| 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:
- Stephen Wisniewski, Ph.D., University of Pittsburgh
- Andrew Nierenberg, M.D., Massachusetts General Hospital
- Diane Warden, Ph.D., University of Texas Southwestern Medical Center
- Louise Ritz, M.B.A., NIMH
- Grayson Norquist, M.D., University of Mississippi
- Robert Howland, M.D., University of Pittsburgh
- Barry Lebowitz, Ph.D., University of California, San Diego
- Patrick McGrath, M.D., Columbia University
- Kathy Shores-Wilson, Ph.D., University of Texas Southwestern Medical Center
- Melanie Biggs, Ph.D., University of Texas Southwestern Medical Center
- G.K. Balasubramani, Ph.D., University of Pittsburgh
- Maurizio Fava, M.D., Massachusetts General Hospital
Q&As for more information on the Star-D study:
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.
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Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov. |
