Mother, tell your children not to take Lariam

One of the near-universal experiences of working in development (or even just visiting an underdeveloped country) is the need to take malaria prophylaxis. Indeed, malaria is so prevalent across the developing world that it’s impossible not to think about its consequences for public health and economic growth – especially since we did our best to ban DDT spraying, the most effective means of getting rid of malaria, shortly after it was eradicated in the US.

Wikipedia's map of malaria risk. I don't know - do *you* see a pattern?

These days the main preventive technologies are DEET-treated bednets and antimalarial pills. If you visit a travel medicine clinic, they’re probably going to try to offer you Lariam, generically known as mefloquine. The clinicians may mention side-effects, but most people talk about vivid dreams and downplay or completely disregard the more serious issues with the drug, some of which are very disturbing. They’re particularly bad given Lariam’s extremely poor effectiveness profile, which is detailed in that same Wikipedia article.

But the Wikipedia article doesn’t even get into the worst thing I’ve heard about Lariam, which is that in certain people it can trigger schizophrenia and amnesia. The anecdotes I’ve heard certainly don’t constitute proof, and proper scientific evidence on the matter is going to be hard to . However, This American Life has David MacLean’s first-hand account of severe mental side-effects from Lariam in an episode they recently re-ran in their podcast feed; it’s the last segment, titled “The Answer to the Riddle is Me”.  You can click the “listen now” button, or get the mp3 via this link (it’s no longer free on iTunes). Thanks to Ophira Vishkin for helping me find the download link.

Here’s my question, which I’m hoping my co-bloggers can help me answer: why in God’s name are we still prescribing this drug? Based on what I’ve been able to find it appears to be on average less effective and more risky than all its competitors, and even discounting the possibility of induced schizophrenia it has immense downside risks that other drugs do not. It’s also on a weekly schedule that seems like it would badly reduce compliance.

Is there any case to be made in Lariam’s favor? NB that I wouldn’t consider having taken it and done okay to be valid evidence; that’s similar to vouching for Russian Roulette just because you played and won.

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19 Responses to Mother, tell your children not to take Lariam

  1. naman shah says:

    1) Because it works. The current FDA approved dosing regimen for prophylaxis may be suboptimal but mefloquine is a very effective antimalarial without reported drug resistance in most parts of the world.
    2) As with all drugs there are contraindications and side-effects but mefloquine is part of the first-line treatment for P. falciparum in several countries (Bolivia, Peru, Venezuela, Thailand, Cambodia) and is used safely, at much higher doses, to cure thousands of patients every year.

    This reads like the health section of the Huffington Post – amateur blogging of complex medicine based on superficial searching and scare stories. I expect better.

    • Jason Kerwin says:

      >As with all drugs there are contraindications and side-effects

      I’m unaware of any indication that proguanil or doxycycline that cause permanent mental illness. Lest we come away from this thinking that such side effects are rare, I should note that central nervous system side effects occur in one quarter of all users. Moreover, extensive warnings about severe mental side effects, including the statement that “In some patients these serious side effects can go on after Lariam is stopped”, are written on the drug’s packaging. Here is the FDA’s medication guide to the product:

      Using the fact that it is a first-line treatment for malaria in many countries as part of the case in its favor is begging the question.

  2. naman shah says:

    The FDA has to be risk averse and highlight even tenuous links. Notice the statement is careful to say associated, not caused, and only specifies suicides which occurred in traumatized war veterans…. That said yes, our clinical experience indicates there are certainly neuropsychiatric side effects, a term that sounds misleadingly severe which is why grading the adverse event matters – common “vivid” dreams are one thing, amnesia or seizures are another.

    On the matter of frequency, the 25% you mention self-reported in a small non-representative convenience sample. We really don’t know how frequent side effects for mefloquine are, especially by severity. In the absence of prospective data in some representative cohort, we can look at reports of SAEs post-registration in the context of large-scale use which is why I mention the countries using mefloquine as their first-line. Three are middle income with decent health systems and would certainly pick up anything beyond the very rare after using the treatment in thousands of patients for many years.

    Asking questions is good. But making medical pronouncements is silly.

  3. naman shah says:

    PS just a note on the alternatives

    Doxycycline increases photosensitivity which can be problem for pale people in already hot places. It’s also the weakest antimalarial of the three prophylactic regimens leading to many breakthrough infections (we believe) and requires daily dosing (mefloquine is weekly).

    Atovaquone-proguanil is the best with a shorter pre and post travel regimen and great activity but is the most expensive and is dosed on a daily basis. There may also be failures in areas with high SP failures due to cross resistance.

    Primaquine in non-contraindicated groups can also be a great option (also daily dosed).

    So there’s no clear best among the four options and will depend on the patient’s needs. This is all besides the point but just fyi.

  4. Jason Kerwin says:

    Are there attempts to monitor treated groups in those populations for mental health problems? My sense is that mental illness is heavily underreported outside of the developed world.

    That 25% figure is the only one I’m aware of. If you know of better data, please do post it here (or add it to the Wikipedia article). The sources I’ve seen broadly support the view that mefloquine has far more serious and more permanent side-effects than, say, doxycycline.

  5. naman shah says:

    See this review paper:
    “Despite a negative media perception, large pharmaco-epidemiological studies have shown that serious adverse events are rare.”

    In RCT trials mefloquine does have more adverse events relative to others (16%), but the absolute rate is still low (<5%) and are mostly mild anyways.

    What does concluding "far more" mean? From what sources? Use rigor and ask around before posting. Sorry for being critical, I like most of your writing, but this is a pet peeve.

    • Jason Kerwin says:

      That study more or less corroborates my critique: mefloquine has uniformly more common effects and the authors conclude it’s associated with “adverse neuropsychiatric effects”.

      But “far more” is a value judgment about the severity of the side effects of each drug; no amount of objective evidence can tell us which of two different side effects is worse. I’m most concerned about the psychiatric problems Lariam causes, and the fact that some of them may be permanent, albeit mainly in individuals who are generally screened out of treatment with the drug.

      That said, I did not mean to imply that it would be better to stop using mefloquine entirely in the countries where it’s used as a front-line treatment. This is one of the situations where the morbid logic of cost-effectiveness is binding: we can’t afford the best treatments for everyone who needs them.

  6. naman shah says:

    No it doesn’t because the events were mild. Moreso, in the real world absolute rates, not relative ratios, matter and they were low. You should know this as an economist. Second, measurement of self-reported symptoms is difficult in trials and have lots of bias so its good to compare against pharmaco-epi studies (in the review) which do not draw that conclusion.

    But you’re missing the point – you clearly didn’t search for any real information before writing about a specialized subject, have no training or experience in medicine or malaria, and yet are brazen enough to make value judgements and advice.

    • Jason Kerwin says:

      >you clearly didn’t search for any real information before writing about a specialized subject

      If that’s the point then I stand by the FDA’s medication guide as a source of real information.

      >and yet are brazen enough to make value judgements

      I continue to stick with that value judgment. Irrespective of their higher prevalence, I consider the nature of Lariam’s side effects to be worse than those carried by other drugs. To be clear, whether sun sensitivity is worse than adverse neuropsychiatric events is a matter of subjective opinion and not empirical fact.

      However, I appreciate your taking the time to make the case for mefloquine, which was exactly what I was hoping for.

  7. schwartz1983 says:

    A few more thoughts, though I broadly agree with Naman.

    Why do we use mefloquine?

    Chloroquines are useless in much of the world, especially where P. falciparum (the deadliest malarial parasite) is endemic.

    In addition to severe photosensitivity doxycycline, there are other reasons not use doxycycline.
    1) It can cause some unpleasant GI symptoms. Now, these symptoms are probably preferable to schizophrenia, but are more common AND a huge reason people stop taking doxy. If they stop taking it, they are not protected and they can get malaria.
    2) While it is harder for some people to remember the weekly dosing regimen of mefloquine, the problem with the daily dosing of doxy is that if you aren’t consistent with taking it at the same time, you run the risk of having low levels of the drug in your system, increasing susceptibility. It may be easy to remember to take a drug every day, but taking it at the same time every day (with food to avoid those nasty GI side effects!). Is there one time a day where you are always 100% sure you will have access to food, water and your pills every day?
    3) Doxy may interfere with oral contraceptives (aka, the pill). Getting malaria is worse than getting pregnant, but if alternatives, they are worth considering in a woman of child bearing age.
    4) Taking doxy for a month after leaving a malaria endemic area is tough. People are not good at taking medication when they are sick, and they are even worse at taking it when they are healthy. It’s hard enough to convince a healthy person in a malarial area to take prophylaxis, convincing them to take it for 4 weeks afterward is even harder.

    Malarone (combination atovaquone/proguanil) is crazy expensive. $6 to $8 a pill. That may be fine if your insurance covers it (but that really just masks the cost to the health care system- a different issue entirely) or if you are going somewhere for a week, but after a few weeks you start to wonder if a little malarial fever may be worth $45 a week. Also, all the points about daily dosing from doxy apply here. However, if it becomes generic before resistance becomes widespread, mefloquine’s days are numbered.

    Artemisins, as far as I know, are not used for prophylaxis due to short half-lives and the need for multiple daily doses to ensure therapeutic levels.

    Primaquine I know less about in terms of prophylaxis, but I have read that there is concern about possible failure in preventin P. falciparum. Definitely worth studying more.

    I haven’t seen much great comparative effectiveness research looking at malarone v. mefloquine v. doxy in terms of efficacy. I found some sources asserting malarone’s potential superiority, but nothing rock solid. Would love to see whatever you found suggesting mefloquine’s inferiority.

    As for me, I’m irrationally terrified of mefloquine and my insurance covers malarone, so, I take the latter.

  8. naman shah says:

    Adam, thanks. Actually in spite of the similarity in name chloroquine and mefloquine are from related but different chemical families and have different mechanisms of action so no cross-resistance. You’re right that you haven’t seen comparative effectiveness for prevention and that’s because they are near impossible trials to do – how do you prove compliance? So all we have to go on are their treatment efficacy in vivo as well as the strength of each compound in in vitro assays. Doxy here is 1-2 orders of magnitude lower in strength than the others. Note most of the “CNS events” reported are headaches, vivid dreams, and insomnia.

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  11. marie says:

    Can you point me to any research on larium for children. I am looking for effectie ant-malarials for my 5 year old but am concerned regarding the possible mental health effects

  12. a2canadian says:

    N=1 observations are likely to be ill-received at this point but I wanted to chip in with a word about atovaquone/proguanil (Malarone). Though it is undoubtably the most expensive anti-malarial option and is rumoured to have fewer nasty side-effects, people should be aware that the drug is far from perfect. It would be lovely to say that we (this is the ‘royal’ we of course since I am in no way involved in the research and development of anti-malarians) have found a safe, low impact, highly effective anti-Malarial in Malarone; but I expect we would be speaking too soon. From personal experience, the drug can make you extremely sun-sensitive (especially if you happen to be glow-in-the-dark pale) and irritable, brings dreams of the feverish and psychosis-inducing variety, can cause severe heart-burn if not ingested with a meal, and must be taken on a daily basis (not ideal for those of us who cannot even remember to put socks on most mornings).

    Still, I have had a fairly positive experience with Malarone since, after spending 2 years visiting areas with shockingly high prevalence rates, I have zet to aquire Malaria. Some part of me wants to window-shop for a better drug but, from what I have read here and from what my father tells me (he actually IS involved in research and development of new treatments), there really isn’t a ‘better’ option per-se. Seems a bit like choosing the lesser of two evils.

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  14. Mark Ulinski says:

    Have you ever taken this drug nahman shah? I have. I’m curious as to were your proof is that it works. Are you knowledgeable of all the US troops this was pushed in in Somalia that STILL caught Malaria?! Luckily I didn’t but what I deal with from it, I would gladly take the malaria any day. You are more than welcome to head over to the Veterans Against Lariam facebook page. I’m an administrator that would be more than happy to let you read facts I’m sure you don’t know. Some of us had a conference with the FDA this past January and introduced facts THEY WEREN’T aware of…

  15. Reblogged this on livingstonehouse729's Blog and commented:

  16. Carrie Smith says:

    Hello, I don’t know why this drug is still on the market. I took Lariam for 6 months 9 years ago and am still suffering from the effects of what can only be called mental illness. I don’T consider the label indications to be a sufficient warning of the psychological side effects that this drug causes. These are not transitory effects!

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