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
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
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
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.
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.