Lamotrigine vs. Olanzapine/fluoxetine Combination
Updated 1/2009 

Lamotrigine is not as slow as you might think

Here are two lamotrigine dosing approaches, sometimes referred to as "titrations" (meaning to slowly add a new ingredient). 

Week My Usual Approach 
1 12.5 25 
2 25 25 
3 37.5 50 
4 50 50 
5 75 100
6 100 200
7 150 200
8 200 200

People think that this slow "titration" means having to wait for a long time for the benefits of this medication.  However, we already know that 50 mg (week 4, either way) is more effective than a placebo (from a randomized trial years ago).  Indeed, I was pretty sure I had seen people respond even in the first week, and this was shown in a recent study.Brown  Since the result is so stunning, and so few psychiatrists know about it, allow me to show you please. 

A competitor's manufacturer sponsored a study comparing lamotrigine with "olanzapine/fluoxetine combination" (a combination of Zyprexa and Prozac they call Symbyax) for the treatment of depression in patients with bipolar I.. It was already known that this is a very good medication, particularly a good antidepressant in bipolar disorder (except for the massive weight gain that can result, which is why I don't use it at all).  

The manufacturer surely thought that Symbyax would trounce lamotrigine, at least in the first several weeks while the dose of lamotrigine was being slowly increased.  But as you can see in the graph below, Symbyax had a slight edge throughout the study, but lamotrigine did not lag behind:  it showed benefits in the very first week (decreasing scores are good, reflecting less depression; lamotrigine is the dark rectangle, Symbyax the gray circle).

So, having established that whatever benefit  lamotrigine provides, it is not slow; let's now look at the long-term outcome in this same study.

Which would you rather be on long-term, if you could?

Here we have a different question: is the olanzapine/fluoxetine combination better enough, compared to lamotrigine, to justify its long-term metabolic risks of increasing glucose and weight and cholesterol levels?  (not to mention tardive dyskinesia)   Answer: well, olanzapine/fluoxetine combination is better.  But not much better.  Look at this, from the recently published extensionBrown2 of the study above, now reporting a half-year's worth of results:

On the left in this graph you see the same first seven weeks shown above.  Then, after the vertical dotted line at week seven, you see what happens over the next several months.  The two treatments are only barely different, although olanzapine/fluoxetine combination has a slight edge.

Meanwhile, however, what risks does a person face in staying on one or the other of these medications?  By week seven, the rash risk of lamotrigine is nearly gone. But over the course of the study, 34% of the olanzapine/fluoxetine group gained more than 7% of their body weight, compared to 2% of the lamotrigine group.

However, these people have Bipolar I .  Lamotrigine was not effective in this study for preventing return of manic symptoms.  Olanzapine/fluoxetine was much better in that respect.  So lamotrigine is not perfect, especially for bipolar I. It is closer to perfect for patients for whom return of manic symptoms is not such an issue -- namely, bipolar II  and other bipolar variations where the main problem is depression.