The Mefloquine Controversy

There has been recent concern about the  possible neuropsychiatric impact of the anti-malarial drug mefloquine  on Canadian soldiers deployed overseas.

Below are abstracts of recently published  international studies on this important topic.

Adverse Neuropsychiatric Effects Of Antimalarial Drugs.

Grabias B Kumar S Center for Biologics Evaluation and Research, Food and

Drug Administration , Silver Spring , MD , USA.

Expert Opin Drug Saf. 2016 Jul;15(7):903-10

INTRODUCTION: Antimalarial drugs are the primary weapon to treat parasite

infection, save lives, and curtail further transmission. Accumulating data have

indicated that at least some antimalarial drugs may contribute to severe

neurological and/or psychiatric side effects which further complicates their use

and limits the pool of available medications.

AREAS COVERED: In this review article the authors summarize published scientific

studies for evidence of the neuropsychiatric effects that may be attributed to

the commonly used antimalarial drugs administered alone or in combination. Each

individual drug was used as a search term in addition to keywords such as

neuropsychiatric, adverse events, and neurotoxicity.

EXPERT OPINION: Accumulating data based on published reports over several decades have suggested that among the major commonly used antimalarial drugs, only mefloquine exhibited clear indications of serious neurological and/or psychiatric side effects.

A more systematic approach to assess the neuropsychiatric adverse

effects of new or repurposed antimalarial drugs on their safety, tolerability and

efficacy phases of clinical studies and in post-marketing surveillance, is needed

to ensure that these life-saving tools remain available and can be prescribed

with appropriate caution and medical judgment.

Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness, And

Risk-Benefit Analysis In The Australian Defence Force.

McCarthy S.  Headquarters 2nd Division, Australian Army, Randwick Barracks, Randwick, NSW 2031, Australia.

J Parasitol Res. 2015;2015:287651.  Epub 2015 Dec 17.

The Australian Defence Force (ADF) has used mefloquine for malaria

chemoprophylaxis since 1990. Mefloquine has been found to be a plausible cause of a chronic central nervous system toxicity syndrome and a confounding factor in the diagnosis of existing neuropsychiatric illnesses prevalent in the ADF such as posttraumatic stress disorder and traumatic brain injury.

Overall health risks appear to have been mitigated by restricting the drug’s use; however serious risks were realised when significant numbers of ADF personnel were subjected to clinical trials involving the drug. The full extent of the exposure, health impacts for affected individuals, and consequences for ADF health management including mental health are not yet known, but mefloquine may have caused or aggravated neuropsychiatric illness in large numbers of patients who were subsequently misdiagnosed and mistreated or otherwise failed to receive proper care.

Findings in relation to chronic mefloquine neurotoxicity were foreseeable,

but this eventuality appears not to have been considered during risk-benefit

analyses. Thorough analysis by the ADF would have identified this long-term risk

as well as other qualitative risk factors. Historical exposure of ADF personnel

to mefloquine neurotoxicity now also necessitates ongoing risk monitoring and

management in the overall context of broader health policies.

Rational Risk-Benefit Decision-Making In The Setting Of Military Mefloquine

Policy.

Nevin RL.  Department of Mental Health, Johns Hopkins Bloomberg School of Public Health.

J Parasitol Res. 2015;2015:260106

Mefloquine is an antimalarial drug that has been commonly used in military

settings since its development by the US military in the late 1980s. Owing to the

drug’s neuropsychiatric contraindications and its high rate of inducing

neuropsychiatric symptoms, which are contraindications to the drug’s continued

use, the routine prescribing of mefloquine in military settings may be

problematic.

Due to these considerations and to recent concerns of chronic and

potentially permanent psychiatric and neurological sequelae arising from drug

toxicity, military prescribing of mefloquine has recently decreased. In settings

where mefloquine remains available, policies governing prescribing should reflect

risk-benefit decision-making informed by the drug’s perceived benefits and by

consideration both of the risks identified in the drug’s labeling and of specific

military risks associated with its use. In this review, these risks are

identified and recommendations are made for the rational prescribing of the drug

in light of current evidence.

Acute And Long-Term Psychiatric Side Effects Of Mefloquine: A Follow-Up On Danish Adverse Event Reports.

Ringqvist Å, Bech P, Glenthøj B, Petersen E.

Department of Health Sciences, Lund University, Lund, Sweden.

Skane University Hospital, Lund, Sweden.

Faculty of Health and  Medical Sciences, University of Copenhagen.

Copenhagen University Hospital.

Department of Infectious Diseases, Aarhus University  Denmark.

Travel Med Infect Dis. 2015 Jan-Feb;13(1)

BACKGROUND: The aim of the study was to explore the profile of acute and

long-term psychiatric side effects associated with mefloquine.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

The Adverse Effects Of Mefloquine In Deployed Military Personnel.

Adshead S.

J R Nav Med Serv. 2014;100(3):232-7.

INTRODUCTION: Mefloquine is an effective anti-malarial prescribed to

over 35 million travellers world-wide as chemoprophylaxis. However, it has been

the subject of increased scrutiny and media attention due to its association with

significant neuropsychiatric adverse events. Anecdotal evidence suggests that

patient trust in the drug is waning.

METHODS: A prospective questionnaire-based cohort study of 150 deployed military  personnel prescribed mefloquine as anti-malaria chemoprophylaxis. The primary study objective was to assess the rate of adverse reactions. In addition, an audit of mefloquine prescriptions and subsequent patient follow-up was conducted.

RESULTS: Among a cohort of 111 individuals taking mefloquine, 54% reported at

least one adverse effect and 13% required a change in prescription to a

second-line anti-malarial, due to significant side-effects. All females

prescribed mefloquine reported at least one adverse reaction. There were two

cases of clinically significant adverse reactions.

CONCLUSIONS: There was a higher rate of adverse events reported amongst deployed  military personnel than has been reported among civilian patients. This may be partly due to the stressful environment in which deployed personnel operate.