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March 30, 2007 — According to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a large placebo-controlled trial of community-dwelling patients with bipolar depression who were receiving mood stabilizers, adjunctive antidepressant therapy did not reduce symptoms of depression, but neither did it increase the risk for mania. These results are reported online in the March 28 Early Release issue of The New England Journal of Medicine and will appear in the April 26 print issue.

Lead author Gary S. Sachs, MD, from Massachusetts General Hospital in Boston, explained to Medscape, "One group of experts was saying 'When people get depressed, you should add an antidepressant,' and another group of experts was saying 'When you get depressed, if you do a really good job with a mood stabilizer, you don't need an antidepressant.' This study proved that the latter group was correct, and that it is perfectly reasonable to treat patients without the addition of antidepressant, as long as you are doing a good job with mood stabilizers."

Dr. Sachs and his team write that although antidepressants are effective in treating unipolar depression, data supporting their use in bipolar depression are scarce and not strong enough to guide clinical practice, and this raises concerns among some clinicians that these agents could increase the risk for new episodes of mania. Despite the lack of Food and Drug Administration approval of standard antidepressants for the treatment of bipolar depression, these agents are commonly added as an adjunct to mood stabilizers for these patients.

STEP-BD is sponsored by the National Institute of Mental Health and was designed to evaluate the effectiveness of treatments of bipolar disorder and provide results for routine clinical practice. The current report is from a controlled trial within STEP-BD.

STEP-BD was conducted between 1999 and 2005 and enrolled 4360 patients with bipolar I or II disorder seeking treatment at 22 centers in the United States. Of 2689 patients who had at least 1 major depressive episode and were eligible for the study, 366 patients were enrolled. Subjects were assigned to receive up to 26 weeks of treatment with a mood stabilizer (lithium, valproate, carbamazepine, or any Food and Drug Administration–approved antimanic agent) and either placebo or a standard antidepressant (paroxetine or bupropion). These representative antidepressants are associated with low rates of switch to mania early in the course of treatment (treatment-emergent affective switch). Patients who had a history of intolerance or nonresponse to these agents were excluded.

The primary outcome was durable recovery, defined as euthymia for at least 8 consecutive weeks, which is considerably longer than outcomes used in typical efficacy studies. The secondary outcomes included the rate of treatment-emergent affective switch.

No Increases in Efficacy, More Study Needed

Dr. Sachs and colleagues found that treatment with an antidepressant added to a mood stabilizer did not confer any benefit over treatment with a mood stabilizer alone. A durable recovery was achieved by 42 ( 23.5%) of 179 patients who received a mood stabilizer and antidepressant and by 51 (27.3%) of 187 patients who received a mood stabilizer and placebo (P = .40). Rates of treatment-emergent mania were similar among patients receiving placebo or antidepressant (10.7% vs 10.1%, respectively).

Dr. Sachs cautioned that concerns could be raised that the results of this study taken alone might not generalize to all patients, since many otherwise eligible patients chose not to participate, possibly because they had poor outcomes when they had taken bupropion or paroxetine in the past. He added that the STEP-BD investigators also conducted a quasi-experimental analysis of results for patients with depression who did not participate in the randomized study and found no evidence that those treated with antidepressants benefited more than those treated without antidepressants. Since the outcomes in the open study were "almost the same" as for the 366 randomized study participants, it is likely that the results generalize to routine clinical practice. They plan to publish these results in the future.

Dr. Sachs stressed the importance of measuring durable remission, a much more rigorous outcome than typically used. "It really is the beginning of what would be a meaningful benefit. I think we need to keep everybody focused on that idea," he said, explaining that the concept of a durable remission in bipolar disease would be similar to the idea of a 5-year survival rate after cancer.

Further, More Representative Studies Needed

Robert H. Belmaker, MD, from Ben Gurion University in Beersheva, Israel, who wrote an accompanying editorial commented to Medscape, "The most important message is that the danger of mania with treating bipolar depression with serotonergic or dopaminergic antidepressants is probably low, but on the other hand, their efficacy is also low. The clinician therefore should probably be thinking more in terms of adding a mood stabilizer, or going to antidepressants that are mixed noradrenaline and serotonin-reuptake inhibitors."

Dr. Belmaker added that the 10% recruitment rate is "too low to be really representative of bipolar patients in a way to change our practice." He writes that clinicians should still be vigilant about checking for a history of mania before initiating antidepressant therapy in patients with depression.

Further studies of newly suggested treatments such as inositol and n-3 fatty acids are warranted, he writes. These will require study designs and perhaps new ethical consent tools that capture data from a more representative sample. "I think that the most important thing is that in the future we look at bipolar disorder not as an entity but as different subgroups of patients with bipolar disorders," he said.

The study was supported by a grant from the National Institute of Mental Health. The Massachusetts General Hospital Bipolar Research Program and the University of Pittsburgh Clinical Epidemiology Center coordinated the study. Antidepressant medications were donated by Glaxo Wellcome and SmithKlineBeecham (now GlaxoSmithKline). Several of the authors have disclosed financial relationships with Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Sanofi, and Wyeth. A complete list of the financial disclosures is published in the article.

N Engl J Med. Published online March 28, 2007.

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

  • List mood stabilizing medications used to treat bipolar disorder.
  • Compare treatment with mood stabilizer medications alone or in combination with antidepressants in the management of bipolar disorder.

Clinical Context

The foundation of treatment of bipolar disorder is the use of mood stabilizer medications, including lithium and valproate, and the use of atypical antipsychotics as mood stabilizers, including olanzapine and quetiapine. While antidepressants are frequently used as adjunctive medications to improve the depressive symptoms of bipolar disorder, these medications also have been suspected of provoking manic episodes in these patients. The authors of the current study report that there is little research into the practical benefits or risks associated with antidepressant medications among patients with bipolar disorder, and their research addresses this issue.

Study Highlights

  • Patients at least 18 years of age with a diagnosis of bipolar I or II disorder were eligible for study participation. Patients with a history of concomitant other psychiatric disease could participate in the trial, but those receiving active short-term therapy for substance abuse were not included.
  • Patients continued with the mood stabilizer they were receiving prior to the study. In addition to this medication, they were randomized to receive placebo, paroxetine, or bupropion. Paroxetine and bupropion were titrated up to maximum dosages of 40 mg daily and 375 mg daily, respectively, and the study treatment period could last as long as 26 weeks.
  • The main study outcome was durable recovery, which was defined by at least 8 consecutive weeks of euthymia. The authors also measured shorter periods of euthymia (transient remission) and incidence of treatment-emergent affective switch from depression to mania or vice versa. Researchers used the Clinical Monitoring Form to assess these outcomes, and analysis was by intent-to-treat.
  • 366 patients were enrolled in the study, but more than one quarter of these patients did not achieve an adequate dose of mood stabilizing medication. Lithium and valproate were the most common mood stabilizing medications used. Approximately one third of participants did not reach a study-defined outcome, and the mean treatment period was 86 days.
  • Baseline characteristics were similar between the groups receiving mood stabilizer plus antidepressant and mood stabilizer plus placebo. The average age of subjects was 40 years, and 43% of participants were men. More than two thirds of the study cohort received psychosocial treatment during the study period.
  • Rates of durable recovery were 23.5% and 27.3% in the antidepressant and placebo groups, respectively — a nonsignificant difference. The respective rates of transient remission were 17.9% and 21.4% (P = .40).
  • Treatment-emergent affective switch occurred at rates of 10.1% and 10.7% in the antidepressant and placebo groups, respectively.
  • Rates of discontinuing study medication because of adverse events were 12.3% and 9.1% in the antidepressant and placebo groups, respectively. This difference was not statistically significant. 3 participants in each treatment group were hospitalized for suicidal ideation.

Pearls for Practice

  • The foundation of treatment of bipolar disorder is the use of mood stabilizer medications, including lithium and valproate, and the use of atypical antipsychotics as mood stabilizers, including olanzapine and quetiapine. There has been little previous research into the role of antidepressants in bipolar disorder.
  • The current study suggests that antidepressants do not improve rates of euthymia among patients with bipolar disorder who are receiving mood stabilizing medications. Antidepressants also do not appear to promote increased rates of conversion from depression to mania in these patients.
 

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