This large, randomized, placebo-controlled effectiveness study found no evidence that treatment with a mood stabilizer and an antidepressant confers a benefit over treatment with a mood stabilizer alone. Rates of treatment-emergent mania or hypomania observed prospectively were similar among subjects receiving adjunctive antidepressants and those receiving placebo. Our data suggest that the short-term addition of bupropion or paroxetine to mood-stabilizer therapy does not increase the risk of cycling from depression to mania or hypomania. However, we did not study a “pure” placebo group (one in which no active psychotropic medication was administered) and hence cannot establish the effectiveness of treatment with a mood stabilizer alone.

There were several differences in the design of our study and that of previous studies. We primarily enrolled subjects who were already receiving clinical treatment at participating sites and who continued care with their usual provider. Our eligibility criteria permitted the entry of subjects with bipolar I or bipolar II disorder, including those with coexisting anxiety disorders, substance-abuse disorders, or psychotic symptoms, since epidemiologic evidence shows that most patients with bipolar disorder have such features.20 We also allowed subjects to receive additional pharmacotherapy or psychotherapy. These differences may explain the disparity between our findings and those from the meta-analysis of efficacy studies by Gijsman et al.,21 which found standard antidepressants to be efficacious in the treatment of bipolar depression.

Our study design also differed from that of most efficacy studies in that it featured equipoise-randomization strata. This design allowed the entry of subjects who preferred to avoid one of the standard antidepressants, by eliminating the possibility that the subjects would be randomly assigned to a treatment they did not want to receive. Finally, our a priori, clinically meaningful, primary outcome of durable recovery was met if subjects had euthymia for 8 consecutive weeks. In contrast, most short-term efficacy studies designate as the primary outcome change from the baseline score on symptom-severity scales at a single visit. Our results are therefore likely to be more in accord with the expectations of clinicians and patients in the general population for treatment effectiveness than are the results of previous efficacy studies.

Our study had several limitations. First, since antidepressants are not a homogeneous class, we cannot rule out the possibility that other antidepressant medications may be more efficacious or have a greater propensity to induce manic symptoms than our study medications. Nevertheless, bupropion and paroxetine are two of the most frequently recommended antidepressants for patients with bipolar disorder.22 Some studies suggest that antidepressants vary in their tendency to cause a switch to mania or hypomania, even when used as adjuncts to mood-stabilizing treatments.17,23,24 Notably, the largest of these studies — the double-blind comparison of bupropion, sertraline, and venlafaxine by the Stanley Foundation Bipolar Network — found no difference in efficacy among the treatments but did find a significantly higher rate of switch from depression to mania or hypomania among subjects receiving venlafaxine than among those receiving bupropion or sertraline.9,24 Therefore, although neither paroxetine nor bupropion was associated with an increased rate of treatment-emergent affective switch in our study, other antidepressants may be. Our results are, however, largely in agreement with those from studies that associate selective serotonin-reuptake inhibitors and bupropion with lower rates of treatment-emergent affective switch than venlafaxine or desipramine.17,23

Second, our efficacy and safety findings are based on a relatively brief period of observation. The primary outcome of 8 consecutive weeks of euthymia, however, reflects a considerably longer period than do the cross-sectional outcomes (response or remission) used in typical efficacy studies. Although an 8-week period of recovery may be too brief to be clinically meaningful for patients, an 8-week interval of wellness may be a better predictor of long-term outcome than are scores on cross-sectional rating scales. Effectiveness outcomes such as those used in our study may be more applicable to clinical practice than are short-term cross-sectional outcomes, since the apparent benefit based on cross-sectional outcomes may not be persistent and since nearly all traditional efficacy trials define outcomes on the basis of improvement in depression-rating scores without correction for rates of treatment-emergent affective switch. Results from traditional efficacy studies can thereby misclassify patients with emergent hypomania or mania as having had a response. The Stanley Foundation Bipolar Network, using outcome criteria corrected for rates of treatment-emergent affective switch, reported that 33.3% of patients with bipolar depression had a response to treatment with bupropion, 41.4% had a response to sertraline, and 35.6% had a response to venlafaxine24; these response rates are similar to the treatment-effectiveness response rates reported here.

Third, many of our study subjects received some form of psychosocial intervention. Although the efficacy of psychosocial therapies has not been established for patients with acute bipolar depression,25,26 it is possible that the adjunctive use of psychosocial interventions limits the generalizability of our results or reduced our ability to detect the effects of antidepressant therapy. Psychosocial intervention did not appear to affect the two study groups differently. The two groups had similar percentages of subjects who received psychosocial interventions, and similar response rates were found in the subgroups receiving any form of psychosocial intervention and in the subgroup that declined psychosocial treatment. Results of a longer-term STEP-BD study do provide support for use of the psychosocial interventions used in our study.18

Fourth, some of our findings rely on last-observation-carried-forward analyses. Such analyses generally involve the imputation of data, which raises concern about the degree to which incomplete follow-up influenced the results. However, data imputation was not required for analysis of the primary outcome (durable recovery) or of the majority of secondary outcomes reported in our study. These categorical outcomes represent subjects who actually reached a study-defined outcome. Some data for the change in SUM-D and SUM-ME scores were imputed, but this is unlikely to have influenced our outcomes, as it was required for only about one third of the subjects in each group.

Fifth, patients who had recently had a manic episode were likely to be underrepresented in our study. Clinicians caring for these potential subjects might have judged them to be at high risk for a switch from depression to mania or hypomania and therefore might have avoided enrolling them into our double-blind study that exposed subjects to a standard antidepressant. Thus, our results are likely to be applicable only to those patients with bipolar depression who are considered appropriate candidates for treatment with standard antidepressants.

In summary, for the treatment of bipolar depression, we found that mood-stabilizing monotherapy provides as much benefit as treatment with mood stabilizers combined with a standard antidepressant. There was no significant difference in the adverse effects, including switch to mania, between patients who received adjunctive antidepressants and those that did not. Further research examining the efficacy of different mood stabilizers for bipolar depression may be useful.