Veterans Affairs Committee on Oct. 25th, 2016

[Dr. Elspeth Ritchie]

Yes. In the past, one reason we used mefloquine was because of cost issues, and also it was believed that people would be more compliant with a once-weekly dosage. However, the cost is little compared to the cost of lives or things like massacres. In terms of compliance, what we find is that people are less compliant with mefloquine because they've heard about it and the scary side effects, so they don't take it and are more likely to develop malaria.

[The Chair, Liberal, Neil Ellis]

Thank you.

Go ahead, Mr. Eyolfson.

[Doug Eyolfson, Liberal, Charleswood—St. James—Assiniboia—Headingley, MB]

Thank you very much, everyone, for coming.

The first question I have is this. There are other anti-malarial drugs. Has there been any association with these neuropsychiatric symptoms with any of the other ones, or is this unique to mefloquine?

[Dr. Remington Nevin]

I'd like to address that question. That is the subject of some of my recent research with Dr. Croft, a military colleague from the U.K. Mefloquine is a member of a class of drugs known as quinolines. In fact, it's not the first quinoline that militaries have used that has had these effects. We have to go back to World War II to see the first widespread use of a synthetic quinoline drug, atebrin, or quinacrine. I believe it's marketed as mepacrine here and in the U.K. It was associated with similar reports of confusional associative psychosis, anxiety, and panic attacks. At the time, there was some evidence that it was associated with chronic effects, as well.

A number of experimental drugs that were developed by the U.S. military during World War II to replace atabrine also had similar effects. There's good reason to believe that chloroquine, the mainstay quinoline derivative drug used throughout much of the last century, also shares these properties to some extent.

I've been exploring the unusual and quite novel hypothesis that some of what we have attributed to combat stress throughout the years may actually be due to the lasting effects of various quinoline drugs, not just mefloquine, but going back to World War II.

There are safer classes of drugs today. The anti-malarial drugs that are available now for use on a daily basis do not share the neurotoxic, intoxicating, encephalopathic effects of the quinoline drugs. There are some mild side effects reported with the use of these drugs, but unlike mefloquine, these side effects do not require the immediate discontinuation of the drug in order to prevent potentially permanent adverse effects.

[Doug Eyolfson, Liberal, Charleswood—St. James—Assiniboia—Headingley, MB]

All right, thank you.

With regard to the currently used drugs, doxycycline and Malarone, in your estimation, is there any question about their effectiveness as an anti-malarial, other than the question of whether or not soldiers will comply because the drugs are daily?

[Dr. Remington Nevin]

Absolutely not. Both doxycycline and Malarone are as effective, if not more effective, than mefloquine. There's no area in the world that we send troops to where those drugs are not effective. In contrast, a large part of the world demonstrates some resistance to mefloquine.

As for questions about whether soldiers will be as compliant with a daily dose versus a weekly dose, these issues have long since been settled. When the U.S. military shifted from mefloquine as its preferred drug to doxycycline, and later to Malarone in 2009, we saw rates of malaria decline precipitously. As Dr. Ritchie alluded to before, this was because soldiers are, in general, compliant with their doxycycline and Malarone. With mefloquine, on the other hand, based on the guidance in the product insert, we should expect somewhere around a third of soldiers taking mefloquine to discontinue the drug in accordance with the product insert guidance. It's simply not a practical drug to use if soldiers are permitted to discontinue it in accordance with the label; they'll do it themselves and simply not tell their commander.

The U.S. military probably presents the best anecdotal example of the differential effectiveness of these drugs. In 2003, we deployed a few hundred marines on shore to Liberia for a humanitarian mission. Within a few weeks, the mission was scuttled. Dozens were evacuated with suspected malaria. They were all taking mefloquine, or supposedly taking mefloquine. Contrast that disastrous experience with mefloquine with our recent, very successful operations in Liberia. Thousands of personnel spent months in the very same malaria-endemic area, but they were taking the much safer daily drugs, doxycycline and Malarone. There were zero cases of malaria. I think that is sufficient evidence.

[Doug Eyolfson, Liberal, Charleswood—St. James—Assiniboia—Headingley, MB]

All right, thank you.

I throw this open to all of the panellists. Now we're talking about different types of studies. Of course, with your levels of evidence, there's no way you can form the gold standard of the randomized clinical trial with such a thing. In regard to the associations, when you're looking at the types of research going on, what are the sample sizes of people involved? How many military personnel are involved? How many were deployed? How many were on Malarone? What kind of sample sizes are we talking about in the studies?

[Dr. Elspeth Ritchie]

Maybe I could take that question.

First of all, there is absolutely minimal research done, so we can't tell you the sample sizes. A lot of the research that was done initially was rat research. By the way, it was done on male rats, so if we talk about female service members—which is a whole different discussion about effects on pregnancy and reproduction—we have no information.

At this point, it is not ethical to do a perspective study, because we know mefloquine has serious neuropsychiatric side effects. What we are beginning to do at the VA in Washington, DC, in what's called WRIISC, the war related illness and injury study center, is look at people who say they've been exposed to mefloquine and try to characterize their symptoms. At the moment, we have 51 people who have self-identified.

If you start expanding this—I think this has been part of Dr. Nevin's experience, and it is part of my experience, too—you would very quickly get many service members who come in and say, “I have some symptoms. Study me.” That's probably a reasonable first step for our northern neighbours, to look systematically at the people who come in.

Often these people feel like they've been blown off by the military and nobody has taken them seriously. Just to be studied.... We can tell you a little more about how we do it and which studies, whether it's an MRI, a PET scan, vestibular testing—which is one of the things we are starting with—neuropsychological testing, or looking at effects on reproduction. That's a growing science. That's where I would begin—look at the sailors, soldiers, and airmen you have now and see what their symptoms are.

[The Chair, Liberal, Neil Ellis]

Ms. Jolibois, go ahead.

[Georgina Jolibois, NDP, Desnethé—Missinippi—Churchill River, SK]

You talked about the lack of treatment plan available. Do you foresee what that would look like?

[Dr. Donald Passey]

As I've already mentioned, we have standard pharmacotherapy. Most of the medications we use for PTSD are not actually recommended for PTSD in regard to things like sleep, curtailment of irritability, etc.

We know that pharmacology, by itself, is not the answer. The talking therapies, similarly.... Even in good studies, you don't get much above about 60% success rate, and there is always the relapse down the line.

The reality is that we need to engage in looking at new types of treatment. I've mentioned two individuals who are going in that direction, Dr. Mark Gordon and Dr. Marty Hinz. They are looking at a totally different direction, utilizing blood analysis and urine analysis in an attempt to determine which metabolic pathways are actually abnormal in these types of disorders.

[Dr. Elspeth Ritchie]

I'll add to that. One of the real challenges is knowing how to treat it.

Unfortunately, mefloquine is still used in the Peace Corps. I've had the unfortunate luxury of seeing a number of returning Peace Corps volunteers, who sometimes have been medevaced out with psychosis. The question is, do you treat them with an antipsychotic agent, or is that contraindicated? I've also seen people whose symptoms have lasted for some years, depression and anxiety, but we don't know.

I totally agree with Dr. Passey that more treatments are needed. By the way, we realize we have never met until today.

The direction I have been going, in general, for post-traumatic stress disorder is complementary with alternative medicines, integrated medicine, yoga, meditation, and exercise. I recommend exercise to all my patients with post-traumatic stress disorder. I would like to explore how helpful these treatments may be for people with mefloquine-induced toxicity. My hypothesis is that they would help calm down the jangle that you see with people on mefloquine.

I have a couple of other points, briefly. There are some accommodations that can be used, things like sunglasses—there is a lot of photosensitivity. A cane can be used for accommodation. Finally, again, what I have found so helpful is when service members or their spouses.... It's often the spouse who is reaching out and saying, “Ah, this is it. He was okay until he went to West Africa or Afghanistan”, and this is an explanation that makes sense.

[Dr. Remington Nevin]

I'll emphasize Dr. Ritchie's previous comment. In my experience speaking with a number of veterans who have discovered that mefloquine could be the cause of their symptoms, there's an extraordinary amount of relief that I believe has real therapeutic value to learning what the cause of their symptoms is.

They come home from taking mefloquine, with their personalities in many cases fundamentally altered. They can't make sense of why they feel the way they do and why they are suddenly burdened with these many problems. To learn that it isn't a psychiatric disorder, but that it's in essence a poisoning can be very therapeutic.

We are working to try to reduce the stigma associated with psychiatric diagnoses. But for many soldiers, to know that it's not actually a psychiatric diagnosis, that they're not weak, that there's no character flaw underlying their symptoms, that it's the effect of a poison, this is extraordinarily therapeutic for many of them.

We should continue to combat stigma, but we do need to acknowledge that this is therapeutic for many soldiers to learn.

[Georgina Jolibois, NDP, Desnethé—Missinippi—Churchill River, SK]

I'm curious. Currently when service members deploy to those countries or they go and visit, are there other drugs that they're on besides this medication? Do you know?

[Dr. Remington Nevin]

I cannot speak to practices in the Canadian Forces. Perhaps Dr. Passey can. I can speak to my knowledge of practices in the U.S. military. In fact, some of my early research focused on this very point. The work I did while in Afghanistan determined that a sizeable fraction of our force was taking psychotropic medications: antidepressants, anti-anxiety drugs, and in some cases even anti-psychotic drugs that had been prescribed to them for prevalent mental disorders.

In many cases the soldiers were not disclosing that they were taking these drugs when they were being evaluated for which anti-malarial drug to use while deploying overseas.

As a result, my research showed that one in seven service members with some contraindicating condition, such as the use of a psychiatric drug, were nonetheless prescribed mefloquine. Certainly the U.S. experience is that there has been, at least historically, a high risk of co-prescribing mefloquine with psychotropic medications. I would imagine that's similar in other countries.

[Dr. Donald Passey]

Very briefly, I can't speak now...because I'm not in the military, but certainly during my time I treated individuals with PTSD, a major depression. For instance, I put them on antidepressants, got them to a point where they were deployable; and so they did deploy overseas on psychiatric medications, but you have to screen those individuals very carefully. I'm not aware of whether or not that was ever looked at in regard to actually prescribing mefloquine.

[Georgina Jolibois, NDP, Desnethé—Missinippi—Churchill River, SK]

Okay.

[Dr. Elspeth Ritchie]

If I may add—

[The Chair, Liberal, Neil Ellis]

You'll have to make it quick.

[Dr. Elspeth Ritchie]

—l took your question to refer to local drugs of abuse and we do see opiates in combat areas or Afghanistan. We see methamphetamines mailed over there. In Somalia it was khat.

We don't know a lot about the interaction with drugs of abuse and mefloquine, but based on what we do know we would expect their effects on the liver, the effects on the kidney, the effects on the brain probably have a synergistic, negative effect on the brain.

Sergeant Bales apparently was on steroids and alcohol, and my hypothesis is whether his use of mefloquine was recent or chronic or long term. We know he was on it. It's that those drugs affected his already impaired brain in a very dangerous way.

[The Chair, Liberal, Neil Ellis]

Thank you.

Mrs. Lockhart.

[Alaina Lockhart, Liberal, Fundy Royal, NB]

Thank you all for your insight into this drug. From what I hear you saying, it points an awful lot to the difficulty in disseminating all of these factors to try to determine what the core issue is, but it's some very compelling evidence that you've said today.

One of the things that Dr. Nevin said was that veterans are finding comfort, for lack of a better word, in being diagnosed with an injury versus this vague term of mental illness. I think as we move forward and study mental illness more in depth and are able to provide physical reasons, it will be helpful to veterans.

I have a few specific questions about the drug. First of all, I wanted to know whether there other drugs that may not be prescribed for malaria that have a similar impact as mefloquine. Is there any other drug that we can draw a parallel to that we see having these neurological impacts?

[Dr. Remington Nevin]

I'll speak briefly, and then I think I'll defer to my colleagues in psychiatry, who are perhaps much more familiar with other classes of drug.

I mentioned earlier that it's this entire class of synthetic quinoline drugs, including mefloquine, I suspect chloroquine, certainly atebrin or mepacrine during World War II, and possibly even quinine—which we all have enjoyed at some point in our tonic water—that may have this propensity because of a class effect.

I have written in a few manuscripts that the effects of mefloquine intoxication or encephalopathy do resemble that seen in extreme cases with certain other drugs, including some recreational drugs. One thing I will point out is that the particular combination of symptoms and neurological injury caused by this class of drug, I do feel, is unique. The quinolines were discovered in World War II to cause this absolutely fascinating pattern of microscopic, cell-specific injury to various centres in the brain stem and deep brain, in the limbic system—extraordinary, as described by the authors of that time. To my knowledge, this finding really hasn't been replicated in any other class of drug.

So while some of the effects—I think the psychosis, the memory loss, the changes in behaviour—are certainly shared by a number of other intoxicants, the combination of psychiatric and neurological effects, I do think, is unique to this class.

[Alaina Lockhart, Liberal, Fundy Royal, NB]

This may seem completely off, but I know there are a few drugs that help people to stop smoking, for example, and I've heard anecdotal stories about their having a long-term impact.

Would that be similar at all?

[Dr. Remington Nevin]

I'll defer to my colleagues in psychiatry for that question.