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Star d study
1. Star *D Research
Hooman Rowshan, M.D., MSc
Department of Psychiatry
Northern Ontario School Of Medicine
Sudbury, Ontario, Canada
2. Background
Stands for Sequenced Treatment Alternatives to
Relieve Depression (STAR*D) trial
the largest antidepressant effectiveness trial ever
conducted
Presented evidence that antidepressants had
significant effect in relieving depression when
compared to placebo
But the studies protocol and final data have generated
many controversies
3. Background Cont.
designed to identify the best next-step treatment for
the many patients who fail to get adequate relief from
their initial SSRI trial
funded by the NIMH at a cost of $35 million and took
six years to conduct
substantial public health and scientific significance
was the overall aim of the study
The study was deemed reliable because it was
funded with public funds without the involvement from
the pharmaceutical special interest
4. The Sources of Data
STAR*D data came from two sources
One Source was the percentage of patients whose
depression remitted
The other source was percentage of remitted
patients who stayed well during the one-year
follow-up
We use these two sources to review whether the
NIMH and the STAR*D investigators accurately
reported their results, and also whether they disclosed
all the relevant data
5. Basics of Study Design
Basic goal was to test whether a multistep, flexible use
of medications could produce remission in a high
percentage of depressed outpatients
Stage I: Participants were placed on citalopram for the
initial period of three months
Stage II: those who did not respond to stage I trial were
either put on a different antidepressant or given a
second drug to augment an antidepressant
Stage III: participants again had the option of either
switching to a different medication or adding on to their
existing medication
6. Basics of Study Design Cont.
Stage III: participants were also randomly prescribed
lithium — a mood stabilizer commonly used to treat
bipolar disorder
Stage IV: monoamine oxidase inhibitor (MAOI) and or
the combination of venlafaxine extended release
(Effexor XR) with mirtazapine (Remeron)
The design of the STAR*D study reflects what is done in
clinical practice because it allowed study participants to
choose certain treatment strategies most acceptable to
them and limited the randomization of each participant
only to his/her range of acceptable treatment strategies
7. Misrepresentation of Data
In the years following the initial data release from
Star*D study, subsequent investigators have
discovered some blatant misrepresentation of data
by the study’s investigators
The subjects who started on Celexa in the initial step
of the trial but then dropped out without having their
symptoms measured were supposed to be counted as
treatment failures
The study investigators did not count these patients
as failures when they calculated the remission and
response rates
8. Symptoms Measurement
The study protocol called for the use of Hamilton
Rating Scale of Depression (HRSD) to measure the
severity of depression for enrollment into the study
and for determination of response and remission rates
The study protocol required enrollment of subjects
with major depression however the investigators
included participants with mild depression as
evidenced by their HRSD scores
The net effect was to to inflate the study’s reported
response and remission rates
9. Symptoms Measurement Cont.
Although the primary instrument for measuring the
participants symptoms was HRSD, the study
investigator violated their own study protocol and
changed rating instruments
switched to reporting outcomes as measured by the
Quick Inventory of Depressive Symptoms-Self
Report (QIDS-SR) scale
HRSD and QIDS-SR are not equivalent scales and
their results are not interchangeable
QIDS-SR had a dramatic impact on inflating
STAR*D's published remission and response rates
10. Study Participants
There were a total of 4,041 patients who entered the
study
The primary investigators reported a 40% total
remission rate at the conclusion of the study six years
later
The actual remission rate as evidenced by the data after
adjusting for other study flaws such as change in the
symptoms measurements and including the drop outs
as failures, the actual remission rate was only around
3%
The revised number of patients who actually showed
remission was only 108/40,41 or about 3%
11. The Stay-Well Data
investigators designed the study to maximize the stay-
well rate during a one-year period of "continuing care
higher percentage for those who remitted in stage four
of treatment compared to Stage I program
it seemed that a majority of the remitted patients had
stayed well, which was fairly encouraging
The total remission rate was said to be around 40%
12. The Stay-Well Data Cont.
The real remission rate during the stay well period
really around 3%. But was this number even
accurate?
many of the 108 stay-well patients may have come
from the group of 607 patients who had a baseline
HRSD score ≤14, and shouldn't have been included
in the analysis in the first place
This means even the adjusted 3% overall success
rate may even be too misleading because patient
with mild depression should not have been included
as subjects
13. Summary of Misleading Data
40% of all patients who entered the trial had recovered
and stayed well, when in fact only 3% or less of the
entering patients had a "sustained remission”
Even the 3% success rate may be inflated if we
assume some of the participants had only mild
depression at the beginning of the study and should not
have been included in the first place
They reported remission rates based on the QIDS-SR
scale, even though the pre-specified primary outcome
scale was the HRSD, and this switch inflated the
remission numbers
14. Investigators’ Response
One of the study authors is Maurizio Fava who is a
well regarded psychiatrist at Massachusetts General
Hospital affiliated with Harvard Medical School
He has acknowledged that the low remission and
stay-well rates reported by critics of the study are
accurate
He has acknowledged the STAR*D investigators knew
they were reporting the data in a misleading fashion
and that the real information was in their published
reports but could not be easily discerned
15. What About “treatment-
emergent" suicidal ideation
In the Journal of Clinical Psychopharmacology article,
the STAR*D investigators wrote that "suicidal
ideation was the least common treatment-
emergent symptom”
They reported suicidal ideation was present only in
.7% of patients
They concluded that "this study provides new
evidence to suggest little to no relation between
use of a selective serotonin reuptake inhibitor and
self-reported suicidal ideation."
16. treatment-emergent" suicidal
ideation Cont.
More than 6% of patients taking Celexa
experienced treatment-emergent suicidal ideation
This comes from FDA’s own data, which was
collected during the approval process for Celexa
Other SSRI drugs have similar data regarding
possible link between treatment and suicidal ideation
It seems the Star*D investigators wanted to remove
the link between SSRIs and the risk of suicide
17. Why Did they misrepresent the
data on Suicidal Ideation
The Star*D investigator had a conflict of interest
They were filing for a patent on a biomarker they
claimed they found to identify the patients who may
have suicidal ideation secondary to taking SSRIs
A high suicidal ideation rate would have rendered
their patent much more valuable so why minimize the
suicidal ideation risk?
All the investigators had close financial relationship
with the maker of Celexa
18. Pharmaceutical Companies
and Their Influence On
Research
Many researchers have direct or indirect interests in
pharmaceutical industry and those interests are often at
odds with academic or scientific integrity. This problem is
particularly disturbing in the United States where most
studies originate
Researchers will sift through the data for various
populations or groups and then publish results that make
the drug look good. This is called “data mining”
By so doing the researchers are using a subset of data
and presenting them as global evidence to support a
particular proposition against or in favor of a particular
drug
19. Why Did Researchers Change
From HRSD To QIDS-SR
It was discovered by the critics of Star*D study that
one of the investigators had a specific conflict of
interest
John Rush owned the copyright for the QIDS-SR
Thus, using the QIDS-SR to assess outcomes in this
prominent trial would serve to validate its use, and
this promised to make the copyright much more
valuable
This conflict of interest was not disclose
20. What can we take away from
Star*D Study
antidepressants are only "marginally efficacious” as
compared to placebo
In other words, if you're trying to look at sustained
benefit, you're only looking at 3 % which is pretty low
There are likely some people for whom
antidepressants are truly beneficial beyond placebo
right now we simply have no way of knowing who
those people are
21. Take Away Message Cont.
It's doesn't mean that clinicians shouldn't use
antidepressants, but they should recognize that
there's a limitation to their effectiveness
Lack of long-term efficacy for antidepressants
study suggests the importance of developing
biomarkers to identify patients who really need
these antidepressants both in the short and the
long term
Clinician should not alter their current use of
antidepressant therapy because Star*D results are
biased and cannot be relied upon