The latest round of results from the national institute of Mental Health's
STAR*D (Sequenced Treatment alternatives to relieve Depression)
trial underscore the difficult challenge clinicians and patients face with
depression that does not respond to an adequate course of antidepressant
Two new articles from STAR*D investigators, appearing in the
September American Journal of Psychiatry, detail the results from
levels 3 and 4 of the complex study. While far from encouraging, these reports
indicate that remission is still possible, even after a patient fails to
achieve the elimination of nearly all symptoms after taking as many as three
rounds of antidepressant therapy.
Perhaps more important, the collective reports from STAR*D's
four levels (see FIG1 below)
may provide clinicians and their patients with the study's greatest legacy: a"
road map" of sorts showing them how to navigate the multi-drug
route through depression treatment on the way to remission.
In an editorial accompanying the reports, Marcia valenstein, M.D., an
assistant professor of psychiatry at the University of Michigan School of
Medicine concludes that STAR*D "has provided important
evidence applicable to clinical decision making by ordering treatments by
relative efficacy or tolerability at specific therapeutic junctures."
However, future studies, she added, must build on STAR*D's
"The STAR*D program has provided the best quantitative
data available on the likely result of moving through a rational sequence of
treatments for patients who do not achieve remission from firstline SSri
treatment," said Darrel regier, M.D., M.P.H., director of APA's Division
of research and executive director of the american Psychiatric institute for
research and education.
"These additional studies show that some patients, unresponsive to
previous treatments, do eventually improve, thereby increasing overall
response and remission rates," regier told Psychiatric News.
according to the six reports of STAR*D results published to date
(more data remain to be analyzed and published), a total of 1,191 (41.5
percent) of the original 2,876 patients in the four-level STAR*D
analysis achieved remission.
The six-year, $35 million STAR*D project was designed to study
the types of patients most likely to be seen in everyday clinical practice:
those likely to have comorbid disorders, including additional medical
diagnoses and the possibility of more than one axis i disorder. The protocol
aimed to determine what the "next best steps" are for that
majority of depression patients (70 percent on average) who find either
inadequate relief or intolerable side effects with the first medication they
In the first of the two current AJP articles, STAR*D
investigator andrew nierenberg, M.D., an associate professor of psychiatry at
Harvard Medical School and Massachusetts General Hospital, and his colleagues
report on outcomes of patients in the augmentation pathway of the study's
Each of the 142 patients in the level 3 augmentation pathway had previously
failed to achieve remission or encountered unacceptable side effects with
12-14 weeks of citalopram monotherapy in level 1, and a second treatment
option in level 2.
To augment each patient's medication regimen from level 2, patients were
randomly assigned to one of two level 3 options: either lithium or
triiodothyronine (the thyroid hormone, T3). Treatment assignments and dosing
were not masked to participants or their treating clinicians, and dosing was
Lithium was chosen, the report noted, because of preclinical data
indicating that it increases the presynaptic formation, storage, and release
of serotonin. It is thought that lithium may have a synergistic effect on the
mechanism of action of serotonergic antidepressants. In addition, there is
limited clinical trial evidence that lithium is effective in augmenting the
therapeutic effects of tricyclic antidepressants.
There is also evidence that supplementation with thyroid hormone in
patients with depression may be useful in boosting antidepressant efficacy,
even if a patient's thyroid function is normal. Some have postulated that
supplementing T3 may desensitize inhibitory 5-HT1a receptors; directly affect
gene expression; and increase brain metabolism.
Patients in level 3 who had augmented citalopram with buspirone or
sustained-release bupropion in level 2 discontinued the augmenting agent
without tapering. Lithium or T3 was added to the patients' assigned level 2
Lithium was initiated at 450 mg per day, then increased after one week to
900 mg per day. T3 was initiated at 25 mcg per day for the first week, then
increased to 50 mcg per day. Patients were allowed to take anxiolytics and
sedative hypnotics, but other psychotropic medications were not permitted by
The primary outcome measure was remission, defined (throughout every level
of the protocol) as a score of 7 or less on the 17-item Hamilton Depression
Rating Scale (HamD-17). Baseline scores on the HamD-17 and other measures
indicated that the patients beginning treatment in level 3 on average"
had a moderate degree of symptom severity...[with] very poor life
satisfaction and function."
The overall mean duration of level 3 treatment was 9.6 weeks out of the
possible 14. Mean daily doses at exit were 860 mg for lithium and 45.2 mcg for
T3. Serum lithium levels were only obtained in 39 of 69
participants (57 percent) taking the drug, with the mean blood level being 0.6
meq/liter—on the low end of the recommended therapeutic range of 0.6
meq/liter to 1 meq/liter.
Overall, 15.9 percent of the group augmenting with lithium achieved
remission compared with 24.7 percent of those augmenting with T3.
There were no significant differences between the two groups taking the
different augmenting agents. In addition, no statistically significant
differences were found in the proportion of patients achieving remission based
on what level 2 agent they were augmenting.
Few participants experienced serious adverse events. More patients taking
lithium reported significant side effects compared with those taking
T3; however, the difference was statistically significant only for
the frequency, not intensity or burden, of side effects. Significantly more
patients taking lithium withdrew from the study because of side effects.
The researchers noted that the "modest remission rates observed with
lithium augmentation may have been due to the low doses used as a result of
limited toleration of side effects. Nevertheless, these results probably
reflect what clinicians can expect with lithium augmentation in actual
They concluded that the two augmenting agents were statistically effective,
yet noted that "T3 has slight [numerical] advantages over lithium in
effectiveness and tolerability. T3 also offers the advantages of
ease of use and lack of a need for blood level monitoring."
The second STAR*D article appearing in this month's
AJP, with Patrick McGrath, M.D., co-director of the Depression
Evaluation Service at New York State Psychiatric Institute as the lead author,
details outcomes of the 109 patients who entered level 4 of the protocol.
Each of these patients failed to achieve remission or was unable to
tolerate adverse events with their level 3 switch or augmentation protocol
In level 4, patients discontinued their previous antidepressant therapy and
were switched to either the monoamine oxidase inhibitor tranylcypromine or a
combination of venlafaxine-extended release and mirtazapine. Again, treatment
was open label.
Tranylcypromine was initiated at 10 mg per day for the first two weeks,
followed by increases of 10 mg per day each week until a target dose of 60 mg
per day was reached. All patients taking tranylcypromine completed a two-week
washout of their level 3 medications prior to their first dose in level 4.
For the combination treatment, venlafaxine XR was started at 37.5 mg per
day for the first week and titrated up to a target of 300 mg per day after
week eight. Mirtazapine was initiated at 15 mg per day and increased to 45 mg
per day after week eight.
McGrath and his colleagues reported that remission rates did not differ
significantly, with 7 percent of subjects taking tranylcypromine reaching
remission compared with 14 percent of patients taking the venlafaxine
XR/mirtazapine combination. However, the percentage of reduction in depressive
symptoms was significantly greater for patients taking the combination therapy
(25 percent compared with 6 percent for tranylcypromine.)
"Though remission rates were modest for either tranylcylpromine or
the combination treatment, the response to the medications was adequate enough
to justify either as a treatment alternative," McGrath said in a press
However, Valenstein noted in her editorial that "unless a drug
produces a very large benefit, its placement later in a trial sequence frames
much of the subsequent discussion. Drugs used later can be discussed only in
the context of `down-line' options." Yet, she added, those"
down-line" options in the study protocol should not be viewed as"
last resort" options.
While the full impact of the massive volume of STAR*D data will
not likely be determined for some time, many are hopeful the study will
advance the treatment of depression in multiple clinical settings.
Noting that 40 percent of STAR*D participants were followed in
their primary care settings, Frank DeGruy, M.D., a professor and chair of
family medicine at the University of Colorado Health Sciences Center, wrote in
a second accompanying editorial that "STAR*D and a few
confirmatory studies should make it possible for primary care clinicians
themselves to push care decisions to the third or fourth step before seeking a
However, rather than resulting in an overall decrease in consultation
between psychiatry and primary care, DeGruy added, the result would likely be"
the seeking of consultations for more complicated patients and even
more difficult problems."
Both articles, as well as the two accompanying editorials, are