Lamotrigine vs. Olanzapine/fluoxetine Combination

Table of Contents

Yes, you have to start slowly

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

Week My Usual Approach (mg) Manufacturer’s recommendations (mg)
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

But that don’t mean she’s slow

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.

The study was sponsored by Eli Lilly.  They make fluoxetine and olanzapine.  So if there was any funny business here, it would be set up to favor their combination product.  For example, as you’ve seen, it takes at least 6 weeks to get lamotrigine up to full strength. So they made the study only 7 weeks long (most are at least 8, many are 12).

A telling result

Lilly 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.

(updated 11/2020)

Do Benzos Treat Depression?

Around 50 controlled trials have tested benzodiazepines in depression, and the results are surprising. In this episode we look at the controversies surrounding this research and what it means for practice.

Read More »

Get Smarter About Mental Health

Our Brain Bulletin decodes mental health updates for you.

It’s free.