WHAT CAN WE LEARN FROM STAR*D (Sequenced Treatment Alternatives to Relieve Depression)

1
WHAT CAN WE LEARN FROM STARD(Sequenced
Treatment Alternatives to Relieve Depression)

• Ira Lesser, M.D.
• Chair, Department of Psychiatry
• Harbor-UCLA Medical Center
• Professor, Department of Psychiatry and
  Biobehavioral Sciences
• Geffen School of Medicine at UCLA

2
DISCLOSURES

• Grant support
• National Institute for Mental Health
• Bristol-Myers Squibb
• Forest Pharmaceuticals
• Aspect Medical Systems

3
Disclosures

• None of my slides and/or handouts contain any
  advertising, trade names or product-group
  messages. Any treatment recommendations I make
  will be based on clinical evidence or guidelines.
• Ira Lesser, M.D.
• Harbor-UCLA Medical Center

4
Focus of Presentation

• Discuss consequences of untreated/partially
  treated depression
• Discuss treatment resistant depression
• Discuss research approaches to study this, e.g.
  efficacy vs effectiveness trials
• Discuss the STARD trial and methodology
• Discuss the STARD results and implications for
  clinical practice

5
Health Burden Of Depression

• MDD is common and recurrent and can be disabling
• Lifetime prevalence 10-15
• Women are affected more than men
• Over 2/3 of people have recurrences
• Depressed adults have twice the annual health
  care costs as non-depressed
• World-wide is the 4th most disabling medical
  condition, climbing to 2nd by 2020

6
Definitions of Response and Remission
Reduction in Score
7
Nonremission is Common

• 3545 remission
• 1020 response with residual symptoms
• 15 partial response
• 25 nonresponse
• 715 intolerant

Depression in Primary Care, Vol. 2. Treatment of
Major Depression. Rockville, MD US Dept. of
Health and Human Services, AHCPR Publication No.
93-0550, 1993.
8
Staging Treatment Resistance
Stage I Inadequate response to 1 monotherapy
Stage II Inadequate response to 2 adequate monotherapy trials (different classes)
Stage III Stage II resistance plus inadequate response to 1 augmentation trial
Stage IV Stage III resistance plus inadequate response to a second augmentation trial
Stage V Stage IV resistance plus inadequate response to bilateral ECT
Adapted from Thase ME, Rush AJ. J Clin
Psychiatry. 199859(suppl 5)5Souery D et al.
Eur Neuropsychopharmacol. 1999983
9
Pharmacological Options After Failure of First
Antidepressant

• Optimize dose and address adherence
• Change to another antidepressant
• Same class
• Different class
• Add a second antidepressant
• Add a non-antidepressant
• Lithium or other mood stabilizer
• Thyroid hormone
• Psychostimulant
• Atypical antipsychotic

10
Efficacy vs Effectiveness Randomized Clinical
Trials

• EFFICACY
• Aims for pure populations
• Assesess safety and efficacy
• Co-morbid conditions excluded
• Rates for MDD response are about 50, 20-30
  remission

• EFFECTIVENESS
• Looks for real world subjects
• Assesess effectivenenss
• Co-morbid conditions are OK
• Rates for MDD response are low

11
The Sequenced Treatment Alternatives to Relieve
Depression (STARD) Trial Rationale and
Design(www.star-d.org)

• A. John Rush, M.D.University of Texas
  Southwestern Medical CenterDallas, Texas

12
Importance of STARD

• The largest clinical trial of depression ever
• Conducted in primary care as well as psychiatric
  settings
• Few exclusion criteria, making it real world
• Included large numbers of minority patients
• Included cognitive therapy
• Combined randomization and patient choice
• The outcome was remission rather than response

13
Why Remission Was the End Point

• Remitters have less disability, better role
  function, life satisfaction, and less recurrences

14
Consequences of Nonremission

• Poor function (e.g., work, family)
• Poor prognosis (e.g., increased recurrence)
• Psychiatric or general medical complications
  (e.g., substance abuse)
• Health service utilization
• Death from
• Medical comorbidities
• Suicide
• Treatment resistance

15
Median Weeks to Relapse Following Response
250
231
200
150
Weeks
100
68
50
0
Remission (n 155)
Improved Without Remission (n 82 )
Relapse defined as onset of new major depressive
episode. Adapted from Judd LL et al. J Affect
Disord. 19985097-108.
16
STARD Overview - I

• Duration 7 years (October 1999 - September 2006)
• Funding National Institute of Mental Health
• National Coordinating Center, UT Southwestern
  Medical Center, Dallas
• Data Coordinating Center, Pittsburgh

17
STARD Overview - II

• 14 Regional Centers
• 41 Clinical Sites
• 18 Primary Care Settings
• 23 Psychiatric Care Settings

18
Overall Aim of STARD

• Define preferred treatments for patients who
  failed one SSRI
• All subjects begin on citalopram
• Doses are maximized
• Remitters enter follow-up
• If no remission, go to level 2 and subsequent
  levels

19
Participants

• Major depressive disorder
• Nonpsychotic
• Representative primary and specialty care
  practices (nonacademic)
• Self-declared patients

20
Inclusion Criteria

• Clinician deems antidepressant medication
  indicated.
• 18-75 years of age.
• Baseline HRSD17 ?14.
• Most concurrent Axis I, II, III disorders allowed.

21
Multiple Research Outcomes

• Symptoms
• Function
• Side effect burden
• Patient and clinician satisfaction
• Utilization and costs of health care services

22
Clinical Procedures

• Open treatment with randomization
• Symptoms/side effects measured at each clinical
  visit
• Clinicians guided by algorithms/supervision
• Dose adjustmentsmandatory to achieve remission
  (QIDS-C16)
• Education for all patients

23
Level 1 Findings
24
Demographic Baseline Features (N2876)
Age (yrs.) 40.8 (13.0) Female 63.7 Race
White 75.8 African-American 17.6
Others 6.6 Latino 13.0 Age Groups 18-30
years 26.2 31-50 years 48.0 51
years 25.8 Education (yrs.) 13.4 (3.2)
Trivedi et al., Am J Psychiatry, 163(1)28-40,
2006
25
Demographic Baseline Features (N2876)
Education lt High School 12.6 High School lt
College 62.2 gt College 25.2 Insurance Private
51.1 Public 14.2 None 34.7 Primary
Care 37.9
Mean (SD) Household Income ( mo.) 2358 (3030)
Trivedi et al., Am J Psychiatry, 163(1)28-40,
2006
26
Social Baseline Features (N2876)
Marital Status Never Married 28.7 Married 41.
7 Divorced 26.5 Widowed 3.1 Employment
Status Employed 56.2 Unemployed 38.2 Retired 5
.6
Trivedi et al., Am J Psychiatry, 163(1)28-40,
2006
27
Clinical Baseline Features (N2876)
Recurrent Depression 75.7 Onset age lt 18
yrs. 37.8 Positive Family History of
Depression 55.5 History of Attempted
Suicide 17.9 Current MDE gt 24 months 25.3 Anxious
Depression 53.2
Trivedi et al., Am J Psychiatry, 163(1)28-40,
2006
28
Clinical Baseline Features (N2876)
Mean
(SD) HRSD17 (ROA) 21.8 (5.2) QIDS-SR16 16.2
(4.0) Age at First Onset (yrs.) 25.3 (14.4) of
MDEs 6.0 (11.4) Length of Current MDE (mos.) 24.6
(51.7) Length of Illness (yrs.) 15.5 (13.2)
Trivedi et al., Am J Psychiatry, 163(1)28-40,
2006
29
Majority Had Concurrent Axis I Disorders at
Baseline (N2876)

Concurrent Axis I Disorders
Trivedi et al., Am J Psychiatry, 163(1)28-40,
2006
30
Concurrent Baseline Axis I Disordersa (N2876)
Generalized Anxiety Dis. 23.6 Obsessive
Compulsive Dis. 14.3 Panic Disorder 13.1 Social
Phobia 31.3 Posttraumatic Stress
Dis. 20.6 Agoraphobia 11.8 Alcohol
Abuse/Dependence 12.1 Drug Abuse/Dependence
7.4 Somatoform Dis. 2.4 Hypochondriasis 4.4 Bulim
ia 13.0
a Defined by PDSQ.
Trivedi et al., Am J Psychiatry, 163(1)28-40,
2006
31
Treatment and Symptom Outcomes (n2876)

• Response (without remission)
• 50 decrease in baseline QIDS-SR16
• Remission
• HAMD17 lt 7
• QIDS-SR16 lt 5
• Citalopram
• Dose (at level exit) 41.8 mg (S.D. 16.8)
• Duration 10.0 weeks (S.D. 4.2)

Trivedi et al., Am J Psychiatry 200616328-40
32
Treatment Outcome Level 1(N2876)
HAMD-1717-item Hamilton Rating Scale for
Depression QIDS-SR-1616-item Quick Inventory of
Depressive Symptomatology Self-Report Trivedi
et al., Am J Psychiatry 200616328-40
33
Similar Outcomes in Primary and Psychiatric Care
Settings (N2876)

Trivedi et al., Am J Psychiatry 200616328-40
34
Remission vs. Non-remission

• Remitters stayed in treatment longer (12 vs. 9.3
  weeks)
• Remitters stayed on final dose longer (6.6 vs.
  4.4 weeks)
• Remitters had less side effect burden

35
Of Ultimate Remitters,1/2 Remitted by Week 6
52.9
n2,876 Remission QIDS-SR16 lt 5
Trivedi et al., Am J Psychiatry, 163(1)28-40,
2006
36
Remission vs. Non-Remission Significant Baseline
Differences

• Female gender
• Being employed
• Caucasian (vs. African-American)
• Being married or co-habitating
• Being more educated
• Having private insurance

• Having less medical problems
• Having less psychiatric co-morbidities
• Lower baseline severity
• Better baseline physical and mental function
• Greater life satisfaction
• Shorter current episode

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Summary Level 1

• Over one-third of patients have been depressed
  for gt2 years and 2/3 have concurrent GMCs
• About 1/3 will remit
• Response occurs in 1/2 AFTER 6 weeks
• Measurement Based Care is feasible and works
• Studies of remission require longer study periods
  than 8 weeks
• When protocol-based care is given, results are
  equivalent in primary and specialty care

38
Level 2 Findings
39
(No Transcript)
40
Level 2
AugmentationOptions
SwitchOptions
41
Acceptability of Treatment Options

• 41 chose only to have medication switch
• 30 chose only to have medication augmentation
• 11 chose to have any augmentation (meds or CBT)
• 7 chose to have any switch (meds or CBT)
• 1.4 chose to have any available option

42
Level 2 Medication Switch
43
Treatment Outcomes Level 2 Switch( remission)
(N-239) (N 238) (N 250)
Rush et al., N Engl J Med 2006354(12)1231-42
44
Level 2 Medication Augmentation
45
Treatment Outcomes Level 2 Augmentation(
remission)
(N 279)
(N 286)
Trivedi et al., N Engl J Med 2006354(12)1243-52
46
Summary Level 2 (switch)

• Mean doses/day bupropion282.7mg
  sertraline135mg venlafaxine193mg
• 25 achieve remission after switching to
  another antidepressant
• No significant differences among various
  antidepressants in achieving remission changing
  class of medication did not make a difference
• Intolerance to citalopram did not predict
  intolerance to sertraline
• Perhaps venlafaxine dose too low

47
Summary Level 2 (augment)

• Mean doses/day bupropion267mg buspirone41mg
• 30 achieve remission augmenting citalopram,
  with no absolute difference between treatments
• Citalopram plus bupropion led to greater degree
  of improvement across subjects
• Bupropion was better tolerated

48
Level 2 Cognitive Therapy Findings
49
Cognitive Therapy Arm

• Certification process for CT therapists
• Session twice weekly for weeks 1-4, then once
  weekly for remaining 8 weeks (16 visits)
• If there was response without remission, could
  offer additional 8 sessions
• 469/1439 (26) of those eligible chose CT as a
  possible option
• 65 switched to CT 36 augmented with CT

50
Treatment Outcomes ( Remission)(L-2 CT vs. Med
Switch)
(N 36)
(N 86)
Thase et al., in preparation
51
Treatment Outcomes ( Remission)(L-2 CT vs. Med
Augment)
(N 65)
(N 117)
Thase et al., in preparation
52
CT Conclusions

• CT is both an acceptable switch and augmentation
  option in the second step
• Benefit of CT as augmentation was slower (up to 3
  weeks) compared to augmenting with medication
• Whether CT responders/remitters fare better in
  follow-up is to be analyzed
• CT was not as popular as expected, thus limiting
  statistical power

53
Level 3
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Level 3 Treatment Features

• Medication switch
• Mirtazapine mean final dose was 42.1 mg
• Nortriptyline mean final dose was 96.8 mg
• Medication augmentation
• Lithium mean final dose was 860 mg
• T3 mean final dose was 45 µg

55
Treatment Outcomes Level 3 Switch (
Remission)
(N 114)
(N 121)
Fava et al., Am J Psychiatry, in press
56
Treatment Outcomes Level 3 Augmentation (
remission)
(N 69)
(N 73)
Nierenberg et al., Am J Psychiatry, submitted
57
Summary Level 3 (switch)

• Remission rates (lt20) and side effect profiles
  with nortriptyline and mirtazapine were not
  different
• Low remission rates raises questions about
  sequential use of single agents after two failed
  trials, even with different pharmacologic action

58
Summary Level 3 (augment)

• Remission rates with switching was modest, at
  best
• Remission rates augmenting with Li or Thyroid
  hormone were not different
• Questions as to whether lithium was adequately
  dosed
• T3 augmentation was better tolerated

59
Level 4
60
Treatment Outcomes Level 4 ( Remission)
(N 58)
(N 51)
McGrath et al., Am J Psychiatry, submitted
61
Summary Level 4

• Mean doses/dayTranylcypromine37mg
  Venlafaxine210mg Mirtazapine36mg
• Dosing was lower than might have been expected
• Tranylcypromine required a washout and had higher
  early dropouts
• Overall remission rates were low, with no
  difference between treatments
• VEN-XR/MIRT had some advantages (tolerability)
  over TCP

62
Remission Rates by Levelsa
Level 1 (2876) 32.9
Level 2 (1439) Switch (789) Augment (650) 30.6 27.0 35.0
Level 3 (377) Switch (235) Augment (142) 13.6 10.3 19.1
Level 4 (109) 14.7
a By QIDS-SR16 lt5 at level exit
63
Follow-up Findings
64
Follow up

• Follow up was naturalistic visits recommended
  every two months
• Patient were told to continue what was effective
  before, but any medication dose change or
  psychotherapy was allowed
• Response and remission defined by QIDS-SR score
  as in acute phase relapse defined by QIDS-SR gt
  11 ( equal to HAM-D of 14)

65
Level 1 Follow-Up
Relapse QIDS-IVR16 gt 11
66
Level 2 Follow-Up
Relapse QIDS-IVR16 gt 11
67
Level 3 Follow-Up
Relapse QIDS-IVR16 gt 11
68
Level 4 Follow-Up
Relapse QIDS-IVR16 gt 11
69
Relapse in Follow-up for Participants Remitting
with Different Numbers of Acute Treatment Steps
plt.0001
1 Step 2 Steps 3 Steps 4 Steps (N1085)
(N383) (N35) (N15)
Relapse QIDS-IVR16 gt 11.
70
Relapse in Follow-up for Participants Not
remitting to Different Numbers of Acute Treatment
Steps
1 Step 2 Steps 3 Steps 4 Steps (N388)
(N237) (N66) (N34)
plt.0001
Relapse QIDS-IVR16 gt 11.
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Summary Follow Up

• Failure to reach remission during acute treatment
  portends a worse prognosis
• Remitters at entry to F/U had better prognosis
  than those who improved, but did not remit
• Relapse rates were higher for those who entered
  F/U after more acute treatment steps
• For those who relapse, mean time to relapse was
  shorter for those who required gt2 steps

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Conclusions

• Cumulative remission rate is over 50 with first
  2 steps
• Both within-class and out-of-class switches are
  equally effective (level 2)
• The duration of acute treatment needed to see
  response was 8-10 weeks
• With careful symptom and medication review
  results are similar in primary and specialty care
• Patient preference plays a big role in strategy
  selection

73
Conclusions

• Pharmacologic distinctions do not lead to large
  clinical differences
• Cognitive therapy is viable switch or augmenting
  option, though many chose not to partake in it
• It is important not to change course too quickly
  nor to give up on multiple sequential strategies
• Psychosocially disadvantaged patients did more
  poorly and may need innovative approaches

74
Future Directions

• Further analyze the cognitive therapy data
• Report multiple sub-analyses
• We need newer approaches to the treatment
  refractory patient
• Develop new medications and treatment protocols
  to address non-remission, e.g. should patients
  with chronic depression be started on two
  medications simultaneously?
• What about combination medication and
  psychotherapy approaches?

75
The STARD Study Investigators

• National Coordinating Center
• A. John Rush, MD
• Madhukar H. Trivedi, MD
• Diane Warden, PhD, MBA
• Melanie M. Biggs, PhD
• Kathy Shores-Wilson, PhD
• Diane Stegman, RNC
• Michael Kashner, PhD, JD
• Data Coordinating Center
• Stephen R. Wisniewski, PhD
• G.K. Balasubramani, PhD
• James F. Luther, MA
• Heather Eng, BA.
• University of Alabama
• Lori Davis, MD

• University of California, Los Angeles
• Andrew Leuchter, MD
• Ira Lesser, MD
• Ian Cook, MD
• Daniel Castro, MD
• University of California, San Diego
• Sidney Zisook, MD
• Ari Albala, MD
• Timothy Dresselhous, MD
• Steven Shuchter, MD
• Terry Schwartz, MD
• Northwestern University Medical School, Chicago
• William T. McKinney, MD
• William S. Gilmer, MD

76
The STARD Study Investigators

• University of Kansas, Wichita and Clinical
  Research Institute
• Sheldon H. Preskorn, MD
• Ahsan Khan, MD
• Massachusetts General Hospital, Boston
• Jonathan Alpert, MD
• Maurizio Fava, MD
• Andrew A. Nierenberg, MD
• University of Michigan, Ann Arbor
• Elizabeth Young, MD
• Michael Klinkman, MD
• Sheila Marcus, MD

• New York State Psychiatric Institute and Columbia
  College of Physicians and Surgeons, New York
• Frederic M. Quitkin, MD
• Patrick J. McGrath, MD
• Jonathan W. Stewart, MD
• Harold Sackeim, PhD
• University of North Carolina, Chapel Hill
• Robert N. Golden, MD
• Bradley N. Gaynes, MD

77
The STARD Study Investigators

• Laureate Healthcare System, Tulsa
• Jeffrey Mitchell, MD
• William Yates, MD
• University of Pittsburgh Medical Center,
  Pittsburgh
• Michael E. Thase, MD
• Edward S. Friedman, MD
• Vanderbilt University Medical Center, Nashville
• Steven Hollon, PhD
• Richard Shelton, MD

• The University of Texas Southwestern Medical
  Center, Dallas
• Mustafa M. Husain, MD
• Michael Downing, MD
• Diane Stegman, RNC
• Laurie MacLeod, RN
• Virginia Commonwealth University, Richmond
• Susan G. Kornstein, MD
• Robert K. Schneider, MD

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Pharmaceutical Industry Support

• STARD medications were provided gratis by
  Bristol-Myers Squibb Company, Forest
  Pharmaceuticals Inc., GlaxoSmithKline, King
  Pharmaceuticals, Organon Inc., Pfizer Inc., and
  Wyeth-Ayerst Laboratories.

79
References
Rush AJ, Fava M, Wisniewski SR et al Sequenced
Treatment Alternatives to Treat Depression
(STARD) rationale and design. Control Clin
Trials 2004 25119-142 Trivedi MH, Rush AJ,
Wisniewski SR et al Evaluation of outcomes with
citaloprram for depression using
measurement-based care in STARD Implications
for clinical practice. Am J Psychiatry 2006
1631-13 Rush AJ, Trivedi M, Wisniewski SR et al
Bupropion-SR, sertraline, or Venlafaxine-XR
after failure of SSRIs for depression. N Engl J
Med 20063541231-42 Trivedi MH, Rush AJ,
Wisniewski SR et al Medication augmentation
after the failure of SSRIs for depression. N
Engl J Med 20063541243-1252
80
References
Fava M, Rush AJ, Wisniewski SR et al A
comparison of mirtazapine and nortriptyline
following two consecutive failed medication
treatments for depressed outpatients a STARD
report. Am J Psychiatry 20061631161-1172
Insel T Beyond efficacy the STARD Trial. Am
J Psychiatry 2006 1635-7 Nierenberg AA, Fava M,
Trivedi MH et al A comparison of lithium and
T3 augmentation following two failed medication
treatments for depression a STARD report. Am
J Psychiatry 20061631519-1530 McGrath PJ,
Stewart JW, Fava M et al Tranylcypromine versus
venlafaxine plus mirtazapine following three
failed antidepressant medication trials for
depression A STARD report. Am J
Psychiatry 20061631531-1541
81
References
Rush AJ, Trivedi MH Wisniewski SR et al Acute
and longer-term outcomes in depressed outpatients
requiring one or several treatment steps a
STARD report. Am J Psychiatry
20061631905-1917 Rubinow DR Treatment
strategies after SSRI failuregood news and bad
news. N Engl J Med 20063541305-1307 Valenstein
M Keeping our eyes on STARD. Am J
Psychiatry 20061631484-1486 Menza M STARD
the results begin to roll in. Am J Psychiatry
2006 1631123-1125 Nelson CJ The STARD study
a four-course meal that leaves us wanting more.
Am J Psychiatry 20061631864-1866 Rush AJ
STARD What have we learned? Am J
psychiatry 2007164201-204Insel T Beyond
efficacy the STARD Trial. Am J Psychiatry
2006 1635-7