Antimalarial chemoprophylaxis and the risk of neuropsychiatric disorders

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Travel Medicine and Infectious Disease (2013) xx, 1e10

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Antimalarial chemoprophylaxis and the riskof neuropsychiatric disorders

Cornelia Schneider a, Miriam Adamcova b, Susan S. Jick c,Patricia Schlagenhauf d, Mary K. Miller e, Hans-Georg Rhein b,Christoph R. Meier a,c,f,*

aBasel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology,Department of Pharmaceutical Sciences, University Basel, Basel, Switzerlandb Safety Risk Management, F. Hoffmann-La Roche Ltd., Basel, SwitzerlandcBoston Collaborative Drug Surveillance Program, Boston University School of Medicine, Lexington,MA, United StatesdUniversity of Zuerich Centre for Travel Medicine, Institute for Social and Preventive Medicine,Zuerich, SwitzerlandeDepartment of Epidemiology, Genentech Inc., South San Francisco, USAfHospital Pharmacy, University Hospital Basel, Basel, Switzerland

Received 26 February 2013; accepted 28 February 2013

KEYWORDSMefloquine;Atovaquone;Proguanil;Chloroquine

* Corresponding author. Basel PharmSwitzerland. Tel.: þ41 61 556 53 69; f

E-mail addresses: [email protected] (P. Schlagenhauf), hans-

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1477-8939/$ - see front matter ª 201http://dx.doi.org/10.1016/j.tmaid.20

Summary Background: Case reports and epidemiological studies have associated the use ofmefloquine with neuropsychiatric adverse events.Methods: We used the General Practice Research Database to conduct a follow-up study with anested caseecontrol analysis. We assessed the risk of developing first-time anxiety, stress-related disorders/psychosis, depression, epilepsy or peripheral neuropathies in patients usingmefloquine, chloroquine and/or proguanil, or atovaquone/proguanil for malaria chemoprophy-laxis, as compared to unexposed travelers.Results: Compared to non-users of antimalarials, the adjusted odds ratio in the nestedcaseecontrol analysis for users of mefloquine, chloroquine and/or proguanil, or atovaquone/proguanil were 0.71 (95% CI 0.56e0.90), 1.04 (95% CI 0.74e1.46), and 0.73 (95% CI 0.61e0.86)for anxiety or stress-related disorders combined, 0.54 (95% CI 0.41e0.71), 1.06 (95% CI0.71e1.59), and 0.75 (95% CI 0.62e0.91) for depression, 0.69 (95% CI 0.35e1.36), 1.41 (95% CI0.54e3.67), and 0.75 (95% CI 0.42e1.36) for epilepsy, and 1.22 (95% CI 0.50e2.99), 1.59 (95%CI 0.41e6.15), and 1.05 (95% CI 0.54e2.03) for neuropathies, respectively. The risk of all out-comes was higher in females than in males across all exposure categories.

acoepidemiology Unit, Hospital Pharmacy, University Hospital Basel, Spitalstrasse 26, CH-4031 Basel,ax: þ41 61 265 88 70.s.ch (C. Schneider), [email protected] (M. Adamcova), [email protected] (S.S. Jick), [email protected]@roche.com (H.-G. Rhein), [email protected], [email protected] (C.R. Meier).

hneider C, et al., Antimalarial chemoprophylaxis and the risk of neuropsychiatric disorders, Travel3), http://dx.doi.org/10.1016/j.tmaid.2013.02.008

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2 C. Schneider et al.

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Conclusions: The risk of neuropsychiatric disorderswas similar for users and for non-users of anti-malarial chemoprophylaxis, with evidence for elevated risks in some subgroups.ª 2013 Elsevier Ltd. All rights reserved.

Introduction

Several case reports describe neuropsychiatric events withthe use of mefloquine.1 This association has been reportedin observational studies2 and in randomized controlled tri-als.3 The term “neuropsychiatric disorder” is poorly definedand encompasses a variety of neurological and/or psychi-atric disorders. The mechanisms by which neuropsychiatricevents are triggered by anti-malarial drugs are poorly un-derstood, but certain risk factors, such as a personal orfamily history of seizures or affective disorders are thoughtto play a role.4 Sex may also be a risk factor as there is anincreased propensity for neuropsychiatric adverse events inwomen, particularly in those with low BMI.3,5e9 These dif-ferences may be due to sex differences in pharmacoki-netics, adherence, BMI, body weight, or reporting bias. Asmefloquine is highly lipophilic, it is hypothesized that bodyweight might have an influence on the risk of developingneuropsychiatric adverse events. Some studies stratified bybody weight or BMI, reported that patients with low BMI orbody weight were at an increased risk of neuropsychiatricadverse events5,8,10 while others did not find such an as-sociation.5,11 Mefloquine chemoprophylaxis is contra-indicated in the UK for individuals with psychiatricdisturbances. Both mefloquine and chloroquine are con-traindicated in patients with epilepsy because of theincreased risk of convulsions.12 This study investigates therisk of developing a first-time diagnosis of depression,anxiety disorders, stress-related disorders, psychosis, neu-ropathies, or epilepsy associated with use of malariachemoprophylaxis compared to travelers not exposed toany anti-malarial drugs.

Methods

Data source

We conducted a follow-up study with a person-time analysisand a nested caseecontrol analysis using data from the UK-based General Practice Research Database (GPRD).13e16

This study was approved by the Independent ScientificAdvisory Committee (ISAC) of the GPRD.

Study design

Definition of the study populationWe identified in the GPRD all patients who had �1prescription of mefloquine, chloroquine and/or proguanil oratovaquone/proguanil between January 1, 2001 andOctober1, 2009, and who had a pre-travel consultation within 1 weekof the prescription. The start of follow-upwas the date whenthe patient received the first prescription. We identified atrandom a comparison group of patients not exposed to anyanti-malarial and who had a pre-travel consultation. Their

hneider C, et al., Antimalarial ch3), http://dx.doi.org/10.1016/j.t

start of follow-up was the date of their first pre-travelconsultation during the study period. One such non-userwas matched to one user on age, sex, and general practice.The caseecontrol analysis was nested in the study popula-tion, whereby we identified all cases with an incidentneuropsychiatric disorder of interest during follow-up andcompared them to a random sample of patients from thestudy population who did not develop a neuropsychiatricdisorder (i.e. the controls).

We only included subjects who used anti-malarial drugsfor malaria prophylaxis. We identified prescriptions forwhich the GP recorded - within a week of the anti-malarialdrug prescription - specific codes indicating that the personreceived the prescription for malaria prophylaxis, such as“travel advice” or “prophylactic drug use”. Furthermore,individuals had at least 12 months of information on pre-scribed drugs and medical diagnoses before the first pre-scription date for a study drug. In addition, subjects hadrecorded activity (diagnoses or drug prescriptions) at anytime after the prescription for an anti-malarial drug toinclude only subjects who returned to the UK.

ExposureA case was considered to have current or past exposure to astudy drug (mefloquine, chloroquine and/or proguanil oratovaquone/proguanil) if they received a prescriptionwithin 540 days prior to the index date (date the case wasdiagnosed). We used a 540-day exposure window becauseany incident neuropsychiatric disorder occurring one and ahalf years after stopping a drug of interest was unlikely tobe associated with former drug use.

Current use started at the date of a prescription and endedone week after the end of the alleged time period of the drugprescription. Current exposure time was calculated differentlyfor all study drugs since the regimen for these drugs differs.Webased the assessment on the number of tablets recorded by theGP, and calculated thealleged current exposure timeas followsfor the four study drugs:

Mefloquine: number of tablets prescribed multiplied by 7plus 28 days.

Atovaquone/proguanil: number of tablets plus 7 daysChloroquine: Tablets: number of tablets multiplied by 7 anddivided by 2 plus 28 days.

Syrup: ml divided by 30 multiplied by 7 plus 28 days.Proguanil: number of tablets prescribed divided by 2 plus

7 days.Chloroquine/Proguanil: number of tablets prescribed

plus 7 days.We added 90 days to each exposure to capture events

occurring during travel which came to the attention of theGP after returning to the UK. Past use started at day 91 andended at a maximum of 540 days after the end of currentexposure. Non-exposed had no antimalarial prescriptionduring the study period or 540 days after anti-malarialprescription.

emoprophylaxis and the risk of neuropsychiatric disorders, Travelmaid.2013.02.008

Antimalarial chemoprophylaxis and the risk of neuropsychiatric disorders 3

+ MODEL

Case definitionWe defined cases as people with an incident diagnosis of aneuropsychiatric disorder including anxiety, stress-relateddisorders or psychosis, depression, epilepsy or peripheralneuropathies during or after anti-malarial drug use. Weexcluded all patients with a diagnosis of malaria prior to thestart of anti-malarial drug use, patients with a history ofcancer, alcoholism, rheumatoid arthritis; or with anoutcome of interest prior to using anti-malarial drugs. Thedate of the first neuropsychiatric disorder was the indexdate for each case.

ControlsFrom the study population we selected at random up to sixcontrols per case for the nested caseecontrol analysis, i.e.patients who did not develop an outcome of interest duringfollow-up. We matched controls to cases on age (year ofbirth), sex, general practice, and calendar time (byassigning each control the same index date as theirmatched case). Controls also had to be alive at the indexdate and had to have some GPRD activity (diagnoses orprescriptions) recorded after the index date. We appliedthe same exclusion criteria to controls and cases.

Analysis

Person-time analysisWithin the study population, we accumulated person-timefor each subject from the start of follow-up until the personbecame a case, died, 540 days post exposure, or the com-puter record ended. Incidence rates were estimated for‘non-exposed’, ‘current’, and ‘past’ users.

Chloroquine can be prescribed alone or in combinationwith proguanil, but the combination of the two drugs ismore common. We categorized these drugs together intoone exposure group. For subjects who used more than onestudy drug consecutively, exposure time for the first drugended when another anti-malarial drug was prescribed.From then on, the person contributed person-time to thelatter drug. We provided the incidence rates in five age-strata, two gender-strata and six BMI-strata.

Nested case-control analysisIn the nested caseecontrol analysis we categorized sub-jects into current or past use exposure groups. In theperson-time analysis, subjects were classified according tothe last drug used, which led to mutually exclusive usergroups. Since certain subjects might have used two or moreanti-malarial drugs concomitantly, we classified users in thecaseecontrol analysis differently: subjects who used morethan one anti-malarial drug concomitantly (except for thepredefined proguanil/chloroquine or atovaquone/proguanilgroup) were classified as ’mixed users’, and we assessedthe relative risk estimates for those separately. Wecompared the risk of developing a first-time diagnosis of anoutcome of interest during current or past exposure tomefloquine, chloroquine and/or proguanil or atovaquone/proguanil using the unexposed travelers as reference group.We provided risk estimates for all neuropsychiatric disor-ders combined and stratified by subgroups. We conductedmultivariate conditional logistic regression analyzes and

Please cite this article in press as: Schneider C, et al., Antimalarial chMedicine and Infectious Disease (2013), http://dx.doi.org/10.1016/j.t

adjusted the relative risk estimates (odds ratios, OR) in theanalyses for potential confounders. We adjusted for age,sex, practice, calendar time, smoking (non, current, past,unknown) and body mass index (BMI; <18.5, 18.5e19.9,20.0e22.9, 23.0e24.9, 25.0e29.9, 30þ kg/m2, unknown) inthe multivariate analyses. In addition, we did a sensitivityanalysis in which we stratified the four exposure groups byBMI (<18.5, 18.5e29.9, 30þ kg/m2, or unknown).

The statistical analyses were conducted using the soft-ware program SAS, Version 9.2 (SAS Institute, Inc., Cary, NC).

Results

Person-time analysis

Within the study population, we identified 952 patientswith an incident diagnosis of anxiety, stress-related disor-der or psychosis, 739 patients with an incident depressiondiagnosis, 86 patients with incident epilepsy diagnosis, and56 patients with an incident diagnosis of peripheral neu-ropathy during follow-up. The incidence rates per 1000person-years (py) of mefloquine use were 6.2 (95% CI5.1e7.5) for anxiety, stress-related disorders or psychosis,4.2 (95% CI 3.3e5.4) for depression, 0.8 (95% CI 0.5e1.4) forepilepsy, and 0.5 (95% CI 0.2e0.9) for peripheral neuropa-thies. The incidence rates of these outcomes for the otheranti-malarial drugs were similar (Table 1).

Nested caseecontrol analysis

Women were more likely to develop depression, anxiety,stress-related disorder, psychosis or epilepsy than men. Themajority of cases were 18e65 years old (Table 2).

The odds ratios (ORs) of developing any anxiety orstress-related disorder or psychosis adjusted for BMI andsmoking were 0.71 (95% CI 0.56e0.90), 1.04 (95% CI0.74e1.46) and 0.73 (95% CI 0.61e0.86) for mefloquineusers, users of chloroquine and/or proguanil, or users ofatovaquone and/or proguanil compared to non-users ofanti-malarials. In a sensitivity analysis we further stratifiedthe group of outcomes described above. The risk of psy-chosis was 2.17 (0.85e5.59) and the risk of stress-relateddisorders was 1.80 (95% CI 0.48e6.79) for users of meflo-quine compared to non-users of anti-malarials. The risk forphobia, anxiety or panic attacks was not elevated for usersof mefloquine. The results for mefloquine, chloroquineand/or proguanil and atovaquone/proguanil are provided inTable 3. A sensitivity analysis stratifying the results by BMIdid not show any increased risks for any BMI category (datanot shown).

The odds ratios of developing depression adjusted forBMI and smoking were 0.54 (95% CI 0.41e0.71), 1.06 (95% CI0.71e1.59) and 0.75 (95% CI 0.62e0.91) for mefloquineusers, users of chloroquine and/or proguanil, or users ofatovaquone and/or proguanil compared to non-users ofantimalarials. In a sensitivity analysis stratified by BMI, wefound a tendency towards increased risks for most under-weight exposure groups compared to unexposed, normal oroverweight people, yielding increased ORs of depression of2.96 (95% CI 0.85e10.34) for mefloquine use, of 2.64 (95% CI0.23e30.14) for use of atovaquone/proguanil, of 0.78 (95%


Table 1 Incidence rates stratified by neuropsychiatric disorder, anti-malarial exposure, age, BMI and sex.

Mefloquine Chloroquine/proguanil Atovaquone/proguanil Unexposed

n PT IR 95% CI n PT IR 95% CI n PT IR 95% CI n PT IR 95% CI

Anxiety or stress-related disorders or psychosisTotal 99 15,995 6.2 (5.1e7.5) 47 4422 10.6 (8.0e14.1) 268 37,192 7.2 (6.4e8.1) 537 54 882 9.8 (9.0e10.6)Age in years

<40 65 10,218 6.4 (5.0e8.1) 26 2802 9.3 (6.3e13.6) 148 19,117 7.7 (6.6e9.1) 306 30 765 9.9 (8.9e11.1)40e49 15 2501 6.0 (3.6e9.9) 9 613 14.7 (7.7e27.7) 42 6090 6.9 (5.1e9.3) 104 8646 12 (9.9e14.6)50e59 5 1787 2.8 (1.2e6.5) 5 531 9.4 (4.0e21.9) 46 6268 7.3 (5.5e9.8) 71 8170 8.7 (6.9e10.9)60e69 10 1080 9.3 (5.0e17.0) 2 328 6.1 (1.7e21.9) 24 4245 5.7 (3.8e8.4) 45 5362 8.4 (6.3e11.2)70þ 4 409 9.8 (3.8e24.9) 5 148 33.8 (14.5e76.6) 8 1472 5.4 (2.8e10.7) 11 1939 5.7 (3.2e10.1)Sex

Male 33 7591 4.3 (3.1e6.1) 10 2088 4.8 (2.6e8.8) 77 17,600 4.4 (3.5e5.5) 187 26 000 7.2 (6.2e8.3)Female 66 8404 7.9 (6.2e10.0) 37 2335 15.8 (11.5e21.8) 191 19,593 9.7 (8.5e11.2) 350 28 882 12.1 (10.9e13.4)BMI

<18.5 2 205 9.7 (2.7e34.8) 0 49 NA NA 12 541 22.2 (12.7e38.4) 12 791 15.2 (8.7e26.3)18.5e19.9 3 489 6.1 (2.1e17.9) 3 165 18.1 (6.2e52.0) 15 1469 10.2 (6.2e16.8) 23 1848 12.4 (8.3e18.6)20.0e21.9 21 2182 9.6 (6.3e14.7) 11 573 19.2 (10.8e34.1) 56 6718 8.3 (6.4e10.8) 104 7773 13.4 (11.1e16.2)22.0e24.9 9 1730 5.2 (2.7e9.9) 11 473 23.2 (13.0e41.1) 49 5443 9.0 (6.8e11.9) 85 6386 13.3 (10.8e16.4)25.0e29.9 17 3109 5.5 (3.4e8.7) 8 762 10.5 (5.3e20.6) 54 8261 6.5 (5.0e8.5) 111 10 524 10.5 (8.8e12.7)30þ 17 1601 10.6 (6.6e16.9) 6 397 15.1 (6.9e32.5) 28 3229 8.7 (6.0e12.5) 66 4919 13.4 (10.6e17.0)Unknown 30 6679 4.5 (3.1e6.4) 8 2002 4.0 (2.0e7.9) 54 11,532 4.7 (3.6e6.1) 136 22 642 6.0 (5.1e7.1)Timing of exposure

Past 57 10,828 5.3 (4.1e6.8) 29 3004 9.7 (6.7e13.8) 178 28,171 6.3 (5.5e7.3) NA NA NA NACurrent 42 5167 8.1 (6.0e11.0) 18 1419 12.7 (8.0e20.0) 90 9021 10.0 (8.1e12.2) NA NA NA NA

DepressionTotal 68 16,032 4.2 (3.3e5.4) 34 4443 7.7 (5.5e10.7) 214 36,987 5.8 (5.1e6.6) 423 54 861 7.7 (7.0e8.5)Age in years

<40 39 10281 3.8 (2.8e5.2) 17 2823 6.0 (3.8e9.6) 107 19,101 5.6 (4.6e6.8) 238 30 939 7.7 (6.8e8.7)40e49 15 2477 6.1 (3.7e10.0) 10 612 16.3 (8.9e29.8) 52 5975 8.7 (6.6e11.4) 82 8565 9.6 (7.7e11.9)50e59 7 1779 3.9 (1.9e8.1) 4 526 7.6 (3.0e19.4) 37 6162 6.0 (4.4e8.3) 64 8026 8.0 (6.3e10.2)60e69 5 1080 4.6 (2.0e10.8) 2 334 6.0 (1.6e21.6) 14 4275 3.3 (2.0e5.5) 23 5410 4.3 (2.8e6.4)70þ 2 415 4.8 (1.3e17.4) 1 148 6.7 (1.2e37.2) 4 1474 2.7 (1.1e7.0) 16 1922 8.3 (5.1e13.5)Sex


<18.5 4 200 20 (7.8e50.3) 1 52 19.2 (3.4e101) 4 538 7.4 (2.9e19.0) 11 768 14.3 (8.0e25.5)18.5e19.9 1 492 2.0 (0.4e11.4) 0 169 NA NA 13 1453 8.9 (5.2e15.2) 23 1904 12.1 (8.1e18.1)20.0e21.9 12 2207 5.4 (3.1e9.5) 8 559 14.3 (7.3e28.0) 48 6677 7.2 (5.4e9.5) 70 7734 9.1 (7.2e11.4)22.0e24.9 7 1732 4.0 (2.0e8.3) 5 475 10.5 (4.5e24.4) 27 5422 5.0 (3.4e7.2) 56 6423 8.7 (6.7e11.3)25.0e29.9 21 3123 6.7 (4.4e10.3) 9 771 11.7 (6.1e22.0) 47 8178 5.7 (4.3e7.6) 92 10 413 8.8 (7.2e10.8)30þ 10 1586 6.3 (3.4e11.6) 6 416 14.4 (6.6e31.1) 35 3127 11.2 (8.1e15.5) 65 4732 13.7 (10.8e17.5)

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Unknown 13 6691 1.9 (1.1e3.3) 5 2001 2.5 (1.1e5.8) 40 11,592 3.5 (2.5e4.7) 106 22 887 4.6 (3.8e5.6)Timing of exposure

Past 52 10849 4.8 (3.7e6.3) 28 3018 9.3 (6.4e13.4) 173 28,005 6.2 (5.3e7.2) NA NA NA NACurrent 16 5182 3.1 (1.9e5.0) 6 1425 4.2 (1.9e9.2) 41 8982 4.6 (3.4e6.2) NA NA NA NA

EpilepsyTotal 14 16,601 0.8 (0.5e1.4) 7 4786 1.5 (0.7e3.0) 20 40,149 0.5 (0.3e0.8) 45 58 795 0.8 (0.6e1.0)Age in years

<40 11 10,378 1.1 (0.6e1.9) 5 2919 1.7 (0.7e4.0) 14 19,930 0.7 (0.4e1.2) 30 31 984 0.9 (0.7e1.3)40e49 1 2667 0.4 (0.1e2.1) 1 712 1.4 (0.2e7.9) 2 6789 0.3 (0.1e1.1) 5 9578 0.5 (0.2e1.2)50e59 2 1943 1.0 (0.3e3.7) 0 598 NA NA 1 7059 0.1 (0.0e0.8) 4 9101 0.4 (0.2e1.1)60e69 0 1169 NA NA 0 389 NA NA 3 4773 0.6 (0.2e1.8) 3 6038 0.5 (0.2e1.5)70þ 0 443 NA NA 1 168 5.9 (1.0e32.9) 0 1598 NA NA 3 2092 1.4 (0.5e4.2)Sex


<18.5 1 214 4.7 (0.8e26.0) 0 57 NA NA 0 612 NA NA 0 834 NA NA18.5e19.9 1 511 2.0 (0.3e11.0) 0 182 NA NA 1 1620 0.6 (0.1e3.5) 0 2064 NA NA20.0e21.9 1 2304 0.4 (0.1e2.5) 1 645 1.6 (0.3e8.7) 2 7329 0.3 (0.1e1.0) 12 8513 1.4 (0.8e2.5)22.0e24.9 3 1834 1.6 (0.6e4.8) 2 530 3.8 (1.0e13.7) 1 6031 0.2 (0.0e0.9) 4 7061 0.6 (0.2e1.5)25.0e29.9 0 3324 NA NA 1 881 1.1 (0.2e6.4) 4 9057 0.4 (0.2e1.1) 8 11 573 0.7 (0.4e1.4)30þ 0 1697 NA NA 2 464 4.3 (1.2e15.6) 1 3624 0.3 (0.0e1.6) 3 5531 0.5 (0.2e1.6)Unknown 8 6717 1.2 (0.6e2.3) 1 2027 0.5 (0.1e2.8) 11 11878 0.9 (0.5e1.7) 18 23 218 0.8 (0.5e1.2)Timing of exposure

Past 8 11250 0.7 (0.4e1.4) 6 3259 1.8 (0.8e4.0) 12 30,448 0.4 (0.2e0.7) NA NA NA NACurrent 6 5351 1.1 (0.5e2.4) 1 1528 0.7 (0.1e3.7) 8 9701 0.8 (0.4e1.6) NA NA NA NA

NeuropathyTotal 8 16,763 0.5 (0.2e0.9) 3 4898 0.6 (0.2e1.8) 20 40,884 0.5 (0.3e0.8) 25 59 771 0.4 (0.3e0.6)Age in Years

<40 2 10,544 0.2 (0.1e0.7) 0 3003 NA NA 3 20,444 0.1 (0.0e0.4) 9 32 648 0.3 (0.1e0.5)40e49 2 2670 0.7 (0.2e2.7) 1 723 1.4 (0.2e7.8) 4 6892 0.6 (0.2e1.5) 1 9718 0.1 (0.0e0.6)50e59 2 1945 1.0 (0.3e3.7) 1 611 1.6 (0.3e9.2) 6 7131 0.8 (0.4e1.8) 3 9237 0.3 (0.1e1.0)60e69 1 1165 0.9 (0.2e4.8) 1 392 2.6 (0.5e14.3) 3 4811 0.6 (0.2e1.8) 7 6085 1.2 (0.6e2.4)70þ 1 439 2.3 (0.4e12.8) 0 170 NA NA 4 1605 2.5 (1.0e6.4) 5 2082 2.4 (1.0e5.6)Sex


<18.5 0 217 NA NA 0 61 NA NA 0 625 NA NA 1 901 1.1 (0.2e6.3)18.5e19.9 0 522 NA NA 0 188 NA NA 0 1650 NA NA 0 2107 NA NA20.0e21.9 1 2338 0.4 (0.1e2.4) 2 655 3.1 (0.8e11.1) 2 7484 0.3 (0.1e1.0) 3 8800 0.3 (0.1e1.0)

(continued on next page)

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Table

1(continued)

Mefloquine

Chloroquine/p

rogu

anil

Atova

quone/p

rogu

anil

Unexp

osed

nPT

IR95

%CI

nPT

IR95

%CI

nPT

IR95

%CI

nPT

IR95

%CI

22.0e24

.91

1840

0.5

(0.1e3.1)

154

11.8

(0.3e10

.4)

361

160.5

(0.2e1.4)

371

880.4

(0.1e1.2)

25.0e29

.93

3333

0.9

(0.3e2.6)

090

0NA

NA

992

111.0

(0.5e1.9)

611

607

0.5

(0.2e1.1)

30þ

216

941.2

(0.3e4.3)

047

9NA

NA

436

651.1

(0.4e2.8)

755

191.3

(0.6e2.6)

Unkn

own

168

190.1

(0.0e0.8)

020

74NA

NA

212

,133

0.2

(0.0e0.6)

523

649

0.2

(0.1e0.5)

Tim

ingofexposu

re

Past

311

,364

0.3

(0.1e0.8)

333

360.9

(0.3e2.6)

1431

,000

0.5

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NA

NA

NA

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Current

554

000.9

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015

62NA

NA

698

830.6

(0.3e1.3)

NA

NA

NA

NA

IR:Incidence

rate

per10

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ars,PT:persontimein

years;95

%CI:95

%co

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interval.


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CI 0.27e2.25) for use of chloroquine/proguanil, and of 1.82(95% CI 0.90e3.67) if unexposed.

The ORs of developing epilepsy, adjusted for BMI andsmoking, were 0.69 (95% CI 0.35e1.36), 1.41 (95% CI0.54e3.67) and 0.75 (95% CI 0.42e1.36) for mefloquineusers, users of chloroquine and/or proguanil, or users ofatovaquone and/or proguanil, as compared to non-users ofantimalarials.

The adjusted ORs of developing peripheral neuropathieswere 1.22 (95% CI 0.50e2.99), 1.59 (95% CI 0.41e6.15) and1.05 (95% CI 0.54e2.03) for mefloquine users, users ofchloroquine and/or proguanil, or users of atovaquone and/or proguanil, compared to non-users of antimalarials. Inmen, the ORs were 1.92 (95% CI 0.55e6.69), 3.21 (95% CI0.52e19.85) and 1.96 (95% CI 0.82e4.65), respectively, andin women 0.71 (95% CI 0.18e2.85), 0.80 (95% CI 0.09e7.39)and 0.35 (95% CI 0.10e1.17), respectively (data not shown).

Timing of exposure did not materially change theoutcome results (Table 3). The findings of a more detailedanalysis of the group with anxiety and stress-related dis-orders are displayed in Table 4.

Discussion

In this large UK-based observational study we foundrelatively little evidence for an increased risk of neuro-psychiatric disorders in travelers with current or pastexposure to mefloquine or other antimalarials. These re-sults apply only to patients without a previous history ofthese disorders; in the UK, mefloquine is contraindicatedin people with a history of convulsions, depression, anxi-ety disorder, psychosis, schizophrenia, or other majorpsychiatric disorders.

The risk of developing a first-time diagnosis of an anxietydisorder was not elevated in users of anti-malarial drugprophylaxis. We further stratified cases with anxiety disor-ders into more specific outcomes and found a non-statistically significant increased risk of psychosis in usersof mefloquine (OR 2.17, 95% CI 0.85e5.59). The risk of phobicdisorders, panic attacks or anxiety was not increased for anyof the anti-malarial regimens. These results differ from aprevious study were we found an increased risk of panic at-tacks for users of mefloquine.2 In that previous study,we focused on three well-defined outcomes, and comparedcurrent users of anti-malarial drugs to past users. In thecurrent study, we studied a broader range of neuropsychi-atric disorders, and included non-users of anti-malarial drugsas the reference group. These methodological differencesmay account for some differences in the findings. Stress-related disorders were non-significantly increased for mef-loquine users (OR 1.80, 95% CI 0.48e6.79). The numbers ofcases in these sub-groups were too small for a meaningful,BMI-stratified analysis.

As in a previous study2 we did not find an increased risk ofdepression in users of mefloquine. Incidence rates of first-time depression in women were higher than in men for allfour exposure groups, reflecting a generally higher incidencerate of depression inwomen, regardless of anti-malarial drugprophylaxis.17 In a randomized, double-blind four-arm studycomparing mood profiles in people using atovaquone/pro-guanil, chloroquine/proguanil, doxycycline, or mefloquine


Table 2 Characteristics of the study population stratified by neuropsychiatric disorder, nested caseecontrol analysis.

Anxiety or stress-relateddisorders or psychosis

Depression Epilepsy Neuropathy

Cases (%) Controls (%) Cases (%) Controls (%) Cases (%) Controls (%) Cases (%) Controls (%)

Age (in years)

1e2 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (8.1) 31 (6.0) 0 (0.0) 0 (0.0)3e12 10 (1.1) 55 (1.0) 0 (0.0) 0 (0.0) 14 (16.3) 92 (17.8) 1 (1.8) 6 (1.8)13e17 21 (2.2) 136 (2.4) 18 (2.4) 114 (2.6) 6 (7.0) 42 (8.1) 0 (0.0) 0 (0.0)18e65 877 (92.1) 5243 (91.8) 688 (93.1) 4114 (92.8) 53 (61.6) 310 (60.1) 39 (69.6) 237 (70.5)66þ 44 (4.6) 278 (4.9) 33 (4.5) 206 (4.6) 6 (7.0) 41 (7.9) 16 (28.6) 93 (27.7)Sex

Male 307 (32.2) 1842 (32.2) 245 (33.2) 1470 (33.2) 41 (47.7) 246 (47.7) 33 (58.9) 198 (58.9)Female 645 (67.8) 3870 (67.8) 494 (66.8) 2964 (66.8) 45 (52.3) 270 (52.3) 23 (41.1) 138 (41.1)BMI (kg/m2)

<18.5 26 (2.7) 117 (2.0) 20 (2.7) 67 (1.5) 1 (1.2) 10 (1.9) 1 (1.8) 5 (1.5)18.5e19.9 44 (4.6) 266 (4.7) 37 (5.0) 217 (4.9) 2 (2.3) 18 (3.5) 0 (0.0) 6 (1.8)20.0e22.9 192 (20.2) 1114 (19.5) 138 (18.7) 892 (20.1) 16 (18.6) 69 (13.4) 8 (14.3) 60 (17.9)23.0e24.9 154 (16.2) 823 (14.4) 95 (12.9) 612 (13.8) 10 (11.6) 47 (9.1) 8 (14.3) 57 (17.0)25.0e29.9 191 (20.1) 1203 (21.1) 169 (22.9) 1001 (22.6) 13 (15.1) 99 (19.2) 18 (32.1) 87 (25.9)30þ 117 (12.3) 644 (11.3) 116 (15.7) 482 (10.9) 6 (7.0) 38 (7.4) 13 (23.2) 59 (17.6)Unknown 228 (23.9) 1545 (27.0) 164 (22.2) 1163 (26.2) 38 (44.2) 235 (45.5) 8 (14.3) 62 (18.5)Smoking status

Non smoker 485 (50.9) 3312 (58.0) 374 (50.6) 2606 (58.8) 41 (47.7) 228 (44.2) 31 (55.4) 181 (53.9)Ex-smoker 143 (15.0) 695 (12.2) 104 (14.1) 555 (12.5) 9 (10.5) 45 (8.7) 13 (23.2) 71 (21.1)Current smoker 199 (20.9) 870 (15.2) 181 (24.5) 656 (14.8) 7 (8.1) 50 (9.7) 9 (16.1) 48 (14.3)Unknown 125 (13.1) 835 (14.6) 80 (10.8) 617 (13.9) 29 (33.7) 193 (37.4) 3 (5.4) 36 (10.7)


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chemoprophylaxis, there was no evidence for a negativeimpact on overall mood associated with anti-malarialchemoprophylaxis.8 However a later gender stratified anal-ysis of the data showed increased fatigue and confusion inwomen.18 A trial comparing mefloquine with atovaquone/proguanil in 119 people attending a Dutch Travel Clinic re-ported significantly higher scores for depression in meflo-quine users.19 In our study, underweight people (BMI<18.5)as compared to unexposed, normal or overweight people,tended tohavea statistically non-significant increased risk ofdepression with mefloquine, or with other antimalarials(based on small cells and wide confidence intervals). Unex-posed underweight people were at an increased risk ofdepression prompting a cautious interpretation regardingpossible association.

We did not find an elevated risk of epilepsy in meflo-quine users. The numbers were too small for an analysisstratified by BMI. Several spontaneous reports relatedmefloquine use to an increased risk of seizures and con-vulsions, mostly during co-administration with other drugsor in patients with a family or personal history of otherpotential risk factors.20

We did not find evidence for a substantially altered riskof peripheral neuropathies during anti-malarial prophy-laxis. There was a trend towards an increased risk in menfor all three anti-malarial drugs. In the literature there areonly two case reports on mefloquine exposure and neu-ropathies, the first being a case of neuropathy in the oro-facial region,21 the second a peripheral poly-neuropathy.22

This study has important strengths, such as the large sizeof the study population and the high data quality of thedatabase but there are some potential limitations.


Exposure classification of patients is based on computer-recorded prescriptions by GPs. In addition, specializedtravel clinics also prescribe anti-malarial drugs and pro-guanil and chloroquine can be purchased in UK pharmacieswithout prescription. While this may have diminished thesize of the study population, it is unlikely to have intro-duced substantial bias.

Furthermore, not all prescribed drugs are taken by allpatients. Such imprecision in exposure is present to someextent in the current study and might have biased our re-sults towards the null.

Patients taking different anti-malarial drugs are likely tohave different travel destinations. We were not able toadjust for travel destination since this information is notroutinely recorded. While the travel destination is relatedto the choice of an anti-malarial drug, it is unlikely to berelated to the risk of developing a neuropsychiatric disor-der. There might, however, be a difference between pa-tients choosing to travel to destinations with or withoutmalaria risk. They might differ in their risk behavior, whichmight be associated with the risk of developing neuropsy-chiatric disorders. Patients taking different anti-malarialdrugs might also be at a different baseline risk of devel-oping a neuropsychiatric disorder. Mefloquine is contra-indicated in people with a personal or family history ofcertain neuropsychiatric disorders. We excluded all pa-tients with a personal history of recorded neuropsychiatricdisorders from the study population, but family history isnot consistently recorded in the database.

GPs may have missed episodes of CNS disorders if theseoccurred during travel. We assume that a high proportion ofsevere events would have been reported to the GP after


Table 3 Odds ratios for anti-malarial drug exposures in relation to anxiety or stress-related disorders or psychosis, depression,epilepsy and neuropathies.

Cases (%) Controls (%) OR (95% CI) Adj. OR (95% CI) P-value

Anxiety or stress-related disorders or psychosisUnexposed 537 (56.4) 2806 (49.1) 1.00 (ref) 1.00 (ref)Mefloquine 98 (10.3) 741 (13.0) 0.69 (0.54e0.87) 0.71 (0.56e0.90) <0.01

Current 41 (4.3) 293 (5.1) 0.73 (0.52e1.03) 0.76 (0.53e1.08) 0.12Past 57 (6.0) 448 (7.8) 0.67 (0.50e0.89) 0.68 (0.51e0.92) 0.01

Chloroquine/proguanil 47 (4.9) 238 (4.2) 1.04 (0.74e1.46) 1.04 (0.74e1.46) 0.83Current 18 (1.9) 68 (1.2) 1.41 (0.82e2.41) 1.39 (0.81e2.40) 0.23Past 29 (3.0) 170 (3.0) 0.90 (0.60e1.36) 0.90 (0.60e1.36) 0.62

Atovaquone/proguanil 266 (27.9) 1888 (33.1) 0.72 (0.61e0.85) 0.73 (0.61e0.86) <0.01Current 90 (9.5) 509 (8.9) 0.91 (0.71e1.16) 0.92 (0.72e1.18) 0.52Past 176 (18.5) 1379 (24.1) 0.65 (0.54e0.78) 0.65 (0.54e0.79) <0.01

Mixed exposure 4 (0.4) 39 (0.7) 0.53 (0.19e1.48) 0.56 (0.20e1.58) 0.27DepressionUnexposed 423 (57.2) 2181 (49.2) 1.00 (ref) 1.00 (ref)Mefloquine 68 (9.2) 640 (14.4) 0.54 (0.41e0.71) 0.54 (0.41e0.71) <0.01

Current 16 (2.2) 248 (5.6) 0.33 (0.19e0.55) 0.32 (0.19e0.54) <0.01Past 52 (7.0) 392 (8.8) 0.67 (0.49e0.92) 0.68 (0.50e0.94) 0.02


Atovaquone/proguanil 210 (28.4) 1421 (32.0) 0.75 (0.62e0.91) 0.75 (0.62e0.91) <0.01Current 40 (5.4) 368 (8.3) 0.55 (0.39e0.78) 0.56 (0.40e0.80) <0.01Past 170 (23.0) 1053 (23.7) 0.83 (0.68e1.02) 0.83 (0.67e1.02) 0.07

Mixed exposure 5 (0.7) 33 (0.7) 0.80 (0.31e2.06) 0.84 (0.32e2.19) 0.72EpilepsyUnexposed 45 (52.3) 241 (46.7) 1.00 (ref) 1.00 (ref)Mefloquine 14 (16.3) 107 (20.7) 0.71 (0.36e1.38) 0.69 (0.35e1.36) 0.28



Atovaquone/proguanil 20 (23.3) 138 (26.7) 0.78 (0.44e1.40) 0.75 (0.42e1.36) 0.34Current 8 (9.3) 31 (6.0) 1.44 (0.61e3.41) 1.42 (0.59e3.42) 0.44Past 12 (14.0) 107 (20.7) 0.59 (0.30e1.18) 0.56 (0.28e1.14) 0.11

Mixed exposure 0 (0.0) 6 (1.2) NA NA NANeuropathyUnexposed 25 (44.6) 159 (47.3) 1.00 (ref) 1.00 (ref)Mefloquine 8 (14.3) 42 (12.5) 1.20 (0.50e2.89) 1.22 (0.50e2.99) 0.66


Chloroquine/proguanil 3 (5.4) 13 (3.9) 1.47 (0.39e5.58) 1.59 (0.41e6.15) 0.50Current 0 (0.0) 3 (0.9) NA NA NAPast 3 (5.4) 10 (3.0) 1.88 (0.49e7.20) 2.36 (0.58e9.58) 0.23

Atovaquone/proguanil 20 (35.7) 121 (36.0) 1.04 (0.54e2.00) 1.05 (0.54e2.03) 0.89Current 6 (10.7) 27 (8.0) 1.38 (0.51e3.70) 1.51 (0.54e4.21) 0.43Past 14 (25.0) 94 (28.0) 0.93 (0.45e1.94) 0.91 (0.44e1.90) 0.80

Mixed exposure 0 (0.0) 1 (0.3) NA NA NA

OR: odds ratio; adj. OR: odds ratio adjusted for smoking, BMI; 95% CI: 95% confidence interval.


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return to the UK for further diagnostic procedure and/ortreatment.

Finally, we could not adjust for stress-related sleepdeprivation associated with international travel, longerstay abroad, social alcohol use, consumption of illicit drugsduring the trip, use of concomitant medication, or for the


fact that some patients might have pre-existing neuropsy-chiatric disorders or a family history thereof without tellingthe GP prior to using anti-malarial drugs.

In summary, we explored the association between use ofmefloquine or other anti-malarials and the risk of devel-oping a first-time diagnosis of various neuropsychiatric


Table 4 Odd ratios for anti-malarial drug exposure in relation to psychosis, phobia, anxiety or panic attacks.

Cases (%) Controls (%) OR (95% CI) Adj. OR (95% CI) P-value

PsychosisUnexposed 19 (42.2) 136 (50.4) 1.00 (ref) 1.00 (ref)Mefloquine 10 (22.2) 31 (11.5) 2.40 (0.98e5.86) 2.17 (0.85e5.59) 0.11Chloroquine/Proguanil 1 (2.2) 12 (4.4) 0.59 (0.07e5.00) 0.47 (0.05e4.11) 0.49Atovaquone/Proguanil 15 (33.3) 90 (33.3) 1.12 (0.52e2.37) 0.97 (0.44e2.14) 0.93Mixed exposure 0 (0.0) 1 (0.4) NA NA NA

PhobiaUnexposed 92 (56.4) 464 (47.4) 1.00 (ref) 1.00 (ref)Mefloquine 16 (9.8) 114 (11.7) 0.70 (0.38e1.27) 0.73 (0.40e1.34) 0.30Chloroquine/proguanil 7 (4.3) 35 (3.6) 1.04 (0.43e2.49) 1.06 (0.44e2.60) 0.89Atovaquone/proguanil 48 (29.4) 360 (36.8) 0.66 (0.45e0.97) 0.64 (0.43e0.96) 0.03Mixed exposure 0 (0.0) 5 (0.5) NA NA NA

AnxietyUnexposed 293 (58.6) 1463 (48.8) 1.00 (ref) 1.00 (ref)Mefloquine 50 (10.0) 422 (14.1) 0.59 (0.43e0.82) 0.60 (0.43e0.83) <0.01Chloroquine/proguanil 23 (4.6) 130 (4.3) 0.87 (0.54e1.42) 0.86 (0.53e1.40) 0.54Atovaquone/proguanil 131 (26.2) 962 (32.1) 0.66 (0.53e0.84) 0.66 (0.52e0.84) <0.01Mixed exposure 3 (0.6) 23 (0.8) 0.63 (0.19e2.13) 0.66 (0.20e2.24) 0.51

Panic attackUnexposed 121 (56.3) 657 (50.9) 1.00 (ref) 1.00 (ref)Mefloquine 18 (8.4) 150 (11.6) 0.64 (0.37e1.11) 0.68 (0.39e1.17) 0.17Chloroquine/proguanil 10 (4.7) 52 (4.0) 1.04 (0.51e2.09) 1.06 (0.52e2.14) 0.87Atovaquone/proguanil 65 (30.2) 423 (32.8) 0.84 (0.60e1.17) 0.86 (0.61e1.21) 0.38Mixed exposure 1 (0.5) 8 (0.6) 0.67 (0.08e5.43) 0.88 (0.11e7.16) 0.90

OtherUnexposed 12 (41.4) 86 (49.4) 1.00 (ref) 1.00 (ref)Mefloquine 4 (13.8) 24 (13.8) 1.10 (0.31e3.94) 1.80 (0.48e6.79) 0.38Chloroquine/proguanil 6 (20.7) 9 (5.2) 5.17 (1.42e18.77) 6.39 (1.55e26.40) 0.01Atovaquone/proguanil 7 (24.1) 53 (30.5) 0.96 (0.33e2.77) 1.04 (0.32e3.37) 0.94Mixed exposure 0 (0.0) 2 (1.1) NA NA NA

Other: Posttraumatic stress disorder, adjustment disorder, reaction to severe stress.OR: odds ratio; adj. OR: odds ratio adjusted for smoking, BMI; 95% CI: 95% confidence interval.

1 Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacyand Epidemiology, Department of Pharmaceutical Sciences, Uni-versity Basel, Basel, Switzerland.


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disorders. Except for some findings in subgroups (e.g. caseswith acute psychosis) we did not find substantial evidencethat neuropsychiatric disorders are associated with use ofmefloquine compared to no exposure or to exposure toother antimalarials. Our study population encompassedslightly more females, most cases were below the age of 40years, and we had relatively little information on under-weight travelers. Thus, the findings need to be interpretedin the context of the above-mentioned limitations.

Financial support and role of the fundingsource

F. Hoffmann-La Roche Ltd., Basel, Switzerland.The sponsor participated in the design of the study,

conducting the study, interpretation of the data, reviewand approval of the manuscript.

Conflict of interests

Miriam Adamcova and Hans-Georg Rhein are employees ofF. Hoffmann-La Roche.

Mary K. Miller is an employee of Genentech Inc.


Patricia Schlagenhauf has received speakers’ honorariaand research grants from Glaxo Smith Kline and speakers’honoraria, research grants and consultancy fees fromHoffmann-La Roche.

Susan Jick: No conflict.Christoph Meier: No conflict.Cornelia Schneider: No conflict.

Acknowledgment

We thank Pascal Egger1 for his technical support andprogramming.

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Antimalarial chemoprophylaxis and the risk of neuropsychiatric disorders

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