Aug 13 2013

Mefloquine and Psychiatric Side Effects

On a recent episode of The Newsroom one reporter was headed to Africa and was advised by a more senior producer not to take mefloquine for malaria prophylaxis because of the potentially severe psychiatric side effects. I had never heard that before, never having traveled to a malaria area, and malaria prophylaxis being outside my area of medical expertise.

Then I was sent a link to a recent New York Times article called Crazy Pills, which tells an interesting story about David Stuart MacLean’s severe bad reaction to mefloquine – three days delirious in the hospital followed by years of symptoms of anxiety and depression.

Mefloquine was approved by the FDA in 1989 for the prevention of malaria. It was developed by the US military and for a time was the drug of choice for soldiers in malaria-prone areas. It has also been used extensively for civilian travelers.

Initial studies reveals the potential for neuropsychiatric side effects, but suggested that the risk for serious side effects was low, about 1/1000. New evidence presented to the FDA, however, suggests the risk is much higher, leading the FDA to put a black box warning label on the drug. The FDA site on mefloquine (brand name Lariam) states:

Lariam can cause serious mental problems.
• Some people who take Lariam have sudden serious mental problems, including:
• severe anxiety
• paranoia (feelings of mistrust towards others)
• hallucinations (seeing or hearing things that are not there)
• depression
• feeling restless
• unusual behavior
• feeling confused
In some patients these serious side effects can go on after Lariam is stopped.

I looked at the literature and found some conflicting results. A few studies found that mefloquine was tolerated as well as other anti-malarial drugs, and the risk of neuropsychiatric side effects low. The largest study, including over 35,000 subjects, concluded:

The absolute risk of developing psychosis or panic attack appears low with all the antimalarials tested. No evidence was found in this large observational study that mefloquine use increased the risk of first-time diagnosis of depression when compared with the use of other antimalarials investigated in this study.

The study is observational, so undereporting may be an issue. Another study found an increased risk of neuropsychiatric symptoms only in females and patients with a prior psychiatric history.

But – a 2009 review concluded:

Atovaquone-proguanil and doxycycline are the best tolerated regimens, and mefloquine is associated with adverse neuropsychiatric outcomes.

Further, an army epidemiologist, Remington Nevin, who has extensively studied mefloquine, was alarmed by the number of neuropsychiatric side effects he was finding with the drug. This is especially concerning in soldiers who are also under extreme mental stress, who are frequently armed, and who are placed in intense life-and-death situations.

Dr. Nevin was instrumental in pressuring the FDA to increase the black box warning on the drug, which he feels will mean it’s end as a drug routinely used by travelers. Mefloquine use has already declined dramatically, and in the military is used as a drug of last resort. It has not been removed entirely from the market, however.

I find it interesting that the evidence is so mixed on the side effects of the drug. Study population seems to matter a great deal, and military soldiers seem like a terrible population in which to use a drug with these potential side effects.

Making the decision between a black box warning and removing a drug entirely can be difficult. Essentially, the warning are used when a drug still has some usefulness and in some patients the benefits can outweigh the risks, but prescribers need to know about a potential serious side effect and use the drug very selectively and with proper monitoring.

In the case of mefloquine it is kept as a last resort when the other anti-malarial drugs cannot be tolerated. Malaria is a potentially fatal illness, and so some risk in preventing it may be a reasonable trade off. Medicine is often a trade off between unattractive options.

At the same time, the potential for long term and even permanent psychiatric side effect such as depression and anxiety is very serious. I could not find a reliable figure on this, and it seems more study is required, but potential permanence of side effects raises the seriousness to a new level.

Some have speculated, such as Dr. Nevin, that the FDA generally does not take psychiatric symptoms as seriously as other medical side effects. If the side effect were damage to an organ other than the brain, such as liver or kidney failure, you wonder if the drug would already have been pulled. I don’t know if this is true or not. It might be, but it also may be nothing but confirmation bias.

What is true is that psychiatric symptoms tend to be stigmatized and not taken as seriously in general. It may be more difficult for a solder to claim harm because he has chronic anxiety, than if he had liver damage.

In any case, the evidence does support severely limiting the use of mefloquine and relying on other options. The evidence does also point toward the need for new developments. There are two potential benefits of future research – designing a drug that has the anti-malarial effect without the neuropsychiatric side effects, or figuring out how to predict who is going to have those side effects. The latter could entail DNA-based personalized medicine, a concept that is very popular but practically still in its infancy.

Meanwhile, bad press on The Newsroom and the NY Times will likely kill the market for mefloquine. In this case it may not be a bad thing.

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