Questions and Answers About the STEP-BD Acute Depression Medication Trial

March 2007

1. What was the acute depression medication trial and how did it fit into STEP-BD?

The study reported online on March 28, 2007, in the New England Journal of Medicine describes the results of an acute depression medication trial conducted as part of the NIMH-funded Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Participants were initially enrolled in the STEP-BD Best Practice Pathway, which provided rigorous individualized care from STEP-BD-certified treatment providers. Participants age 18 or older whose depression did not improve or who experienced a new depressive episode while in the Best Practice Pathway could enter this randomized controlled trial addressing antidepressant medication treatment options for acute depressive episodes. Of the 2,689 individuals who experienced an acute depressive episode while in the Best Practice Pathway, 366 were eligible and agreed to enter this randomized trial.

Mood-stabilizing, or anti-manic, medication is a necessary component of adequate standard treatment in bipolar disorder. In the acute depression trial, the researchers wanted to determine if adding an antidepressant to a mood stabilizing treatment is more effective in treating a bipolar depressive episode than using a mood stabilizer alone. They also hoped to determine whether use of standard antidepressant medications could lead to a “switch” from depression to mania.

Participants in this study were also offered the opportunity to receive psychosocial treatment (talk therapy) in addition to medication treatment. The results of that aspect of the study will be presented separately.

2. Why is the STEP-BD acute depression medication trial important?

The average person with bipolar disorder typically experiences major depressive episodes more than three times as frequently as symptoms of severe mood elevation or mania. Bipolar depression is difficult to treat, and its persistence and severity is associated with reduced ability to function in daily life. Researchers continue to debate about how best to treat bipolar depression, and whether antidepressants are helpful or might actually worsen the course of bipolar illness by causing manic or hypomanic symptoms (e.g., “affective switch”). The acute depression medication trial of STEP-BD was designed to provide answers to some of these important questions.

3. How was success measured?

The primary outcome measure for this study was the number of participants who achieved a “durable recovery” defined as at least eight consecutive weeks during which a participant had no more than two depressive or two manic symptoms. Although this eight-week “well” interval does not necessarily indicate long-term recovery for people with bipolar disorder, it is a more rigorous outcome measure than what is typically used in research studies in which success often is measured by a score on a depression-rating scale for only one week.

4. How were the STEP-BD participants selected for inclusion in the acute depression medication trial?

Most clinical trials present findings based on a carefully selected group of research participants who may not be similar to persons seeking care in typical practice settings. By contrast, STEP-BD included “real world” patients already receiving care for their bipolar disorder. While in the Best Practice Pathway, participants were evaluated for their depressive status at every follow-up visit using standardized rating scales and assessment tools that recorded and tracked their treatment and assessed their symptoms. If a participant experienced depression, he or she could choose to leave the Best Practice Pathway and enter the acute depression medication trial. Finally, when the participant completed the acute depression trial, he or she could return to the Best Practice Pathway. This ensured that participants received continuity of care for as long as they chose to remain with the overall STEP-BD program.

5. What treatments did participants receive in the acute depression medication trial?

Before entering the acute depression medication trial, participants were required to take an adequate dose of mood-stabilizing medication (e.g., lithium, valproate, carbamazepine, or other anti-manic mood stabilizing medications as they became available). If necessary, study doctors adjusted the dosage levels of participants' mood-stabilizing medication to be certain that participants were receiving the most appropriate dose.

After mood stabilizer doses were optimized, participants were then randomized to receive either one of the antidepressants—paroxetine (Paxil) or bupropion (Wellbutrin)—or a placebo, in addition to their mood stabilizer. The randomization of participants was double-blinded, meaning that neither the researchers nor the participants knew if an antidepressant or placebo was used alongside the mood stabilizer. This type of “placebo-controlled, double-blind, randomized clinical trial” produces objective results, since researchers, participants, and caregivers are not biased by their expectations about how well a medication worked.

Of the 366 participants who entered the randomized depression trial, 179 were assigned to the group that received up to 26 weeks of either paroxetine or bupropion (in addition to the mood stabilizer) to treat their depression. The remaining 187 participants received a placebo, as well as their mood stabilizer. Participants were not assigned medications to which they had bad reactions in the past, that they were strongly opposed to, or that the treating psychiatrist felt was unsuitable for them. Additionally, participants could continue to receive any other necessary medications during the trial.

6. Why were the antidepressants bupropion and paroxetine chosen for this study?

Several antidepressants are used to treat depression associated with bipolar disorder. Bupropion (sustained-release formula) and paroxetine were chosen because they are commonly used for patients with bipolar-related depression. Compared to some other antidepressants, bupropion and paroxetine are less frequently associated with “treatment-emergent affective switch,” a term used to describe bipolar patients' mood changes between depression and mania.

7. What are the results from the STEP-BD acute depression medication trial?

Of the 179 participants who received an antidepressant in addition to a mood stabilizer, 24 percent achieved a durable recovery (at least eight weeks with no more than two depressive or two manic symptoms), compared with 27 percent of the 187 participants who took a mood stabilizer plus placebo. Moreover, adding an antidepressant did not increase the risk of a switch to mania or hypomania. The similar rates of durable recovery indicate that the addition of an antidepressant medication to adequate, optimally dosed mood-stabilizing medications does not improve recovery from bipolar depression any more than adding a placebo.

8. What do the results of the STEP-BD acute depression medication trial mean for people with bipolar depression and the doctors who provide care for them?

This study demonstrated that when treating bipolar depression, using a mood stabilizing medication alone results in a similar outcome compared to using a mood stabilizer plus an antidepressant medication. Therefore, there is no additional benefit from adding the antidepressant medications used in this trial. In addition, the results suggest that there is no increased risk of hypomanic or manic symptoms when paroxetine or bupropion is added to a mood stabilizer.

Finally, because study participants tolerated both treatments well—less than 1 percent of participants suffered severe adverse effects—the results indicate that properly administered mood-stabilizing medication is an acceptable first line treatment for outpatients with bipolar depression.