The latest foray into the controversial issue of antidepressant-induced switching appeared in the February issue of The American Journal of Psychiatry (2006;163:232-239).

The last time TCPR took up this topic (June 2005), we reviewed a meta-analysis of antidepressant use in bipolar disorder. That paper concluded that SSRIs cause the same rate of manic switching as placebo (Am J Psychiatry 2004;161:1537-1547). The authors of the newly published research would beg to differ.

In this study, 159 patients with bipolar depression (all of whom were taking mood stabilizers) were randomized in a double-blind protocol to receive adjunctive treatment with Wellbutrin (bupropion, mean dose, 286 mg/day), Zoloft (sertraline, 192 mg/day), or Effexor (venlafaxine, 195 mg/day). The patients were followed for 10 weeks, though some entered into a continuation treatment arm that went on for up to a year. Overall, 48.7% of patients responded within 10 weeks, and there were no significant differences in response rate between the different ADs.

The focus of the paper, however, was not on treatment response, but rather on whether these medications caused manic switching. The authors reported the overall rate of hypomania or mania as 19.3% within the first 10 wks and 36.8% within a year.

The three agents did not differ significantly in switch risk. Inexplicably, however, the authors created a novel statistical measure that made it appear as though there were differences. They defined two different types of switches: “threshold” switches (what we normally think of when we think of manic switches) and “subthreshold” switches (meaning a switch to a hypomanic state that was too brief to be diagnosable). Their new statistic is the ratio of “threshold switches to subthreshold hypomanias.” If you find yourself scratching your head and wondering why this ratio is useful, welcome to the club!

Nonetheless, when this ratio was used to compare the ADs, Effexor had by far the highest ratio, and Wellbutrin the lowest. According to the authors, this result fits into the theory that dual reuptake agents, like the tricyclic desipramine, are more dangerous to give in bipolar depression than either SSRIs or Wellbutrin. Before you conclude that something nefarious is afoot here, note that this research was funded by both the non-profit Stanley Foundation and the NIMH. And most of the authors have independent financial relationships with an array of drug companies, suggesting that they weren’t biased toward any particular product.

What do we make of these findings? It’s clear from these findings that bipolar patients frequently become manic or hypomanic. However, since there was no placebo group in this study, we don’t know whether these switches simply reflect the natural course of bipolar disorder or whether they reflect the specific action of antidepressants.

Although the authors concluded that “venlafaxine was associated with the highest relative risk of switching and bupropion with the lowest risk,” the actual switch rates do not seem to support this conclusion.

TCPR Verdict:
Manic switching: The answer still eludes us.