Depakote & Relapse in Bipolar Disorder
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Q:  Depakote & Relapse in Bipolar Disorder

Dear Dr. Phelps,

I have been reading that the efficacy of the long term use (more than 3 months) of Depakote in the treatment of BP is not yet established.  

Why cant one stop the medication after a manic episode has subsided and after continuing treatment for around 3 months, and restart if one feels the symptoms coming back.

I had my first manic episode recently triggered by an extremely stressful situation in my personal life and have also been diagnosed as having hyperthyroidism. Could the mania and mood swings be just the hyperthyroidism coupled with stress? I am very stable now and on methimazole too. Do I need to continue my depakote beyond three months. I am worried about the hepatotoxicity and and other side effects.

Lastly, will avoiding stressful situations prevent further episodes or are they inevitable?

Dear A' -- 
You're right, Depakote has not been shown to prevent relapse in bipolar disorder in the way that we would like to see:  multiple large randomized trials showing that people who keep taking Depakote relapse into bipolar symptoms less than those taking placebo.  There is only one large study like that
Bowden and the results were confusing, perhaps because even the placebo group did quite well, which has been thought perhaps related to the way in which the patient were recruited into the study, so that there were a lot of relatively healthy folks in there who just didn't relapse very much, no matter what they were taking (lithium or Depakote or placebo).  

However, even before that study we were recommending that patients with bipolar disorder stay on Depakote after their symptoms got better, and here's why.  It's basically an extension of what we do know about lithium.  You see, people figured out without a lot of formal research that Depakote seemed to act rather like lithium in bipolar disorder.  And lithium has been shown to be an effective agent when taken to prevent relapse.  And after all, we know that bipolar disorder does recur, that's not in doubt.  In some people, when it recurs it can be disastrous.  So, if we have reason to believe that Depakote might prevent relapse, like lithium does, then even without the formal research studies we would like to have (the ones that you are pointing out that we don't have), we recommend staying on it.  

The important point: we don't have studies saying Depakote doesn't  work either.  We just don't have, as you point out, studies saying it does.  We think it does, we just don't have the studies to confirm that yet (because doing such studies requires a tremendous amount of money and effort, the kind that takes some big money -- so if the company, like Abbot Labs who makes Depakote, doesn't see the financial benefit in funding such a study, and they're a pretty small company that has to be pretty careful with this kind of thing, then that research is not going to get repeated (they helped fund the Bowden study).  

One last note:  the studies showing lithium works are "robust", as they say in the research lingo.  People who take lithium relapse at one third the rate of those who take placebo in the existing studies, according to a very large review (Cochrane Database). 

Wait, one more note, after another literature search: there is a new update of the Bowden studyGyulai showing that Depakote prevented relapse into bipolar depression better than lithium did.  I haven't read the text yet but that could change the tune at least a little.  (If I understand the abstract correctly, this would be called a "secondary analysis" and those are not generally regarded as quite as strong a statement as the original study cited above).  Dr. Bowden's recent summary (here's his abstract) of this issue also seems to emphasize the value of valproate and lithium for prevention of mania; the lack of strength of lithium's effect in preventing depression; and the value of lamotrigine as being stronger than lithium for the prevention of depression.  

That's a good question you asked.  Just to be clear: there is very strong consensus in psychiatry that staying on is smarter than going off -- no controversy around that to my knowledge.  So, careful if you start deciding to go the other way just because we don't have the formal data supporting it; there could be some pretty good "clinical experience" supporting this practice.  That's not to say we should keep thinking though; so good on ya' for asking, and thinking. 

Dr. Phelps

Published December, 2003


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