The STAR*D trial was a large, multi-center study that examined the effectiveness of different treatment options for patients with unipolar depression who did not achieve remission with an initial antidepressant. Over 4,000 outpatients were treated across four levels of sequentially increasing treatment intensity. The study found that after two treatment steps, around 67% of patients achieved remission, but relapse rates were high. Patients with more severe and chronic illness required more treatment steps to achieve remission. While the study provided important real-world data on treating depression, it had some limitations like lack of placebo groups and small sample sizes in later levels.

1. STAR*D
Sequenced Treatment Alternatives To Relieve Depression
-Dr.maithri[1st yr pg psychiatry]
Moderator-Dr.Sai kiran Pasupula
Assistant Professor

2. INTRODUCTION

3. STAR*D, funded in 1998, 7-year trial, $35 million, multi-
center, prospective, sequentially randomized controlled trial
of outpatients who had non-psychotic unipolar depression.
14 regional research centers across the USA, over 120
physicians with 23 psychiatry and 18 primary care facilities
used.
Funded by National Institute of Mental Health;
National Coordinating Center at Southwestern Medical
Center, Dallas and Data Coordinating Center at Pittsburgh.

4. RATIONALE

5. • Major depressive disorder is a common, usually recurrent,
and often chronic disorder.
• MDD causes substantial disability
• Actual acceptability, clinical benefit, and side effect burden
of treatment in community populations is not well known.
• It remains unclear how to help depressed persons who
respond to treatment but do not attain full remission.

6. AIMS & OBJECTIVES

7. Primary Objectives:
• To determine the comparative effectiveness of different
treatment options for MDD.
• Evaluate the comparative effectiveness of these treatments
when they are used to either augment the previous treatment
or as new treatments for participants without a satisfactory
response to an initial SSRI medication.
• To correlate clinical outcomes – symptom profile,
functioning, side effect burden, quality of life, and
participant satisfaction.

8. Secondary objectives:
• To determine the incidence, nature, and timing of relapses
(< 6 months after remission) or recurrences (> 6 months
after remission) during follow-up.
• To relate the clinical outcomes to the treatment costs and
feasibility.

9. RESEARCH DESIGN & METHODS

10. • Patient selection
– Inclusion Criteria
– Exclusion Criteria
• Study centres
• Clinical Research Staff
• Randomization
• Assessments
• Statistical Analysis

11. Inclusion criteria:
• Age range: 18–75 years.
• Around 4000 Outpatients with non-psychotic MDD.
• A score of >14 on the HAM-D.
• Outpatients for whom antidepressant treatment is deemed
appropriate by the treating clinician.
• Participants with suicidal ideation are eligible, as long as
outpatient treatment is deemed safe by the clinician.
• Participants who have comorbid General Medical
Conditions are also eligible.

12. Exclusion criteria:
• Non-response or intolerability in the current major
depressive episode to one or more treatments.
• Lifetime history of Bipolar disorder, Schizophrenia,
Schizoaffective disorder, or MDD with Psychotic features.
• Primary diagnosis of anorexia nervosa, bulimia nervosa,
or Obsessive-Compulsive disorder.
• Participants who are likely to require hospitalization
within six months from study entry.
• Substance dependence disorders who require inpatient
detoxification.

13. • Participants with concurrent psychiatric or medical
conditions that are relative or absolute contraindications to
the use of more than one treatment option within the
protocol.

14. Study Centre:
• 23 psychiatry and 18 primary care centres covering various
geographical distribution across USA.

15. Randomization:
Equipoise stratified randomization.
• Developed to allow the greatest number of patients to
contribute data and comparison.
• Clinician defines a list of specific study treatments that are
acceptable and are of rough parity called “equipoise
stratum”.
• Assignment to e-stratum depends on patient’s
characteristics, tolerability to side-effects, response to
treatment or individual preferences.

16. • Finally, ES design randomly assigns each patient to a
specific option within that patient’s e-stratum.
• Advantages: Recruitment open to most patients, Efficient
recruitment process, and Adaptation to patient and clinician
preferences.

17. Level 2A
Level 2
Level 3
Level 4
Level 1
STAR*D Treatment Algorithm
• Initial treatment: Citalopram
• Switch to Bup[SR] / Ven[ER] / Sert / CT
• Augment with Bup[SR] / Bus / CT
• Only for those receiving CT, Switch to Bup /
Ven if exiting level 2
• Switch to Mirt / Nortryp
• Augment with Lithium / T3
• Switch to Tranylcypromine / Mirt + Ven[ER]

18. Assessments:
DOMAIN MEASURE
Symptoms HAM-D,QIDS
Function SF-12
Side Effects FIBSER
Participant Satisfaction PSI

19. • Assessments will be done at weeks 0, 2, 4, 6, 9, and 12 in
clinic visits.
• Psychotherapy visits are to be twice a week for weeks 1- 4,
then once a week for 8 weeks.
• Follow-up research outcomes assessments conducted every
3 months for a period of 12 months.

20. Statistical Analysis:
• Chi-square tests for association,
• Logistic regression,
• Analysis of variance (ANOVA), and
• Analysis of covariance (ANCOVA) were utilized to test the
hypothesis.

21. Overview of STAR*D study

23. RESULTS

24. • Response: At least a 50% reduction from treatment step
entry in QIDS-SR score.
• Remission: QIDS-SR score ≤5; corresponding to an HRSD
score of ≤7.
• Relapse: When the QIDS-SR score collected during the
follow-up phase was ≥11 ; corresponding to an HRSD ≥14.
• Treatment intolerant: If participants left the relevant
acute treatment step prior to 4 weeks for any reason, or if
the reason for leaving was not obtained, or the treatment
step exit form indicated intolerance.

26. LEVEL 1:
• Outcomes from level 1 were reported in January 2006.
• About 30% of patients achieved the goal of remission of
symptoms.
• Mean dose of citalopram was 41.8 mg, and mean duration
of treatment was 47 days.
• Higher rates of remission were associated with: female,
caucasian, higher education level, marriage or cohabitation,
employed, insured, shorter current episode, and fewer
concurrent general medical or psychiatric disorders.

27. • 33.5% of those reaching remission in level 1 were
subsequently relapsed during the follow-up period.
• Thus, for some 70% of patients, citalopram alone is
insufficient to sustain long-term remission.
(Trivedi & Rush et al.,Am J Psychiatry 2006;163:28–40.)

28. LEVEL 2 :
• Results were published in March 2006.
• Intolerance to one SSRI (citalopram) did not predict
intolerance to another SSRI (sertraline).
• In the augmentation phase, approximately 30% of patients
treated with either bupropion-SR or buspirone in addition to
their citalopram achieved remission.
• Long-term relapse rates for level 2 responders totaled an
alarming 47.4%.
• The rate was higher for patients who improved, but did not
achieve remission.
(Trivedi & Fava et al., N Engl J Med 2006;354:1243–52.)

29. LEVEL 3:
• Results were published for the switching phase and
augmentation phase of the study.
• 15.9% of lithium-treated patients and 24.7% of T3 treated
patients achieved remission.
• Authors favored T3 treatment over lithium, because of
advantages in effectiveness and tolerability, and lack of
need for blood level monitoring.
(Fava & Rush et al., Am J Psychiatry 2006;163:1161–72.)

30. • Switch phase of level 3 treatment studied given either
mirtazapine or nortriptyline.
• Remission rates did not differ significantly for these two
medications.
• 12.3% for mirtazapine and 19.8% for nortriptyline.
• There was no difference in tolerability or adverse events.
• Authors suggest there may be only limited utility to three
sequential monotherapies for depression treatment.
(Fava & Rush et al., Am J Psychiatry 2006;163:1161–72.)

31. LEVEL 4:
• Evaluated additional treatment options, MAOI or
combination therapy.
• Participants showed minimal improvement from their level
1 baseline scores.
• The comorbidity burden was high, 64.2% of entrants having
at least one general medical condition.
• 76% had at least one additional Axis I comorbid condition,
and over 19% had at least four.
• The overall remission rate was 13.0%, but 50% of these
remitters subsequently relapsed.

32. • Patients taking the MAOI tranylcypromine were more likely
to exit the study because of side effects.
• More tolerable side effect burden and the lack of dietary
interactions favor combination therapy with venlafaxine-XR
and mirtazapine for highly treatment-resistant depression
patients.
(McGrath & Stewart et al., Am J Psychiatry 2006;163:1531–41.)

33. Overall remission, relapse, and intolerance rates in STAR*D
{Robert Cain, Prim Care Clin Office Pract 34 (2007) 505–519}
N Remission
(%)
Response
(%)
Relapse
(%)
Intolerance
(%)
Level 1 3671 32.9 48.6 33.5 16.3
Level 2 1439 30.6 28.5 47.4 19.5
Level 3 390 13.7 16.8 42.9 25.6
Level 4 123 13.0 16.3 50.0 30.1

35. Acute and Longer-Term Outcomes in Depressed
Outpatients Requiring One or Several Treatment Steps:
A STAR*D Report.
(Rush & Trivedi et al., Am J Psychiatry 2006; 163:1905-1917.)
Conclusions
• After two treatment steps, over 50% of patients achieve
remission if they stay in treatment (36.8% step 1 plus 30.6%
of the remaining 63.2% of patients).
• The theoretical cumulative remission rate after four acute
treatment steps was 67%.
• Greater illness burden (i.e., depression chronicity,
psychiatric or general medical comorbidity) was
characteristic of those who required more treatment steps.

36. • Chances of subsequent remission are much lower.
• At entry into the follow-up phase, remission, as opposed to
improvement without remission, was associated with a
better prognosis.
• Poor outcomes in participants who require more treatment
steps independent of whether or not they were in remission
at entry into the follow-up phase.
• Studies to identify the best multi-step treatment sequences
for individual patients and the development of more broadly
effective treatments are needed.

37. CRITIQUE

38. Strengths:
• Large sample size, multi-center, well funded project.
• Inclusion of patients from both primary care and tertiary
centers.
• Patient is an active participant in the decision process,
mimicking real-world clinical decision-making.
• Broad inclusion criteria ensured a real-world patient
population.
• It is the ‘‘real world’’ focus that makes STAR*D a
landmark study.

39. Limitations:
• Lack of placebo controls make it difficult to account for
nonspecific treatment effects, which have been substantial
in depression studies.
• Use of a single agent (citalopram) at level 1 limits the
generalization, what about the role of other antidepressants
which are potential first line drugs.
• The STAR*D protocols were not blinded to patients or
clinicians, fostering inherent participant and observer bias.
• The number of participants in Level 3 & 4 are small, results
cannot be generalized.

40. • Excluded severe depression with psychotic symptoms or
suicidality requiring hospitalization.
• No mention on role of Electro convulsive therapy.