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The National Institute of Mental Health (NIMH) has released the initial results of the largest clinical trial for depression. The trial allowed researchers to track individuals who became symptom-free and to identify those with treatment resistant depression. The trial, known as STAR*D (Sequenced Treatment Alternatives to Relieve Depression) lasted for 6 years and included 2,876 participants in 41 treatment locations throughout the United States.
The goal of STAR*D was to assess the effectiveness of adequately delivered treatments in real world patients with major depressive disorder and included four levels of treatment. All participants began at Level 1 and were prescribed citalopram. If it was later determined that the individual could not tolerate the side effects, or were not found symptom free after 9 weeks of treatment at full dosage they were allowed to move to Level 2 where they would then try another medication.
The main purpose of the STAR*D study was to identify the best next steps for individuals with depression who need to try more than one treatment. The initial Level 1 results showed that almost a third of participants reached remission, with an additional 10-15 percent experiencing some improvement. The subsequent levels of the study will assist in determining the most successful treatment in those with treatment resistant depression.
The final goal of STAR*D is to prepare protocols for use in routine practice that will allow clinicians to better treat individuals with major depressive disorder by creating more personalized treatment.
January 1, 2006
Initial Results Help Clinicians Identify Patients With Treatment-Resistant Depression
Initial results of the nation’s largest clinical trial for depression have helped clinicians to track “real world” patients who became symptom-free and to identify those who were resistant to the initial treatment. Participants treated in both medical and specialty mental health care settings experienced a remission of symptoms in 12 to 14 weeks during well-monitored treatment with an antidepressant medication. The study, funded by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH), used flexible adjustment of dosages based on quick and easy-to-use clinician ratings of symptoms and patient self-ratings of side effects.
About a third of participants reached a remission or virtual absence of symptoms during the initial phase of the study, with an additional 10 to 15 percent experiencing some improvement. Subsequent phases of the trials will help determine successful treatments for the nearly two thirds of those patients who were identified as treatment-resistant to a first medication in phase one.
The trial, known as the STAR*D study- Sequenced Treatment Alternatives to Relieve Depression- included 2,876 participants and was conducted over six years at a cost of $35 million. (For more information on STAR*D, go to: http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1).
The medication used in this first phase of the study was the serotonin reuptake inhibitor (SSRI) citalopram (Celexa, made by Forest Pharmaceuticals), and response rates were comparable across the 23 psychiatric and 18 primary care treatment sites. John Rush, M.D., and Madhukar Trivedi, M.D., of the University of Texas Southwestern Medical Center (UTSMC), and colleagues report on the results of phase 1 of STAR*D in the January, 2005 American Journal of Psychiatry.
"The real goal of STAR*D is how best to help the 70 percent of patients for whom treatment with a representative SSRI is not enough for remission," said NIMH Director Thomas Insel, M.D. "As the results of subsequent levels of the trial are revealed in the coming months, we will learn the effectiveness of other treatment options."
In the first phase of STAR*D, being well-educated, employed, married, white and female, with few complicating problems, were factors associated with a better antidepressant response. Factors associated with a poorer response included co-occurring anxiety, substance abuse or physical disorders, and lower quality of life.
This study is an effectiveness trial, which typically asks tougher questions than traditional efficacy trials, which measure only the reduction of symptoms. Effectiveness trials, which measure symptom reduction and patient function, also take into account the often untidy realities clinicians face. For example, if a patient is not responding adequately to an initial medication in 4 or 6 weeks, what is the next best treatment option?
Beyond just judging safety and efficacy, STAR*D measured practical outcomes, including, in subsequent phases of the study, how well the individual is actually functioning- even a year later. The goal of the trial was remission. People who become symptom-free generally function better and are less prone to relapse. Efficacy trials normally seek only a reduction in symptoms.
"These trials match the NIMH vision of developing personalized care," explained NIMH Director Dr. Thomas Insel in an accompanying editorial. "By beginning to identify which particular treatment benefits which patient, the STAR*D trial takes us a little closer to realizing this vision for non-psychotic depression."
While efficacy trials typically compare a drug with placebo (inactive pill) for only 8 weeks and exclude patients with complicating or chronic problems, STAR*D compared several active treatments, including a psychotherapy, over much longer periods, and welcomed a broad spectrum of patients with co-occurring drug, alcohol and physical health disorders, or a history of suicide attempts. Instead of recruiting volunteers through ads to research clinics, STAR*D enrolled patients already seeking help in the 41 participating clinics nationwide.
Representative of national ethnic and socioeconomic populations, the study participants were outpatients ages 18-75 who scored high enough on a standard depression rating scale to be diagnosed with major depression. They included some of the most chronic patients with depression. More than a third of the participants were under age 18 when they first experienced depression, 75 percent had at least two episodes of depression, and for 25 percent the current episode of depression had lasted for at least two years.
Clinicians adjusted dosages of citalopram during five to six visits at two to three week intervals, based on a treatment manual and quick and easy-to-use symptom ratings and patient and side-effect ratings. The researchers collected depression ratings and other data by phone, including an automated interactive voice response system.
"Self-rating scales are no longer just research tools," said Rush. "An easy-to-use patient-rated scale proved to be as accurate as the standard depression scale, so the time is ripe for practitioners to begin using them as part of systematic assessments to guide routine treatment. Our results also suggest that to achieve remission, some patients may need to stay in treatment longer and take somewhat higher antidepressant dosages, as warranted by their individualized assessments."
The results were corroborated by "remarkably consistent findings" across both standard and patient-rated depression rating scales, note the researchers. On average, it took patients six to seven weeks of treatment to reach “remission” of their depressive symptoms. The average number of visits for those successfully treated participants was between five and six, with 40 percent of participants who eventually became symptom-free requiring eight or more weeks of treatment (when most efficacy trials normally end). Almost all of the participants who became symptom-free continued on their treatment for over eight weeks, many for 12 weeks.
The 30 percent remission rate is similar to those seen in uncomplicated, non-chronic volunteers enrolled in SSRI efficacy trials. However, efficacy trials with chronic patients more like the STAR*D patients typically produce only a 22 percent remission rate. Again, the researchers attribute this better than expected remission rate to the systematic and comprehensive approach to care, which enlists the patient as a collaborator by providing tools for self-monitoring.
Patients who did not achieve remission or did not tolerate citalopram were invited to participate in phase 2 of STAR*D, in which the drug was either augmented or replaced by other treatments, including cognitive therapy. People who still did not improve sufficiently could enroll in to two additional levels. The researchers followed up successful responders for a year to monitor each treatment’s long-term outcomes.
"Tools used in research settings (depression rating scales, etc.) are not routinely used in practice, which may contribute to the high rates of inadequate treatment with antidepressant medications in routine care," suggest Trivedi, Rush and colleagues. "Our results also suggest that the use of depressive symptom and side effect ratings to guide treatment is feasible in "real world" practices as well as effectiveness trials and can be used to monitor patient progress, to adjust the treatment, and to make clinical decisions."
Other study authors include:
NIMH is part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.