Critical Review of Star D Research Findings

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

22. The End
Thank You!
rowshan_h@rogers.com