Do Antidepressants Cause Worsening of Bipolar Disorder? Two Direct Looks For Switching

Antidepressants are known to cause switching from depression to mania in some people with bipolar disorder; the only remaining question is how often this happens. A very important study recently studied the switch rates on venlafaxine (Effexor in the U.S.) versus bupropion (formerly Wellbutrin). By some interpretations (including mine) this study shows that bupropion does indeed have a much lower rate than venlafaxine (Post and Leverich and colleagues). Because there was no control group in this study, we don't know how close bupropion might have been to some "natural" switch rate, which is very likely not zero even in a 10-week study like this one. (We're lucky to have even these data, and should be grateful to Drs. Post and Leverich and their colleagues in the Stanley Bipolar Network that conducted this research; there was no control group because in this study, people in regular treatment agreed to be randomized, when they were going to be given an antidepressant, to one of three (sertaline/Zoloft was the other one).

Since then another study has been published on this subject. This is not a randomized trial either. A team of researchers looked at patients in ongoing treatment for bipolar disorder who were using a slick program called ChronoRecord, which keeps a mood chart automatically; all the patient has to do is enter a number or two every day (chronorecord.org). They compared the experience of patients on antidepressants to those not on antidepressants. The main point of their paper, by my reading, is that they did not see any more switching amongst those on antidepressants than those not so treated (nearly everybody was on a mood stabilizer) (Bauer and Rasgon and colleagues).

However, as the authors point out, they too did not have a control group and indeed, those patients who are on antidepressants could easily be different than those who are not -- more depressed, for example. That is the other thing which stands out in this paper, as the authors also point out: the patients on the antidepressants are more depressed than those who are not. Odd, isn't it. But on this basis, it seems to me at least that we have to decide: either we're going to accept the design of this study and conclude that antidepressants don't work, and may even make patients more depressed; or we can say that there was so much potential for some sort of selection operating in this study that the patients who got the antidepressants were just so different from those who were not on them, that we can't conclude anything from these data.

I have not corresponded with Dr. Bauer, whose work I greatly respect but who doesn't know me well, and whom I don't want to bother with my little objection. But it did bother me that one conclusion could be presented as though it means perhaps a little something, while this other conclusion about antidepressants associated with greater depression was mentioned but not focused upon. Overall, if either worth noting, this latter one seems to me to be the more powerful finding, or at least both together, but not just the "no increased cycling on antidepressants" finding.

And so with two more studies of the issue, unfortunately nothing is much clearer as regards antidepressant safety in bipolar disorder -- other than to strongly suggest that bupropion is better, if an antidepressant is going to be used, than venlafaxine. That is probably important, as a preliminary conclusion while we await more data (although frankly, this is likely to hammer venlafaxine so hard it would take years to recover even if the next study showed a more neutral finding).

Dr. Phelps
(I've been working on a big article on the Bipolar Spectrum concept so haven't been posting much lately, but will get back to it here soon I hope.)