Volume 99, Issue 3
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Mefloquine (Lariam; Roche Holding AG, Basel, Switzerland) has been linked to acute neuropsychiatric side effects. This is a concern for U.S. veterans who may have used mefloquine during recent Southwest Asia deployments. Using data from the , a population-based study of U.S. veterans who served between 2001 and 2008, we investigated associations between self-reported use of antimalarial medications and overall physical and mental health (MH) using the twelve-item short form, and with other MH outcomes using the post-traumatic stress disorder Checklist-17 and the Patient Health Questionnaire (anxiety, major depression, and self-harm). Multivariable logistic regression was performed to examine associations between health measures and seven antimalarial drug categories: any antimalarial, mefloquine, chloroquine, doxycycline, primaquine, mefloquine plus any other antimalarial, and any other antimalarial or antimalarial combination while adjusting for the effects of deployment and combat exposure. Data from 19,487 veterans showed that although antimalarial use was generally associated with higher odds of negative health outcomes, once deployment and combat exposure were added to the multivariable models, the associations with each of the MH outcomes became attenuated. A positive trend was observed between combat exposure intensity and prevalence of the five MH outcomes. No significant associations were found between mefloquine and MH measures. These data suggest that the poor physical and MH outcomes reported in this study population are largely because of combat deployment exposure.


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  1. Chen LH, Wilson ME, Schlagenhauf P, , 2007. Controversies and misconceptions in malaria chemoprophylaxis for travelers. JAMA 297: 22512263. [Google Scholar]
  2. Tickell-Painter M, Saunders R, Maayan N, Lutje V, Mateo-Urdiales A, Garner P, , 2017. Deaths and parasuicides associated with mefloquine chemoprophylaxis: a systematic review. Travel Med Infect Dis 20: 514. [Google Scholar]
  3. Korhonen C, Petersen K, Bruder C, Jung P, , 2007. Self-reported adverse events associated with antimalarial chemoprophylaxis in Peace Corps volunteers. Am J Prev Med 33: 194199. [Google Scholar]
  4. Alkadi HO, , 2007. Antimalarial drug toxicity: a review. Chemotherapy 53: 385391. [Google Scholar]
  5. Taylor WR, White NJ, , 2004. Antimalarial drug toxicity: a review. Drug Saf 27: 2561. [Google Scholar]
  6. Fukuda M, Raczniak GA, Riddle MS, Forgione M, Magill AJ, , 2017. Special Considerations for US Military Deployments. Available at: https://wwwnc.cdc.gov/travel/yellowbook/2018/advising-travelers-with-specific-needs/special-considerations-for-us-military-deployments/. Accessed November 17, 2017.
  7. Brisson M, Brisson P, , 2012. Compliance with antimalarial chemoprophylaxis in a combat zone. Am J Trop Med Hyg 86: 587590. [Google Scholar]
  8. Department of Veterans Affairs, Epidemiology Program, Post-Deployment Health Group, 2017. Analysis of VA Health Care Utilization among Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) Veterans: Cumulative from 1st Qtr FY 2002 through 3rd Qtr FY 2015 (October 1, 2001–June 30, 2015). Available at: https://www.publichealth.va.gov/epidemiology/reports/oefoifond/health-care-utilization. Accessed January 24, 2018.
  9. Office of the Assistant Secretary of Defense for Health Affairs, 2009. Memorandum: Policy Memorandum on the Use of Mefloquine (Lariam ® ) in Malaria Prophylaxis. Available at: http://www.lariaminfo.org/pdfs/policy-memo-secy-defense%20malaria-prophylaxis.pdf. Accessed September 8, 2017.
  10. Office of the Assistant Secretary of Defense for Health Affairs, 2013. Memorandum: Guidance on Medications for Prophylaxis of Malaria. Available at: https://health.mil/Policies/2013/04/15/Guidance-on-Medications-for-Prophylaxis-of-Malaria.pdf. Accessed November 20, 2017.
  11. Armed Forces Epidemiological Board, 2003. Memorandum: Antimalarials and Current Practice in the Military 2003–13. Available at: http://facadatabase.gov/committee/historyreportdocuments.aspx?flr=3515&cid=354&fy=2003. Accessed November 27, 2017.
  12. Armed Forces Epidemiological Board, 2004. Memorandum: Armed Forces Epidemiological Board (AFEB) Select Subcommittee to Develop Mefloquine Study Options. Available at: http://facadatabase.gov/committee/historyreportdocuments.aspx?flr=3528&cid=354&fy=2004. Accessed November 27, 2017.
  13. Tan KR, Magill AJ, Parise ME, Arguin PM, , 2011. Doxycycline for malaria chemoprophylaxis and treatment: report from the CDC expert meeting on malaria chemoprophylaxis. Am J Trop Med Hyg 84: 517531. [Google Scholar]
  14. Saunders DL, Garges E, Manning JE, Bennett K, Schaffer S, Kosmowski AJ, Magill AJ, , 2015. Safety, tolerability, and compliance with long-term antimalarial chemoprophylaxis in American soldiers in Afghanistan. Am J Trop Med Hyg 93: 584590. [Google Scholar]
  15. Sonmez A, Harlak A, Kilic S, Polat Z, Hayat L, Keskin O, Dogru T, Yilmaz MI, Acikel CH, Kocar IH, , 2005. The efficacy and tolerability of doxycycline and mefloquine in malaria prophylaxis of the ISAF troops in Afghanistan. J Infect 51: 253258. [Google Scholar]
  16. Pagès F, Boutin JP, Meynard JB, Keundjian A, Ryfer S, Giurato L, Baudon D, , 2002. Tolerability of doxycycline monohydrate salt vs. chloroquine-proguanil in malaria chemoprophylaxis. Trop Med Int Health 7: 919924. [Google Scholar]
  17. Lee TW, Russell L, Deng M, Gibson PR, , 2013. Association of doxycycline use with the development of gastroenteritis, irritable bowel syndrome and inflammatory bowel disease in Australians deployed abroad. Intern Med J 43: 919926. [Google Scholar]
  18. Sloan B, Scheinfeld N, , 2008. The use and safety of doxycycline hyclate and other second-generation tetracyclines. Expert Opin Drug Saf 7: 571577. [Google Scholar]
  19. Melles RB, Marmor MF, , 2015. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology 122: 110116. [Google Scholar]
  20. Jong EC, Nothdurft HD, , 2001. Current drugs for antimalarial chemoprophylaxis: a review of efficacy and safety. J Travel Med 8 (Suppl 3): S48S56. [Google Scholar]
  21. Costedoat-Chalumeau N, Dunogué B, Leroux G, Morel N, Jallouli M, Le Guern V, Piette JC, Brézin AP, Melles RB, Marmor MF, , 2015. A critical review of the effects of hydroxychloroquine and chloroquine on the eye. Clin Rev Allergy Immunol 49: 317326. [Google Scholar]
  22. Braga CB, 2015. Side effects of chloroquine and primaquine and symptom reduction in malaria endemic area (Mâncio Lima, Acre, Brazil). Interdiscip Perspect Infect Dis 2015: 17. [Google Scholar]
  23. Ashley EA, Recht J, White NJ, , 2014. Primaquine: the risks and the benefits. Malar J 13: 418. [Google Scholar]
  24. Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET, Magill AJ, , 2006. Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I. Am J Trop Med Hyg 75: 402415. [Google Scholar]
  25. Weinke T, Trautmann M, Held T, Weber G, Eichenlaub D, Fleischer K, Kern W, Pohle HD, , 1991. Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg 45: 8691. [Google Scholar]
  26. Stürchler D, Handschin J, Kaiser D, Kerr L, Mittelholzer ML, Reber R, Fernex M, , 1990. Neuropsychiatric side effects of mefloquine. N Engl J Med 322: 17521753. [Google Scholar]
  27. Schlagenhauf P, 2003. Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study. BMJ 327: 1078. [Google Scholar]
  28. Toovey S, , 2009. Mefloquine toxicity: a literature review. Travel Med Infect Dis 7: 26. [Google Scholar]
  29. Eick-Cost AA, Hu Z, Rohrbeck P, Clark LL, , 2017. Neuropsychiatric outcomes after mefloquine exposure among US military service members. Am J Trop Med Hyg 96: 159166. [Google Scholar]
  30. Ringqvist A, Bech P, Glenthøj B, Petersen E, , 2015. Acute and long-term psychiatric side effects of mefloquine: a follow-up on Danish adverse event reports. Travel Med Infect Dis 13: 8088. [Google Scholar]
  31. Van Riemsdijk MM, Ditters JM, Sturkenboom MC, Tulen JH, Ligthelm RJ, Overbosch D, Stricker BH, , 2002. Neuropsychiatric events during prophylactic use of mefloquine before travelling. Eur J Clin Pharmacol 58: 441445. [Google Scholar]
  32. Van Riemsdijk MM, Sturkenboom MC, Ditters JM, Ligthelm RJ, Overbosch D, Stricker BH, , 2002. Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: a focus on neuropsychiatric adverse events. Clin Pharmacol Ther 72: 294301. [Google Scholar]
  33. Van Riemsdijk MM, Sturkenboom MC, Pepplinkhuizen L, Stricker BH, , 2005. Mefloquine increases the risk of serious psychiatric events during travel abroad: a nationwide case-control study in the Netherlands. J Clin Psychiatry 66: 199204. [Google Scholar]
  34. Tan KR, Henderson SJ, Williamson J, Ferguson RW, Wilkinson TM, Jung P, Arguin PM, , 2017. Long term health outcomes among returned Peace Corps volunteers after malaria prophylaxis, 1995–2014. Travel Med Infect Dis 17: 5055. [Google Scholar]
  35. Food and Drug Administration, 2013. FDA Drug Safety Communication: FDA Approves Label Changes for Antimalarial Drug Mefloquine Hydrochloride Due to Risk of Serious Psychiatric and Nerve Side Effects. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm362227.htm. Accessed April 14, 2015.
  36. McArdle JJ, Sellin LC, Coakley KM, Potian JG, Quinones-Lopez MC, Rosenfeld CA, Sultatos LG, Hognason K, , 2005. Mefloquine inhibits cholinesterases at the mouse neuromuscular junction. Neuropharmacology 49: 11321139. [Google Scholar]
  37. Dursa EK, Reinhard MJ, Barth SK, Schneiderman AI, , 2014. Prevalence of a positive screen for PTSD among OEF/OIF and OEF/OIF-Era veterans in a large population-based cohort. J Trauma Stress 27: 542549. [Google Scholar]
  38. Seal KH, Metzler TJ, Gima KS, Bertenthal D, Maguen S, Marmar CR, , 2009. Trends and risk factors for mental health diagnoses among Iraq and Afghanistan veterans using Department of Veterans Affairs health care, 2002–2008. Am J Public Health 99: 16511658. [Google Scholar]
  39. Lee S, Fonseca VP, Wolters CL, Dougherty DD, Peterson MR, Schneiderman AI, Ishii EK, , 2015. Health care utilization behavior of veterans who deployed to Afghanistan and Iraq. Mil Med 180: 374379. [Google Scholar]
  40. Nevin RL, , 2010. Mefloquine prescriptions in the presence of contraindications: prevalence among US military personnel deployed to Afghanistan, 2007. Pharmacoepidemiol Drug Saf 19: 206210. [Google Scholar]
  41. Eber S, Barth S, Kang H, Mahan C, Dursa E, Schneiderman A, , 2013. The National Health Study for a new generation of United States veterans: methods for a large-scale study on the health of recent veterans. Mil Med 178: 966969. [Google Scholar]
  42. Dillman DA, Smyth JD, Christian LM, , 2014. Internet, Phone, Mail, and Mixed-Mode Surveys: The Tailored Design Method, 4th edition. Hoboken, NJ: John Wiley & Sons.
  43. Peterson AL, Seegmiller RA, Schindler LS, , 2011. Severe neuropsychiatric reaction in a deployed military member after prophylactic mefloquine. Case Rep Psychiatry 2011: 350417: 14. [Google Scholar]
  44. Javorsky DJ, Tremont G, Keitner GI, Parmentier AH, , 2001. Cognitive and neuropsychiatric side effects of mefloquine. J Neuropsychiatry Clin Neurosci 13: 302. [Google Scholar]
  45. Boudreau E, Schuster B, Sanchez J, Novakowski W, Johnson R, Redmond D, Hanson R, Dausel L, , 1993. Tolerability of prophylactic Lariam® regimens. Trop Med Parasitol 44: 257265. [Google Scholar]
  46. Grabias B, Kumar S, , 2016. Adverse neuropsychiatric effects of antimalarial drugs. Expert Opin Drug Saf 15: 903910. [Google Scholar]
  47. Department of Defense (DoD), 2003. Post-Deployment Health Assessment (PDHA) form, 2003. Available at: http://www.jiatfs.southcom.mil/Portals/4/Documents/J4/J4_dd2796.pdf. Accessed September 8, 2017.
  48. Cronbach L, , 1951. Coefficient alpha and the internal structure of tests. Psychometrika 16: 297334. [Google Scholar]
  49. Ware JE, Jr. Kosinski M, Keller SD, , 1996. A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity. Med Care 34: 220233. [Google Scholar]
  50. Weathers FW, Litz BT, Herman DS, Huska JA, Keane TM, , 1993. The PTSD Checklist (PCL): Reliability, Validity, and Diagnostic Utility. Paper Presented at the International Society for Traumatic Stress Studies, San Antonio, TX.
  51. Keen SM, Kutter CJ, Niles BL, Krinsley KE, , 2008. Psychometric properties of PTSD checklist in sample of male veterans. J Rehabil Res Dev 45: 465474. [Google Scholar]
  52. Spitzer RL, Kroenke K, Williams JB, Patient Health Questionnaire Primary Care Study Group; , 1999. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. JAMA 282: 17371744. [Google Scholar]
  53. SAS Institute Inc, 2014. Base SAS ® 9.4 Procedures Guide, 3rd edition. Cary, NC: SAS Institute Inc.
  54. Yoon FB, Jang D, Sukasih A, Kress AM, Barth SK, Mahan CM, Coughlin SS, Dursa EK, Schneiderman AI, , 2013. Adjustments for Misclassification of Deployment Status in a Population Based Health Study of Operation Enduring Freedom and Operation Iraqi Freedom Veterans. JSM Proceedings, Mental Health Statistics Section. Alexandria, VA: American Statistical Association.
  55. Kuha J, Skinner C, , 1997. Categorical data analysis and misclassification. Lyberg LE, Biemer PP, Collins M, de Leeuw ED, Dippo C, Schwarz N, Trewin D, eds. Survey Measurement and Process Quality. New York, NY: John Wiley & Sons.
  56. Barrett PJ, Emmins PD, Clarke PD, Bradley DJ, , 1996. 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 313: 525528. [Google Scholar]
  57. Van Riemsdijk MM, van der Klauw MM, van Heest JA, Reedeker FR, Ligthelm RJ, Herings RM, Stricker BH, , 1997. Neuro-psychiatric effects of antimalarials. Eur J Clin Pharmacol 52: 16. [Google Scholar]
  58. Schlagenhauf P, 1996. Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance. Trop Med Int Health 1: 485494. [Google Scholar]
  59. Schlagenhauf P, Johnson RJ, Schwartz E, Nothdurft HD, Steffen R, , 2009. Evaluation of mood profiles during malaria chemoprophylaxis: a randomized, double-blind, four-arm study. J Travel Med 16: 4245. [Google Scholar]
  60. Ollivier L, Tifratene K, Josse R, Keundjian A, Boutin JP, , 2004. The relationship between body weight and tolerance to mefloquine prophylaxis in non-immune adults: results of a questionnaire-based study. Ann Trop Med Parasitol 98: 639641. [Google Scholar]
  61. Jaspers CA, Hopperus Buma AP, van Thiel PP, van Hulst RA, Kager PA, , 1996. Tolerance of mefloquine chemoprophylaxis in Dutch military personnel. Am J Trop Med Hyg 55: 230234. [Google Scholar]
  62. Schneider C, Adamcova M, Jick SS, Schlagenhauf P, Miller MK, Rhein HG, Meier CR, , 2013. Antimalarial chemoprophylaxis and the risk of neuropsychiatric disorders. Travel Med Infect Dis 11: 7180. [Google Scholar]
  63. Wells TS, Smith TC, Smith B, Wang LZ, Hansen CJ, Reed RJ, Goldfinger WE, Corbeil TE, Spooner CN, Ryan MA, , 2006. Mefloquine use and hospitalizations among US service members, 2002–2004. Am J Trop Med Hyg 74: 744749. [Google Scholar]
  64. Lobel HO, Miani M, Eng T, Bernard KW, Hightower AW, Campbell CC, , 1993. Long-term malaria prophylaxis with weekly mefloquine. Lancet 341: 848851. [Google Scholar]
  65. Kolifarhood G, 2017. Prophylactic efficacy of primaquine for preventing Plasmodium falciparum and Plasmodium vivax parasitaemia in travelers: a meta-analysis and systematic review. Travel Med Infect Dis 17: 518. [Google Scholar]
  66. Ebringer A, Heathcote G, Baker J, Waller M, Shanks GD, Edstein MD, , 2011. Evaluation of the safety and tolerability of a short higher-dose primaquine regimen for presumptive anti-relapse therapy in healthy subjects. Trans R Soc Trop Med Hyg 105: 568573. [Google Scholar]
  67. Schwartz E, Regev-Yochay G, , 1999. Primaquine as prophylaxis for malaria for nonimmune travelers: a comparison with mefloquine and doxycycline. Clin Infect Dis 29: 15021506. [Google Scholar]
  68. Baird JK, United States Naval Medical Research Unit 2 Clinical Trials Team , 2001. Randomized, parallel placebo-controlled trial of primaquine for malaria prophylaxis in Papua, Indonesia. Clin Infect Dis 33: 19901997. [Google Scholar]
  69. Nevin RL, Croft AM, , 2016. Psychiatric effects of malaria and antimalarial drugs: historical and modern perspectives. Malar J 15: 332. [Google Scholar]

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  • Received : 05 Feb 2018
  • Accepted : 08 May 2018
  • Published online : 25 Jun 2018

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