Zyprexa (olanzapine)
(updated 1/2008)

Technically this is an antipsychotic as well as a "mood stabilizer".  (What's an antipsychotic?)  But within weeks of its release by the FDA as an antipsychotic, psychiatrists were figuring out that it had acute mood stabilizing properties.  Since then the manufacturer has obtained FDA approval for marketing olanzapine as a mood stabilizer.  This means that a doctor could offer you an "antipsychotic" when you don't have "psychosis" at all.  Instead, she could be offering it to you simply because it's a very fast, often extremely effective medication for the symptoms of bipolar disorder (it even may help antidepressants work in people who don't clearly have bipolar disorderMarangell). 

This medication can be unbelievably effective, with remarkably few side effects.  But brace yourself, and don't stop reading until the end of this little essay because there may be some good news in sight.  However, you need to know that in routine doses (10-20mg) it can cause a lot of weight gain.  There is a case report of a 58% body mass increaseBryden, and a recent thorough review ranked olanzapine just behind clozapine in the weight gain championships, at 10 lbs in 10 weeks!Wirshing; Allison Twenty-five pounds in a year is not uncommon.  Thus the big risk from this medication, the main limiting factor (beside it's phenomenal cost) to it's use in bipolar disorder, is this risk of weight gain. 

In addition, there is accumulating evidence that this medication can cause diabetes in some people, Gianfrancesco, Caro, Hedenmalm usually -- but not always -- because of the weight gain it can cause.  The FDA requested that Eli Lilly put a warning about this on their package insert.FDA   A 2004 Consensus Statement from the American Diabetes Association, along with the American Psychiatric Association, includes specific warnings about diabetes and even a severe diabetic complication called "DKA" (for more detail on the Consensus Statement as I've reviewed it for doctors, who must present "PAR -- Procedures/Alternatives/Risks" information to patients, see Zyprexa Risks in PAR Discussions). 

Nevertheless, you should be aware of Zyprexa for symptoms that simply must be controlled now.  It can decrease anxiety, agitation, even the overall negative feeling called "dysphoria" -- within 20 to 30 minutes.  It has a profoundly calming effect in many people.  It can stop "racing thoughts" that can be one of the most severe symptoms of bipolar disorder, especially in Bipolar II -- as well as the more obvious symptoms  of paranoia or delusions as seen in Bipolar I.  Sometimes tiny doses are enough to help a lot, and these doses do not seem to so commonly lead to weight gain (2.5mg is the smallest pill; sometimes even half of that is quite useful in bipolar II).  

Because it can treat both mood symptoms and psychotic symptoms, it has a role also in people where the diagnosis is not clear.  The doctor does not have to be certain whether you have bipolar disorder or schizophrenia or even "depression with psychotic features": all will respond. It is like a "broad-spectrum antibiotic" that doctors can use before they are certain just which bacteria you have.  Later more specific medications can be used.  

Why switch , if Zyprexa works well right away?  Fair question.  The risk of weight gain and possibly even getting diabetes is the main reason to consider switching (if you're paying for the medication yourself, that's the other reason -- it's so expensive, you may not want to buy more than a few pills).   The risk of weight gain is higher if you're thin; people who are already overweight are less likely to see big gains from Zyprexa. 

Finally, you should know that research is continuing on the use of  medications to block this weight gain, or even reverse it. There are five main strategies being evaluated:  

H2 blockers
Somehow these medications appear to decrease the appetite drive caused by Zyprexa.  However, the only formal study of this approach concluded that the early apparent benefit seemed to be lost by 4 months.Cavazzoni  Even when it was working, it was not causing weight loss, just less gain.  

Amantidine (updated 1/2008)
A four-month randomized trial of amantadine to prevent weight gain in patients taking olanzapineDeberdt produced the result below (black bars are olanzapine plus placebo; gray bars are olanzapine plus amantadine):


As you can see, patients who were given a placebo in addition to olanzapine continued to gain weight, although only 1 kg (about 2 pounds) over four months. That is not much weight gain for people taking olanzapine; which may be in part explained by the fact that patients entering the study had already gained a very substantial amount of weight.  In the graph above, all of the patients were markedly overweight. Meanwhile, patients who were given amantadine lost about 3 pounds. Compare the results in patients who were not as overweight when the study began:

Here, patients taking olanzapine plus amantadine gained about 2 pounds, where the patients on olanzapine plus placebo gained about 4 pounds.  not That particularly impressive?  Moreover, this study was designed and reported by the manufacturer of Zyprexa. The lead author and several other authors are employees of the company.  Therefore one would expect the results to be presented in the best possible light, suggesting that amantadine can help prevent further weight gain.

Slightly more encouraging is an independent study from a well-known research center, which published the following resultsGraham

Again, this is add-on amantadine or placebo in patients already taking olanzapine, who were already gaining weight.  The question is whether amantadine might be able to stop or reverse that weight gain.  As you can see, it does indeed appear to stop the gain:  patients on placebo gained an additional 8 pounds, while those on amantadine gained no further weight.  

Unfortunately, amantadine carries its own risks. In the first study above, 22% of the amantadine group had problems with insomniac, versus 6% of the placebo group.  Most of the patients in this study had schizophrenia, only a few had bipolar disorder.  Insomnia may not matter as much in schizophrenia, but could be a significant problem in bipolar disorder.

Overall, I do not find these results particularly encouraging.  Perhaps one could argue that amantadine is worth considering and someone who is markedly overweight and must continue to take Zyprexa for one reason or another.   I have tried it with a few patients, who did indeed stop gaining weight, but tremor in particular was a limiting factor and none continued on it.

Here is some basic information about amantadine, and more technical information from another website. 

This is not my favorite drug, in part because people get so excited about it when they hear "weight loss" that they stop evaluating the risks very well.  However, it clearly blocks appetite and clearly leads to weight loss in many people who take it.  But there are now two formal research studies with placebo groups ( reference -- P. Keck: 5th International Bipolar conference) which show this medication does not act like a mood stabilizer, so there is no additional benefit to be generally expected (although there appear to be some people, in my practice at least, who have done extremely well on it -- I just don't know how to predict who's who!).  There is a least one case report of topiramate inducing mania.Jochum  Here's more on Topomax, including information on risks. 

Metformin (updated 1/2008)
Read more general information about metformin (Glucophage) if you wish.  Basically this medication appears to be able to reverse a change in your body to which Zyprexa can lead, called "metabolic syndrome".  This ability led to the medication being studied as an "antidote" of sorts for Zyprexa-induced weight gain. 

Psychiatric interest in this approach began after the publication of a small study with no placebo group.Morrison  More recently,  two randomized trials from Venezuela have yielded conflicting results. the first, published in 2006, showed no difference between a group who continued olanzapine and were given either metformin or a placebo.Baptista(a)

These same research group then published a very similar paper showing a positive effect of metformin.  Indeed, the study design is so similar I'm not certain that these were actually a separate group of patients, or an additional 40 patients added on to the first group of 40 reported initially.  In this second study, the metformin add-on group lost 1.5 kg, while the placebo group maintained a stable weight.Baptista(b) Again, not very impressive.

Overall, my experience with patients taking olanzapine, or one of its weight-gain-producing cousins like quetiapine, who started metformin for whatever reason, has been disappointing: the impact on weight has been or absent.  However, it is quite possible that these patients would have gone on to significant problems with elevated glucose levels and perhaps later even diabetes; they may well have been protected from this faith to some degree by using metformin.  To my knowledge, there is no randomized trial testing metformin in this role; that is, could it prevent the development of diabetes in susceptible individuals?     That would be nice to know.