STAR*D Study

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STAR*D Study

Study objectives

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study was the largest national trial ever designed to determine which treatments work best in people with major depressive disorder (MDD) who have not responded to an antidepres-sant. MDD is characterized by feelings of persistent sadness, worthlessness, guilt, and lack of interest in daily activitiessevere enough to interfere with daily activities.

The goal of the study was to help doctors better understand how to treat depression. Previously, the medical literature had provided doctors with little guidance on which treatments to use on their patients who do not respond to initial treatments. The STAR*D study was designed to help doctors learn which treatment plans (including medication dose and duration) are most effective for improving symptoms in patients with chronic depression and have the fewest side effects. The study also may enable doctors to determine how long they should attempt one therapy before moving on to another type of treatment. And, STAR*D provided information about the risk of relapse , which is defined as the return of depressive symptoms.

Description

The STAR*D study was a six-year, $65 million-effort funded by the National Institute of Mental Health. It involved more than 4,000 participants, ages 18 to 75 years, with chronic or recurrent major depression. The patients were being or were about to be treated for depressive symptoms at primary care or psychiatric facilities. Major depression is of significant concern to doctors, because it can lead to significant functional impairment and mortality.

To reflect real-life treatment situations, STAR*D was conducted at private practices and public clinics, rather than in universities or other research facilities. Also, participants were able to choose their own range of treatments. Researchers selected drugs that were the safest, easiest to take, and most commonly used, so the results could immediately be applied to clinical practice.

Researchers

The study was led by Dr. John Rush of the University of Texas Southwestern Medical Center. The following 13 other research centers also participated in the trial:

Clinical Research Institute—Kansas
Laureate Psychiatric Hospital & Clinic
Massachusetts General Hospital
New York State Psychiatric Institute
Northwestern University
Oklahoma Tuscaloosa VA Medical Center
University of California at Los Angeles
University of California at San Diego
University of Michigan
University of North Carolina at Chapel Hill
University of Pittsburgh
Vanderbilt University
Virginia Commonwealth University

Participants

More than 4,000 participants were initially involved in the study. The average age was 41 years. About 64% of participants were female, and 36% were male. About 76% were Caucasian, 18% were African American, 13% were Hispanic, and 6% were of other races.

Participants were either being treated for depression or were entering into treatment at 41 primary care and psychiatric clinics throughout the United States. All of those involved in the study had moderate to severe depression. Seventy-five percent had had two or more depressive episodes in their lifetime. The other 25% were currently experiencing an episode of depression that had lasted for at least two years.

The STAR*D study had broader participation than most studies of its kind. However, people with schizophrenia, schizoaffective disorder, bipolar disorder , an eating disorder, obsessive-compulsive disorder , or a substance abuse problem were not eligible for the study. Also, those who were already participating in cognitive-behavioral therapy or who were taking psychotropic medications could not participate.

Out of the 4,041 initial participants who entered Level 1 of STAR*D, 1,438 progressed to Level 2, 376 entered Level 3, and 108 moved on to Level 4 (see level descriptions below). Participants left the program because they entered remission, or they desired to leave the program because of side effects, or the opted to leave for personal reasons.

Assessments

At the first visit, participants met with a trained Clinical Research Coordinator (CRC), who had no knowledge of the treatment they were receiving. The CRC asked the participants about the following:

history of depression symptoms
family history of MDD, bipolar disorder, or alcohol and substance abuse
duration of current depressive episode
treatment history for the current depressive episode
past and current substance abuse
history of suicide attempts
current mental illnesses

The CRC also rated the participants’ symptom severity using established psychological scales. Patients completed self-questionnaires to determine their psychiatric disorders and depression score. Participants were later given phone interviews by a computer-based voice response system to ascertain their functioning and quality of life.

At doctor visits, the participants were evaluated for medication effectiveness and side effects. The STAR*D researchers also evaluated the patients to determine whether a change in dosage was necessary.

Treatments

The treatments used in STAR*D were the same as those typically used by doctors to treat clinical depression. Participants received only active medications; no placebos were used.

The following medications were used in the STAR*D study:

bupropion SR (Wellbutrin SR)
buspirone (BuSpar;)
citalopram (Celexa)
lithium (Eskalith, Lithobid)
mirtazapine (Remeron)
nortriptyline (Pamelor, Aventyl)
sertraline (Zoloft)

tranylcypromine (Parnate)
triiodothyronine (T3, Cytomel)
venlafaxine XR (Effexor XR)

The study included four treatment levels, each of which could continue for up to 14 weeks. Participants progressed to the next level when their symptoms did not respond to the current treatment.

The four levels were as follows:

Level 1: All participants received the antidepressant citalopram (brand name, Celexa). Citalopram is a selective serotonin reuptake inhibitor (SSRI). It works by interfering with the ability of nerve cells in the brain to take up the neurotransmitter, serotonin. This neurotransmitter has been associated with symptoms of depression.
Level 2: Participants who did not become symptom-free, or who experienced side effects on citalopram, had a choice of seven different treatment options. Four options involved taking either a new medication or engaging in cognitive behavioral therapy. The other three options added a new medication or cognitive behavioral therapy to the citalopram participants were already taking. All treatments were randomly chosen from those that the participant had deemed acceptable.
Level 3: Participants who did not become symptom-free at the previous level were allowed to try one of four other treatment options. They could switch to therapy with either nortriptyline or mirtazapine, or continue taking their current antidepressant along with either lithium or triiodothyronine.
Level 4: Participants who did not become symptom-free at the previous level were randomly assigned to take either tranylcypromine or a combination of venlafaxine and mirtazapine.

Once participants went into full remission, in which they no longer experienced symptoms of depression, they began a 12-month follow-up process.

Outcomes

The results of the STAR*D study were published in medical and scientific journals in 2006. Outcomes included measures of depressive symptoms, social function, and patient satisfaction.

Researchers found that remission rates were about 37% for participants in Level 1, 31% in Level 2, and 13% in Levels 3 and 4. However, some patients dropped out of the study early.

Overall, the findings suggested that more than half of patients who stay in treatment for one or two

KEY TERMS

Cognitive behavioral therapy —A type of treatment for depression that helps patients identify the negative thoughts that led to their behaviors, so that they can change those behaviors.

Major depressive disorder (MDD) —A psychiatric condition characterized by feelings of persistent sadness, worthlessness, guilt, and lack of interest severe enough to interfere with daily activities.

Placebo —An inactive pill or liquid that is made to resemble an active medication. Placebo is often used in research studies to compare the effects of real medications.

Psychotropic medications —Drugs, such as antide-pressants and antipsychotics, that are used to treat depression and other psychiatric conditions.

Relapse —The return of symptoms after treatment.

Remission —The absence of symptoms of a medical or psychiatric condition, often after treatment.

Selective serotonin reuptake inhibitor (SSRI) —A drug used to treat depression that interferes with the ability of nerve cells in the brain to take up the neurotransmitter, serotonin. This neurotransmitter has been linked to feelings of depression.

steps will achieve remission. But those patients who do not respond after two different treatment courses have a much lower chance of remission, and a higher risk of relapse.

Resources

BOOKS

Appleton, William S. The New Antidepressants and Antian-xieties. New York, NY: Plume, 2004.

Beers, Mark H. The Merck Manual of Medical Information. 2nd Home Edition. New York, NY: Pocket, 2004.

McCullough, James P. Jr. Treating Chronic Depression with Disciplined Personal Involvement: Cognitive Behavioral Analysis System of Psychotherapy (CBASP), first edition. New York, NY: Springer, 2006.

Pettit, Jeremy W., and Thomas E. Joiner.Chronic Depression: Interpersonal Sources, Therapeutic Solutions, Washington, DC:American Psychological Association, 2005.