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 National Health Study for a New Generation of U.S. Veterans, 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.

Mefloquine is one of four antimalarial agents commonly recommended for preventing malaria in travellers to malaria-endemic areas. Despite its high efficacy, there is controversy about its psychological side effects.

To summarize the efficacy and safety of mefloquine used as prophylaxis for malaria in travellers.

We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published on the Cochrane Library; MEDLINE; Embase (OVID); TOXLINE (https://toxnet.nlm.nih.gov/newtoxnet/toxline.htm); and LILACS. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; http://www.who.int/ictrp/en/) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home) for trials in progress, using 'mefloquine', 'Lariam', and 'malaria' as search terms. The search date was 22 June 2017.

We included randomized controlled trials (for efficacy and safety) and non-randomized cohort studies (for safety). We compared prophylactic mefloquine with placebo, no treatment, or an alternative recommended antimalarial agent. Our study populations included all adults and children, including pregnant women.

Two review authors independently assessed the eligibility and risk of bias of trials, extracted and analysed data. We compared dichotomous outcomes using risk ratios (RR) with 95% confidence intervals (CI). Prespecified adverse outcomes are included in 'Summary of findings' tables, with the best available estimate of the absolute frequency of each outcome in short-term international travellers. We assessed the certainty of the evidence using the GRADE approach.

We included 20 RCTs (11,470 participants); 35 cohort studies (198,493 participants); and four large retrospective analyses of health records (800,652 participants). Nine RCTs explicitly excluded participants with a psychiatric history, and 25 cohort studies stated that the choice of antimalarial agent was based on medical history and personal preference. Most RCTs and cohort studies collected data on self-reported or clinician-assessed symptoms, rather than formal medical diagnoses. Mefloquine efficacyOf 12 trials comparing mefloquine and placebo, none were performed in short-term international travellers, and most populations had a degree of immunity to malaria. The percentage of people developing a malaria episode in the control arm varied from 1% to 82% (median 22%) and 0% to 13% in the mefloquine group (median 1%).In four RCTs that directly compared mefloquine, atovaquone-proguanil and doxycycline in non-immune, short-term international travellers, only one clinical case of malaria occurred (4 trials, 1822 participants). Mefloquine safety versus atovaquone-proguanil Participants receiving mefloquine were more likely to discontinue their medication due to adverse effects than atovaquone-proguanil users (RR 2.86, 95% CI 1.53 to 5.31; 3 RCTs, 1438 participants; high-certainty evidence). There were few serious adverse effects reported with mefloquine (15/2651 travellers) and none with atovaquone-proguanil (940 travellers).One RCT and six cohort studies reported on our prespecified adverse effects. In the RCT with short-term travellers, mefloquine users were more likely to report abnormal dreams (RR 2.04, 95% CI 1.37 to 3.04, moderate-certainty evidence), insomnia (RR 4.42, 95% CI 2.56 to 7.64, moderate-certainty evidence), anxiety (RR 6.12, 95% CI 1.82 to 20.66, moderate-certainty evidence), and depressed mood during travel (RR 5.78, 95% CI 1.71 to 19.61, moderate-certainty evidence). The cohort studies in longer-term travellers were consistent with this finding but most had larger effect sizes. Mefloquine users were also more likely to report nausea (high-certainty evidence) and dizziness (high-certainty evidence).Based on the available evidence, our best estimates of absolute effect sizes for mefloquine versus atovaquone-proguanil are 6% versus 2% for discontinuation of the drug, 13% versus 3% for insomnia, 14% versus 7% for abnormal dreams, 6% versus 1% for anxiety, and 6% versus 1% for depressed mood. Mefloquine safety versus doxycyclineNo difference was found in numbers of serious adverse effects with mefloquine and doxycycline (low-certainty evidence) or numbers of discontinuations due to adverse effects (RR 1.08, 95% CI 0.41 to 2.87; 4 RCTs, 763 participants; low-certainty evidence).Six cohort studies in longer-term occupational travellers reported our prespecified adverse effects; one RCT in military personnel and one cohort study in short-term travellers reported adverse events. Mefloquine users were more likely to report abnormal dreams (RR 10.49, 95% CI 3.79 to 29.10; 4 cohort studies, 2588 participants, very low-certainty evidence), insomnia (RR 4.14, 95% CI 1.19 to 14.44; 4 cohort studies, 3212 participants, very low-certainty evidence), anxiety (RR 18.04, 95% CI 9.32 to 34.93; 3 cohort studies, 2559 participants, very low-certainty evidence), and depressed mood (RR 11.43, 95% CI 5.21 to 25.07; 2 cohort studies, 2445 participants, very low-certainty evidence). The findings of the single cohort study reporting adverse events in short-term international travellers were consistent with this finding but the single RCT in military personnel did not demonstrate a difference between groups in frequencies of abnormal dreams or insomnia.Mefloquine users were less likely to report dyspepsia (RR 0.26, 95% CI 0.09 to 0.74; 5 cohort studies, 5104 participants, low certainty-evidence), photosensitivity (RR 0.08, 95% CI 0.05 to 0.11; 2 cohort studies, 1875 participants, very low-certainty evidence), vomiting (RR 0.18, 95% CI 0.12 to 0.27; 4 cohort studies, 5071 participants, very low-certainty evidence), and vaginal thrush (RR 0.10, 95% CI 0.06 to 0.16; 1 cohort study, 1761 participants, very low-certainty evidence).Based on the available evidence, our best estimates of absolute effect for mefloquine versus doxycyline were: 2% versus 2% for discontinuation, 12% versus 3% for insomnia, 31% versus 3% for abnormal dreams, 18% versus 1% for anxiety, 11% versus 1% for depressed mood, 4% versus 14% for dyspepsia, 2% versus 19% for photosensitivity, 1% versus 5% for vomiting, and 2% versus 16% for vaginal thrush.Additional analyses, including comparisons of mefloquine with chloroquine, added no new information. Subgroup analysis by study design, duration of travel, and military versus non-military participants, provided no conclusive findings.

The absolute risk of malaria during short-term travel appears low with all three established antimalarial agents (mefloquine, doxycycline, and atovaquone-proguanil).The choice of antimalarial agent depends on how individual travellers assess the importance of specific adverse effects, pill burden, and cost. Some travellers will prefer mefloquine for its once-weekly regimen, but this should be balanced against the increased frequency of abnormal dreams, anxiety, insomnia, and depressed mood.

Background: Antimalarial drugs affect the central nervous system, but it is difficult to differentiate the effect of these drugs from that of the malaria illness. We conducted a systematic review to determine the association between anti-malarial drugs and mental and neurological impairment in humans.  Methods: We systematically searched online databases, including Medline/PubMed, PsychoInfo, and Embase, for articles published up to 14th July 2016. Pooled prevalence, heterogeneity and factors associated with prevalence of mental and neurological manifestations were determined using meta-analytic techniques.  Results: Of the 2,349 records identified in the initial search, 51 human studies met the eligibility criteria. The median pooled prevalence range of mental and neurological manifestations associated with antimalarial drugs ranged from 0.7% (dapsone) to 48.3% (minocycline) across all studies, while it ranged from 0.6% (pyrimethamine) to 42.7% (amodiaquine) during treatment of acute malaria, and 0.7% (primaquine/dapsone) to 55.0% (sulfadoxine) during prophylaxis. Pooled prevalence of mental and neurological manifestations across all studies was associated with an increased number of antimalarial drugs (prevalence ratio= 5.51 (95%CI, 1.05-29.04); P=0.045) in a meta-regression analysis. Headaches (15%) and dizziness (14%) were the most common mental and neurological manifestations across all studies. Of individual antimalarial drugs still on the market, mental and neurological manifestations were most common with the use of sulphadoxine (55%) for prophylaxis studies and amodiaquine (42.7%) for acute malaria studies. Mefloquine affected more domains of mental and neurological manifestations than any other antimalarial drug.  Conclusions: Antimalarial drugs, particularly those used for prophylaxis, may be associated with mental and neurological manifestations, and the number of antimalarial drugs taken determines the association. Mental and neurological manifestations should be assessed following the use of antimalarial drugs.

Background: Antimalarial drugs affect the central nervous system, but it is difficult to differentiate the effect of these drugs from that of the malaria illness. We conducted a systematic review to determine the association between anti-malarial drugs and mental and neurological impairment in humans.  Methods: We systematically searched online databases, including Medline/PubMed, PsychoInfo, and Embase, for articles published up to 14th July 2016. Pooled prevalence, heterogeneity and factors associated with prevalence of mental and neurological manifestations were determined using meta-analytic techniques.  Results: Of the 2,349 records identified in the initial search, 51 human studies met the eligibility criteria. The median pooled prevalence range of mental and neurological manifestations associated with antimalarial drugs ranged from 0.7% (dapsone) to 48.3% (minocycline) across all studies, while it ranged from 0.6% (pyrimethamine) to 42.7% (amodiaquine) during treatment of acute malaria, and 0.7% (primaquine/dapsone) to 55.0% (sulfadoxine) during prophylaxis. Pooled prevalence of mental and neurological manifestations across all studies was associated with an increased number of antimalarial drugs (prevalence ratio= 5.51 (95%CI, 1.05-29.04); P=0.045) in a meta-regression analysis. Headaches (15%) and dizziness (14%) were the most common mental and neurological manifestations across all studies. Of individual antimalarial drugs still on the market, mental and neurological manifestations were most common with the use of sulphadoxine (55%) for prophylaxis studies and amodiaquine (42.7%) for acute malaria studies. Mefloquine affected more domains of mental and neurological manifestations than any other antimalarial drug.  Conclusions: Antimalarial drugs, particularly those used for prophylaxis, may be associated with mental and neurological manifestations, and the number of antimalarial drugs taken determines the association. Mental and neurological manifestations should be assessed following the use of antimalarial drugs.

Mefloquine was widely prescribed to U.S. military service members until 2009 when use was limited to personnel with contraindications to doxycycline and no contraindications to mefloquine. The need to estimate the occurrence of neuropsychiatric outcomes (NPOs) in service members prescribed mefloquine warranted a comprehensive evaluation of this issue. Active component service members filling a prescription for mefloquine, doxycycline, or atovaquone/proguanil (A/P) between January 1, 2008 and June 30, 2013, were included in the analysis. The risk of developing incident NPOs and the risk of subsequent NPOs among subjects with a history of the condition were assessed. A total of 367,840 individuals were evaluated (36,538 received mefloquine, 318,421 received doxycycline, and 12,881 received A/P). Among deployed individuals prescribed mefloquine, an increased risk of incident anxiety was seen when compared with doxycycline recipients (incidence rate ratio [IRR] = 1.12 [1.01-1.24]). Among nondeployed mefloquine recipients, an increased risk of posttraumatic stress disorder (PTSD) was seen when compared with A/P recipients (IRR = 1.83 [1.07-3.14]). An increased risk of tinnitus was seen for both deployed and nondeployed mefloquine recipients compared with A/P recipients (IRR = 1.81 [1.18-2.79]), 1.51 (1.13-2.03), respectively). Six percent of the mefloquine cohort had an NPO in the year before receiving mefloquine. When comparing individuals with a prior neuropsychiatric history to those without, the ratio of relative risks for adjustment disorder, anxiety, insomnia, and PTSD were higher (not statistically significant) for mefloquine compared with doxycycline. These findings emphasize the continued need for physicians prescribing mefloquine to conduct contraindication screening.

It is well known that both mefloquine and doxycycline are commonly associated with adverse effects when taken for malaria chemoprophylaxis. However, the relative impact of these on travelers' ability to work is not so well understood. The aim of this study was to identify which drug has a lesser impact on the ability to work as measured by self-reported severity of adverse effects via a questionnaire.

This was a questionnaire-based two-arm cohort study. Participants were soldiers selected from 10 consecutive units training in Kenya during 2012 and 2013. The exposure was either doxycycline or mefloquine and the main outcome measure was impact upon ability to work. Each cohort was advised to take doxycycline or mefloquine with exceptions at the individual level where medically or occupationally advised.

Significantly more (p < 0.0001) doxycycline users reported that one or more adverse effects had interfered with their ability to do their job than mefloquine users. Of the 867 mefloquine users, who reported on the impact of adverse effects, 109 (12.6%) reported that one or more adverse effects had impacted upon their ability to do their job, compared to 152 (22.2%) of the 685 doxycycline users who had reported on the impact of any adverse effects. Doxycycline symptoms were predominantly gastrointestinal and dermatological, whereas mefloquine symptoms were neuropsychiatric.

Self-reported symptoms were common in those that responded and, while the true background rate of adverse effects (off any medication) is unknown, doxycycline had a significantly increased rate compared with mefloquine and was associated with a greater occupational impact. Therefore, this study supports the view that, for organizations which provide malaria chemoprophylaxis to employees free of charge, mefloquine should be the first-choice antimalarial drug where the only alternative is doxycycline.

The aim of the study was to explore the profile of acute and long-term psychiatric side effects associated with mefloquine.

Subjects (n = 73) reported to a Danish national register during five consecutive years for mefloquine associated side effects were included. Acute psychiatric side effects were retrospectively assessed using the SCL-90-R and questions based on Present State Examination (PSE). Subjects reporting suspected psychotic states were contacted for a personal PSE interview. Electronic records of psychiatric hospitalizations and diagnoses were cross-checked. Long-term effects were evaluated with SF-36. SCL-90-R and SF-36 data were compared to age- and gender matched controls.

In the SCL-90-R, clinically significant scores for anxiety, phobic anxiety and depression were found in 55%, 51%, and 44% of the mefloquine group. Substantial acute phase psychotic symptoms were found in 15% and were time-limited. Illusions/hallucinations were more frequently observed among women. Cases of hypomania/mania in the acute phase were 5.5%. Significant long-term mental health effects were demonstrated for the SF-36 subscales mental health (MH), role emotional (RE), and vitality (VT) in the mefloquine group compared to matched controls.

The most frequent acute psychiatric problems were anxiety, depression, and psychotic symptoms. Data indicated that subjects experiencing acute mefloquine adverse side effects may develop long-term mental health problems with a decreased sense of global quality of life with lack of energy, nervousness, and depression.

Recent studies of military personnel who have deployed to Iraq and Afghanistan have reported a number of combat-related psychiatric disorders such as posttraumatic stress disorder, depression, and traumatic brain injury. This case report involves a 27-year-old male active-duty US military service member who developed severe depression, psychotic hallucinations, and neuropsychological sequelae following the prophylactic use of the antimalarial medication mefloquine hydrochloride. The patient had a recent history of depression and was taking antidepressant medications at the time of his deployment to the Middle East. Psychiatrists and other health care providers should be aware of the possible neuropsychiatric side effects of mefloquine in deployed military personnel and should consider the use of other medications for malaria prophylaxis in those individuals who may be at increased risk for side effects.

Mefloquine (a marketed anti-malaria drug) prophylaxis has a high risk of causing adverse events. Interestingly, animal studies have shown that mefloquine imposes a major deficit in motor learning skills by affecting the connexin 36 gap junctions of the inferior olive. We were therefore interested in assessing whether mefloquine might induce similar effects in humans. The main aim of this study was to investigate the effect of mefloquine on olivary-related motor performance and motor learning tasks in humans. We subjected nine participants to voluntary motor timing (dart throwing task), perceptual timing (rhythm perceptual task) and reflex timing tasks (eye-blink task) before and 24 h after the intake of mefloquine. The influence of mefloquine on motor learning was assessed by subjecting participants with and without mefloquine intake (controls: n = 11 vs mefloquine: n = 8) to an eye-blink conditioning task. Voluntary motor performance, perceptual timing, and reflex blinking were not affected by mefloquine use. However, the influence of mefloquine on motor learning was substantial; both learning speed as well as learning capacity was impaired by mefloquine use. Our data suggest that mefloquine disturbs motor learning skills. This adverse effect can have clinical as well as social clinical implications for mefloquine users. Therefore, this side-effect of mefloquine should be further investigated and recognized by clinicians.

Malaria infects 10,000 to 30,000 international travellers each year. It can be prevented through anti-mosquito measures and drug prophylaxis. However, antimalaria drugs have adverse effects which are sometimes serious.

To compare the effects of currently used antimalaria drugs when given as prophylaxis to non-immune adult and child travellers who are travelling to regions with Plasmodium falciparum resistance to chloroquine. Specifically, to assess the efficacy, safety, and tolerability of atovaquone-proguanil, doxycycline, and mefloquine compared to each other, and also when compared to chloroquine-proguanil and to primaquine.

In August 2009 we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, LILACS, BIOSIS, mRCT, and reference lists. We handsearched conference proceedings and one specialist journal, and contacted researchers and drug companies. We searched PubMed for drug-related deaths.

Randomized and quasi-randomized controlled trials of any antimalaria drug regimen currently used by non-immune international travellers.

We independently extracted data and assessed eligibility and risk of bias using a standardized data collection form. We resolved any disagreement through discussion. We combined dichotomous outcomes using risk ratio (RR) and continuous data using mean difference (MD), presenting both with 95% confidence intervals (CI).

Eight trials (4240 participants) met the inclusion criteria. Evidence on comparative efficacy from head-to-head comparisons was limited. Atovaquone-proguanil compared to doxycycline had similar adverse events reported. Compared to mefloquine, atovaquone-proguanil users had fewer reports of any adverse effect (RR 0.72, 95% CI 0.6 to 0.85), gastrointestinal adverse effects (RR 0.54, 95% CI 0.42 to 0.7), neuropsychiatric adverse events (RR 0.86, 95% CI 0.75 to 0.99), and neuropsychiatric adverse effects (RR 0.49, 95% CI 0.38 to 0.63), besides a better total mood disturbance score (MD -7.20, 95% CI -10.79 to -3.61). Similarly, doxycycline users had fewer reported neuropsychiatric events than mefloquine users (RR 0.84, 95% CI 0.73 to 0.96). We also examined these three regimens against chloroquine-proguanil; this latter regimen had more reports of any adverse effect (RR 0.84, 95% CI 0.73 to 0.96) and of gastrointestinal adverse effects (RR 0.71, 95% CI 0.6 to 0.85).

Atovaquone-proguanil and doxycycline are the best tolerated regimens, and mefloquine is associated with adverse neuropsychiatric outcomes.

A literature review revealed that mefloquine neurotoxicity has been demonstrated at both the preclinical and clinical levels, with nausea, dizziness, sleep disturbances, anxiety and psychosis, amongst other adverse neuropsychiatric events, reported in users. Females and individuals of low body mass index (BMI) are at apparent greater risk. Mechanisms of possible neurotoxicity may include binding to neuroreceptors and cholinesterases, inhibition of sarcoendoplasmic reticulum ATPase (SERCA) and interference with cellular Ca(2+) homeostasis, accumulation in the CNS, and reductions in CNS efflux in individuals possessing certain MDR1 polymorphisms. It may be prudent to avoid mefloquine in females and low BMI individuals, and in combination with other potentially neurotoxic agents such as the artemisinin antimalarials.

To objectively compare the mood profiles of users of malaria chemoprophylaxis regimens (atovaquone-proguanil, chloroquine-proguanil, doxycycline, or mefloquine) in a group of nonimmune tourists to sub-Saharan Africa.

In a randomized, double-blind, four-arm study with placebo run-in phase conducted at travel clinics in Switzerland, Germany, and Israel, we compared moods and feelings in chemoprophylaxis users (n= 547) by administering the standardized "Profile of Mood States" (POMS) questionnaire. This is designed to provide data on six categories of feelings: tension, depression, anger, vigor, fatigue, and confusion. The questionnaire was administered at four time points: recruitment (T1), 13 to 11 days before departure (T2), 6 to 4 days before departure (T3), and 7 to 14 days after return from Africa (T4).

There were no significant differences with respect to overall mood impact between the medication arms. All scores were in the normal range, and no means were more than 1 SD from the norm. The POMS data were reanalyzed with respect to sex, age, medication group, and control time points (T1-T4). There were significant interaction effects between sex and medication group--women in the mefloquine group showed more "fatigue" (p= .011) and "confusion" (p= .011) than men. Significant effects of age group (below median age 34 y vs median age and above) were noted on the "tension" and "fatigue" scales in that less "tension" (p= .045) and less "fatigue" (p= .000) were noted in those aged 34 years and older. Younger participants, aged <34 years, reported more "confusion" (p= .013) at T2 than at T1 and T4.

Although the overall mood profiles were similar for the users of any of the standard malaria chemoprophylaxis regimens, we found that women using mefloquine showed more fatigue and confusion than men and that younger persons aged less than 34 years, regardless of chemoprophylaxis used, reported more tension and fatigue than their older counterparts.

Mefloquine has been widely used for prophylaxis and treatment of patients with chloroquine-resistant malaria; the drug is usually well tolerated. Rarely, adverse effects may be severe, including gastrointestinal disturbances, neuropsychiatric reactions, cardiovascular manifestations, skin lesions, musculoskeletal symptoms, and bone marrow toxicity. We describe a 67-year-old woman with fever, dyspnea on exertion, peripheral blood eosinophilia, and diffuse pulmonary infiltrates on chest radiography. She had taken mefloquine for malaria prophylaxis for an 8-week trip to South Africa. A thorough work-up led to the diagnosis of eosinophilic pneumonia caused by the mefloquine. Her condition improved after the drug was discontinued. To our knowledge, this is the first report of mefloquine-induced eosinophilic pneumonia. Clinicians should be aware of this rare, potential adverse effect of mefloquine.

Malaria risk is dependent upon the entomological inoculation rate actually faced by the long-term traveler. Risk is cumulative, increases with duration of exposure, is greatest in rural and periurban areas, and least in urban centers. Risk may be zero in some urban centers, especially during dry seasons. Chemoprophylaxis compliance is hindered by the high adverse event rate often reported by users, is often suboptimal in expatriates, and decreases with duration of stay. Compliance with personal protection measures may also be suboptimal, and use of insecticide-treated nets and effective repellents should be encouraged. Alternative strategies to mitigate risk include seasonal chemoprophylaxis, nonuse of chemoprophylaxis with rapid treatment, self-testing, self-treatment where competent care and quality drugs are unavailable, and vector control. Choice of strategies will depend upon assessment of actual risk and likely compliance, with a combination of measures usually appropriate.

We present a case in which suicide was a severe neuropsychiatric reaction to treatment with mefloquine. Physicians must be aware of these serious psychiatric complications and bear them in mind when faced with atypical behavior or suspected suicide.

The body of a 27-year-old man was discovered at his home, covered with multiple knife wounds. The autopsy report concluded that death was due to a craniocerebral wound from a violent blow. Homicide was initially suspected. Suicide during acute psychosis associated with mefloquine was suggested, and toxicologic analyses confirmed this hypothesis.

Serious neurologic and psychiatric adverse events associated with mefloquine (Lariam) have been reported since its introduction in 1985. Mefloquine prophylaxis is recommended for travelers to high-risk areas of chloroquine-resistant plasmodium falciparum. The risk of malarial infection and the proven efficacy of mefloquine to prevent malaria should be weighed against the risk of drug-associated adverse events. Physicians must nonetheless be aware of these serious psychiatric complications, especially when faced with atypical behavior and atypical suicides. The patient's' family and friends should be asked about a possible trips abroad that might have entailed antimalaria treatment, even several months earlier. Testing for mefloquine during toxicological examinations is then essential. The World Health Organization recommendations and contraindications must be followed in prescribing mefloquine.

Few on-site studies involving local doctors have been published.

We conducted a prospective on-site study of health problems occurring among French tourists to Nepal between 1 January 2001 and 31 December 2001, and compared the results with those of an identical study performed in 1984.

Of the 21,457 French tourists who visited Nepal in 2001, 276 (1.3%) consulted the French Embassy doctor in Kathmandu with health complaints. The main reasons for seeking medical advice were diarrhea (26.8%), high-altitude illness (15.6%), lower respiratory tract infections (11.6%), dermatoses (8.7%), and fever (8.7%). Fifteen patients (5.4%) required hospitalization, five required medical evacuation (1.8%), and 14 (5%) were rescued by helicopter in the Himalayas. One patient died of cardiovascular disease. Relative to the 1984 cohort, significantly more patients consulted for high-altitude illness (p<.001), lower respiratory tract infections (p=.001), physical trauma (p=.01), and psychiatric disorders (p<.001), and significantly fewer patients consulted for dermatoses (p=.04), sexually transmitted diseases (p=.001), and upper respiratory tract infections (p=.005).

These results, obtained 17 years apart, illustrate the changes in the pattern of health disorders causing travelers in Nepal to consult a doctor.

We performed a prospective cohort study to gain more insight into risk factors for neuropsychiatric effects of mefloquine among tourists travelling to tropical areas.

We enrolled all patients who consulted the Travel Clinic of the Havenziekenhuis & Institute for Tropical Diseases Rotterdam for mefloquine prophylaxis during the period between 1 May 1999 and 7 March 2000. Each patient was followed from baseline (prior to starting mefloquine) up to 3 weeks after starting weekly intake of 250 mg mefloquine. We compared the intraindividual change in scores between baseline and follow-up visit on the Dutch shortened Profile of Mood States, and on the Continuous Performance Test (CPT) which measures sustained attention.

The final cohort consisted of 151 subjects with a mean age of 38 years. In this population, a significant impairment of mood state was observed in those with a body mass index (BMI) < or = 20 kg m(-2). Stratification for gender showed that the total mood disturbance in females in the lowest BMI category significantly increased by 8.42 points [95% confidence interval (CI) 3.33, 13.50], whereas BMI did not affect the risk in males. Stratification for history of use of mefloquine showed that the risks were highest in first-time users. Analyses of the CPT showed that reaction time in women with a BMI < or = 20 kg m(-2) increased significantly by 22.5 ms (95% CI 7.80, 37.20), whereas reaction time in men showed a slight and nonsignificant decrease.

Risk factors for mefloquine-associated neuropsychiatric adverse events and concentration impairment are female gender, low BMI, and first-time use. The frequency of neuropsychiatric effects is highest in women with a BMI < or = 20 kg m(-2).

2,3-bis(Trifluoromethyl)-4-(3-hydroxyquinuclidinylquinoline) or MC(1) is a new synthetic compound with potent antimalarial activity in vitro and in vivo studies. The IC(50) values of MC(1) and chloroquine in in vitro culture of Plasmodium falciparum are 7.0x10(-8) and 6.06x10(-7)M, respectively. In an in vivo study using Plasmodium berghei infected mice as the test model, the survival time of the infected mice without drug treatment was 6.00+0.58 days. Chloroquine and MC(1) at an equal dose of 7.5mg/kg, orally administered once daily for 4 days, prolonged the survival time of the infected mice from 6 to 14 days, and more than 28 days, respectively. At the doses that exhibit potent antimalarial activity in vivo, there are no observable toxic effects. Preliminary studies of the pharmacodynamic activity of this newly synthesized compound revealed that at the doses which exhibit potent antimalarial activity, there is no alteration in motor activity such as distance traveled, rotational behavior, and stereotypic activity. The blood glucose was not significantly altered. In the spontaneous beating, isolated right atria of mice, MC(1) exhibits direct negative chronotropism at high concentrations (10(-4)M). This effect is augmented in hyper-K(+) bathing solution. A direct negative chronotropic effect was also observed when mefloquine at 5x10(-5)M was used. Preliminary pharmacodynamic study suggested that MC(1) is a potential new antimalarial drug that should be studied further.

Experimental and observational studies have linked mefloquine use to an increased risk of developing neuropsychiatric adverse effects such as depression or psychoses. Most of these reports relied on interview-based information from travellers. We conducted a population-based observational study using a database of medical records to quantify and compare the risk of psychiatric disorders during or after use of mefloquine with the risk during use of proguanil and/or chloroquine, or doxycycline.

The study population was drawn from the large UK-based General Practice Research Database (GPRD). Subjects were aged from 17-79 years and were exposed to mefloquine, proguanil, chloroquine or doxycycline (or a combination of these drugs) at some time between 1990 and 1999. We performed a person-time and a nested case-control analysis to assess the risk of developing a first-time diagnosis of depression, psychosis or panic attack during or after use of these antimalarial drugs.

Within the study population of 35 370 subjects (45.2% males), we identified 580 subjects with a first-time diagnosis of depression (n = 505), psychosis (n = 16) or panic attack (n = 57) and two subjects committed suicide. The incidence rates of first-time diagnoses of depression during current use of mefloquine, proguanil and/or chloroquine, or doxycycline, adjusted for age, gender and calendar year, were 6.9 (95% CI 4.5-10.6), 7.6 (95% CI 5.5-10.5) and 9.5 (95% CI 3.7-24.1)/1000 person-years, respectively. The incidence rates of psychosis or panic attacks during current mefloquine exposure were 1.0/1000 person-years (95% CI 0.3-2.9) and 3.0/1000 person-years (95% CI 1.6-5.7), respectively, approximately 2-fold higher (statistically nonsignificant) than during current use of proguanil and/or chloroquine, or doxycycline. The nested case-control analysis encompassed 505 cases with depression and 3026 controls, 16 cases with psychosis and 96 controls, and 57 cases with a panic attack and 342 controls. Current use of mefloquine was not associated with an elevated risk of developing depression. In a comparison between patients currently using mefloquine with all past users of antimalarials combined, the risk estimate was elevated for current users of mefloquine for both psychosis (odds ratio [OR] 8.0, 95% CI 1.0-62.7; p < 0.05) and panic attacks (OR 2.7, 95% CI 1.1-6.5; p < 0.05).

The absolute risk of developing psychosis or panic attack appears low with all the antimalarials tested. No evidence was found in this large observational study that mefloquine use increased the risk of first-time diagnosis of depression when compared with the use of other antimalarials investigated in this study.