The latest findings from the largest prospective study conducted on treatment outcomes for patients with bipolar disorder shed new light on what factors may lead to recurrence as well as provide results from several competing therapeutic options for treatment-resistant bipolar depression. In one of two reports from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study that were published in the February American Journal of Psychiatry, Roy H. Perlis, MD, and colleagues found that nearly half of patients who achieved initial recovery relapsed within two years, with most having depressive episodes. In an accompanying article, a group led by Andrew A. Nierenberg, MD, observed evidence suggesting that antidepressant augmentation with lamotrigine provided more benefit than did inositol or risperidone in helping improve treatment-resistant bipolar depression.

Funded by the National Institute of Mental Health, the seven-year STEP-BD trial included 4,361 participants throughout the United States. Investigators completed the primary treatment phase and long-term follow-up last fall and are now conducting data analyses. The goal of STEP-BD, which is led by principal investigator Gary Sachs, MD, is to improve treatment for bipolar disorder by determining the effectiveness of available therapies and by answering long-standing questions about the course of the disorder.

RISK FACTORS FOR RECURRENCE

Dr. Perlis’ team examined data from a subset of 1,469 patients who were symptomatic for bipolar disorder at study entry and found that 858 (58%) subsequently achieved recovery. Recovery was defined as two or fewer syndromal features of mania, hypomania, or depression for a minimum of eight weeks. During a follow-up period of up to two years, 416 (49%) patients who had recovered experienced recurrences, with more than twice as many developing depressive episodes as manic, hypomanic, or mixed episodes (298 [35%] versus 118 [14%]). The time until one fourth of patients had a depressive episode was 21.4 weeks, and it took 85 weeks until a quarter of participants experienced a manic/hypomanic/ mixed episode.

"Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence," reported Dr. Perlis and colleagues. "Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic, hypomanic, or mixed episode recurrence." Dr. Perlis is an Assistant Professor of Psychiatry at the Harvard Medical School in Boston.

The researchers characterized the presence of residual mood symptoms early in recovery as a "powerful predictor" of recurrence, particularly for depression. For example, the risk of depressive recurrence increased by 14% for every DSM-IV depressive symptom present at recovery and by 20% for every manic/hypomanic symptom present at recovery.

Another risk factor predictive of recurrence was psychiatric comorbidity. The investigators found that a greater proportion of days with significant anxiety in the year prior to study entry was associated with a greater risk for depressive recurrence. In addition, current substance abuse or dependence was modestly associated with earlier recurrence, and eating disorders appeared to increase the risk for depressive recurrence as well.

"Overall, these results suggest that in spite of modern evidence-based treatment, bipolar disorder remains a highly recurrent, predominantly depressive illness," the researchers concluded. "Predictors of risk of recurrence, which might be useful in stratifying patients to more or less intensive maintenance follow-up and treatment, included early residual symptoms, highlighting the need to target full remission, as in major depressive disorder."

TREATMENT-RESISTANT BIPOLAR DEPRESSION

In the first randomized study that compared competing options for treatment-resistant bipolar depression, Dr. Nierenberg’s team evaluated 66 patients with bipolar I or II disorder. At the time of their inclusion, participants were having a major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. All patients were randomly assigned to receive lamotrigine, inositol, or risperidone for up to 16 weeks, in addition to their current open-label mood stabilizer treatment with active antidepressant.

The researchers found no significant differences between the groups when any pair of treatments were compared regarding rate of recovery, which was defined as having no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for eight weeks. However, they noted, the recovery rate for patients receiving lamotrigine was 23.8%, compared with the rates for those taking inositol (17.4%) and risperidone (4.6%). Patients receiving lamotrigine also had lower depression ratings and greater Global Assessment of Functioning Scale scores compared with those taking the other two drugs.

"The overall recovery rate was low, indicating that treatment-resistant bipolar depression is a serious clinical problem," according to Dr. Nierenberg, Associate Professor of Psychiatry at Harvard Medical School. "The results suggest that few patients would be expected to recover with the addition of risperidone, while adjunctive lamotrigine and inositol may have some potential in treatment-resistant bipolar depression. Lamotrigine was superior to either inositol or risperidone on relevant post hoc secondary measures."

Dr. Nierenberg pointed out that future studies are needed to compare other possible augmenting agents, augmentation to switching strategies, and competing switching strategies.

THE STEP-BD TRIAL

Research for STEP-BD was conducted at 20 clinical sites and included patients with diverse psychiatric and medical co-occurring illnesses, such as anxiety and substance abuse, which are frequently experienced by those with bipolar disorder. Over the next several years, the investigators intend to publish multiple papers that will analyze additional data and information on various issues in bipolar disorder that have been generated from the STEP-BD trial.

—Colby Stong

Suggested Reading
Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006;163:210-216.
Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006;163:217-224.
Sachs GS, Thase ME, Otto MW, et al. Rationale, design, and methods of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Biol Psychiatry. 2003;53:1028-1042.
STEP-BD Web site. The National Institute of Mental Health. www.stepbd.org.

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