lamotrigine (Lamictal)
(revised 1/2009; minor addition August 2013)

Update 10/2008: is the generic lamotrigine as effective as the brand name version? 
Not looking too bad so far; I haven't seen any obvious failures; but it's getting a bit complicated, looking at several recent studies. Here's a summary

Update on that, 2011: no one cares anymore. We all use generic and no one worries about the difference with brand name. Typical. 

The Good Side

Lamotrigine is another anti-seizure medication we psychiatrists have borrowed from the neurologists.  They have been using it now for about 10 years.  Surprisingly, several different research studies have shown that in addition to mood stabilizing effects, lamotrigine has clear antidepressant effects as well.  Unfortunately, it does not have reliable anti-manic effects, so it's not enough, alone, for Bipolar I. But for Bipolar II, it can be fantastic -- indeed, the holy grail: 100% symptom control, 0% side effects. 

Your suspicion ought to be aroused. Why is this guy so openly enthusiastic about this medication? I used to be much quieter with my enthusiasm, because yes, I was taking money from the manufacturer to give talks about bipolar disorder, lots of money. See my Funding page for details, which I hope will convince you that my enthusiasm is not what it sounds like (another doc' taking big bucks from the pharmaceutical companies, etc.). The ways in which I use their money for people who can't afford care, and the reasons why I don't think the money has overly influenced me, are described in detail there. Okay, back to the story...

If I had only one medication for patients with bipolar II, lamotrigine would be it for sure ( a team of experts seems to think likewise, having placed lamotrigine as "Step One" in the treatment of bipolar depression , in the most recent revision of their practice guidelines.  This is the step-by-step guide developed for the entire state of Texas. For more details on these guidelines and the recent change, take this TMAP link.). But wait, where's the evidence that this stuff really works?  (not just Phelps' enthusiasm or the Texas plan -- which itself was criticized for allowing a potential for pharmaceutical company influence, by the way)

Well, after one article which found that lamotrigine was not really any better than a placebo, which a bunch of other lamotrigine enthusiasts found hard to believeCalabrese, the same author participated in another "meta-analysis" (a review of existing studies and re-examination of their data) which found that sure enough, lamotrigine was quite strongly effective in people with severe depression. It was not so impressive in people with mild-moderate depression.Geddes  I wonder if after the first paper, Dr. Calabrese said to himself, wait a minute, that can't be right, I know that stuff works (he had published some of the original research showing it does!). So he repeated the analysis in a more sophisticated way, splitting out the severe depression folks from the rest, and there was the result that matches our clinical experience of the last decade.  This is such an important study, I've written a separate page to show you details if you're interested: lamotrigine works

However, the antidepressant effect could be a bad thing if it can "destabilize" bipolar disorder as typical antidepressants can do.  There is little published evidence of such an effect; indeed, in the largest placebo-controlled study so far, no patients had manic symptoms triggered by lamotrigine.Calabrese   Dr. Calabrese himself speaks very confidently that lamotrigine does not cause manic symptoms.  But I am pretty sure I've seen that happen; and there is one case report describing hypomania apparently induced by lamotrigine.Margolese  However, if this does indeed happen, it appears to be very uncommon, certainly far less than antidepressant-induced hypomania or cycling.  [Update 1/2006: Three cases, carefully selected to suggest lamotrigine's potential to bring on manic symptoms, were just published this month.Raskin The authors comment that a rapid dose increase was used in all three cases and that this might have influenced the apparent association of lamotrigine and the manic symptoms described.  If so, we have another reason to go up slowly on the dose. The main reason to do so is described in the next section. Update 11/2009: a more recent study looked for evidence that lamotrigine might be increasing manic symptoms, in a large group of patients, and found none.Goldberg  I'm still quite convinced it can make some people worse, though, so I pay close attention if a patient reports things getting worse somehow]. 

The Bad Side

The main side effect concern (besides this one, there are amazingly few) for lamotrigine is not really a side effect but an allergy:  this medication can cause a serious skin rash.Calabrese When we first started using it, about 1 person in 10 was getting a rash, which is a high frequency of an allergic reaction to a medication.  However, it seems that starting the medication very slowly decreases the likelihood of this rash.  I use an extremely slow start , about 1/4 of the originally recommended starting rates. (Several of my colleagues had "evolved" similarly slow rates, we discovered when comparing notes!)  Since going this slowly, I've had very few patients develop a rash.  See more on "handling the rash", especially if you're a doctor with concerns about using this medication. 

However, the rash is nearly the only side effect of concern with this medication.  Except for the rash, I've only had to stop the medication in 2 women for ankle swelling.  Sometimes it just doesn't work, and sometimes it seems to potentially be making things worse (like an antidepressant might do), but only extremely rarely is a person simply unable to take the medication due to a side effect problem of any kind.  That is a remarkable track record compared to many of our other medications. No weight gain problems have been described, or seen by me, for example. Now there is a rare chance of a really bad headache, called "aseptic meningitis".but that is so rare, it took years to figure out that this medicine could cause it (40 reported cases in 15 years).

And finally, it definitely works: the antidepressant action seems very beneficial for some patients.  Several patients have said "this makes me feel normal" (unfortunately, one of them got the rash shortly thereafter, as this was before we learned to go so slowly).  This has led me to go slowly with the dose increases to avoid repeating this experience, as explained in "handling the rash").  Lamotrigine seems to have a different quality as a mood stabilizer than Depakote or Trileptal, which are similar; or even lithium.  For more on this medication, see Dr. Ivan’s extensive presentation.Goldberg (b)

One more disadvantage, if you're on quetiapine/Seroquel:  a recent study found a very significant decrease in quetiapine blood levels in people who were also on lamotrigine.Andersson  For patients on both, quetiapine levels (for any given dose) were 60% lower than the levels of patients not on lamotrigine. 

Conclusion: lamotrigine seems to be a different kind of mood stabilizer than divalproex/Depakote or lithium, and has extremely low risk of side effects as long as you don't get the rash -- which is less likely if you go up very slowly on the dose.  For a cross check of my information, and a good deal more about the medication, see Dr. Ivan's answers to 24 common questions about lamotrigine.

Skeptics may wish to know that all of the above, except for the warning ("don't trust me here") and the updates, was written before I was recruited by the lamotrigine manufacturer to speak for them; and that their representatives and I had some spirited discussions of whether I would speak according to company guidelines.  The end result:  I say what I want to say, which usually has more to do with how to diagnose bipolar disorder than what medications to use.   [The 2006 update above, on lamotrigine possibly causing manic symptoms, is an example. Now that this medication is going generic (around June 2008) I can really speak out about this medication, because the company is no longer scheduling speaking programs.  But I do not feel motivated to go back and change anything I've said previously -- except perhaps to express more enthusiasm for this medication, as reflected in my main Web section on treatment.]

Update 2008: How does this stuff work?
Basically unknown; something about glutamate and/or fast sodium channels seems to be involved. I added this note just so that I could link an interesting article on volunteers who took lamotrigine and experienced a reduction in anxiety while public speaking. The medication decreased the cortisol response to this stress.Makatsori

A second 2008 article on this subject: might lamotrigine actually do something to Serotonin, perhaps in a fashion similar to typical antidepressants like Paxil/paroxetine?  A research paper describing changes in serotonin concentrations similar to those produced by Paxil was just published.Sagud  The authors did a good job tracking other variables that might have influenced their findings. At this stage, their results are just a very preliminary signal that perhaps lamotrigine does indeed do something "serotonergic", possibly similar to what conventional antidepressants do.