Mefloquine Neurotoxicity?
Mefloquine Neurotoxicity?
By Lin H. Chen, MD
Dr. Chen is Assistant Clinical Professor, Harvard Medical School, Director, Travel Medicine Center, Mt. Auburn Hospital, Cambridge, MA.
Dr. Chen reports no financial relationships relevant to this field of study.
Synopsis: A randomized and double-blind study found no significant differences in mood among users of atovaquone-proguanil, chloroquine-proguanil, doxycycline, and mefloquine, although women on mefloquine had more fatigue and confusion than men, and age < 34 years was associated with more tension and fatigue.
Source: Schlagenhauf P, et al. Evaluation of mood profiles during malaria chemoprophylaxis: A randomized, double-blind, four-arm study. J Travel Med 2009;16:42-45.
Schlagenhauf, et al. utilized the standardized Profile of Mood States (POMS) questionnaire to conduct a randomized, double-blind, four-arm study with placebo run-in phase to compare moods and feelings in travelers using chemoprophylaxis. The following areas of feelings were explored: tension, depression, anger, vigor, fatigue, and confusion. Subjects were enrolled at travel clinics in Switzerland, Germany, and Israel, and responded to the questionnaire at 4 points: recruitment, 13-11 days before departure, 6-4 days before departure, and 7-14 days after return from Africa.
The agents studied were atovaquone-proguanil (AP), chloroquine-proguanil (CP), doxycycline, and mefloquine. Among 547 subjects who completed the POMS questionnaires at the 4 time points, there were 154 on AP, 135 on CP, 142 on doxycycline, and 138 on mefloquine. The investigators found no significant differences regarding mood impact among the medication arms. Scores were in the normal range overall, and there was no more than 1 standard deviation from the norm. Analysis for differences regarding gender, age, medication group, and time point found no significant differences between males and females. However, women in the mefloquine group had more "fatigue" and "confusion" than men. Participants younger than 34 years had more "tension" and "fatigue." "Tension" and "total mood disturbance" were lowest after return than at all 3 earlier times points. "Vigor" was highest at recruitment, and "fatigue" was highest at the second and third time points.
Commentary
The Schlagenhauf study is notable for its rigorous methodology, randomized and double-blind, in assessing mood during malaria chemoprophylaxis. The results should have scientific validity, and the lack of significant mood difference among the medications is important given the publicity mefloquine has received regarding its neuropsychiatric side effects.
In a recent review, Toovey summarized published data regarding mefloquine neurotoxicity since its initial report in 1987.1 He highlighted some studies on mefloquine chemoprophylaxis that found mefloquine to be associated with increased neuropsychiatric adverse events2-4 (such as depression, anger, fatigue), especially in females,5,6 and with a low body mass index (BMI).6,7 In a study on mood, van Riemsdijk et al found that mefloquine affected mood scores (compared to travelers' baseline) in the 3 weeks preceding travel.8
On the other hand, Toovey noted that healthy Australian volunteers exhibited no increased incidence of neuropsychiatric adverse events,9 and a study on drivers found an increase in tracking performance with mefloquine – possibly psychostimulatory properties.10 An evaluation of trainee pilots through a triaxial flight simulator found no impairment in performance but decreased sleep time.11
Toovey also reviewed ototoxicity and found rare cases of hearing loss associated with mefloquine, some permanent and some reversible, as well as ototoxicity associated with other antimalarials: artemisinins, sulfadoxine-pyrimethamine, azithromycin, chloroquine, hydroxychloroquine. He discussed possible mechanisms of neurotoxicity, including "binding to neuroreceptors and cholinesterases, inhibition of sarcoendoplasmic reticulum ATPase and interference with cellular calcium homeostasis, accumulation in the CNS, and reductions in CNS efflux in persons with certain MDR1 polymorphisms."1
For readers interested in details of studies and types of studies grouped into randomized-controlled and double-blind studies, "other" study methods (database analysis, cross-sectional, case-control, open label, Cochrane review), and observational studies (postal and telephone surveys, retrospective reviews, reports to manufacturer), see Table 2 in reference 12.12 The Schlagenhauf study provides some messages for travel medicine providers regarding chemoprophylaxis and mood, and can be useful in assessing the appropriateness of mefloquine for certain travelers:
- mood scores were in the normal range overall for AP, CP, doxycycline, and mefloquine;
- women using mefloquine had more "fatigue" and "confusion" than men;
- travelers younger than 34 years using any chemoprophylaxis had more "tension" and "fatigue" than older travelers;
- chemoprophylaxis may affect "vigor," although the trip preparation and travel itself also may impact "vigor"
- "tension and "total mood disturbance" were lowest after return, which also may be attributed to travel preparation and travel itself rather than chemoprophylaxis.
References
- Toovey S. Mefloquine neurotoxicity: A literature review. Travel Med Infect Dis 2009;7:2-6.
- van Riemsdijk MM, Sturkenboom MC, Ditters JM, et al. Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: A focus on neuropsychiatric adverse events. Clin Pharmacol Ther 2002;72:294-301.
- Barrett PJ, Emmins PD, Clarke PD, et al. Comparison of adverse events associated with the use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: Postal and telephone survey of travellers. BMJ 1996;313:525-528.
- Meier CR, Wilcock K, Jick SS. The risk of severe depression,psychosis or panic attacks with prophylactic antimalarials. Drug Saf 2004;27(3):203-213.
- Schlagenhauf P, Tschopp A, Johnson R, et al. Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: Multicentre, randomised, double blind, four arm study. BMJ 2003;327(7423):1078-1081.
- van Riemsdijk MM, Sturkenboom MC, Ditters JM, et al. Low body mass index is associated with an increased risk of neuropsychiatric adverse events and concentration impairment in women on mefloquine. Br J Clin Pharmacol 2004;57(4):506-512.
- Ollivier L, Tifratene K, Josse R, et al. The relationship between body weight and tolerance to mefloquine prophylaxis in non-immune adults: Results of a questionnaire based study. Ann Trop Med Parasitol 2004;98(6):639-641.
- van Riemsdijk MM, Ditters JM, Sturkenboom MC, et al. Neuropsychiatric events during prophylactic use of mefloquine before travelling. Eur J Clin Pharmacol 2002;58(6):441-445.
- Davis TM, Dembo LG, Kaye-Eddie SA, et al. Neurologic, cardiovascular and metabolic effects of mefloquine in healthy volunteers: A double-blind, placebo-controlled trial. Br J Clin Pharmacol 1996;42(4):415-421.
- 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):475-482.
- Schlagenhauf P, Lobel HO, Steffen R, et al. Tolerability of mefloquine in Swissair trainee pilots. Am J Trop Med Hyg 1997;56:235-240.
- Chen LH, Wilson ME, Schlagenhauf P. Controversies and misconceptions in malaria chemoprophylaxis in travelers. JAMA 2007;297(20):2251-2263.
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