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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.
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: