| Abstract|| |
Malaria is one of the most common infectious diseases, resulting in the deaths of millions of children around the world. The disease causes approximately half a million to 2.5 million people to die annually. People can only get malaria by being bitten by an infective female Anopheles mosquito that transmits malaria from infected individuals. The increase in international travel and the spread of malaria around the world has resulted in an increased risk of malaria infection. Prophylactic drugs are used to prevent the spread of malaria and to protect individuals in endemic areas. The most efficacious drug for treatment and prophylaxis against malaria is mefloquine (MQ), an antimalarial drug used especially as a prophylaxis against Plasmodium falciparum and as a treatment for malaria. MQ is also used to prevent the treatment of chloroquine-resistant P. falciparum malaria. This review focuses on the advantages of MQ and its adverse events.
Keywords: Malaria, mefloquine (MQ), neuropsychiatric
|How to cite this article:|
Al-Amer O. Neuropsychiatric adverse events during prophylaxis against malaria by using mefloquine before traveling. Ann Trop Med Public Health 2015;8:159-63
|How to cite this URL:|
Al-Amer O. Neuropsychiatric adverse events during prophylaxis against malaria by using mefloquine before traveling. Ann Trop Med Public Health [serial online] 2015 [cited 2021 Apr 14];8:159-63. Available from: https://www.atmph.org/text.asp?2015/8/5/159/159851
| Introduction to Malaria|| |
Malaria is one of the most common infectious diseases, resulting in the deaths of millions of children around the world. The disease causes approximately half a million to 2.5 million people to die annually (Simpson et al.).  Fever, vomiting, shivering, anemia, and retinal damage are the most common symptoms of malaria. The disease is caused by protozoan parasites of the genus Plasmodium, including Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. People can only get malaria by being bitten by an infective female Anopheles mosquito that transmits malaria from infected individuals. The pathogenesis of malaria starts with the injection of sporozoites from the saliva of an infected mosquito as it feeds on blood. Within 30 min, sporozoites begin to multiply asexually in the hepatocytes for a period of 6-15 days, which is known as the exoerythrocytic phase. In the liver the sporozoites differentiate into merozoites. The erythrocytic stage then starts with the merozoites escaping into the blood and infecting red blood cells, which multiply asexually and invade fresh red blood cells (Miller et al.).  Geographic distribution is a significant factor in malaria infection. Malaria is more common in rural areas than in cities and is an endemic disease in South America, many parts of Asia, and much of Africa (Greenwood and Mutabingwa).  Tropical climates and poverty are also major factors related to malaria infection (Sachs and Malaney). 
| Prevention and Treatment of Malaria|| |
The increase in international travel and the spread of malaria around the world has resulted in an increased risk of malaria infection. Prophylactic drugs are used to prevent the spread of malaria and to protect individuals in endemic areas. These drugs cause mosquitos to be eradicated and so prevent mosquito bites. Up-to-date pretravel advice is also necessary. There are several types of drugs used as therapy and prophylaxis to treat malaria. Chloroquine is an antimalarial drug and was the prophylactic drug of choice for many years in most parts of the world, but its effect is now limited against P. falciparum due to its increasing resistance. Thus, chloroquine is now ineffective because it fails to cure P. falciparum infection in the most endemic areas. In areas of increased resistance, proguanil is sometimes combined with chloroquine as a moderate drug, but it does not appear to be as efficacious as mefloquine (MQ). Doxycycline is an antimalarial and prophylactic drug that interferes with parasite ribosomal activity during the blood phase. It is used in areas of chloroquine resistance and is equivalent to MQ. The most efficacious drug for treatment and prophylaxis against malaria is MQ, an antimalarial drug used as a prophylaxis, especially against P. falciparum and as a treatment for malaria. MQ is also used to prevent the treatment of chloroquine-resistant P. falciparum malaria (Jong and Nothdurft). 
| Mefloquine|| |
The history of MQ dates back to the early 1960s. It was developed during a 40-year effort of the US Army Antimalarial Drug Development Program (Wongsrichanalai et al.).  Pharmacologically, MQ is a 4-quinoline methanol that is active against the blood stage of the P. falciparum, P. vivax, and P. malariae. The gametocytes or the exoerythrocytic stage of parasites do not act as a target for MQ, whereas the trophozoite stage of the malaria parasite is only the target stage for MQ. The efficacy of MQ is more than 91% for nonimmune travelers to areas of chloroquine-resistant P. falciparum (Jong and Nothdurft).  It is metabolized in the hepatocytes and excreted mainly in feces. The half-life required to eliminate MQ is 2-6 weeks, with an average of 3 weeks (Wongsrichanalai et al.).  Generally, MQ is recommended as the drug of choice for travelers going to areas with chloroquine-resistant P. falciparum malaria by the health authorities in the USA, the UK, and Israel, in addition to other countries (Schwartz et al.). 
MQ is an orally administered antimalarial drug. Originally, a single dose of 15 mg/kg of MQ was recommended, whereas increasing the dose up to 25 mg/kg has been recommended now to improve its efficacy because of P. falciparum's resistance to MQ in certain places. It is taken in split doses from 6-12 h to avoid high dose intolerance. MQ is considered a very effective drug because only 250 mg per week is required (Wongsrichanalai et al.). 
| Benefits of Mq|| |
Recently, the numbers of cases of malaria have increased dramatically for several reasons. The first reason is an increase in traveling, for holiday and for business around the world and in endemic areas. The second reason is the resistance of P. falciparum to all available antimalarial drugs in South America, East and West Africa, and many parts of Asia. The traveler thus requires prophylaxis against malaria. MQ is beneficial in areas where chloroquine resistance is widespread, as it is effective against P. falciparum (Breckenridge). 
| The Adverse Effects of Mq|| |
Despite the effectiveness of MQ for treatment and prophylaxis of chloroquine-resistant malaria, it can also cause adverse effects. The more recent studies on MQ indicate some mild side effects, include dizziness, nausea, headaches, sleeping disturbances, fatigue, and diarrhea fatigue, and diarrhea (Rendi-Wagner et al.)  Some rare, serious neurologic and psychiatric side effects are also reported, including acute psychosis, severe anxiety, severe depression with suicidal tendencies, seizures, and delirium (Jong and Nothdurft).  The incidence of serious events for MQ has been reported to have occurred approximately in 1:10,000 patients for chemoprophylaxis and in 1:200-1200 patients for treatment (Dow et al.). 
Several studies suggest that the adverse neuropsychiatric reactions are associated with the central nervous system (CNS) toxicity that results from the use of MQ. Apart from the adverse neuropsychiatric reactions, the effects of MQ on the CNS remain unclear (Tran et al., Schlagenhauf and Steffen). , On a biochemical level, MQ shows evidence of disrupting endoplasmic reticulum calcium homeostasis and inducing a stress response in rat neurons that may contribute to the acute neurotoxicity of the drug (Dow et al.).  Cruikshank et al. found that MQ inhibits Cx36 and Cx50 gap junctional channels and also blocks coupling between interneurons in neocortical slices (Cruikshank et al.).  In one study, the neuropsychiatric adverse effects of MQ was a post-hepatic syndrome caused by primary liver damage or thyroid disturbance (Croft and Herxheimer). 
Today, there are many types of antimalarial drugs used for chemoprophylaxis. Chloroquine remains the drug of choice for the prevention and treatment of malaria in some countries. Nausea, vomiting, headaches, dizziness, blurred vision, and itching are the minor side effects. The chloroquine resistance of P. falciparum is the major problem with chloroquine. The second antimalarial drug is proguanil; mouth ulcers and hair loss are the side effects reported in association with its use. Doxycycline is an antimalarial drug equivalent to MQ, but it is not regarded as adequate prophylaxis for P. vivax. Its many side effects include esophagitis, nausea, photosensitivity resulting in an exaggerated sunburn reaction, and vaginal candidiasis. The adverse reactions of the atovaquone/proguanil antimalarial combination drug (Malarone), however, tend to be rare and may include abdominal pain, nausea, vomiting, and headaches. Comparing the side effects of MQ with those of other drugs, MQ tends to be the choice drug for chloroquine-resistant P. falciparum areas (Jong and Nothdurft). 
| Safety for Mq Uses|| |
For safety reasons, the incidence of neuropsychiatric disorders related to MQ is an important issue regarding the chemoprophylaxis of malaria in travelers. Travelers should be informed about the risk of malaria and the side effects of MQ in addition to being carefully screened to identify individuals with a high risk of contracting malaria (Fuller et al.).  MQ should always be started at least 1 week before traveling when used as malarial prophylaxis, to determine any idiosyncratic reaction and to attain steady-state plasma concentrations (Breckenridge). 
In case of individuals with a history of neuropsychiatric disorders, MQ prophylaxis can be contraindicated for patients with a history of seizures or psychiatric disorders. Thus, all current guidelines do not recommend MQ for individuals with a personal or family history of psychiatric disorders, and for individuals with depression (Chen et al.). 
Malaria in pregnant woman is mainly caused by P. falciparum and P. vivax, and is responsible for 5-12% of all low birth weights (LBW), and each year malaria contributes overall to the death of 75,000-200,000 infants (Newman et al.).  Malaria is also responsible for up to 60% of spontaneous abortions and up to l0% of maternal mortality rates (Phillips-Howard et al.).  Therefore, the antimalarial drug that is used must be safe for the mother, the fetus, and later for the breast-feeding infant. The safety of MQ during pregnancy has been evaluated through different prospective studies in Thailand and Malawi. The studies indicated that MQ was safe for women who took either 125 mg/week or 250 mg/week for prophylaxis during the third trimester, as no increase in the incidence of stillbirths or spontaneous abortions was observed (Nosten et al., Steketee et al.). , On the other hand, another study in Thailand showed a significantly increased risk of stillbirth in women exposed to MQ during pregnancy (Nosten et al.). 
| Evaluation of The Safety of Mq With Relation to Its Benefits|| |
Currently, many countries use MQ as the first choice in malaria prophylaxis for travelers to areas with chloroquine-resistant P. falciparum malaria. A dose of 250 mg weekly or a single dose up to 1500 mg is generally tolerated by the body (Jha and Kumar).  During the last few years, some neuropsychiatric adverse events have been reported for MQ use. To evaluate the safety of MQ, many studies of MQ effects should be screened.
In 1996, Barrett et al. from the London School of Hygiene and Tropical Medicine made a study involving people who had traveled to chloroquine-resistant areas between November 1993 and February 1995. From 4953 questionnaires, 3851 were answers the questionnaire with percentage 77.8%. 1214 travelers took MQ (50.7%) and 1181 took proguanil plus chloroquine (49.3%) for malaria chemoprophylaxis. When the data were analyzed, the neuropsychiatric side effects were reported. As a report, 333 travelers suffering from neuropsychiatric problems after using MQ antimalaria (27%) whereas 189 travelers suffered from neuropsychiatric problems after using proguanil plus antimalarial chloroquine (16%). This study reported some status of disabling neuropsychiatric adverse effects that represent 0.7% of travelers taking MQ and 0.09% of those taking proguanil plus chloroquine. Finally, this study reported only two statuses of serious adverse events related to MQ chemoprophylaxis (Barrett et al.). 
Another study was carried out in 1996 by the Traveller's Medical and Vaccination Centres (TMVC) clinics in Adelaide and Melbourne (Australia), on travelers to high-risk chloroquine-resistant areas between November 1993 and October 1994. This study demonstrated that 285 travelers used MQ (250 mg/week), whereas 383 travelers used doxycycline (100 mg/day). After analyzing the data, an excess of CNS-type complaints and neuropsychiatric side effects were reported. Among MQ users, 41 travelers (14.4%) suffered from dizziness, 31 travelers (10.9%) suffered from headaches, 29 travelers (10.2%) suffered from nightmares, 27 travelers (9.5%) suffered from sleep disturbance, 14 travelers (4.9%) suffered from mood change, 13 travelers (4.6%) suffered from anxiety, and 10 travelers (3.5%) suffered from palpitation. The travelers who used antimalarial doxycycline also suffered from these symptoms, but with lower percentages (Phillips and Kass). 
In 2000, a study was carried out by a travel clinic at the Bnai Zion Medical Center. This study consisted of a two-phase questionnaire. The first phase involved the travelers answering if they suffered from neurologic or psychiatric symptoms, and the second phase was concerned with the most common neuropsychiatric problems in travelers who responded positively to the first question. Out of the 2500 travelers who responded in the first phase, 1340 travelers answered the questionnaire (53.6%). This study indicated that 948 travelers (70.7% of respondents) took MQ and 68 (5%) took chloroquine alone or combined with proguanil. Among those, 151 travelers (11.3%) suffered from neuropsychiatric problems. In the second phase, 117 of 151 answered the questionnaire (77.5%). As the study indicated, sleeping disturbances (52.1%), fatigue (48.7%), and dizziness (39.3%) were the most common neuropsychiatric problems (Potasman et al.). 
In 2002, a study was carried out by the Travel Clinic of the Havenziekenhuis and Institute for Tropical Diseases, Rotterdam, the Netherlands. In that study, 179 (89.5%) out of 200 travelers to areas with chloroquine-resistant P. falciparum malaria between 1 May 1999 and 7 March 2000 were enrolled. All 179 travelers used MQ as prophylaxis before traveling. The study reported neuropsychiatric adverse events for 58 travelers (21 males and 37 females) due to the use of MQ. Insomnia was the most frequently reported adverse event for travelers. This study also indicated that females suffer from neuropsychiatric adverse events more frequently than males (P = 0.005). Finally, this study found that the mild neuropsychiatric adverse events are common during the first weeks of MQ use. Thus, some countries start MQ prophylaxis 3 weeks before traveling to areas with chloroquine-resistant P. falciparum malaria. If adverse events develop, another antimalarial drug can be used instead of MQ (van Riemsdijk et al.). 
A study was also carried out in the Netherlands between 1 September 1997 and 1 June 2000. This study was made to determine if MQ was a factor that increases the risk of neuropsychiatric adverse events during travel abroad. The final population number in this study was 111 cases of psychiatric disturbance and 453 controls. This study found that many factors contributed and increased the neuropsychiatric adverse events during travel abroad, including female sex, marital status, traveling alone, and a history of psychiatric disease in addition to the use of antimalarial drugs for prophylaxis. After analyzing the data, depression, anxiety, psychosis, and insomnia were found to be the most frequent psychiatric effects. Twenty-two (22) persons out of 111 suffered from neuropsychiatric adverse events after using MQ, in which MQ was more pronounced among females than males. Finally, this study demonstrated that the use of MQ is associated with an increased risk of psychiatric events in patients with a history of psychiatric diseases (van Riemsdijk et al.). 
In 2007, a study was carried out by the Japan Ground Self-Defense Force (JGSDF) with its members between April 2002 and September 2003. Among the 1,831 members who responded to the questionnaire (97%), 447 (24.4%) suffered from neuropsychiatric adverse events after using MQ. The study found that 130 members (7.1%) suffered from dizziness/vertigo, which was the most common neuropsychiatric adverse effect, followed by sleep disturbance (2.7%) and nightmares (2.2%). After these results, JGSDF reported that MQ prophylaxis was generally safe for the Japanese despite some neuropsychiatric effects, as none of them were severe (Fujii et al.). 
In 2007 a study was carried out by the Travel Clinic in Switzerland between October 2003 and September 2004 to investigate which drug was chosen by travelers. By analyzing the data to choose one antimalarial drug from among MQ, Malarone, and doxycycline, from the 1073 travelers who responded in this study, MQ was chosen by 45% of travelers, Malarone by 21%, doxycycline by 18%, 10.8% said "I do not know," and 4.6% said "I do not want a prophylaxis." This study also found that 32.7% of the responding travelers used those antimalarial drugs because they had more acceptable adverse effects (compared to other drugs) in addition to some other reasons, such as price (21.4%), prior use of the drug (14.8%), regimen (8.7%), prophylaxis duration (6%), and miscellaneous reasons (16.3%) (Senn et al.). 
Barbara Bannister made a study relating to the Health Protection Agency (HPA), whose the UK guidelines for 2006-2007 allow the use of mosquito avoidance only without prophylactic drugs for travelers to areas or countries with lower malaria risk than in previous years such as northern and southern India, much of Bangladesh (except the Chittagong Hill Tracts), and most of Sri Lanka (except for northern areas). For areas with high malaria risk, prophylaxis is recommended and chloroquine plus proguanil is the most suitable method. In contrast, for areas of chloroquine-resistant P. falciparum with high malaria risk, such as West and East African countries, the UK guidelines recommend the use of MQ, atovaquone plus proguanil, or doxycycline, rather than chloroquine plus proguanil, prophylaxis with regard to travelers' circumstances and preferences (Bannister). 
| Discussion and Conclusion|| |
This essay demonstrates that neuropsychiatric adverse effects are related to the use of the MQ antimalarial drug during travel and that females are more susceptible to the resulting neuropsychiatric illnesses than males. MQ has acetylcholinesterase-inhibiting properties, which affect the CNS, resulting in neuropsychiatric adverse effects including anxiety, disrupted concentration and memory, confusion, restlessness, sleep disturbances, and convulsions (van Riemsdijk et al.). 
Despite the side effects of MQ, almost all travelers and pharmacists choose MQ because it is effective in most areas. From the results of many studies it was found that the neuropsychiatric effects related to MQ were mild except in a few instances. Finally, to use MQ chemoprophylaxis safely and avoid its side effects, caution should be exercised. First, individuals with depression or psychiatric disorders should avoid the MQ. Second, it should only be taken when going to areas of chloroquine-resistant P. falciparum with high malaria risk. Third, it should be taken exactly as prescribed. Fourth, travelers should start taking MQ 3 weeks before traveling and continue taking it for 4 weeks after returning. Finally, individuals should consult health professionals before their travels.
| References|| |
Simpson JA, Watkins ER, Price RN, Aarons L, Kyle DE, White NJ. Mefloquine pharmacokinetic-pharmacodynamic models: Implications for dosing and resistance. Antimicrob Agents Chemother 2000;44:3414-24.
Miller LH, Baruch DI, Marsh K, Doumbo OK. The pathogenic basis of malaria. Nature 2002;415:673-9.
Greenwood B, Mutabingwa T. Malaria in 2002. Nature 2002;415:670-2.
Sachs J, Malaney P. The economic and social burden of malaria. Nature 2002;415:680-5.
Jong EC, Nothdurft HD. Current drugs for antimalarial chemoprophylaxis: A review of efficacy and safety. J Travel Med 2001;8(Suppl 3):S48-56.
Wongsrichanalai C, Prajakwong S, Meshnick SR, Shanks GD, Thimasarn K. Mefloquine - its 20 years in the Thai Malaria Control Program. Southeast Asian J Trop Med Public Health 2004;35:300-8.
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;65:189-92.
Breckenridge A. Risks and benefits of prophylactic antimalarial drugs. BMJ 1989;299:1057-8.
Rendi-Wagner P, Noedl H, wernsdorfer WH, Wiedermann G, Mikolasek A, Kollaritsch H. Unexpected frequency, duration and spectrum of adverse events after therapeutic dose of mefloquine in healthy adults. Acta Trop 2002;81:167-73.
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.
Tran TM, Browning J, Dell ML. Psychosis with paranoid delusions after a therapeutic dose of mefloquine: A case report. Malar J 2006;5:74.
Schlagenhauf P, Steffen R. Neuropsychiatric events and travel: Do antimalarials play a role? J Travel Med 2000;7:225-6.
Cruikshank SJ, Hopperstad M, Younger M, Connors BW, Spray DC, Srinivas M. Potent block of Cx36 and Cx50 gap junction channels by mefloquine. Proc Natl Acad Sci U S A 2004;101:12364-9.
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.
Fuller SJ, Naraqi S, Gilessi G. Paranoid psychosis related to mefloquine antimalarial prophylaxis. P N G Med J 2002;45:219-21.
Chen LH, Wilson ME, Schlagenhauf P. Controversies and misconceptions in malaria chemoprophylaxis for travelers. JAMA 2007;297:2251-63.
Newman RD, Parise ME, Slutsker L, Nahlen B, Steketee RW. Safety, efficacy and determinants of effectiveness of antimalarial drugs during pregnancy: Implications for prevention programmes in Plasmodium falciparum-endemic sub-Saharan Africa. Trop Med Int Health 2003;8:488-506.
Phillips-Howard PA, Steffen R, Kerr L, Vanhauwere B, Schildknecht J, Fuchs E, et al
. Safety of mefloquine and other antimalarial agents in the first trimester of pregnancy. J Travel Med 1998;5:121-6.
Nosten F, Karbwang J, White NJ, Honeymoon NA, Bangchang K, Bunnag D, et al
. Mefloquine antimalarial prophylaxis in pregnancy: Dose finding and pharmacokinetic study. Br J Clin Pharmacol 1990;30:79-85.
Steketee RW, Wirima JJ, Slutsker L, Khoromana CO, Heymann DL, Breman JG. Malaria treatment and prevention in pregnancy: Indications for use and adverse events associated with use of chloroquine or mefloquine. Am J Trop Med Hyg 1996;55(Suppl):50-6.
Nosten F, Vincenti M, Simpson J, Yei P, Thwai KL, de Vries A, et al
. The effects of mefloquine treatment in pregnancy. Clin Infect Dis 1999;28:808-15.
Jha S, Kumar R, Kumar R. Mefloquine toxicity presenting with polyneuropathy - a report of two cases in India. Trans R Soc Trop Med Hyg 2006;100:594-6.
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;313:525-8.
Phillips MA, Kass RB. User acceptability patterns for mefloquine and doxycycline malaria chemoprophylaxis. J Travel Med 1996;3:40-5.
Potasman I, Beny A, Seligmann H. Neuropsychiatric problems in 2,500 long-term young travelers to the tropics. J Travel Med 2000;7:5-9.
van Riemsdijk MM, Ditters JM, Sturkenboom MC, Tulen JH, Ligthelm RJ, Overbosch D, et al
. Neuropsychiatric events during prophylactic use of mefloquine before travelling. Eur J Clin Pharmacol 2002;58:441-5.
van Riemsdijk MM, Sturkenboom MC, Pepplinkhuizen L, Stricker BH. Mefloquine increases the risk of serious psychiatric events during travel abroad: A nationwide case-control study in the Netherlands. J Clin Psychiatry 2005;66:199-204.
Fujii T, Kaku K, Jelinek T, Kimura M. Malaria and mefloquine prophylaxis use among Japan Ground Self-Defense Force personnel deployed in East Timor. J Travel Med 2007;14:226-32.
Senn N, D'Acremont V, Landry P, Genton B. Malaria chemoprophylaxis: What do the travelers choose, and how does pretravel consultation influence their final decision. Am J Trop Med Hyg 2007;77:1010-4.
Bannister B. Malaria in the UK: New prevention guidelines for UK travellers. Br J Gen Pract 2007;57:4-6.
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk
Source of Support: None, Conflict of Interest: None