRefGoogle Scholar
  144. 144.
    Takeda a, Takada S, Ando M, et al. Impairment of recognition memory and hippocampal long-term potentiation after acute exposure to clioquinol. Neuroscience. 2010;171(2):443–50.PubMedCrossRefGoogle Scholar
  145. 145.
    Ferrier TM, Schwieger AC, Eadie MJ. Delayed onset of partial epilepsy of temporal lobe origin following acute clioquinol encephalopathy. J Neurol Neurosurg Psychiatry. 1987;50(1):93–5.PubMedCentralPubMedCrossRefGoogle Scholar
  146. 146.
    Schmidt IG, Schmidt LH. Neurotoxicity of the 8-aminoquinolines; lesions in the central nervous system of the rhesus monkey induced by administration of plasmocid. J Neuropathol Exp Neurol. 1948;7(4):368–98.PubMedCrossRefGoogle Scholar
  147. 147.
    Schmidt IG, Schmidt LH. Neurotoxicity of the 8-aminoquinolines; reactions of various experimental animals to plasmocid. J Comp Neurol. 1949;91(3):337–67.PubMedCrossRefGoogle Scholar
  148. 148.
    Schmidt IG, Schmidt LH. Neurotoxicity of the 8-aminoquinolines. III. The effects of pentaquine, isopentaquine, primaquine, and pamaquine on the central nervous system of the rhesus monkey. J Neuropathol Exp Neurol. 1951;10(3):231–56.PubMedCrossRefGoogle Scholar
  149. 149.
    Hanes DA, McCollum G. Cognitive-vestibular interactions: a review of patient difficulties and possible mechanisms. J Vestib Res. 2006;16(3):75–91.PubMedGoogle Scholar
  150. 150.
    Redfern MS, Furman JM, Jacob RG. Visually induced postural sway in anxiety disorders. J Anxiety Disord. 2007;21(5):704–16.PubMedCentralPubMedCrossRefGoogle Scholar
  151. 151.
    Jacob RG, Furman JM, Durrant JD, Turner SM. Panic, agoraphobia, and vestibular dysfunction. Am J Psychiatry. 1996;153(4):503–12.PubMedCrossRefGoogle Scholar
  152. 152.
    Yardley L, Britton J, Lear S, Bird J, Luxon LM. Relationship between balance system function and agoraphobic avoidance. Behav Res Ther. 1995;33(4):435–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Mental HealthJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  2. 2.Uniformed Services University of the Health SciencesBethesdaUSA

Personalised recommendations