Thank you very much, Mr. Chair. It is a great privilege to be invited to address the committee today to discuss the anti-malarial drug mefloquine.
I'm Dr. Remington Nevin. I'm a former U.S. Army preventive medicine physician. I received my medical training at the Uniformed Services University School of Medicine, and I've earned master's and doctoral degrees in public health from Johns Hopkins University. I completed residency training at the Walter Reed Army Institute of Research, and I'm currently completing a post-doctoral fellowship in occupational and environmental medicine at Johns Hopkins University.
I have 14 years of active U.S. medical service, including overseas tours in malaria-endemic areas in Africa and Afghanistan, where I had the honour of serving briefly alongside Canadian Forces personnel at Kandahar.
It was in Afghanistan where I first became interested in mefloquine, particularly in the adverse mental health effects of the drug. In the nearly decade since, I have authored or co-authored three dozen book chapters, letters, and peer-reviewed articles in various scientific and medical journals on the topic of malaria or anti-malarial drugs, including mefloquine to include, with Dr. Ritchie, what was the first review in the forensic psychiatric literature of the drug's affects.
I've received a $264,000 grant from the U.S. Army to study the genetic basis of susceptibility to mefloquine's adverse effects, and I've undertaken a number of other pharmacovigilance studies of the drug, including a detailed analysis of reported adverse event data that is pending publication. My doctoral thesis from Johns Hopkins is titled “Pharmacovigilance of Neuropsychiatric Adverse Reactions to Mefloquine”.
In recent years, my research in this area has broadly informed the rapidly changing military policies on the use of mefloquine, as well as a recent regulatory re-evaluation of the drug in the United States and in Europe. For instance, I offered evidence to the U.S. Food and Drug Administration prior to its directing the edition of a boxed warning to the approved mefloquine drug label in 2013. My work also directly informed the prohibition on the use of the drug among personnel of the U.S. Army special operations command later that year. I've previously offered evidence concerning mefloquine to committees of the U.S. Senate and the U.K. Parliament. I've also been retained or offered evidence in a number of civil and criminal cases on behalf of clients alleging adverse effects from the drug.
I should emphasize that I have not accepted sponsorship or received any funding from pharmaceutical companies for my work, and the opinions I offer today are my own and not necessarily those of my employer, Johns Hopkins University.
Mr. Chair, I would like to offer members of the committee, to begin, a brief review of what is now known of the drug's chronic adverse mental health effects, and then describe how in certain other countries, including the United States, growing awareness of these effects has recently been informing improved evaluation and care of veterans who may have been prescribed or otherwise have been issued mefloquine during their military service.
For many years it was believed, erroneously, that mefloquine had no long-term mental health effects. It was believed that, once the drug was fully cleared from one's system, any adverse mental healths would resolve. However, as drug regulators in both United States and Europe have specifically acknowledged, in some patients, the use of the drug is associated with a risk of mental health effects that can last for years after use and in some cases may even be permanent. The reasons for this are not yet fully understood, but it is known that unlike some other safer and better tolerated anti-malarial drugs, mefloquine is a neurotoxicant, meaning that as with lead or mercury, it is a substance that is capable of causing serious disruptions in the function of cells in the central nervous system and potentially causing permanent injury to these cells. More concisely, the intoxicating effects of mefloquine can cause an encephalopathy and then a neurotoxic injury to the brain.
In retrospect, it appears this property of mefloquine has been known for some time. For example, ever since the drug's licensing in the United States, over a quarter of a century ago, in 1989, the original drug manufacturer, Roche, has alluded to this potential warning on the drug labelling that if certain so-called “prodromal symptoms” developed during use of the drug, such as anxiety, depression, restlessness, or confusion, the drug should be immediately discontinued to reduce the risk of what was euphemistically referred to as “a more serious event”. In extreme cases, this more serious event was even acknowledged as encephalopathy, and often manifesting as a deep confusion, or delirium, or severe amnesia, along with certain other severe symptoms such as psychosis.
As the boxed warning in the United States and similar warnings in Europe now suggest, this same encephalopathy is also now understood to carry a risk of much subtler but still lasting, and perhaps even permanent, alterations in mood, personality, cognition, behaviour, and sleep, including symptoms of insomnia, nightmares, anxiety, depression, and personality change.
Particularly among returning veterans, these lasting symptoms may risk being misdiagnosed, including as the effects of traumatic brain injury or post-traumatic stress disorder. However, as recent drug labelling changes in the United States and Europe should now make clear, in many cases these symptoms may actually have nothing to do with combat exposures, but simply reflect nothing more than the toxic encephalopathic effects of the drug.
For example, in one recent study of Danish travellers who had previously reported adverse effects while using mefloquine, 21% of those reporting nightmares and 33% of those reporting cognitive dysfunction while taking the drug identified that these adverse reactions as still persisting over three years after use of the drug.
Unfortunately, in Canada, veterans, physicians, and even government officials may not be aware of this. Unlike in the United States and Europe, Health Canada has not yet directed an update to the mefloquine drug labelling to reflect this new knowledge. Perhaps as a result, the Minister of Veterans Affairs, the Honourable Kent Hehr, recently informed a Canadian veteran, quite incorrectly, that there are no long-term effects from taking mefloquine.
In contrast, in a growing number of other countries, including the United States and Australia, these long-term effects are at least reluctantly acknowledged. Steps are beginning to be taken to care for veterans who may have been affected by them. In the United States, the U.S. Army special operations command issued an order acknowledging that the effects of mefloquine “may confound the diagnosis of PTSD and TBI”, and directed that commanders and medical personnel “address and assess the possibility and impact of mefloquine toxicity in their populations”.
The U.S. Department of Veterans Affairs is taking steps to begin to study affected veterans, and recently awarded the first long-term disability claim for symptoms, in this case chronic sleep impairment and frequent panic attacks attributed to service-connected use of the drug.
This year, legislation was introduced in the U.S. Congress to expand the mission of various centres, including the Center for Deployment Health Research, and the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, so as to include the clinical evaluation, diagnosis, management, and epidemiological study of adverse health effects among U.S. veterans following exposure to mefloquine.
In Australia, their Repatriation Medical Authority, or RMA, has recognized a number of conditions as being potentially caused by mefloquine and for which disability benefits may be awarded. These include primarily lasting neurological disorders associated with use of the drug, but also certain psychiatric disorders, including depressive disorder and bipolar disorder. RMA is reviewing the role of mefloquine in anxiety disorder, panic disorder, and suicide and attempted suicide as well.
It is on this issue of suicide that I will conclude my prepared remarks.
Today we recognize that symptoms of severe encephalopathy that can occur most commonly during use of the drug may also carry a strong risk of suicidal ideation, completed suicide, and, in some cases, a risk of extreme aggression and even violence directed towards others. We are also beginning to recognize the role of this toxic encephalopathy in affecting the risk of suicide even many years after use. Almost all suicides need to be understood in a broader context of mental illness. As mefloquine increases the risk of lasting symptoms of mental illness, and as symptoms of mental illness are strongly associated with suicide, it should not be surprising that veterans who have been prescribed the drug appear to be at significantly increased risk of suicide.
However, we must also acknowledge how the potential mistreatment of mefloquine veterans may be further contributing to this risk. Although we know that some mefloquine veterans may be receiving care for their symptoms under a diagnosis of TBI or PTSD, we also know that many other veterans, including those without traumatic exposures or who had never suffered a concussion, and in whom these lasting symptoms may not be easily explained, have been accused of malingering, of having a personality disorder, or have been told it's all in their heads.
In some cases, these veterans have been discharged without medical benefits and left to fend for themselves. It should not be surprising to learn that some of these mefloquine veterans, mentally injured and cast out by the military that unwittingly poisoned them, would later take their own lives in desperation.
We have seen this, unfortunately, even in countries such as Australia and the United States where steps have been taken to recognize and acknowledge the problem. More needs to be done, and quickly, to acknowledge and better understand the lasting effects of the drug and how these effects may be treated, and to ensure that no veteran affected by these effects continues to suffer alone and without the care that they, through their service, rightly deserve.
That concludes my prepared statement and I would be pleased to take questions from members of the committee.