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The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study evaluated feasible treatment strategies to improve clinical outcomes for real-world patients with treatment-resistant depression. Although the study found no clear-cut "winner", it does provide guidance on how to start therapy and how to proceed if initial treatment fails.
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Associate Professor of Psychiatry, University of
North Carolina School of Medicine; Investigator,
Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) study
University of Texas Southwestern Medical Center
at Dallas; Professor of Clinical Sciences and
Psychiatry; Principal Investigator, STAR*D study
The STAR*D study:
Treating depression in the real world
The Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) study evaluated feasible treatment strategies to
improve clinical outcomes for real-world patients with
treatment-resistant depression. Although the study found
no clear-cut “winner, it does provide guidance on how to
start therapy and how to proceed if initial treatment fails.
Remission (ie, complete relief from a depressive episode)
rather than response (merely substantial improvement)
should be the goal of treatment, as it is associated with
a better prognosis and better function.
Should the first treatment fail, either switching treatment
or augmenting the current treatment is reasonable.
For most patients, remission will require repeated trials of
sufficiently sustained, vigorously dosed antidepressant
medication. Physicians should give maximal but tolerable
doses for at least 8 weeks before deciding that an
intervention has failed.
After two well-delivered medication trials, the likelihood
of remission substantially decreases. Such patients likely
require more complicated regimens. Given the thin
existing database, these patients are best referred to
a psychiatrist for more complex treatments.
With persistent and vigorous treatment, most patients will
enter remission: about 33% after one step, 50% after two
steps, 60% after three steps, and 70% after four steps
(assuming patients stay in treatment).
can be treated successfully by
primary care physicians under “real-
world” conditions.
Furthermore, the particular drug or drugs
used are not as important as following a rational
plan: giving antidepressant medications in ade-
quate doses, monitoring the patient’s symptoms
and side effects and adjusting the regimen
accordingly, and switching drugs or adding new
drugs to the regimen only after an adequate trial.
These are among the lessons learned from
the Sequenced Treatment Alternatives to
Relieve Depression (STAR*D) study, the
largest prospective clinical trial of treatment
of major depressive disorder ever conducted. It
was funded by the National Institutes of
Health and directed by A. John Rush, MD.
Depression, a common and debilitating condi-
tion, affects approximately one in eight people
in the United States.
It is expected
to be the
second-leading cause of disability in the world
by the year 2020; today, it is the second-lead-
ing cause of disability-adjusted life years in
those 15 to 44 years old.
Nevertheless, the available evidence base
for treatment is limited, since most partici-
pants in clinical trials are recruited by adver-
tisement rather than from representative prac-
tices, and they are often selected to have few
University of Pittsburgh School of Medicine;
Associate Professor of Epidemiology; Data
Coordinating Center, STAR*D study
University of North Carolina School of Medicine;
Professor of Family Medicine; Investigator,
STAR*D study
Massachusetts General Hospital, Boston;
Professor of Psychiatry; Investigator, STAR*D
University of Texas Southwestern Medical Center
at Dallas; Professor of Psychiatry; National
Coordinating Center, STAR*D study
The authors’ disclosures of potential conflicts of interest are listed at the
end of this paper.
This project was funded by the National Institute of Mental Health,
National Institutes of Health, under Contract N01MH90003 to UT
Southwestern Medical Center at Dallas (Principal Investigator A.J. Rush).
The content of this publication does not necessarily reflect the views or
policies of the Department of Health and Human Services, nor does
mention of trade names, commercial products, or organizations imply
endorsement by the US Government.
comorbid disorders, either medical or psychi-
atric. In addition, those with chronic depres-
sion or current suicidal ideation are exclud-
These uncomplicated and “pristine” par-
ticipants are unlike typical patients seen by
primary care physicians or psychiatrists.
Similarly, the protocols used in these tri-
als do not represent usual clinic practice.
Patients in clinical trials undergo more assess-
ment and more frequent follow-up than in
real-world practice, they have no say in treat-
ment decisions, the doses are fixed, and the
patients and physicians are blinded to the
intervention. Consequently, how to translate
the results of these efficacy trials into practice
is unclear.
Further, even in relatively uncomplicated
cases, only about one-half of outpatients with
nonpsychotic major depressive disorder ini-
tially treated with a single medication or with
psychotherapy will experience a clinically sig-
nificant improvement in symptoms (ie, a
response) during the 8 to 12 weeks of acute-
phase treatment,
and only 20% to 35% of
patients will reach remission,
the aim of
The remission rates are even
lower in treatment-resistant depression.
How to manage most patients—those whose
depression does not remit with the first, sec-
ond, or third step of treatment—is unclear.
Accordingly, the overall objective of
STAR*D was to develop and evaluate feasible
treatment strategies to improve clinical out-
comes for real-world patients with treatment-
resistant depression, who were identified
prospectively from a pool of patients in a cur-
rent major depressive episode.
ally, STAR*D aimed to determine prospec-
tively which of several treatments is the most
effective “next step” for patients who do not
reach remission with an initial or subsequent
treatment or who cannot tolerate the treat-
Nearly 10% of all primary care office visits are
Primary care physicians
provide nearly half the outpatient care for
depressed patients.
Indeed, primary care
physicians log approximately as many outpa-
tient visits for depression as psychiatrists do.
Medical comorbidity is especially common in
primary care settings.
When to refer to a
psychiatrist is not clear.
STAR*D involved a national consortium of
14 university-based regional centers, which
oversaw a total of 23 participating psychiatric
and 18 primary care clinics. Enrollment began
in 2000, with follow-up completed in 2004.
Entry criteria were broad and inclusive
Patients had to:
Be between 18 and 75 years of age
Have a nonpsychotic major depressive
disorder, identified by a clinician and con-
firmed with a symptom checklist based on
the Diagnostic and Statistical Manual,
fourth edition revised,
and for which
antidepressant treatment is recommended
Score at least 14 on the 17-item Hamilton
Rating Scale for Depression (HAM-
Not have a primary diagnosis of bipolar
disorder, obsessive-compulsive disorder, or
an eating disorder, which would require a
different treatment strategy, or a seizure
disorder (which would preclude bupropi-
on as a second-step treatment).
Dosing recommendations were flexible
but vigorous
Medications often were increased to maximal-
ly tolerated doses. For example, citalopram
(Celexa) was started at 20 mg/day and
increased by 20 mg every 2 to 4 weeks if the
patient was tolerating it but had not achieved
remission, to a maximum dose of 60 mg/day.
Treatment could be given for up to 14 weeks,
during which side effects
and clinical rat-
were assessed by both patients and study
Measurement-based care
We used a systematic approach to treatment
called “measurement-based care,”
involves routinely measuring symptoms
side effects
and using this information to
modify the medication doses at critical deci-
sion points. This algorithmic approach pro-
Primary care
physicians log
as many
visits for
depression as
psychiatrists do
vided flexible treatment recommendations to
ensure that the dosage and duration of antide-
pressant drug treatment were adequate.
The severity of depression was assessed by
the clinician-rated, 16-item Quick Inventory
of Depressive Symptomatology (QIDS-C16).
The QIDS-SR16 (the self-report version) can
substitute for the QIDS-C16
to make this
approach more feasible. Both tools are avail-
able at
This approach was easily worked into busy
primary care and specialty care office work-
flows (clinic physicians, most with limited
research experience, provided the treatment),
and could be translated into primary care
practice in the community as well.
Four-step protocol
The protocol had four treatment levels, each
lasting up to 14 weeks (
FIGURE 1). All patients
started at level 1; if they had not entered
remission by 14 weeks, they moved up to the
next level; if they had achieved remission,
they stayed at the same level and were fol-
lowed for up to 1 year.
A unique feature of the study design was
that the patients, in consultation with their
physicians, had some choice in the treatments
based care can
easily be used
in clinical
STAR*D algorithm: Treatment levels
Level 1 Citalopram (Celexa)
Level 2 Patients could choose one of the following:
(stop citalopram, be randomized (keep citalopram, be randomized
to receive one of the following) to also receive one of the following)
Bupropion sustained-release (Wellbutrin SR) Bupropion sustained-release
Venlafaxine extended-release (Effexor XR) Buspirone (BuSpar)
Sertaline (Zoloft) Cognitive therapy
Cognitive therapy
Level 2a SWITCH
(only for those (stop cognitive therapy, be randomized
receiving cognitive to receive one of the following)
therapy in level 2) Bupropion sustained-release or
Venlafaxine extended-release
Level 3 Patients could choose one of the following
(stop current therapy, (keep current therapy,
be randomized to receive be randomized to also receive
one of the following) one of the following)
Mirtazapine (Remeron) Lithium
Nortriptyline (Pamelor) T3 thyroid hormone (Cytomel)
Level 4 SWITCH
(stop current therapy, be randomized to receive one of the following)
Tranylcypromine (Parnate)
Mirtazapine plus venlafaxine extended-release
Patients could refuse cognitive therapy as a randomization option. All treatments were unblinded. Patients advanced to succes-
sively higher treatment levels if they failed to achieve remission with their current regimen.
they received. In this “equipoise-stratified ran-
domized design,”
at levels 2 and 3 the
patient could choose either to switch thera-
pies (stop the current drug and be randomized
to receive one of several different treatments)
or to augment their current therapy (by
adding one of several treatments in a random-
ized fashion). Patients could decline certain
strategies as long as there were at least two
possible options to which one might be ran-
At level 2, one of the options for both
switching and augmentation was cognitive
therapy, although patients could decline that
option. Conversely, if they definitely wanted
cognitive therapy, they could choose to be
randomized to either cognitive therapy alone
or to cognitive therapy added to citalopram.
Also, anyone who received cognitive therapy
in level 2 and failed to enter remission was
additionally randomized to either bupropion
or venlafaxine (level 2a) to ensure that all
patients had failed trials on two medications
before entering level 3.
When switching to medications other than
a monoamine oxidase inhibitor (MAOI), the
clinician could choose either to stop the current
medication and immediately begin the next one,
or to decrease the current medication while
starting the new one at a low dose and then
tapering and titrating over 1 week. (Switching to
an MAOI, used only in the final level of treat-
ment, required a 7- to 10-day washout period.)
Outcomes measured
Remission (complete recovery from the
depressive episode), the primary study out-
come, was defined as a HAM-D17 score of 7
or less, as assessed by treatment-blinded raters.
A secondary remission outcome was a QIDS-
SR16 score of 5 or less. Of note, the HAM-
D17 remission rates were slightly lower than
the rates based on the QIDS-SR16, since
patients who did not have a HAM-D17 score
measured at exit were defined as not being in
remission a priori. Thus, the QIDS-SR16 rates
might have been a slightly better reflection of
actual remission rates.
Response, a secondary outcome, was
defined as a reduction of at least 50% in the
QIDS-SR16 score from baseline at the last
The patients seen in primary care clinics were
surprisingly similar to those seen in psychiatric
The two groups did not differ in
severity of depression, distribution of severity
scores, the likelihood of presenting with any of
the nine core criteria of a major depressive
episode, or the likelihood of having a con-
comitant axis I psychiatric disorder in addi-
tion to depression (about half of participants
in each setting had an anxiety disorder).
Recurrent major depressive disorders were
common in both groups, though more so in
psychiatric patients (78% vs 69%, P < .001),
while chronic depression was more common
in primary care than in psychiatric patients
(30% vs 21%, P < .001). Having either a
chronic index episode (ie, lasting > 2 years) or
a recurrent major depressive disorder was com-
mon in both groups (86% vs 83%, P = .0067).
That said, primary care patients were
older (44 years vs 39 years, P < .001), more of
them were Hispanic (18% vs 9%, P < .001),
and more of them had public insurance (23%
vs 9%, P < .001). Fewer of the primary care
patients had completed college (20% vs 28%,
P < .001), and the primary care patients tend-
ed to have greater medical comorbidity.
Psychiatric patients were more likely to have
attempted suicide in the past and to have had
their first depressive illness before age 18.
At level 1, all the patients received citalo-
pram. The mean dose was 40.6 ± 16.6 mg/day
in the primary care clinics and 42.5 ± 16.8
mg/day in the psychiatric clinics, which are
adequate, middle-range doses and higher than
the average US dose.
Approximately 30% of patients achieved
remission: 27% as measured on the HAM-
D17 and 33% on the QIDS-SR16. The
response rate (on the QIDS-SR16) was 47%.
There were no differences between primary
and psychiatric care settings in remission or
response rates.
Patients were more likely to achieve
remission if they were white, female,
The average
time needed to
remission was
almost 7 weeks
employed, more educated, or wealthier.
Longer current episodes, more concurrent psy-
chiatric disorders (especially anxiety disorders
or drug abuse), more general medical disor-
ders, and lower baseline function and quality
of life were each associated with lower remis-
sion rates.
What is an adequate trial?
Longer times than expected were needed to
reach response or remission. The average
duration required to achieve remission was
almost 7 weeks (44 days in primary care; 49
days in psychiatric care). Further, approxi-
mately one-third of those who ultimately
responded and half of those who entered
remission did so after 6 weeks.
Forty percent
of those who entered remission required 8 or
more weeks to do so.
These results suggest that longer treat-
ment durations and more vigorous medication
dosing than generally used are needed to
achieve optimal remission rates. It is impru-
dent to stop a treatment that the patient is
tolerating in a robust dose if the patient
reports only partial benefit by 6 weeks; indeed,
raising the dose, if tolerated, may help a sub-
stantial number of patients respond by 12 or
14 weeks. Instruments to monitor depression
severity (eg, self-report measures) can be use-
ful. At least 8 weeks with at least moderately
vigorous dosing is recommended.
When switching to a new drug,
does it matter which one?
In level 2, if patients had not achieved
remission on citalopram alone, they had the
choice of switching: stopping citalopram and
being randomized to receive either sertraline
(Zoloft, another SSRI), venlafaxine extend-
ed-release (XR) (Effexor XR, a serotonin and
norepinephrine reuptake inhibitor), or bupro-
pion sustained-release (SR) (Wellbutrin SR, a
norepinephrine and dopamine reuptake
inhibitor). At the last visit the mean daily
doses were bupropion SR 282.7 mg/day, ser-
traline 135.5 mg/day, and venlafaxine-XR
193.6 mg/day.
The remission rate was approximately
one-fourth with all three drugs
•With bupropion SR—21.3% by HAM-
D17, 25.5% by QIDS-SR16
•With sertraline—17.6% by HAM-D17,
26.6% by QIDS-SR16
•With venlafaxine-XR—24.8% by HAM-
D17, 25.0% by QIDS-SR16. The remis-
sion rates were neither statistically nor
clinically different by either measure.
Though the types of side effects related
to specific medications may have varied, the
overall side-effect burden and the rate of
serious adverse events did not differ signifi-
When adding a new drug,
does it matter which one?
Again, no.
Instead of switching, patients in level 2
could choose to stay on citalopram and be
randomized to add either bupropion SR or
buspirone (BuSpar) to the regimen (augmen-
tation). The mean daily doses at the end of
level 2 were bupropion SR 267.5 mg and bus-
pirone 40.9 mg.
Rates of remission
•With bupropion SR—29.7% on the
HAMD-D17, 39.0% on the QIDS-SR16
•With buspirone—30.1% on the HAM-
D17, 32.9% on the QIDS-SR16.
However, the QIDS-SR16 scores declined
significantly more with bupropion SR than
with buspirone (25.3% vs 17.1%, P < .04).
The mean total QIDS-SR16 score at the last
visit was lower with bupropion SR (8.0) than
with buspirone (9.1, P < .02), and augmenta-
tion with bupropion SR was better tolerated
(the dropout rate due to intolerance was
12.5% with bupropion-SR vs 20.6% with bu-
spirone 20.6%; P < .009).
Can we directly compare the benefits
of switching vs augmenting?
Patients could choose whether to switch
from citalopram to another drug or to add
another drug at the second treatment level.
Consequently, we could not ensure that the
patient groups were equivalent at the point of
randomization at the beginning of level 2,
and, indeed, they were not.
STAR*D cannot
tell us if adding
another drug is
better than
Those who benefitted more from citalo-
pram treatment and who better tolerated it
preferred augmentation, while those who ben-
efitted little or who could not tolerate it pre-
ferred to switch. Consequently, those in the
augmentation group at level 2 were somewhat
less depressed than those who switched.
Whether augmentation is better even if the
initial treatment is minimally effective could
not be evaluated in STAR*D.
What about cognitive therapy?
There was no difference between cognitive
therapy (either as a switch or as augmenta-
tion) and medication (as a switch or as aug-
Adding another drug was more
rapidly effective than adding cognitive thera-
py. Switching to cognitive therapy was better
tolerated than switching to a different antide-
Of note, fewer patients accepted cogni-
tive therapy as a randomization option than
we expected, so the sample sizes were small.
Possible reasons were that all patients had
to receive a medication at study entry
(which may have biased selection towards
those preferring medication), and cognitive
therapy entailed additional copayments and
visiting still another provider at another
After two levels of treatment,
how many patients reach remission?
About 30% of patients in level 1 achieved
remission, and of those progressing to level 2,
another 30% achieved remission. Together,
this adds up to about 50% of patients achiev-
ing remission if they remained in treatment
(30% in level 1 plus 30% of the roughly 70%
remaining in level 2).
If switching again to another drug,
does it matter which one?
In level 3, patients could choose to stop
the drug they had been taking and be ran-
domized to receive either mirtazapine
(Remeron) or nortriptyline (Pamelor).
Switching medications was not as effec-
tive as a third step as it was as a second step.
Remission rates:
•With mirtazapine—12.3% on the HAM-
D17, 8.0% on the QIDS-SR16
•With nortriptyline—19.8% on the HAM-
D17, 12.4% on the QIDS-SR16.
Response rates were 13.4% with mirtaza-
pine and 16.5% with nortriptyline. Statistically,
neither the response nor the remission rates dif-
fered by treatment, nor did these two treat-
ments differ in tolerability or side-effect burden.
Does choice of augmentation agent matter:
Lithium vs T3?
Similarly, after two failed medication treat-
ments, medication augmentation was less
effective than it was at the second step.
two augmentation options tested, lithium and
T3 thyroid hormone (Cytomel), are common-
ly considered by psychiatrists but less com-
monly used by primary care doctors.
Lithium is believed to increase serotoner-
gic function, which may have a synergistic
effect on the mechanism of action of antide-
pressants; a meta-analysis of placebo-con-
trolled studies supports lithium’s effectiveness
as adjunctive treatment.
Its side effects,
however, must be closely monitored.
primary monitoring concern is the small dif-
ference between the therapeutic blood level
(0.6–1.2 mEq/L) and potentially toxic blood
levels (> 1.5 mEq/L).
Lithium was started at 450 mg/day, and at
week 2 it was increased to the recommended
dose of 900 mg/day (a dose below the target
dose for bipolar disorder). If patients could not
tolerate 450 mg/day, the initial dose was 225
mg/day for 1 week before being increased to
450 mg/day, still with the target dose of 900
mg/day. The mean exit dose was 859.9 mg/day,
and the median blood level was 0.6 mEq/L.
Thyroid hormone augmentation using T3
is believed to work through both direct and
indirect effects on the hypothalamic-pituitary-
thyroid axis, which has a strong relationship
with depression. The efficacy of T3 augmenta-
tion is supported by a meta-analysis of eight
and T3 is effective whether or not
thyroid abnormalities are present.
In STAR*D, T3 was started at 25 µg/day
for 1 week, than increased to the recommend-
ed dose of 50 µg/day. The mean exit dose was
45.2 µg/day.
Fewer patients
therapy as a
option than we
Remission rates:
•With lithium augmentation—15.9% by
the HAM-D17, 13.2% by the QIDS-
•With T3 augmentation—24.7% by both
Response rates were 16.2% with lithium
augmentation and 23.3% with T3 augmenta-
While neither response nor remission
rates were statistically significantly different
by treatment, lithium was more frequently
associated with side effects (P = .045), and
more participants in the lithium group left
treatment because of side effects (23.2% vs
9.6%; P = .027). These results suggest that in
cases in which a clinician is considering an
augmentation trial, T3 has slight advantages
over lithium in effectiveness and tolerability.
T3 also offers the advantages of being easy to
use and not necessitating blood level moni-
toring. These latter benefits are especially rel-
evant to the primary care physician. However,
T3’s potential for long-term side effects (eg,
osteoporosis, cardiovascular effects) were not
examined, and it is not clear when to discon-
tinue it.
Switch to mirtazapine plus venlafaxine XR
or tranylcypromine?
Patients who reached level 4 were considered
to have a highly treatment-resistant depressive
illness, so treatments at this level were, by
design, more aggressive. Accordingly, at level 4
we investigated treatments that might be con-
sidered more demanding than those a primary
care physician would use. Approximately 40%
of patients in each treatment group were from
primary care settings.
Remission rates
•With the combination of mirtazapine
(mean dose 35.7 mg/day) and venlafaxine
XR (mean dose 210.3 mg/day)—13.7% by
the HAM-D17 and 15.7% by the QIDS-
•With the MAOI tranylcypromine (Parnate,
mean dose 36.9 mg/day)—6.9% by the
HAM-D17 and 13.8% by the QIDS-SR16.
Response rates were 23.5% with the com-
bination and 12.1% with tranylcypromine.
Neither remission nor response rates differed
However, the percentage reduction in
QIDS-SR16 score between baseline and exit
was greater with the combination than with
tranylcypromine. Further, more patients
dropped out of treatment with tranyl-
cypromine because of side effects (P < .03).
Tranylcypromine also has the disadvantage
of necessitating dietary restrictions.
A significant limitation of this compari-
son is that patients were less likely to get an
adequate trial of tranylcypromine, an MAOI,
than of the combination. When the 2-week
washout period (required before switching to
an MAOI) is subtracted from the total time in
treatment, approximately 30% of participants
in the tranylcypromine group had less than 2
weeks of treatment, and nearly half had less
than 6 weeks of treatment.
Therefore, even though the remission and
response rates were similar between groups,
the combination of venlafaxine-XR plus mir-
tazapine therapy might have some advantages
over tranylcypromine. These results provided
the first evidence of tolerability and at least
modest efficacy of this combination for treat-
ment-resistant cases.
Overall, what was the cumulative
remission rate?
The theoretical cumulative remission rate
after four acute treatment steps was 67%.
Remission was more likely to occur during the
first two levels of treatment than during the
last two. The cumulative remission rates for
the first four steps were:
Level 1—33%
Level 2—57%
Level 3—63%
Level 4—67%.
Patients with a clinically meaningful response
or, preferably, remission at any level could
enter into a 12-month observational follow-
up phase. Those who had required more treat-
ment levels had higher relapse rates during
this phase.
Further, if a patient achieved
Lithium can be
an adjunctive
treatment for
depression, but
its side effects
must be closely
remission rather than just response to treat-
ment, regardless of the treatment level, the
prognosis at follow-up was better, confirming
the importance of remission as the goal of
Results also provided a warning—the
greater the number of treatment levels that a
patient required, the more likely that patient
and physician would settle for response.
Whether the greater relapse rates reflect a
harder-to-treat depression or the naturalistic
design of the follow-up phase (with less con-
trol over dosing) is unclear.
•Measurement-based care is feasible in pri-
mary care. Primary care doctors can ensure
vigorous but tolerable dosing using a self-
report depression scale to monitor response, a
side-effects tool to monitor tolerability, and
medication adjustments at critical decision
points guided by these two measures.
Remission, ie, complete recovery from a
depressive episode, rather than merely sub-
stantial improvement, is associated with a bet-
ter prognosis and is the preferred goal of treat-
Pharmacologic differences between psy-
chotropic medications did not translate into
substantial clinical differences, although
tolerability differed. These findings are con-
sistent with a large-scale systematic evi-
dence review recently completed by the
Agency for Healthcare Research and
Quality that compared the effectiveness of
Given the difficulty in
predicting what medication will be both
efficacious for and tolerated by an individ-
ual patient, familiarity with a broad spec-
trum of antidepressants is prudent.
Remission of depressive episodes will most
likely require repeated trials of sufficiently sus-
tained, vigorously dosed antidepressant med-
ication. From treatment initiation, physicians
should ensure maximal but tolerable doses for
at least 8 weeks before deciding that an inter-
vention has failed.
If a first treatment doesn’t work, either
switching or augmenting it is a reasonable
choice. Augmentation may be preferred if
the patient is tolerating and receiving par-
tial benefit from the initial medication
choice. While bupropion SR and buspirone
were not different as augmenters by the pri-
mary remission outcome measure, secondary
measures (eg, tolerability, depressive symp-
tom change over the course of treatment,
clinician-rated Quick Inventory of Depres-
sive Symptomatology) recommended bupro-
pion-SR over buspirone.
If physicians switch, either a within-class
switch (eg, citalopram to sertraline) or an out-
of-class switch (eg, citalopram to bupropion
SR) is effective, as is a switch to a dual-action
agent (eg, venlafaxine XR).
The likelihood of improvement after two
aggressive medication trials is very low and
likely requires more complicated medication
regimens, and the existing evidence base is
quite thin. These primary care patients should
likely be referred to psychiatrists for more
aggressive and intensive treatment.
For patients who present with major
depressive disorder, STAR*D suggests that
with persistence and aggressive yet feasible
care, there is hope: after one round, approxi-
mately 30% will have a remission; after two
rounds, 50%; after three rounds, 60%; and
after four rounds, 70%.
While STAR*D excluded depressed
patients with bipolar disorder, a depressive
episode in a patient with bipolar disorder can
be difficult to distinguish from a depressive
episode in a patient with major depressive dis-
order. Primary care physicians need to consid-
er bipolar disorder both in patients presenting
with a depressive episode and in those who
fail an adequate trial.
Subsequent STAR*D analyses will compare in
greater depth outcomes in primary care vs psy-
chiatric settings at each level of treatment.
Given the greater risk of depression persis-
tence associated with more successive levels of
treatment, subsequent research will focus on
ways to more successfully treat depression in
the earlier stages, possibly through medication
combinations earlier in treatment (somewhat
analogous to a “broad-spectrum antibiotic”
approach for infections).
persistence and
aggressive yet
feasible care,
there is hope
Dr. Gaynes has received grants and research support from the National
Institute of Mental Health, Agency for Healthcare Research and Quality,
Robert Wood Johnson Foundation, Pfizer, and Ovation Pharmaceuticals. He
has performed as an advisor or consultant for Pfizer; Shire Pharmaceuticals;
and Wyeth-Ayerst. He has also received a speaker’s honorarium from
Dr. Rush has provided scientific consultation to or served on Advisory Boards
for Advanced Neuromodulation Systems;AstraZeneca; Best Practice Project
Management; Bristol-Myers Squibb Company; Cyberonics; Forest
Pharmaceuticals; Gerson Lehman Group; GlaxoSmithKline; Jazz Pharmaceuticals;
Eli Lilly & Company; Magellan Health Services; Merck & Co.; Neuronetics; Ono
Pharmaceutical; Organon USA; PamLab, Personality Disorder Research Corp.;
Pfizer; The Urban Institute; and Wyeth-Ayerst Laboratories. He has received
royalties from Guilford Publications and Healthcare Technology Systems, and
research/grant support from the Robert Wood Johnson Foundation, the National
Institute of Mental Health, and the Stanley Foundation; has been on speaker
bureaus for Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, and Eli Lilly &
Company; and owns stock in Pfizer.
Dr. Trivedi has received research support from Bristol-Myers Squibb
Company; Cephalon; Corcept Therapeutics; Cyberonics; Eli Lilly &
Company; Forest Pharmaceuticals; GlaxoSmithKline; Janssen
Pharmaceutica; Merck; National Institute of Mental Health; National
Alliance for Research in Schizophrenia and Depression; Novartis; Pfizer;
Pharmacia & Upjohn; Predix Pharmaceuticals; Solvay Pharmaceuticals; and
Wyeth-Ayerst Laboratories. He has served as an advisor or consultant for
Abbott Laboratories; Akzo (Organon Pharmaceuticals); Bayer; Bristol-Myers
Squibb Company; Cephalon; Cyberonics, Inc.; Forest Pharmaceuticals;
GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Johnson & Johnson
PRD; Eli Lilly & Company; Meade Johnson; Parke-Davis Pharmaceuticals;
Pfizer; Pharmacia & Upjohn; Sepracor; Solvay Pharmaceuticals; and Wyeth-
Ayerst Laboratories. He has received speaker honoraria from Akzo
(Organon Pharmaceuticals); Bristol-Myers Squibb Company; Cephalon;
Cyberonics; Forest Pharmaceuticals; Janssen Pharmaceutica Products, LP;
Eli Lilly & Company; Pharmacia & Upjohn; Solvay Pharmaceuticals; and
Wyeth-Ayerst Laboratories.
Dr. Wisniewski has received grants and research support from the
National Institute of Mental Health. He has performed as a consultant for
Cyberonics Inc. and ImaRx Therapeutics.
Dr. Spencer has no disclosures to report.
Dr. Fava has received research support from Abbott Laboratories,
Alkermes, Aspect Medical Systems, Astra-Zeneca, Bristol-Myers Squibb
Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals,
GlaxoSmithKline, J & J Pharmaceuticals, Lichtwer Pharma GmbH, Lorex
Pharmaceuticals, Novartis, Organon Inc., PamLab, LLC, Pfizer, Pharmavite,
Roche, Sanofi/Synthelabo, Solvay Pharmaceuticals, and Wyeth-Ayerst
Laboratories. He has served on Advisory Boards and done Consulting for
Aspect Medical Systems, Astra-Zeneca, Bayer AG, Biovail Pharmaceuticals,
BrainCells, Bristol-Myers Squibb Company, Cephalon, Compellis, Cypress
Pharmaceuticals, Dov Pharmaceuticals, Eli Lilly & Company, EPIX
Pharmaceuticals, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals,
GlaxoSmithKline, Grunenthal GmBH, Janssen Pharmaceutica, Jazz
Pharmaceuticals, J & J Pharmaceuticals, Knoll Pharmaceutical Company,
Lundbeck, MedAvante, Neuronetics, Novartis, Nutrition 21, Organon,
PamLab, LLC, Pfizer, PharmaStar, Pharmavite, Roche, Sanofi/Synthelabo,
Sepracor, Solvay Pharmaceuticals, Somaxon, Somerset Pharmaceuticals, and
Wyeth-Ayerst Laboratories. Dr. Fava has served on the speaker’s bureau for
Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Company,
Cephalon, Eli Lilly & Company, Forest Pharmaceuticals, GlaxoSmithKline,
Novartis, Organon, Pfizer, PharmaStar, and Wyeth-Ayerst Laboratories. He
has equity in Compellis and MedAvante.
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ADDRESS: Bradley N. Gaynes, MD, MPH, Department of Psychiatry,
University of North Carolina at Chapel Hill, First Floor, Neurosciences
Hospital, Room 10306, CB#7160, Chapel Hill, NC 27599; e-mail
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... In the cases of partial or non-response to medications, drug augmentation could be trialled as part of the study design. This would enhance the clinical applicability of findings, given that drug augmentation following partial or non-response is a common clinical pathway (Fredman et al., 2000;Gaynes et al., 2008), which has not been explored in the TBI literature. There are a number of meta-analyses in non-TBI samples examining the efficacy, acceptability and tolerability of augmentation agents for treatment resistant depression from which guidance could be sort while TBI specific evidence builds (Strawbridge et al., 2019;Zhou et al., 2015). ...
... Following cessation of intervention, it is also important to assess the maintenance of treatment effects and rates of relapse for specific anti-depressant drugs. Based on preliminary evidence in TBI samples (Rapoport et al., 2010) and substantial evidence in non-TBI samples (Keller et al., 1992;Gaynes et al., 2008;Ramana et al., 1995), it would be expected that a number of patients will experience relapse and recurrence of symptoms after a single medication trial. Indeed, for most non-TBI patients research suggests remission will require repeated trials of sufficiently sustained anti-depressants, with only a minority of patients entering long-term remission after one medication trial (Gaynes et al., 2008). ...
... Based on preliminary evidence in TBI samples (Rapoport et al., 2010) and substantial evidence in non-TBI samples (Keller et al., 1992;Gaynes et al., 2008;Ramana et al., 1995), it would be expected that a number of patients will experience relapse and recurrence of symptoms after a single medication trial. Indeed, for most non-TBI patients research suggests remission will require repeated trials of sufficiently sustained anti-depressants, with only a minority of patients entering long-term remission after one medication trial (Gaynes et al., 2008). Relapse prevention management has been examined in TBI samples by providing continuation therapy with citalopram following remission of symptoms (Rapoport et al., 2010). ...
Full-text available
Symptoms of depression are common following traumatic brain injury (TBI), impacting survivors’ ability to return to work, participate in leisure activities, and placing strain on relationships. Depression symptoms post TBI are often managed with pharmacotherapy, however, there is little research evidence to guide clinical practice. There have been a number of recent systematic reviews examining pharmacotherapy for post TBI depression. The aim of this umbrella review was to synthesize systematic reviews and meta-analyses of the effectiveness of pharmacotherapy for the management of post TBI depression in adults. Eligible reviews examined any pharmacotherapy against any comparators, for the treatment of depression in adults who had sustained TBI. Seven databases were searched, with additional searching of online journals, Research Gate, Google Scholar and the TRIP Medical Database to identify published and unpublished systematic reviews and meta-analyses in English up to May 2020. A systematic review of primary studies available between March 2018 and May 2020 was also conducted. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. The results are presented as a narrative synthesis. Twenty-two systematic reviews were identified, of which ten reviews contained a meta-analysis. No new primary studies were identified in the systematic review. There was insufficient high quality and methodologically rigorous evidence to recommend prescribing any specific drug or drug class for post TBI depression. The findings do show, however, that depression post TBI is responsive to pharmacotherapy in at least some individuals. Recommendations for primary studies, systematic reviews and advice for prescribers is provided. Review Registration PROSPERO (CRD42020184915).
... The studies investigating CYP2C19*17 also concluded that the clinical implication of their findings was unclear and warranted further study [205,214,215]. Further, a 2008 study involving the STAR*D sample (n=1,953) did not find any significant link between polymorphisms in CYP2C19, CYP2D6 and CYP3A4 and tolerance or response to antidepressants [216]. ...
In this thesis, I investigate the impact of genetic variation on adverse drug reactions to psychotropic medications, with a focus on the metabolic and sleep related side effects of psychotropic drugs. In addition to reviewing published literature, I have considered this research topic in three main ways. Chapter one is a systematic review and meta-analysis of the impact of CYP2D6 genetic variation on antipsychotic-induced hyperprolactinaemia and weight gain, which are a relatively common but understudied adverse-drug reactions. Chapters two, three and four are based on data from UK Biobank, where I have conducted a hypothesis-driven analyses of known pharmacogenes and their association with two common adverse drug reactions: increased diabetes risk and sleep disturbance. In working on this thesis, two key limitations became apparent. Firstly, inconsistencies in genotyping and phenotyping make some findings difficult to interpret. Secondly, the nature of my analysis using cross-sectional UK Biobank data makes it difficult to draw firm conclusions on the causal direction of any observations. Chapter five aim to address these limitations. Here, I describe the set-up of a clinical study to assess pharmacogenetic interventions in a psychiatric patient population. Although only pilot data is available, due to a pause in recruitment during the Covid-19 pandemic, I describe the scientific rationale for the study and outline the work conducted to set-up and gain ethical approvals for the study. In addition, I outline my contribution to drafting clinical guidelines for the implementation of pharmacogenetic testing in the NHS.
... Such subgroups would not only explain the failure to identify 1 biomarker and thus 1 biological mechanism, but also the diverse symptomatology 81 and variability in treatment response. 82 The possibility of subgroups identifiable by different biomarkers that might benefit from different types of medication is endorsed by studies showing better effects with antiinflammatory treatment among patients with high baseline inflammatory markers. 83,84 However, many antidepressants seem to affect a variety of biological systems, 85,86 and evi-dence implies a high degree of interaction between different neurocircuits, indicating a highly complex etiology. ...
Importance: Depression has been associated with alterations in neurotransmitters, hormones, and inflammatory and neurodegenerative biomarkers, and biomarkers quantified in the cerebrospinal fluid (CSF) are more likely to reflect ongoing biochemical changes within the brain. However, a comprehensive overview of CSF biomarkers is lacking and could contribute to the pathophysiological understanding of depression. Objective: To investigate differences in quantified CSF biomarkers in patients with unipolar depression compared with healthy control individuals. Data sources: PubMed, EMBASE, PsycINFO, Cochrane Library, Web of Science, and were searched for eligible trials from database inception to August 25, 2021. Study selection: All studies investigating CSF biomarkers in individuals 18 years and older with unipolar depression and healthy control individuals were included. One author screened titles and abstracts, and 2 independent reviewers examined full-text reports. Studies that did not include healthy control individuals or included control individuals with recent hospital contacts or admissions that might affect CSF biomarker concentrations were excluded. Data extraction and synthesis: Data extraction and quality assessment were performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. Meta-analyses were performed using standardized mean differences (SMDs) calculated with random-effects models. A third investigator was consulted if the 2 reviewers reached different decisions or when in doubt. Main outcomes and measures: Quantifiable CSF biomarkers. Results: A total of 167 studies met eligibility criteria, and 97 had available data and were included in the meta-analysis. These 97 studies comprised 165 biomarkers, 42 of which were quantified in 2 or more studies. CSF levels of interleukin 6 (7 studies; SMD, 0.35; 95% CI, 0.12 to 0.59; I2 = 16%), total protein (5 studies; SMD, 0.53; 95% CI, 0.35 to 0.72; I2 = 0%), and cortisol (2 studies; SMD, 1.23; 95% CI, 0.89 to 1.57; I2 = 0%) were higher in patients with unipolar depression compared with healthy control individuals, whereas homovanillic acid (17 studies; SMD, -0.26; 95% CI, -0.39 to -0.14; I2 = 11%), γ-aminobutyric acid (4 studies; SMD, -0.50; 95% CI, -0.92 to -0.08; I2 = 55%), somatostatin (5 studies; SMD, -1.49; 95% CI, -2.53 to -0.45; I2 = 91%), brain-derived neurotrophic factor (3 studies; SMD, -0.58; 95% CI, -0.97 to -0.19; I2 = 0%), amyloid-β 40 (3 studies; SMD, -0.80; 95% CI, -1.14 to -0.46; I2 = 0%), and transthyretin (2 studies; SMD, -0.82; 95% CI, -1.37 to -0.27; I2 = 0%) were lower. The remaining 33 biomarkers had nonsignificant results. Conclusions and relevance: The findings of this systematic review and meta-analysis point toward a dysregulated dopaminergic system, a compromised inhibitory system, hypothalamic-pituitary-adrenal axis hyperactivity, increased neuroinflammation and blood-brain barrier permeability, and impaired neuroplasticity as important factors in depression pathophysiology.
... A rendere ancor più significativa la gravità della malattia è la limitata efficacia dei trattamenti antidepressivi attualmente impiegati 6 . A oggi, nonostante il considerevole aumento delle opzioni terapeutiche, circa un terzo dei pazienti con MDD non risponde in modo soddisfacente ai trattamenti attualmente disponibili [7][8][9] . I pazienti che in seguito a due o più trattamenti antidepressivi somministrati con dosaggio e durata adeguati presentano una riduzione della sintomatologia depressiva inferiore al 50% (misurata tramite scale di valutazione psichiatrica quali Hamilton Rating Scale for Depression o Montgomery-Asberg Depression Rating Scale) 10 ricevono solitamente l'ulteriore etichetta diagnostica di "depressione resistente al trattamento" (treatmentresistant depression -TRD) 11 . ...
Full-text available
About a third of patients with major depressive disorder (MDD) do not have an adequate response to first-line antidepressant treatment, i.e., develop a treatment-resistant depression (TRD). The partial understanding of MDD pathophysiology currently constitutes the major barrier to clinical and research progress on this topic. However, recent advances in genome editing techniques as well as in induced pluripotent stem cells (iPSC) technology are offering unprecedented opportunities in both human disease modelling and drug discovery. These technology progresses have been enabling to set up disease-relevant patient-specific in vitro disease modeling for various mental disorders. The resulting models have the potential to significantly improve pathophysiologic understanding of MDD and then overcome some limitations inherent to animal and post-mortem models. More recently, psychiatry started to deal with the fast acting antidepressant ketamine and its derivates. Although ketamine appears to have the potential to transform the treatment of depression, its specific mechanisms of action are only partially known. Such knowledge is necessary to develop a model to understand the mechanisms behind fast-acting antidepressants, which may enable the discovery of novel glutamatergic compounds for the treatment of MDD. After discussing both the current understanding of ketamine's mechanisms of action, and the state of the art of human iPSC technology, the authors will introduce the implementation of a TRD model based on iPSC human technology and aimed at studying the ketamine's fast acting antidepressant mechanisms of action.
Background Although its effect has not been verified, family therapy – such as family psychoeducation (FPE) – is a widely used intervention for treating major depressive disorder (MDD). To our knowledge, no systematic review and meta-analysis exists that examines the effect of FPE on MDD. Aims To assess evidence on the effectiveness of FPE on depressive symptoms in people with MDD. Method We searched several databases – including PubMed, MEDLINE and Web of Science, among others – to identify eligible studies on the topic published up to March 2022. Our criteria included studies on participants with a primary MDD diagnosis and their family members and excluded studies on people with bipolar disorders and other mental illnesses. In the included studies, family members in the control groups did not receive FPE. Participants in both the intervention and control groups received standard treatment. Two researchers independently selected relevant publications, extracted data and evaluated methodological quality using the Cochrane risk of bias assessment tool and GRADE evaluation. The protocol was registered with PROSPERO (no. CRD42020185884). Results The meta-analysis included five studies with 301 patients with MDD and their family members. The effect of FPE on patients’ symptom severity, compared with the control condition, at 16 weeks was available for five comparisons of four randomised control trials (RCTs); a final follow-up was available for six comparisons of five RCTs. The meta-analysis showed a statistically significant improvement in patients’ symptoms, compared with control, at 16 weeks (s.m.d. = −0.52, 95% CI −1.03 to −0.01) and at a final follow-up (s.m.d. = −0.53, 95% CI −0.98 to −0.08). The meta-analysis on the effect of FPE on family functioning showed a non-significant improvement both at 16 weeks and at final follow-up. Conclusions FPE had a small but statistically significant effect on depressive symptoms in people with MDD, in both the short and long term. However, according to the GRADE framework, all outcomes are graded very low on certainty; therefore, more high-quality research is needed.
Introduction Pharmacogenetic testing is proposed to minimize adverse effects when considered in combination with pharmacological knowledge of the drug. As yet, limited studies in clinical settings have investigated the predictive value of pharmacokinetic (pk) gene variation on therapeutic drug levels as a probable mechanism of adverse effects, nor considered the combined effect of pk gene variation and drug level on antidepressant treatment response. Methods Two depression cohorts were investigated for the relationship between pk gene variation and antidepressant serum concentrations of amitriptyline, venlafaxine, mirtazapine and quetiapine, as well as treatment response. For the analysis, 519 patients (49% females; 46.6±14.1 years) were included. Results Serum concentration of amitriptyline was associated with CYP2D6 (higher concentrations in poor metabolizers compared to normal metabolizers), of venlafaxine with CYP2C19 (higher concentrations in intermediate metabolizers compared to rapid/ultrarapid metabolizers) and CYP2D6 (lower metabolite-to-parent ratio in poor compared to intermediate and normal metabolizers, and intermediate compared to normal and ultrarapid metabolizers). Pk gene variation did not affect treatment response. Discussion The present data support previous recommendations to reduce starting doses of amitriptyline and to guide dose-adjustments via therapeutic drug monitoring in CYP2D6 poor metabolizers. In addition, we propose including CYP2C19 in routine testing in venlafaxine-treated patients to improve therapy by raising awareness of the risk of low serum concentrations in CYP2C19 rapid/ultrarapid metabolizers. In summary, pk gene variation can predict serum concentrations, and thus the combination of pharmacogenetic testing and therapeutic drug monitoring is a useful tool in a personalized therapy approach for depression.
Une large proportion de patients souffrant de troubles mentaux est en échec thérapeutique. Les médicaments utilisés en psychiatrie sont métabolisés par des enzymes dont l’activité dépend de facteurs pharmacogénétiques en fonction desquels il est possible d’adapter la posologie et d’optimiser le traitement. Les équipes officinales peuvent jouer un rôle clé dans l’implémentation de la pharmacogénétique des traitements psychiatriques en France.
Background Major depressive disorder (MDD) is a highly prevalent psychiatric condition, yet many patients do not receive adequate treatment. Novel and highly scalable interventions such as internet-based cognitive-behavioral-therapy (iCBT) may help to address this treatment gap. Anhedonia, a hallmark symptom of MDD that refers to diminished interest and ability to experience pleasure, has been associated with reduced reactivity in a neural reward circuit that includes medial prefrontal and striatal brain regions. Whether iCBT can reduce anhedonia severity in MDD patients, and whether these therapeutic effects are accompanied by enhanced reward circuit reactivity has yet to be examined. Methods Fifty-two MDD patients were randomly assigned to either 10-week iCBT ( n = 26) or monitored attention control (MAC, n = 26) programs. All patients completed pre- and post-treatment assessments of anhedonia (Snaith–Hamilton Pleasure Scale; SHAPS) and reward circuit reactivity [monetary incentive delay (MID) task during functional magnetic resonance imaging (fMRI)]. Healthy control participants ( n = 42) also underwent two fMRI scans while completing the MID task 10 weeks apart. Results Both iCBT and MAC groups exhibited a reduction in anhedonia severity post-treatment. Nevertheless, only the iCBT group exhibited enhanced nucleus accumbens (Nacc) and subgenual anterior cingulate cortex (sgACC) activation and functional connectivity from pre- to post-treatment in response to reward feedback. Enhanced Nacc and sgACC activations were associated with reduced anhedonia severity following iCBT treatment, with enhanced Nacc activation also mediating the reduction in anhedonia severity post-treatment. Conclusions These findings suggest that increased reward circuit reactivity may contribute to a reduction in anhedonia severity following iCBT treatment for depression.
Cytochromes from the P450 family (CYP) play a central role in the primary metabolism of frequently prescribed antidepressants, potentially affecting their efficacy and tolerance. There are however important differences in the drug metabolic capacities of each individual resulting from a combination of intrinsic and environmental factors. This variability can present an important risk for patients and increases the difficulty of drug prescription in clinical practice. Pharmacogenetic studies have uncovered a number of alleles defining the intrinsic metabolizer status, however, additional factors affecting cytochrome activity can modify this activity and result in a phenoconversion. The present study investigates the discrepancy between the genetically predicted and actually measured activities for the six most important liver cytochromes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) in a cohort of patients under antidepressant treatment, previously shown to have a high proportion of patients with low metabolizing activities. We now performed the genetic characterization of this cohort to determine the extent of the genetic versus environmental contribution in these decreased activities. For all enzyme tested, we observed an important rate of phenoconversion, affecting between 33 % and 65 % of the patients, as well as a significant (p < 1E-06) global reduction in the effective but not predicted activities of CYP2D6, CYP2C9 and CYP2C19 compared to the general population. Our results highlight the advantages of phenotyping versus genotyping as well as the increased risk of treatment failure or adverse effect occurrence in a polymedicated population.
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We undertook a study to confirm and extend preliminary findings that participants with major depressive disorder (MDD) in primary care and specialty care settings have with equivalent degrees of depression severity and an indistinguishable constellation of symptoms. Baseline data were collected for a distinct validation cohort of 2,541 participants (42% primary care) from 14 US regional centers comprised of 41 clinic sites (18 primary care, 23 specialty care). Participants met broadly inclusive eligibility criteria requiring a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of MDD and a minimum depressive symptom score on the 17-item Hamilton Rating Scale for Depression. The main outcome measures were the 30-item Inventory of Depressive Symptomatology--Clinician Rated and the Psychiatric Diagnostic Screening Questionnaire. Primary care and specialty care participants had identical levels of moderately severe depression and identical distributions of depressive severity scores. Both primary care and specialty care participants showed considerable suicide risk, with specialty care participants even more likely to report prior suicide attempts. Core depressive symptoms or concurrent psychiatric disorders were not substantially different between settings. One half of participants in each setting had an anxiety disorder (48.6% primary care vs 51.6% specialty care, P = .143), with social phobia being the most common (25.3% primary care vs 32.1% specialty care, P = .002). For outpatients with nonpsychotic MDD, depressive symptoms and severity vary little between primary care and specialty care settings. In this large, broadly inclusive US sample, the risk factors for chronic and recurrent depressive illness were frequently present, highlighting a clear risk for treatment resistance and the need for aggressive management strategies in both settings.
Major depressive disorder is expected to become the second leading cause of disability worldwide by the year 2020. A large proportion of this disability can be attributed to the large number of patients (>70%) who do not achieve sustained remission following initial treatment. Presently, the evidence available to guide management for treatment-resistant depression (TRD) is quite limited. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study has been designed to evaluate treatment options to improve clinical outcomes for depressed outpatients who do not achieve a satisfactory outcome after one or more treatment attempts. STAR*D helps to define the best "next-step" treatments for patients with TRD, and it will provide descriptive information on the longer-term benefits of successful treatments, as well as the side-effect burden and economic costs associated with different treatments. The study has enrolled over 4,000 patients recruited from primary care and psychiatric settings in the public and private sectors. Preliminary baseline findings are currently being reported. Final results regarding preferred treatment options are expected by May 2006.
Context.— Psychotropic medications are widely prescribed, but how new classes of psychotropic medications have affected prescribing patterns has not been well documented.Objective.— To examine changes between 1985 and 1994 (data from 1993 and 1994 were combined) in the prescribing patterns of psychotropic medications by office-based primary care physicians, psychiatrists, and other medical specialists.Design.— National estimates for the number of visits during which a physician prescribed a psychotropic medication based on the National Ambulatory Medical Care Surveys conducted in 1985, 1993, and 1994.Setting.— Office-based physician practices in the United States.Participants.— A systematically sampled group of office-based physicians.Main Outcome Measures.— National estimates of visits that included a psychotropic medication.Results.— The number of visits during which a psychotropic medication was prescribed increased from 32.73 million to 45.64 million; the proportion of such visits, as a proportion of all visits, increased from 5.1% to 6.5% (P≤.01). Antianxiety or hypnotic drug visits, previously the largest category, decreased as a proportion of psychotropic drug visits (P≤.01) and are now surpassed by antidepressant visits. Visits for depression increased from 10.99 million in 1988 to 20.43 million in 1993 and 1994 (P≤.01). Stimulant drug visits increased from 0.57 million to 2.86 million (P≤.01). Although visits for depression doubled for both primary care physicians and psychiatrists, the proportion of visits for depression during which an antidepressant was prescribed increased for psychiatrists but not for primary care physicians.Conclusions.— The patterns of psychotropic medication use in outpatient medical practice changed dramatically during the study period, especially in psychiatric practice.
Depressive disorders can affect all aspects of a person's functioning and are often associated with significant psychosocial impairment. Such psychosocial problems promote studies of the efficacy of short-term psychotherapy for depressive disorders. This report summarizes the literature on acute-phase, short-term psychotherapy for adult outpatients with major depressive disorder and is an updated component of a larger review commissioned by the United States Public Health Services Agency for Health Care Policy and Research (AHCPR review on "Short-term Psychotherapy for Depression," Jarrett and Maguire [1991]; Jarrett and Down [in press] during the preparation of the Clinical Practice Guidelines in primary care (Depression Guideline Panel 1993). The short-term psychotherapies reviewed here and studied most often include behavior therapy, cognitive therapy, interpersonal psychotherapy, and brief dynamic psychotherapy, which all aim to reduce depressive symptoms. We comment on the state of the literature and raise some of the questions which await data.