Q:  McMan's Opinion on Lamictal

Dear Dr. Phelps:
You are familiar with John McManamy and his website.  He comments unfavorably on Lamictal research and suggests strongly that Lamictal is not effective for alleviating acute depression or bipolar disease. Your comments please about his take on Lamictal.  Do you still believe it is a useful drug for bipolar illness?

Sincerely,


Dear Mr. W. --

John and I discussed lamotrigine (Lamictal) before he wrote that column on the research on this medication. We agreed quite strongly on the problems with the research so far. However, we may come away with a different interpretation of its role at this point in treatment, certainly a different one than that which you have drawn here (although I can easily see how you arrive at this interpretation).

This medication is a perfect example of the tension between drawing conclusions from one's clinical experience versus relying primarily on the research literature. When Zyprexa first came out, for example, it did not take long before many clinicians discovered how powerfully effective it was. I remember the excitement about this quite vividly. This proceeded many of the studies which have subsequently demonstrated this high level of effectiveness. In other words, we figured it out from clinical experience quite quickly. Unfortunately, we also figured out shortly thereafter that it caused weight gain of dramatic proportions.

Likewise, with lamotrigine, upon using it in people with rapid cycling bipolar disorder and predominantly depressive symptoms, I think many clinicians very quickly realized how dramatically effective this medication can be. By contrast, the arrival of numerous other medications to quite a bit longer to impress us. This would include geodon and even perhaps aripiprazole, which have their place, but are not so stunningly effective, in my experience.

However, relying on one's clinical experience like this is very risky. One can have some early successes and be overly impressed, yet maintain that initial positive impression for months thereafter based on one's initial experience. Therefore, much more reliable in the long run is to rely on randomized clinical trials in which the medication is compared against a placebo. Unfortunately, however, these large clinical trials are designed by the company who makes the medication, and can sometimes be designed in such a way to make the results more likely to be favorable. That is what happened with the Lamictal studies. Using a so-called "enriched design", they manage to work around the usual starting place of randomly assigning patients to either the medication or placebo. This is the story John McManamy describes.

What we really need is a study by some lamotrigine skeptic, and indeed, recently we have seen something that comes fairly close: a competitor company, Eli Lilly, manufacturer of Zyprexa, sponsored a study comparing Zyprexa/Prozac in combination, versus lamotrigine. One would think that they may have tried to stack the deck in favor of their medication combination, if any error in the design was committed. One rather obvious such twist was to make the study only seven weeks in duration, which would have been thought to disadvantage lamotrigine. Surprisingly, lamotrigine performed very well in this study, almost as well as the Eli Lilly drug, with much less side effect burden. Most strikingly, it was almost as fast and producing response as the Zyprexa/Prozac combination. Unfortunately, there was no placebo group in this study; otherwise, this might have been one of the best demonstrations of lamotrigine effectiveness, largely replacing, in my view, the bigger "registration trials" originally produced by the lamotrigine company.

Boiling all this down, I think the trick is to be able to combine one's interpretation of the research studies with one's clinical experience. Indeed, this is generally agreed upon as a valid way of proceeding in our business, given the lack of impartial research studies we often face. While it is true that if there is any doubt, one should probably rely more heavily on the research data than on one's own experience, I think we are beyond that point with lamotrigine.

For example, there is a well-known adage in my business: "When a new medication comes out, use it quick before it stops working". In other words, there is usually an initial excitement and an initial impression that a medication is very effective. After a while, the excitement dies down, and we often discover that the medication was not as effective as we originally thought. I have been using lamotrigine for over five years, which would generally be enough time for that kind of excitement to disappear. My interest in this medication remains, however, and indeed I don't think we have yet figured out how many people might respond well to it, as I continue to find patients whose predominant bipolar symptom is anger, or anxiety, which are not the typical symptoms which might lead us to try and lamotrigine, and yet it does seem that sometimes it can be effective even for this presentation as well.

Mind you, all of the above must be taken with a huge grain of salt, because I have received thousands of dollars in honoraria from Glaxo SmithKline, the manufacturer of lamotrigine. It is quite possible that all that money has skewed my impression of this medication, preventing me from the usual disillusionment which might accompany a medication which is not as effective as we had initially thought.

Sorry to go on at such length. You can see that this is a complicated issue. Basically I agree with John that the research is not what we would wish to see, and is considerably weaker in the design and in the number of positive studies relative to the number of negative studies, compared to some other medications like Zyprexa. Nevertheless, when it works well, I think the results are unequivocal; and by that point, the patient is beyond the big risk with this medication (severe rash), with very little in remaining risk even if she or he stays on the medication for years thereafter -- and certainly far less risk in long-term use than nearly any other alternative medication. Thus one of the reasons why I favor this medication so strongly is not so much the evidence for its effectiveness, but the risk my patients face if they do well on it and are going to continue it, relative to those risks with any other approach we might have chosen.

I hope that makes sense. Thank you for your question.

Dr. Phelps

Published July, 2007