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Early Findings from Largest NIMH-Funded Research Program on Bipolar Disorder Begin to Build Evidence-Base on Best Treatment Options

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Science Update

Below is an update on the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a large, national research program determining the best treatment practices for bipolar disorder. This study, which began in 1998 and concluded in September 2005, included a total of 4,360 participants with bipolar disorder who were followed long-term to determine which treatment(s), or combination of treatments are most effective for treating the episodes of depression and mania in bipolar disorder and for preventing recurrence.

Findings from an NIMH research program on bipolar disorder provide much needed long-term data on the chronic, recurrent course of the disorder, and begin the work of building an evidence-base on the best treatments for those with the disorder. Also known as manic-depressive illness because of its recurring episodes of mania and depression, bipolar disorder is a serious, chronic illness which causes shifts in a person's mood, energy, and ability to function.

The newest findings, published in two articles in the February issue of the American Journal of Psychiatry, are the first of many analyses which will become available over the coming months as researchers examine the largest dataset ever created on treatment outcomes for those with bipolar disorder.

Predictors of Recurrence in Bipolar Disorder

Little is currently known about the factors that can help predict when a person with bipolar disorder will have a recurrence of manic or depressive episodes. Researchers analyzed a subset of the 4,360 STEP-BD patients; the 1,469 patients analyzed were those who had least two years of participation in the STEP-BD Best Practice Treatment Pathway. The researchers found that slightly more than half (58%) of this group of patients achieved recovery, defined as having only two symptoms of the disorder for a period of at least 8 weeks, during the 2-year follow-up period. In addition, almost half of the recovery group had a recurrence during the up to 2 years of follow-up, and the majority (70%) of recurrences were characterized by a return to a depressive state1. According to the researchers, these results indicate that in spite of modern, evidence-based treatment, bipolar disorder remains a highly recurrent, predominantly depressive illness.

One strong predictor of recurrence was the presence of residual symptoms (of depression or mania) still present at recovery, a finding consistent with other research. This finding may indicate that complete symptomatic remission, i.e, the absence of all symptoms, should be the goal of treatment, as it is in non-bipolar, major depression.

Another important predictor of recurrence in this group of patients was the presence of other psychiatric illnesses. For instance, patients in this group who also suffered from anxiety, eating disorders or substance abuse disorders had a greater risk of depressive symptoms recurring. More research is needed to better understand how these predictors (residual symptoms and other psychiatric illnesses) work to increase the chance of recurrence.

Caring for Those with Treatment-Resistant Bipolar Disorder

Because of the chronic, episodic nature of the disease, there are some people who may not get better after several treatment attempts. Researchers designed a randomized clinical trial within STEP-BD to determine whether adding any one of three medications — lamotrigine, inositol, or risperidone — improved the outcomes of these treatment-resistant bipolar patients who chose to enter the trial2. Lamotrigine is a mood stabilizer; inositol is a naturally-produced chemical that affects neurotransmitter function and may have some antidepressant effects; and risperidone is an atypical antipsychotic medication.

The results from this small trial (66 participants) indicate that overall, regardless of medication, the rates of recovery are low in this difficult-to-treat group of people with bipolar disorder. The findings also provide some direction for future, larger studies in that there is some suggestion that lamotrigine may have greater benefit compared with inositol and risperidone.

Over the next several years, many other papers will be published that will analyze additional data and information generated from the STEP-BD trial. For more information about STEP-BD, including available and upcoming publications, visit STEP-BD at ClinicalTrials.gov

About Bipolar Disorder and the STEP-BD Trial

Today, about 5.7 million American adults have bipolar disorder, and its episodic, chronic nature means that in many cases, no single medication or therapy is effective in treating it, making it a complicated puzzle to solve. Typical treatment for bipolar disorder includes both medication and talk therapy. Mood stabilizers (e.g., lithium, valproate) are commonly used to even out mood swings, and additional medications are often used to suppress the phases of acute mania and depression and prevent relapse.

Unlike the many good quality but narrowly-focused traditional clinical trials which guide current practice, STEP-BD differs in several important ways:

  • It is the largest (4,360 patients enrolled) study of its kind.
  • It included patients with diverse psychiatric and medical co-occurring illnesses (anxiety, substance abuse) which are commonly experienced by those with bipolar disorder.
  • It recruited patients living in communities throughout the United States.

STEP-BD's size, scope, and inclusion of "real world" patients will make its findings more generalizable to all those seeking the most effective care for the disorder.

In this first of its kind research program conducted at 20 clinical sites throughout the U.S., patients were systematically evaluated upon entry, provided best-practice treatments (known as the Best Practice Pathway), and were monitored throughout their entire participation in the study. The participating doctors were provided expert training, and became "STEP-BD-certified" in the best treatments for bipolar disorder. STEP-BD best-practice treatment options included the use of mood-stabilizing medications, both newer and older classes of antidepressants, atypical antipsychotics, and psychosocial interventions (e.g., talk therapies). (See Sachs et al3 and http://www.clinicaltrials.gov/ct/show/NCT00012558?order=1  for a detailed description of the STEP-BD protocol.)

If and when participants experienced an episode of mania or depression, they could choose to leave the Best Practice Pathway and enter the "clinical trial" portion of the STEP-BD program: Randomized Care Pathways designed to answer specific treatment questions using traditional clinical trials methodology. Patients who entered these Randomized Care Pathways remained with their STEP-BD doctors during and after the randomized trials' duration.

A unique feature of the STEP-BD dataset that is expected to make a significant contribution to the field of bipolar treatment research is its ability to compare outcomes from the randomized controlled trials with the best practice treatment (non-controlled) provided by STEP-BD certified doctors. This kind of simultaneous replication of results, in a real-world setting, will be very valuable.

Researchers, using various pieces of the STEP-BD dataset, are asking multiple and sharply-focused research questions, such as how best to treat each phase of the disorder (manic or depressive episodes) and prevent recurrence. Other research questions include attending to the special needs of women with the disorder, and evaluating the treatment outcomes for those with co-morbid medical or mental disorders. STEP-BD researchers will also evaluate how treatments affect quality of life, including the ability to work and social functioning, the cost-effectiveness of the combinations of treatments, as well as factors that affect the continued use of each treatment.

STEP-BD is funded by the National Institute of Mental Health (NIMH), National Institutes of Health, an agency of the U.S. Department of Health and Human Services.

The trial was conducted at research centers around the United States. Massachusetts General Hospital (Boston, MA) and the University of Pittsburgh, School of Medicine (Pittsburgh, PA) were the coordinating centers for the study. Clinical sites included: University of Arizona (Tucson, AZ); Stanford University (Stanford, CA); University of California San Diego (La Jolla, CA); University of Colorado (Denver, CO); Rush-Presbyterian- St. Luke's Medical Center (Chicago, IL); University of Louisville (Louisville, KY); Massachusetts General Hospital (Boston, MA); University of Massachusetts (Worcester, MA); University of Missouri (Kansas City, MO); State University of New York Buffalo (Buffalo, NY); Cornell University (Ithaca, New York); New York Presbyterian Hospital (New York, NY); New York University (New York, NY); Case Western Reserve University (Cleveland, OH); University of Oklahoma (Tulsa, OK); University of Pittsburgh (Pittsburgh, PA); University of Pennsylvania (Philadelphia, PA); Baylor College of Medicine (Houston, TX); University of Texas San Antonio (San Antonio, TX); and Howard University (Washington D.C.).

References

1. Perlis RH, Ostacher MJ, Patel J, Marangell LB, Zhang H, Wisniewski SR, Ketter TA, Miklowitz DJ, Otto M, Gyulai L, Reilly-Harrington N, Nierenberg A, Sachs GS, & Thase M. (2006). Predictors of recurrence in bipolar disorder: Primary outcomes from the Systematic Treatment Enhancement Program for Bipolar disorder (STEP-BD) . The American Journal of Psychiatry, 163:2, 217-224.

2. Nierenberg AA, Ostacher MJ, Calabrese JR, Ketter TA, Marangell LB, Miklowitz DJ, Miyahara S., Bauer MS, Thase ME, Wisniewski SR & Sachs GS (2006). Treatment-Resistant Bipolar Depression: A STEP-BD Equipoise Randomized Effectiveness Trial of Antidepressant Augmentation with Lamotrigine, Inositol, or Risperidone . The American Journal of Psychiatry, 163:2, 210-216.

3. Sachs GS, Thase ME, Otto MW, Bauer M, Miklowitz D, Wisniewski SR, Lavori P, Lebowitz B, Rudorfer M, Frank E, Nierenberg AA, Fava M, Bowden C, Ketter T, Marangell L, Calabrese JR, Kupfer D,. & Rosenbaum, JF. (2003) Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD) . Biological Psychiatry, 53: 1028-1042.

For more information on STEP-BD, visit