Lamotrigine and Folate

[added 2/2016; updated 7/2016]

Summary:  new evidence suggests that folic acid supplementation somehow interferes with lamotrigine’s benefits. If you’re going to take lamotrigine, ask your provider about stopping any folate supplement you might be taking.  And if you’re already taking lamotrigine, careful about adding any such supplement. In fact, if you eat much wheat flour, maybe even cut that back some if flour is enriched with folic acid in your country (as it is in the U.S.).

First, which folate are we talking about?

Folate is the compound found in broccoli, spinach, peas and other foods. Folic acid comes in pills. It is converted through your liver to several forms of folate in your blood. Finally, there’s a different pill version called l-methylfolate which is more costly but works around a genetic barrier that about 15% of the U.S. population carries. If you’re one of those 15%, you’d need the spendy version if for some reason you want to take folate.

How are you supposed to find out?  What is special about folate, anyway?  Why would you want to get extra folate?  For these questions, see my page on Folate.  Short answer: some very limited evidence suggests that extra folate might help treat depression. That’s why the research team used it in the study described below; then they stumbled on this possibility that folic acid supplements might interfere with lamotrigine.

Folic acid supplement interferes with lamotrigine?

Here’s the study on which that concern is based. Geddes  In patients with bipolar depression, who all were taking quetiapine/Seroquel, the investigators added either lamotrigine or folic acid or both.  The main purpose of the study was to see if lamotrigine, added to quetiapine, was better than adding a placebo, so there was a placebo group as well.   So there are four different groups of patients in this study, whose outcomes were compared to one another, in blue below:

folic acid no folic acid
lamotrigine A: lamotrigine and folic acid B: lamotrigine alone
placebo C: placebo and folic acid D: placebo, no folic acid

Remember, everyone is getting quetiapine as well, and many patients were also taking other stuff — moderately complex and sometimes very complex soup. Despite that, several signals were clear in this study.

What did they find?  Their depression measure used is called a QIDS-SR (exactly what that is, if you don’t know it, doesn’t matter much here). A reduction of 4 points, on this 16 point scale, is a pretty big drop. That’s what lamotrigine alone produced, compared to placebo: 4 points more reduction than a placebo (comparing groups B and D above). In this business, that is a very solid signal of effectiveness.

But the group that got lamotrigine and folic acid (Group A above) — well you might expect them to do maybe even a little better, with a second potential antidepressant on board? Nope, they didn’t do better than Group C, folic acid plus placebo.  The benefit that lamotrigine provided in Group B was lost when lamotrigine was combined with folic acid (Group A).

Huh? What’s going on here? The study authors speculate that folate and lamotrigine might both be trying to bind to the same spot on neurons (there is some old evidence to suggest this might be so). Or that maybe folic acid interferes with the absorption of lamotrigine.  In any case, they are clearly concluding that this apparent interaction between lamotrigine and folic acid is real, and substantial.

Indeed,  their study shows:

  1. adding lamotrigine to quetiapine really works, clearly better than a placebo (for up to 52 weeks in this long study; Group B versus Group D); and
  2. “if a patient with bipolar disorder needs folic acid therapy, then lamotrigine should be avoided and vice versa”  (their quote, emphasis mine).

They also note: “The result raises an intriguing question about the likely efficacy of lamotrigine in countries which fortify wheat flower with folic acid: the US programme has been estimated to provide 100–200 μg of folic acid per day in women of childbearing age.  It is unclear if this amount is sufficient to reduce the treatment effect.”


Treating the Mood Spectrum