Findings from the latest phase of the National Institute of Mental Health's
STAR*D (Sequenced Treatment Alternatives to Relieve Depression)
study indicate that patients who require multiple antidepressant drug trials
to reach remission not only have significantly higher rates of relapse but
also relapse sooner, compared with patients who require only one or two drug
trials. Nonetheless, with persistence, about two-thirds of people with
depression can reach remission if they are willing to try different
This latest report, which appeared in the November American Journal of
Psychiatry, is the 38th article on STAR*D published in
peer-reviewed journals. It details the outcomes of the series of acute
treatment steps that patients took to be well enough to progress to follow-up
or maintenance treatment. Because the report connects acute treatment outcomes
to longer-term prognosis in a well-characterized patient population of more
than 3,600 patients, it may end up being one of the most important ever
published on the treatment of major depression.
The STAR*D protocol consisted of a series of four randomized
controlled treatment trials (each referred to as a "treatment
step") with outpatients who met DSM-IV criteria for
nonpsychotic major depressive disorder. Remission was the goal of each step,
defined as a score of less than or equal to 5 on the Quick Inventory of
Depressive Symptomatology—Self Report (QIDS-SR16) equivalent
to a score of less than or equal to 7 on the 17-item Hamilton Depression
Rating Scale. If patients did not achieve remission by the end of the 14-week
step or could not tolerate a treatment step, they were encouraged to proceed
to the next acute treatment step.
Those who achieved remission and tolerated their acute treatment could
enter a 12-month naturalistic follow-up phase, as could those with "at
least a meaningful improvement and acceptable tolerability." During the
follow-up phase, relapse was defined as a QIDS-SR16 of equal to or
greater than 11.
The study was conducted at 41 clinical sites; 18 provided primary care,
while 23 provide psychiatric care. The results of the successive treatment
steps have been reported previously (Psychiatric News, January 20,
April 21, July 7, September 15).
In the latest report, researchers consolidated an enormous amount of data
on 3,671 patients who entered the protocol at the first step and their
subsequent quest for remission through the four potential treatment steps.
All patients started the study in step 1, taking citalopram (Celexa). Those
who did not do well on citalopram could progress to step 2, which involved
either switching to a different antidepressant or augmenting citalopram with a
second drug. For those who still were not well enough to enter follow-up, step
3 again offered a switch to a different antidepressant or augmentation of the
patients' step 2 drug regimen. Step 4 offered a final opportunity to switch
medications or augment a patients' step 3 regimen. Each of the individual
steps in the protocol lasted for up to 14 weeks, and the follow-up phase of
the study lasted for 12
The STAR*D team found a couple of unexpected results that were"
counterintuitive," said A. John Rush, M.D., in an interview. Rush
is STAR*D's principal investigator and a professor of psychiatry
and Distinguished Chair in Mental Health at the University of
Texas—Southwestern Medical Center in Dallas.
"First, the proportion of patients who took multiple treatment steps
was not really different between primary care sites and psychiatric
sites—which is a very good finding. Most would have thought patients at
psychiatric treatment sites would have fared better. Second, ethnic minorities
have often been characterized as potentially more likely to leave treatment
early, have higher levels of noncompliance, and higher levels of
treatment-resistance. Again, we didn't find any significant differences
between groups with different races or ethnicities [with respect to the
average number of treatment steps taken to enter
"It's a sort of good-news, bad-news thing," said Rush."
This report can basically be broken down into three domains, each
looking at a specific question: Who are the people who seem to require more
treatment steps? What is the benefit achieved from multiple acute treatment
steps? And what is the longer-term outlook in relation to different numbers of
acute treatment steps?"
Regarding the first question, he continued, empirical data are now
available that can help identify patients who may require more treatment steps
to reach remission. Those data largely validate what clinicians and
researchers have suspected for many years.
"We found that patients with more severe depression, greater general
medical or psychiatric comorbidity, and chronicity made up the group that
needed more treatment steps" to reach follow-up—either by
achieving remission or at least a meaningful improvement with acceptable
tolerability, Rush said. "So, the more problems you enter treatment
with, the more steps you'll likely need."
Moreover, Rush pointed out, the patients who took more steps to enter
follow-up were significantly less likely to be in full remission when they
entered the follow-up phase of their treatment, compared with the patients who
took only one or two steps.
This finding shouldn't surprise anyone, said Rush, but it is the first time
that it's been demonstrated in depression.
"With most patients who have other chronic medical
disorders—for example, heart failure—you see the same decline in
outlook. The tougher-to-treat patients take more treatment steps, and since
they are tougher to treat, it is likely that outcomes will not be as good with
later treatment steps."
Another significant finding, Rush said, is the mean number of weeks
patients remained in a treatment step (range: 8.6 to 10.1).
"These patients were treated for a significant period of time,"
Rush said. "This wasn't a typical four- or six-week clinical trial. In
addition, we were looking for remission, not just response."
The study design was based on the principle that an adequate dose of a
given medication needs to be tried for an adequate period of time in order to
determine the drug's effectiveness, and the results validate this principle as
a model for clinicians to follow. "otherwise," Rush noted,"
you could be throwing away a treatment that the patient may have
benefited from, just in the interest of time."
Dosing of medications in STAR*D was flexible, but guided by a
requirement to measure symptoms and side effects at each clinical visit. On
the basis of those measurements, study physicians were strongly encouraged to
increase the dose for a patient who had not achieved full benefit, as long as
the patient was not experiencing any intolerable side effects.
"Dosing was pretty vigorous," Rush said, "and might be a
bit more vigorous than you would find in routine practice."
The bottom line of the acute-outcomes data, Rush said, is that over the
four acute treatment steps, 67 percent of the patients achieved remission."
That's a pretty good overall outcome, but it assumes that everyone
stays in treatment as long as it takes to reach remission—it assumes no
In the follow-up phase, the STAR*D protocol recommended that
patients continue their previously effective acute treatment medication(s) at
the doses used during acute treatment.
The most important finding from the follow-up phase of the study, Rush
said, is "that the more steps a patient has to take to be well enough to
go into follow-up, the worse the longer-term prognosis is."
For example, he said, after six months of follow-up, about 65 percent of
patients who entered follow-up from step 1 remained well (while about 35
percent had relapsed). In contrast, at the six-month follow-up, only about 53
percent of patients from step 2 remained well, compared with less than 40
percent of those from either step 3 or step 4 (see chart).
"This is very discouraging," Rush continued. "After
working hard through multiple steps, the patient is finally well enough to
enter follow-up, then the medication that got them well enough to begin with
doesn't keep them well over the longer-term."
Usually, he continued, "when people talk about treatment resistance,
they are referring to not being able to get the patient well enough to begin
with. But now we need to expand our thinking on what constitutes treatment
resistance. Now we've got a second issue—of not being able to keep the
There is also something else implicit in the survival curves, Rush said. In
step 1, two-thirds of patients entering follow-up were in remission, whereas
only one-third of patients entering follow-up from steps 3 or 4 were in
"We now see some evidence," Rush theorized, "that the
more steps [needed] to get to follow-up, the more likely it may be that the
doctor and the patient are accepting something short of remission, a sort of
`this is as good as it gets.'"
The patient, he continued, may be thinking, `Well, I've tried really hard
over a long period of time, and yes, I am a whole lot better. But, even if I'm
not completely in remission, let's not risk changing anything.'"
However, settling for less than remission may not be a good decision over
"[P]eople who entered [follow-up] in remission had a significantly
better long-term result—that is, in avoiding relapse—compared with
those who went into follow-up not in remission," Rush explained.
So, the take-home message, Rush emphasized, is that a positive longer-term
prognosis for patients with depression is dependent on achieving and
sustaining full remission, regardless of how many treatment steps it takes to
"It also tells us," Rush added, "we must be more vigilant
with patients who are in follow-up, especially [with] those who have required
several steps to get there."
Nonetheless, over the longer term, the STAR*D results confirm
that major depression is a chronic, remitting-relapsing disorder. They also"
highlight the need for more effective short- and longer-term
treatments, to both achieve and sustain remission in more patients earlier in
their treatment sequence."
"Acute and Longer-Term Outcomes in Depressed Outpatients
Requiring One or Several Treatment Steps: A STAR*D Report" is