Dr. Remington Nevin

 

Mefloquine prescriptions in the presence of contraindications: prevalence among U.S. military personnel deployed to Afghanistan, 2007.

Pharmacoepidemiology and Drug Safety 2010;19:206-210.


For safety reasons, the anti-malaria drug mefloquine is contraindicated in patients with certain mental health conditions, such as depression, in whom it may increase the risk of serious adverse events including suicide. This research merged DoD deployment and health databases with pharmacy data to explore whether, and how often, mefloquine had been prescribed to service members for whom it was contraindicated. This research found that 1 in 7 service members with contraindications had recently been prescribed mefloquine. Its publication preceded significant improvements in mefloquine policy within DoD .

Low validity of self-report in identifying recent mental health diagnosis among U.S. service members completing Pre-Deployment Health Assessment (PreDHA) and deployed to Afghanistan, 2007: a retrospective cohort study.

BMC Public Health 2009;9:376.


Despite efforts at improving post-deployment screening to identify mental health conditions such as PTSD, pre-deployment screening forms have remained unchanged since 1999. This research examined how accurately these forms identified disqualifying mental health conditions, and found that many service members with disqualifying conditions are erroneously deployed through current methods. This research confirmed concerns first raised in the popular press. Its publication preceded sweeping changes in pre-deployment screening and deployment-limiting medical policies.

Mental health standards for combat deployment.

Psychiatric Services 2011;62:805.


Despite nearly ten years of combat, relatively few publications in the mental health literature describe the effectiveness of military pre-deployment mental health screening standards and practices. Despite evidence in the literature of deficiencies noted years earlier, compliance with current military screening standards remains suboptimal, and evidence suggests that medical providers performing pre-deployment screening remain mostly unaware of the mental health histories of the deploying personnel that they evaluate. This letter summarizes and comments on recent published research, and encourages greater efforts towards compliance with policies designed to identify and restrict from deployment those at-risk personnel who do not meet current mental health standards.

Mefloquine neurotoxicity and gap junction blockade: Critical insights in drug repositioning.

Neurotoxicology 2011;32:986-987.


In recent years, the antimalarial drug mefloquine has become well-characterized as a potent neurotoxin and has been demonstrated to produce blockade of neuronal gap junctions, causing significant psychotropic effects. Owing to its toxicity and effective brain penetration, mefloquine is being investigated for the treatment of brain tumors, progressive multifocal leukoencephalopathy, and other potentially life-threatening conditions. This letter summarizes recent research on the neurotoxicity of the drug and comments on the need for additional research to better understand and characterize these toxic effects.

Hallucinations and persecutory delusions in mefloquine-associated suicide.
American Journal of Forensic Medicine and Pathology 2012;33:e8.


The antimalarial drug mefloquine has been linked to spectacular cases of suicide and suicide attempt, but until recently the pathophysiology underlying this association has been unclear. This letter comments on a recent case report of a stunning suicide by skull stab wounds associated with mefloquine, and references recent biological evidence suggesting that among susceptible individuals, mefloquine may induce a dissociative hallucinogenic state that mimics phencyclidine (PCP) toxicity. Such evidence provides insight into the known epidemiological association of mefloquine with acts of violence, and into earlier ecological and case-series reports of suicide associated with the drug.

Investigating channel blockers for the treatment of multiple sclerosis: Considerations with mefloquine and carbenoxolone.

Journal of Neuroimmunology 2012;243:106-107.


Although neurotoxic, mefloquine is a potent immunomodulator and has been demonstrated to block connexin gap junction intercellular communication and pannexin hemichannels. Recently, a related gap junction channel blocker, carbenoxolone, has shown intriguing potential against the neuroimmune disorder multiple sclerosis. This letter comments on the potential utility of investigating mefloquine for this indication, but cautions on the need to be alert for the possibility of serious neuropsychiatric adverse effects with any such treatment.

Pharmacokinetic considerations in the repositioning of mefloquine for treatment of progressive multifocal leukoencephalopathy.

Clinical Neurology and Neurosurgery 2012;114:1204-1205.


Mefloquine has shown intriguing therapeutic potential against JC virus infection and progressive multifocal leukoencephalopathy, yet recent trials of mefloquine have reportedly demonstrated disappointing results for this indication. This letter comments on the potential significance of heterogeneity in mefloquine pharmacokinetics and posits that host genetic or pharmacologic factors may contribute to variation in brain accumulation of mefloquine and may thus underlie the differential response to treatment observed across recent case reports.

Limbic encephalopathy and central vestibulopathy caused by mefloquine: A case report.

Travel Medicine and Infectious Diseases 2012;10:144-145.

Despite over 20 years of licensed use, the pathophysiological mechanisms underlying mefloquine’s neuropsychiatric and physical side effects and the clinical significance of the drug’s neurotoxicity have remained poorly understood. In this report, an adverse reaction to mefloquine chemoprophylaxis is described characterized by prodromal symptoms of anxiety with subsequent development of psychosis, short-term memory impairment, confusion and personality change accompanied by complaints of disequilibrium and vertigo, with objective findings of central vestibulopathy. This report is the first published description of this idiosyncratic neurotoxic syndrome.

Mefloquine blockade of connexin 36 and connexin 43 gap junctions and risk of suicide.

Biological Psychiatry 2012;71:e1-2


Recent studies have demonstrated a significantly reduced expression of the gap junction protein connexin 43 (Cx43) in the dorsal lateral prefrontal cortex of suicide completers. Mefloquine has been associated in the medical literature with often spectacular cases of suicide and suicide attempt and is known to effect a potent blockade of Cx43 and connexin 36 (Cx36) gap junctions. This letter comments on evidence that mefloquine blockade of gap junctions may modify a host of behaviorally relevant processes in regions of the brain with significant Cx36 expression, including the reticular activating system, ventral tegmental area, hypothalamus, hippocampus, and amygdala; and discusses the likely role of Cx43 gap junction blockade in contributing to these effects.

Prevalence of contraindications to mefloquine use among USA military personnel deployed to Afghanistan.

Malaria Journal 2008;7:30.


In this study, military medical surveillance and pharmacosurveillance databases were utilized to identify contraindications to mefloquine use among a cohort of 11,725 active duty U.S. military personnel recently deployed to Afghanistan. A total of 9.6% of the cohort had evidence of a contraindication, including a history of certain psychiatric and neurological disorders. These findings underscore the importance of proper systematic screening prior to prescribing and dispensing mefloquine, and the need to provide alternatives to mefloquine suitable for long-term administration among deployed U.S. military personnel.

Limitations of postmarketing surveillance in the analysis of risk of pregnancy loss associated with maternal mefloquine exposure.

Clinical Infections Diseases 2012;55:1167-1168.


Use of the mefloquine has been associated in careful epidemiological studies with an increased risk of miscarriage and stillbirth. However recent recommendations, based on evidence from postmarketing surveillance, have suggested that mefloquine may be used cautiously during pregnancy. This letter discusses the limitations of such recent data, and urges caution in recommending the broader use of mefloquine during the periconceptional period given mounting evidence of a plausible biological mechanism by which mefloquine may adversely affect the viability of the implanting embryo and of the developing placenta.

Mass administration of the antimalarial drug mefloquine to Guantánamo detainees: a critical analysis.

Tropical Medicine and International Health 2012;17:1281-1288.


Administration of the antimalarial drug mefloquine at treatment doses is associated with a very high risk of physical side effects including debilitating nausea, vomiting, and severe vertigo, as well as worrisome psychiatric side effects including hallucinations, persecutory delusions, and amnesia. In this report, the unprecedented practice of administering treatment doses of mefloquine to asymptomatic and uninfected Guantánamo detainees is contrasted with accepted forms of mass antimalarial administration. This analysis suggests the troubling possibility that use of the drug among Guantánamo detainees may have been motivated in part by knowledge of the drug's adverse effects.

Mefloquine gap junction blockade and risk of pregnancy loss.

Biology of Reproduction 2012;87:65.


Mefloquine causes blockade of gap junction intercellular communication (GJIC) critical to successful embryonic implantation and early placental development. During routine use, mefloquine crosses the blood-placental barrier and may plausibly accumulate in developing decidua and trophoblast at concentrations sufficient to interfere with GJIC and thus cause deleterious effects on fetal outcomes. This conclusion is supported by epidemiological evidence which demonstrates use of the drug during early development is associated with an increased risk of miscarriage and stillbirth. This minireview summarizes available evidence to caution against the routine use of mefloquine during the periconceptional period.

Falling rates of malaria among U.S. military service members in Afghanistan substantiate findings of high compliance with daily chemoprophylaxis.

American Journal of Tropical Medicine and Hygiene 2012;87:957-958.

Rates of malaria have fallen dramatically in recent years among U.S. military personnel in Afghanistan, and as much as 70% since 2009. This decline is coincident with policy changes prohibiting the widespread use of the antimalarial drug mefloquine and favoring the use of safer daily antimalarials. In this letter, it is argued that falling rates of malaria are explained by improved compliance with daily medications, and that contrary to conventional wisdom, compliance with weekly mefloquine is low owing to rising concerns of psychiatric side effects and neurotoxicity. These observations add to growing evidence that mefloquine may be unsuitable for continued use among U.S. combat troops.

Dr. Nevin publishes the results of his research primarily on topics related to the adverse effects of antimalarial drugs. A selection of his recent publications are available below. Additional publications may be found referenced in PubMed or listed in his curriculum vitae. Some of these documents may be available only through institutional or subscription access. Researchers and interested members of the public may request an electronic reprint of any of these documents by contacting Dr. Nevin.  

Psychiatric Side Effects of Mefloquine: Applications to Forensic Psychiatry.

Journal of the American Academy of Psychiatry and the Law 2013;41:224-235.

Mefloquine is an antimalarial medication with potent psychotropic potential. Severe psychiatric side effects due to mefloquine intoxication are well documented, and exposure to the drug has been associated with acts of violence and suicide. In this article, plausible mechanisms of mefloquine’s psychotropic and neurotoxic action are described, and considerations for the application of claims of mefloquine intoxication in legal and forensic settings are discussed. This information is anticipated to be useful when forensic psychiatrists are asked to consult on cases where legal implications from exposure to the drug are alleged.

Idiosyncratic quinoline central nervous system toxicity: Historical insights into the chronic neurological sequelae of mefloquine.

International Journal for Parasitology: Drugs and Drug Resistance 2014;4:118-125.

European and U.S. product labeling for mefloquine now warn of a risk of permanent and irreversible neurological sequelae including vertigo, loss of balance and symptoms of polyneuropathy. In this opinion, it is proposed that many of the reported lasting adverse neurological effects of mefloquine are consistent with the chronic sequelae of a well characterized but idiosyncratic central nervous system (CNS) toxicity syndrome associated with a risk of permanent neuronal degeneration within specific CNS regions including the brainstem.

Antimalarial Adverse Effects

Military Mental Health

Population estimates of undocumented incident traumatic brain injuries among combat-deployed US military personnel

Journal of Head Trauma Rehabilitation 2015; 2015;30:E57-64.


This analysis examines the burden of traumatic brain injury (TBI) among combat-deployed personnel, particularly during the early years of the recent wars, and uses statistical techniques to estimate the number of personnel with undocumented injuries. It concludes that a sizable majority of Iraq and Afghanistan combat veterans who experienced incident TBI while deployed prior to November 2006 are likely to have had their injuries undocumented, creating challenges for clinical care, disability evaluation, and future research

A Memoir of Mefloquine Amnesia: A Review of The Answer to the Riddle is Me by David Stuart MacLean.

American Journal of Bioethics Neuroscience 2014;5:88-91.

The Answer to the Riddle is Me, by David Stuart MacLean (Houghton Mifflin Harcourt, New York, NY, 2014, $25, hardcover), is a fascinating narrative of the author’s recovery from a profound amnesia and psychosis caused by the antimalarial drug mefloquine. His book “serves as a frightful cautionary tale that the intoxicating effects of mefloquine can happen to anyone, at any time, and leave individuals incapable of recognizing and acting on their symptoms”, and “should be considered required reading for anyone contemplating the drug’s use, as it serves to educate prospective users about some of its worst effects better than any case report or product insert possibly could”.

Organic Depersonalization as a Chronic Sequela of Mefloquine Intoxication.

Psychosomatics 2015;56:103.

Mefloquine intoxication is associated with a risk of chronic symptoms of depersonalization and derealization. Mefloquine is neurotoxic and may plausibly cause injury to structures of the limbic system including the hippocampus. In this letter, it is argued that the chronic dissociative symptoms caused by mefloquine may reflect the sequela of an underlying toxic encephalopathy affecting the limbic system. The intoxication syndrome (or toxidrome) caused by mefloquine may provide critical opportunities to better elucidate the pathophysiology of a broad range of psychiatric symptoms linked to the drug's use, including symptoms of dissociation.

Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy.

Clinical Case Reports 2015;3:379-387.

Currently available synthetic quinoline antimalarials, including chloroquine, exhibit idiosyncratic neuropsychiatric effects when administered at low doses used for chemoprophylaxis. Susceptibility to quinoline antimalarial intoxication may reflect individual genetic and drug-induced variation in neuropharmacokinetics. In this report, we describe a case of chloroquine intoxication that appeared to be prolonged by subsequent use of multiple psychotropic medications. This case highlights important new considerations for the management of quinoline antimalarial intoxication.

Mefloquine and Posttraumatic Stress Disorder

Textbook of Military Medicine: Forensic and Ethical Issues in Military Behavioral Health. U.S. Army Borden Institute 2015:275-296.


In this chapter published in the U.S. Army’s Textbook of Military Medicine series, the history of mefloquine’s development and its use within the US military are reviewed, and then the clinical features of the mefloquine toxidrome are described. The chapter then highlights how specific psychiatric symptoms caused by mefloquine, including certain chronic symptoms, may readily confound PTSD diagnostic criteria. This review ends with a discussion of applications of this information to forensic psychiatry and presents a representative case study illustrating challenges in the diagnosis of mefloquine intoxication among military personnel.

Malaria

Issues in the Prevention of Malaria Among Women at War

Women at War. Oxford University Press 2015; 93-119.


This chapter, published in the book Women at War, provides an overview of the epidemiology of malaria in U.S. military servicewomen and discusses strategies for the prevention of malaria in women at war, including the use of mosquito-avoidance measures. The chapter also discusses special considerations for the safer use of prophylactic antimalarials in women, including issues related to reproductive and behavioral toxicity. The chapter concludes with recommendations for improving U.S. military malaria prevention policy to accommodate the needs of women at war.

Unexpected pharmacological and toxicological effects of tafenoquine

Occupational Medicine 2015;65:417


Tafenoquine is a transmission-blocking 8-aminoquinoline antimalarial currently in late-stage drug development.  This letter comments on recent findings of unexpected pharmacological effects, as well as the unexpected toxicological effects of the 8-aminoquinoline class, including idiosyncratic brainstem neurotoxicity. This letter recommends that additional pre-licensing studies be performed on tafenoquine to more thoroughly define its potentially complex pharmacology and toxicology prior to its more widespread use, particularly among asymptomatic populations in planned antimalarial mass drug administration campaigns.

Rational Risk-Benefit Decision-Making in the Setting of Military Mefloquine Policy

Journal of Parasitology Research 2015:260106


In military 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. Consideration of the issues in this review may aid militaries in formulating rational policies for the safer use of the drug, or may serve to motivate further prohibitions on the use of mefloquine in line with those already in place in a growing number of military settings.

The Mefloquine Intoxication Syndrome: A Significant Potential Confounder in the Diagnosis and Management of PTSD and Other Chronic Deployment-Related Neuropsychiatric Disorders

Posttraumatic Stress Disorder and Related Diseases in Combat Veterans. Springer Verlag 2015:257-278.


Mefloquine intoxication has significant but previously overlooked relevance in military and veteran populations. Only recently has intoxication with mefloquine been recognized as potentially confounding the diagnosis and management of certain deployment-related neuropsychiatric disorders, including posttraumatic stress disorder.

U.S. Military Surveillance of Mental Disorders, 1998-2013

Psychiatric Services 2016; 67:248-251.


Feature articles in the Medical Surveillance Monthly Report (MSMR) reflect the U.S. military’s health surveillance priorities. This study examined whether the recent rise in the number of ambulatory encounters for mental disorders in the U.S. military associated with the Iraq and Afghanistan wars was reflected in a proportional increase in MSMR feature articles on this topic. This analysis found that the increased number of encounters for mental disorders has been met with a proportional but delayed increase in the number of MSMR feature articles focusing on these disorders. The delayed focus on mental disorders suggests a need to prioritize the routine surveillance of these conditions.

Bias in Military Studies of Mefloquine

Journal of Travel Medicine 2016;23:tav028.


The challenges of complying with the special requirements for safer use of mefloquine now make the drug’s widespread military use impractical. Military studies of mefloquine risk lacking internal validity owing to selection and information bias. Military studies that conclude there may be occasions where mefloquine should remain the first-choice antimalarial are generally unsupported by data, and are increasingly at odds with the policies of a growing number of international militaries that increasingly favor more practical, safer and better tolerated daily drugs.

Military-Civilian Health Policy

Prohibiting direct medical care by US military personnel in foreign disaster relief: arguments from the Ebola disaster

Medicine, Conflict and Survival 2016;32:14-20.


The humanitarian community has questioned the ethical nature of military personnel providing direct medical care during foreign disaster relief (FDR), arguing military care is acceptable only as a “last resort”. In this analysis it is proposed that the novel prohibition on the military providing direct medical care to civilians during the recent Ebola disaster should motivate a formal change in FDR policy to ensure that among U.S. uniformed personnel, only the Public Health Service Commissioned Corps will provide healthcare services during future disasters.

Neuropsychiatric Adverse Reactions to Mefloquine: a Systematic Comparison of Prescribing and Patient Safety Guidance in the US, UK, Ireland, Australia, New Zealand, and Canada

Neurology and Therapy 2016;5:69-83.


Mefloquine use is associated with neuropsychiatric reactions, some of which may predict the development of more serious and potentially permanent and disabling effects. In this study, drug labels and medication guides from six countries were reviewed to identify possible prodromal reactions — such as sleep disturbance — for which there is complete or partial international agreement in prescribing and patient recommendations to discontinue mefloquine or consult a physician at their occurrence.

The timeliness of the US military response to the 2014 Ebola disaster: a critical review

Medicine, Conflict and Survival 2016;32:40-69.


In the face of an unprecedented epidemic of Ebola Virus Disease, in September 2014, the US military began sending thousands of personnel to Liberia and supporting areas in Senegal in its largest deployment to the African continent in over two decades. In this review, media reports, published photographs and official statements are evaluated and summarized to identify and describe key time points in the US military response. The review concludes with a discussion and critical evaluation of the timeliness of this US military response in the context of the original expectations of the humanitarian community and government officials.

Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives

Malaria Journal 2016;15:332.


Historically, even mild forms of malaria have been associated in the literature with a broad range of psychiatric effects. In this article, the history of psychiatric effects attributed to malaria and post-malaria syndromes is reviewed. This review concludes with a discussion of the potentially confounding role of the adverse effects of anti-malarial drugs, particularly of the quinoline class, in the unique attribution of certain psychiatric effects to malaria, and of the need for a critical reevaluation of the literature in light of emerging evidence of the chronic nature of these adverse drug effects.

FDA Black Box, VA Red Ink? A Successful Service-Connected Disability Claim for Chronic Neuropsychiatric Adverse Effects From Mefloquine

Federal Practitioner 2016;33:20-24


In the coming years, many veterans are likely to present to the VA with service-connected claims for adverse effects related to exposure to the prophylactic antimalarial drug mefloquine commonly used by the military for more than 2 decades. This report presents a case of a nondeployed veteran exposed to mefloquine during an early military postmarketing study who developed chronic neuropsychiatric symptoms linked to the drug that were recently deemed service-connected. This report concludes with some comments on the likely implications of this case for future similar disability claims.

Stellate Ganglion Block in the Treatment of Post-traumatic Stress Disorder: A Review of Historical and Recent Literature

Pain Practice 2017; 17:546-553.


Concerns over the rising prevalence of post-traumatic stress disorder (PTSD), particularly among military service members returning from combat, and over barriers that hinder individuals from seeking out or adhering to standard therapies have contributed to interest in alternative therapies for the disorder. This review of the recent and historical literature related to SGB finds evidence of substantial beneficial psychiatric effects and substantiates that this fast-acting, somatic treatment may provide positive results for patients with PTSD and may reduce barriers to therapy, particularly among military populations.

Mefloquine-associated dizziness, diplopia and central serous chorioretinopathy: a case report

Journal of Medical Case Reports 2016;10:305.


Many acute and chronic neurological sequelae from the quinoline derivative antimalarial drug mefloquine, including dizziness and effects on the visual system such as diplopia and blurred vision, may be attributable to focal central nervous system. In this article, a case of dizziness, diplopia and central serous chorioretinopathy that developed following mefloquine use is presented. It is proposed that central serous chorioretinopathy be considered a potential ophthalmological sign of mefloquine central nervous system toxicity, and for this effect to potentially indicate susceptibility to other neuropsychiatric effects of mefloquine intoxication.

Identification of a Syndrome Class of Neuropsychiatric Adverse Reactions to Mefloquine from Latent Class Modeling of FDA Adverse Event Reporting System Data

Drugs in R&D 2017;17:199-210.


Although mefloquine use is known to be associated with a risk of severe neuropsychiatric adverse reactions that are often preceded by prodromal symptoms, specific combinations of neurologic or psychiatric reactions associated with mefloquine use are not well described in the literature. This study confirms the existence of a severe mefloquine neuropsychiatric syndrome class associated with common symptoms that may be considered prodromal. Clinical identification of the characteristic symptoms of this syndrome class may aid in improving case finding in pharmacovigilance studies of more serious adverse reactions to the drug.

Screening for Symptomatic Mefloquine Exposure Among Veterans With Chronic Psychiatric Symptoms

Federal Practitioner 2017;34:12-14.


As the recent mefloquine boxed warning indicates, certain psychiatric symptoms that occur with mefloquine use may become chronic and may confound psychiatric diagnosis. Particularly among veterans, these symptoms risk being misattributed, potentially affecting treatment decisions. Clinicians caring for veterans with persistent psychiatric symptoms should therefore screen for prior symptomatic mefloquine exposure and consider the possible adverse effects of the drug when formulating a differential diagnosis and treatment plan. This article provides guidance to aid clinicians in screening both for exposure to the drug and for the development of specific neuropsychiatric symptoms during prophylaxis or following the treatment of malaria.

A serious nightmare: psychiatric and neurologic adverse reactions to mefloquine are serious adverse reactions

Pharmacology Research & Perspectives 2017;5:e00328.


Recent changes to international labeling for mefloquine serve to imply that psychiatric and neurologic reactions during use in prophylaxis may be an early warning of an impending more serious reaction that may further jeopardize the patient with continued use of the drug. To prevent these more serious effects, international drug labels now warn that mefloquine should be discontinued and that patients seek immediate medical intervention to obtain an alternative antimalarial drug when psychiatric or neurologic symptoms occur. This opinion discusses implications of this updated labeling for the reporting of adverse reactions and for the continued use of the drug in malaria prophylaxis.

Misclassification and Bias in Military Studies of Mefloquine

American Journal of Tropical Medicine and Hygiene 2017;97:305.


This letter comments on recent U.S. military findings of a nearly doubled risk of diagnosis of PTSD among those prescribed mefloquine as compared with those prescribed atovaquone-proguanil, after adjusting for common confounders. Although a significant association of PTSD diagnosis with mefloquine was not seen in comparison to doxycycline, this letter argues that this may reflect the effects of differential exposure misclassification and selection bias. This letter makes recommendations for future research to better study the association between mefloquine use, and symptoms which may mimic and confound diagnosis of PTSD. 

Confounding by Symptomatic Mefloquine Exposure in Military Studies of Post-Traumatic Stress Disorder

Behavioral Medicine 2018;44:171-172.


Mefloquine is known to cause chronic adverse effects which may mimic certain symptoms of PTSD. The confounding of PTSD diagnosis by symptomatic mefloquine exposure is likely to emerge as a significant concern in the interpretation of much of the recent military PTSD literature. Owing to the significant threats to validity that may result from such confounding, researchers reporting the results of new studies of PTSD among those deployed to combat areas should ensure they control as best as possible for such exposure

Implications of Changes to the Mefloquine Product Monograph

Canadian Journal of Hospital Pharmacy 2017;70:323-324.


In August 2016, Health Canada approved significant changes to the Canadian product monograph for mefloquine. These changes mirror those made in the  United States and Europe, including the addition of a “serious warnings and precautions” box (or “boxed warning”) which warns of a risk of permanent effects from the drug. This letter discusses important implications of these changes for Canadian pharmacists, including the need to ensure that patients are properly counseled that they should discontinue the drug at the onset of very common psychiatric or neurologic symptoms.

Mefloquine Exposure May Confound Associations and Limit Inference in Military Studies of Posttraumatic Stress Disorder

Military Medicine 2017;182:1757.


Few studies of PTSD have assessed current or prior mefloquine exposure, a potentially significant confounder. Confounding by mefloquine exposure threatens to become a significant concern in the interpretation of much recent military PTSD literature. Because of the very significant threats to validity that can arise from this confounding, researchers conducting studies of PTSD among those deployed to combat areas should attempt as best as possible to report current and prior mefloquine exposure status among their study subjects, and control for this exposure in analysis.

Ethical Dilemmas in the Forensic Psychiatric Evaluation of Guantánamo Detainees Mass-Administered Mefloquine

Ethics Challenges in Forensic Psychiatry and Psychology Practice. Columbia University Press. 2018:223-236.


Mefloquine is an antimalarial drug that may cause a range of chronic adverse psychiatric effects. Mefloquine was mass administered to all Guantánamo detainees upon arrival, purportedly for public health purposes. Some have speculated instead that mefloquine was used intentionally for its adverse psychiatric effects to facilitate interrogation. The chapter considers the likely ethical dilemmas that may be encountered by the military psychiatrist in the attribution of chronic adverse psychiatric effects among Guantánamo detainees to mefloquine.

A Rearguard Defence: Mefloquine, Tafenoquine, and the Australian Army Malaria Institute.

Journal of Military and Veterans’ Health. 2018;26:6-7.


This letter challenges revisionist claims in a recent article that mefloquine and tafenoquine have been used safety by the Australian Army, including during clinical trials in East Timor sponsored by the Australian Army Malaria Institute. The letter argues that this apparent rearguard defense of mefloquine and tafenoquine stands to serve as a record of the institutional failings of these institutions in relation to these drugs. The letter also encourages these institutions to acknowledge the historical misuse of these drugs, and the resultant harms this misuse has caused to Australian military veterans.

Re: “A Decade of War: Prospective Trajectories of Posttraumatic Stress Disorder Symptoms Among Deployed US Military Personnel and the Influence of Combat Exposure”

American Journal of Epidemiology. 2018;187:1573-1574.


This letter, published in response to military research on PTSD, cautions that because many clinicians do not screen for prior symptomatic mefloquine exposure when conducting psychiatric evaluations, there is a risk that chronic adverse effects from the drug could be misattributed to PTSD in research studies. This letter cautions researchers conducting studies of PTSD among military personnel deployed to combat areas to measure symptomatic mefloquine exposure among their study participants.

Considerations in the repurposing of mefloquine for prevention and treatment of osteoporosis

Bone. 2018;114:304-305.


This letter, published in response to research suggesting that mefloquine could be repurposed for the management of bone loss, argues that mefloquine is unlikely to find utility for new indications other than life-threatening conditions, owing to the drug’s association with chronic encephalopathy and permanent and irreversible neuropsychiatric adverse events. Drug regulators now warn to discontinue mefloquine at the onset of psychiatric or neurologic symptoms, which are considered prodromal to this more serious adverse event.

Measurement of Mefloquine Exposure in Studies of Veterans' Sleep Disorders

Journal of Clinical Sleep Disorders. 2018;14:1273-1274.


This letter notes that as mefloquine exposure is correlated with deployment, and as mefloquine exposure provides a separate causal pathway for many outcome variables associated with sleep disorders, unmeasured mefloquine exposure may serve as a potentially critical confounder in studies of sleep disorders among deployed military personnel and veterans. Unmeasured mefloquine exposure has been previously identified as a significant concern in the interpretation of recent military studies of PTSD and emergence delirium. This letter  concludes that owing to the potential for confounding, researchers conducting studies of sleep disorders among veterans should measure prior symptomatic exposure and control for its effects in future analysis.

Bias and Confounding in Studies of Chronic Mental Health Effects from Mefloquine Exposure

American Journal of Tropical Medicine and Hygiene.
2019;100:476-477.


This letter responds to a recent VA study which suggested combat deployment exposure is a more significant predictor of subsequent mental health symptoms than the adverse effects of mefloquine. This letter notes that the authors of the VA study failed to adjust for symptomatic mefloquine exposure and that the VA study’s conclusions are likely invalid as a result, owing to unmeasured confounding. The letter concludes by encouraging use of the two-question White River Mefloquine Instrument (WRMI-2) to identify veterans in research studies who have a history of symptomatic mefloquine exposure.