A pair of new reports from the team crunching the data gathered during the
National Institute of Mental Health's STAR*D (Sequenced Treatment Alternatives
to Relieve Depression) study show that more than half of all patients
originally enrolled achieved remission with the second antidepressant they
The companion reports, published in the March 23 New England Journal of
Medicine, detail findings from the study's level 2, which followed
patients who did not achieve remission while taking citalopram (Celexa) during
STAR*D's level 1 protocol (Psychiatric News, January 20).
One-third of the 2,876 patients who entered level 1 of the study achieved
remission—the near absence of any depressive symptoms—and an
additional 10 percent to 15 percent were deemed responders.
However, when level 1 results were announced, the question left hanging in
the air was, What do you do with the remaining two-thirds of patients who do
not achieve remission with their first antidepressant? With the release of the
two level 2 reports, clinicians are closer to answering that question.
"These findings provide important treatment options to mental health
clinicians and millions of Americans who struggle with treatment-resistant
depression," Elias Zerhouni, M.D., director of the National Institutes
of Health, said in a press release.
"If the first treatment attempt fails, patients should not give
up," added Thomas Insel, M.D., director of the National Institute of
Mental Health. "By remaining in treatment and working closely with
clinicians to tailor the most appropriate next steps, many patients may find
the best single or combination treatment that will enable them to become
STAR*D, Insel noted, is "the largest trial ever done on
depression." The $35 million, six-year study was designed to address the
question of "how to successfully treat people who've not sufficiently
recovered after the first [antidepressant medication]." And in each
level of the four-stage study, Insel emphasized, "the goal was to find
treatments that help people get well, not just get better."
"The major message from level 2 of STAR*D," A. John Rush, M.D.,
professor and vice chair of research in psychiatry at the University of
Texas/Southwestern Medical Center in Dallas, said during a conference call for
the media announcing study results, "is that depressive symptoms can be
eliminated—that is, symptomatic remission can be achieved in over 50
percent of people who receive two treatment steps. One-third get well after
the first step. And results from this second step show that about 30 percent
of the two-thirds who are left [with significant symptoms] get well with the
second step. So the second step is nearly as effective as the first
That message, said Rush, who is the principal author on one of the New
England Journal of Medicine reports, is an important one for patients and
their clinicians. "It is important to not give up if the first treatment
fails or causes [intolerable] side effects."
Treatment in level 2 of STAR*D—a real-world effectiveness
trial—was offered to all patients who did not experience remission
during level 1 of the study, either because of lack of efficacy or because of
intolerable side effects. The 1,439 eligible patients who did not experience
remission during level 1 were offered seven treatment options within two arms
of the study. Patients were educated on the options and asked which options
were acceptable to them.
The first arm of level 2 involved patients discontinuing the citalopram
taken in level 1 of the study and switching to one of three antidepressant
medications (bupropion-SR, sertraline, or venlafaxine-XR) or to cognitive
The second arm involved patients continuing the citalopram through level 2
and augmenting the drug with a second (bupropion-SR or buspirone) or with
Only a few participants (21 out of 1,439, or 1.5 percent) said that all of
the choices were equally acceptable to them and gave consent to researchers to
assign them randomly to one of the seven possibilities. Each of the remaining
patients identified at least one of the possible treatments as being
unacceptable and therefore limited the possible treatments to which
researchers could randomly assign them.
A total of 727 patients entering level 2 (51 percent) chose options that
included switching to a different medication. Some 565 patients (39 percent)
chose options that included augmenting the citalopram they were already
taking. The remaining 147 patients (10 percent) chose options involving
cognitive therapy. (Results of the cognitive therapy options will be presented
in a future report.)
Rush and his coauthors reported that 25.5 percent of the patients switched
from citalopram to bupropion-SR achieved remission by the end of the 12 weeks
of level 2 treatment, compared with 26.6 percent of those switched to
sertraline, and 25.0 percent of those switched to venlafaxine. Rush and his
team found no statistically significant differences in efficacy, safety, or
tolerability between the groups switched to the three medications.
"No one medication was clearly better," Rush said. "Even
though these three treatments differ in how we believe they work in the
brain—that is, they have different pharmacologic mechanisms of
action—which treatment is used [as the second-step choice] may be less
important than [ensuring] that the drugs be used diligently and appropriately
with proper dose adjustments and careful measurement of symptoms and side
Importantly, Rush added, "Doctors should know that they should not
give up on a treatment after four weeks—which is currently common
practice." Nearly one-third of patients who achieved remission during
level 1 or 2 of STAR*D, Rush explained, did so after four or six weeks of
medication at adequate therapeutic doses. Average doses of the three
medications at the end of level 2 (week 12) were 283 mg/day of bupropion-SR,
136 mg/day of sertraline, and 194 mg/day of venlafaxine-XR.
The second arm of level 2, the augmentation study, found that both
medications were effective when added to concurrent citalopram therapy.
However, those results, reported by Madhukar Trivedi, M.D., a professor of
psychiatry at the University of Texas/Southwestern Medical Center, showed one
drug slightly edged out the other.
While both combinations produced roughly similar results as far as patients
achieving remission (39 percent with citalopram plus bupropion-SR, compared
with 32.9 percent with citalopram plus buspirone; not a statistically
significantly difference), patients who received citalopram augmented by
bupropion-SR experienced statistically significantly greater reductions in
depressive symptoms over the 12 weeks of the level 2 study, significantly
lower overall depression ratings at week 12, and fewer adverse effects leading
to discontinuation of the drug combination.
"Further research is clearly called for," Rush concluded,"
because we have to better learn how to match the individual treatments
to individual patients, and we have to learn how to predict what is the better
treatment from the outset."
Both STAR*D reports and an accompanying editorial can be accessed at<http://content.nejm.org/content/vol354/issue12/index.shtml>.
Patient self-report tools are posted at<www.star-d.org>.▪