Questions and Answers for the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Study — Background

March 2007

1. What is the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Study?

A. STEP-BD is the largest, federally-funded treatment study ever conducted for bipolar disorder¹. It is a long-term outpatient study that enrolled 4,360 participants from 22 sites over seven years (1998 to 2005). STEP-BD was designed to find out which treatments, or combinations of treatments, are most effective for treating episodes of depression and mania and for preventing recurrent episodes in people with bipolar disorder. STEP-BD is different from typical clinical trials that test one potential new treatment. It is a broad research program that includes several different studies, each aimed at a different aspect of treatment for the illness.

Multiple treatments, including medications and psychotherapies, currently are available for people with bipolar disorder, but doctors are often uncertain which of these treatments actually work best for specific aspects of the illness.² STEP-BD’s size, scope and broad criteria for inclusion of participants will make its findings relevant to all patients seeking the most effective care for the disorder, and provide much needed information to help doctors choose treatments for the everyday care of those with the disorder.

2. How is the STEP-BD study different from other treatment studies of bipolar disorder?

A. STEP-BD differs from traditional bipolar disorder clinical trials in several important ways. Because the main goal of STEP-BD is to improve treatment and outcomes for all people with bipolar disorder, it was designed as a large-scale, public health study that included real-world patients contending with multiple mental and/or physical illnesses who are seeking care in their own communities. Most other clinical research studies exclude people with co-existing disorders, thus limiting those studies’ real-world applicability.

In addition, STEP-BD was long-term. In most clinical trials, individuals are usually asked to participate for a relatively short period of time (e.g., 8-12 weeks), and receive only one of a few treatments being studied. In contrast, STEP-BD offered participants long-term continuity of care. Once enrolled, participants could receive care for as long as they were in the program — up to five years — and were monitored systematically, even when they were feeling well.

STEP-BD also assessed participants’ “clinical status” every three to six months at a minimum for as long as they were in the program, a different process from other bipolar illness clinical studies in which a treatment’s success may be measured with only a single measurement at one point in time. At each follow-up, participants were determined to be recovered, recovering, continuing to have residual symptoms, or in a full mood episode (depression, mania, hypomania, or mixed). Finally, unlike other trials, doctors participating in STEP-BD were extensively trained in the use of evidence-based treatments to become “STEP certified.” STEP-BD’s rigorous treatment and measurement process, known as the Best Practice Pathway, allowed clinicians to evaluate their patients’ full range of symptoms and monitor the course of the illness.

If participants experienced a change in clinical status, such as a depressive episode, they could choose to enter a STEP-BD “randomized controlled clinical trial.” The randomized controlled clinical trials of STEP-BD were designed to answer a specific treatment question using traditional clinical trials methodology. Regardless of the outcome of care within the randomized controlled trials, participants could remain in STEP-BD and under the care of their STEP-BD clinician.

3. What treatments did each participant receive in the STEP-BD program?

A. STEP-BD aimed to determine which treatments or combination of treatments are most effective for treating episodes of depression and mania and for preventing recurrent episodes. STEP-BD assessed the outcomes of many of the most established treatments used for bipolar disorder, including; mood-stabilizing medications; antidepressants; atypical antipsychotic medications; and standardized psychosocial interventions that included family-focused treatment, interpersonal and social rhythm therapy, and cognitive behavioral therapy, all of which were compared to a brief psychosocial control treatment. All psychotherapy treatments were geared toward helping participants and their families better understand the disorder, develop coping strategies and stick to treatment plans, and were always given in conjunction with medication treatment. Medication and dosing recommendations were derived from published, evidence-based treatment guidelines.

Best Practice Pathway treatments

Best Practice Pathway participants, all of whom were age 15 and older, received individualized care based on their symptoms, past history, medical conditions, and other factors. Most received mood-stabilizing (anti-manic) medication and, where necessary, additional medications as indicated by best practices guidelines. Participants and their doctors worked together to decide on the best treatment plan, and changed these plans if needed. Those wishing to stay on their current treatment plan upon entering STEP-BD could also do so in this pathway.

Randomized Trials

Participants in the Best Practice Pathway who were 18 years and older could enter a STEP-BD randomized clinical trial if they met certain eligibility requirements. The largest randomized trial studied treatment options for the acute depressive episode and included both medication and psychotherapy. In the randomized trials, participants were never assigned medications to which they had bad reactions in the past, that they were strongly opposed to, or that the doctor felt was unsuitable for them. Participants in the randomized trials could return to the Best Practice Pathway for their treatment at any time.

Having both a Best Practice Pathway and randomized clinical trials allowed the researchers to compare outcomes from each trial (all of which focused on a specific research question) with outcomes from those who remained in the Best Practice Pathway. This is important because it gave researchers an opportunity to understand if the results might differ for subjects willing to accept treatment assigned at random under double — blind conditions, versus those who might find such treatment unacceptable.

4. How were placebos used in STEP-BD?

A. Participants in STEP-BD received at least one type of active mood stabilizing medication throughout the study; at no time were participants ever medication-free. However, in the double-blind randomized clinical trial involving the use of antidepressants to treat bipolar depression, placebo (in combination with mood stabilizing medications) was used as a control. Participants, all of whom continued to take a mood stabilizing medication, were randomized to either an antidepressant as an adjunctive, or to a placebo as an adjunctive. The trial aimed to determine if the adjunctive antidepressant was more effective than a mood stabilizer by itself in treating bipolar depression.

5. Who participated in STEP-BD?

A. Overall, 4,360 individuals were enrolled in STEP-BD. All had a diagnosis of bipolar disorder. STEP-BD also included individuals with other co-existing psychiatric disorders (such as anxiety disorders or personality disorders) and/or physical illnesses.

Throughout their involvement in the study, participants met with their STEP-BD doctor for periodic evaluations and/or treatment adjustments. These visits were more frequent earlier in the study, or when a new treatment was added. Participants also completed various self-evaluation forms during the study. However, participants could decline to answer any questions, and could remain in the study even if their participation was inconsistent

Because STEP-BD was designed to manage and evaluate participants’ long-term outcomes, the research program was active for seven years, and participants were involved for as long as they wanted during this time. Those participants who were involved in any randomized studies and who responded well to their treatment were asked to stay on that study medication for up to six months. Participants could return to the Best Practice Pathway for continued individualized treatment and monitoring after that.

6. How will STEP-BD help doctors care for people with bipolar disorder?

A. Researchers are using the extensive data from STEP-BD to ask multiple, sharply focused research questions, such as how best to treat individuals with various expressions of the disorder (e.g., manic, mixed, or depressive episodes, rapid cycling, bipolar II vs. bipolar I disorder) and prevent recurrence. Other research questions include evaluating the special needs of women with the disorder, and evaluating treatment outcomes for those with co-occurring medical or mental illnesses. STEP-BD researchers will also evaluate how treatments affect a person’s quality of life, such as social functioning and the ability to work; the cost-effectiveness of the combinations of treatments; and factors that affect a person’s continued use of each treatment. Therefore, many different findings have and will be published, as researchers analyze available data. For a list of findings published to date, see Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) 

7. Who provided the medication for the study?

A. STEP-BD medications used in the Best Practice Pathway were paid for by participants through their own individual insurers and/or out of pocket. In the randomized controlled clinical trials, medications were provided to participants free of charge. These medications were donated by the following pharmaceutical companies:

• Lithium (Lithobid) - Solvay Company
• Valproate (Depakote) - Abbott Laboratories
• Bupropion (Wellbutrin) - Glaxo-Smith Kline
• Paroxetine (Paxil) - Glaxo-Smith Kline
• Lamotrigine (Lamictal) - Glaxo-Smith Kline
• Risperidone (Risperdal) - Janssen Pharmaceuticals
• Omega 3 (DHA) - Martek Biosciences

Pharmaceutical companies were invited to provide feedback on the recommended dosing of their own medications. However, the pharmaceutical companies had no input into the design or implementation of the study, planning or conducting of the data analyses, or preparation of manuscripts for publication.

8. What other information will doctors and patients be able to learn from STEP-BD in the future?

A. STEP-BD has collected DNA from more than 2,300 participants. This genetics repository, which will be the largest DNA collection to be used exclusively for studying bipolar disorder, will be used along with the clinical data to study how genes may affect bipolar disorder. It also may help us predict who will respond best to what treatment, and lead to more personalized care.

In addition, a STEP-BD-related genetics project, a type of patient registry called the Family Association Study, is ongoing. Researchers are collecting blood samples from biological parents and siblings of the STEP-BD genetics participants. These samples will be used to help identify genes that contribute to bipolar disorder. The STEP-BD dataset will make a significant contribution to the field of bipolar treatment research.

9. Where was the study conducted?

A. After a competitive, peer-reviewed process, NIMH selected the Massachusetts General Hospital in Boston, MA to implement the STEP-BD study. The trial was led by Dr. Gary S. Sachs of the Massachusetts General Hospital and Harvard Medical School, with the help of Dr. Michael E. Thase of the University of Pittsburgh Western Psychiatric Institute and Clinic, and Dr. Mark S. Bauer of the Providence Veterans Affairs Medical Center and Department of Psychiatry and Human Behavior, Brown University. The Epidemiology Data Center at the University of Pittsburgh, led by Dr. Stephen R. Wisniewski, collected and analyzed the study data.

Over the course of the seven years of the study, 22 research centers around the United States enrolled and treated participants. Thirteen centers participated for the majority of the active project, and participants from these centers comprise 90 percent of the total number enrolled.

• Baylor College of Medicine; Houston, TX
  Principal Investigator, Lauren B. Marangell, MD
• Case Western Reserve University; Cleveland, OH
  Principal Investigator, Joseph R. Calabrese, MD
• University of Colorado Health Sciences Center; Denver, CO
  Principal Investigator, Michael Allen, MD
• University of Louisville School of Medicine; Louisville, KY
  Principal Investigator, Rif El-Mallakh, MD
• Massachusetts General Hospital and Harvard School of Medicine; Boston, MA
  Principal Investigator, Andrew A. Nierenberg, MD
• University of Massachusetts Medical School; Worcester, MA
  Principal Investigator, Jayendra Patel, MD
• University of Missouri School of Medicine; Kansas City, MO
  Principal Investigator, Kemal Sagduyu, MD
• University of Oklahoma College of Medicine - Tulsa; Tulsa, OK
  Principal Investigator, Mark D. Fossey, MD
• University of Pennsylvania School of Medicine and Medical Center; Philadelphia, PA
  Principal Investigator, Laszlo Gyulai, MD
• University of Pittsburgh Western Psychiatric Institute and Clinic; Pittsburgh, PA
  Principal Investigator, Michael E. Thase, MD
• Portland Veteran’s Administration Medical Center; Portland, OR
  Principal Investigator, Peter Hauser, MD
• Stanford University School of Medicine; Stanford, CA
  Principal Investigator, Terence A. Ketter, MD
• University of Texas Health Science Center at San Antonio, San Antonio, TX
  Principal Investigator, Charles Bowden, MD

Additional centers involved in STEP-BD were: Howard University, Washington DC; Rush-Presbyterian St. Luke’s Medical Center, Chicago, IL; State University of New York at Buffalo, Buffalo, NY; Weill Medical College of Cornell University and New York Presbyterian Hospital, NY, NY; New York University School of Medicine, NY, NY; University of California San Diego, La Jolla, CA; University of Arizona, Tucson, AZ; and Medical University of South Carolina, Charleston, SC.

Citations

1. 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, J, Kupfer, D, Rosenbaum, JF. Rationale, Design, and Methods of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Biological Psychiatry 2003, 53:1028-1042..

2. Kogan JN, Otto MW, Bauer MS, Dennehy EB, Miklowitz DJ, Zhang H, Ketter T, Rudorfer MV, Wisniewski SR, Thase ME, Calabrese J, Sachs GS. Demographic and diagnostic characteristics of the first 1000 patients enrolled in the Systematic Treatment Enhancement Program for bipolar disorder (STEP-BD) Bipolar Disorders 2004; 6: 460-469.