Transcript Treatment Resistant Depression: What Is It and What To Do

WHAT CAN WE LEARN FROM
STAR*D
(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
DISCLOSURES

Grant support
• National Institute for Mental Health
• Bristol-Myers Squibb
• Forest Pharmaceuticals
• Aspect Medical Systems
Disclosures

None of my slides and/or handouts contain
any advertising, trade names or productgroup messages. Any treatment
recommendations I make will be based on
clinical evidence or guidelines.
Ira Lesser, M.D.
Harbor-UCLA Medical Center
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 STAR*D trial and methodology
Discuss the STAR*D results and implications
for clinical practice
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
Definitions of Response
and Remission
% Reduction in Score
Remission
>75%
Response
50% - 74%
Partial Response 25% - 49%
Nonresponse
<25%
Nonremission is Common





35–45% remission
10–20% response with residual symptoms
15% partial response
25% nonresponse
7–15% 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.
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 IV resistance plus inadequate
response to bilateral ECT
Stage V
Adapted from: Thase ME, Rush AJ. J Clin Psychiatry. 1998;59(suppl 5):5
Souery D et al. Eur Neuropsychopharmacol. 1999;9:83
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
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
The Sequenced Treatment
Alternatives to Relieve
Depression (STAR*D) Trial
Rationale and Design
(www.star-d.org)
A. John Rush, M.D.
University of Texas Southwestern Medical Center
Dallas, Texas
Importance of STAR*D







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”
Why Remission Was the
End Point
Remitters have less disability,
better role function, life
satisfaction, and less recurrences
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
Median Weeks to Relapse*
Following Response
250
231
Weeks
200
150
100
50
68
0
Improved
Without
Remission
(n = 82 )
Remission
(n = 155)
*Relapse defined as onset of new major depressive episode.
Adapted from Judd LL et al. J Affect Disord. 1998;50:97-108.
STAR*D 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
STAR*D Overview - II

14 Regional Centers

41 Clinical Sites

18 Primary Care Settings

23 Psychiatric Care Settings
Overall Aim of STAR*D

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
Participants

Major depressive disorder

Nonpsychotic

Representative primary and
specialty care practices
(nonacademic)

Self-declared patients
Inclusion Criteria

Clinician deems antidepressant
medication indicated.

18-75 years of age.

Baseline HRSD17 14.

Most concurrent Axis I, II, III
disorders allowed.
Multiple Research Outcomes

Symptoms

Function

Side effect burden

Patient and clinician satisfaction

Utilization and costs of health
care services
Clinical Procedures

Open treatment with randomization

Symptoms/side effects measured at
each clinical visit

Clinicians guided by algorithms/
supervision

Dose adjustments”mandatory” to
achieve remission (QIDS-C16)

Education for all patients
Level 1 Findings
Demographic Baseline Features
(N=2876)
Age (yrs.)
% Female
Race
% White
% African-American
% Others
% Latino
Age Groups
18-30 years
31-50 years
51+ years
Education (yrs.)
Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006
40.8 (13.0)
63.7
75.8
17.6
6.6
13.0
26.2
48.0
25.8
13.4 (3.2)
Demographic Baseline Features
(N=2876)
Education
< High School
High School < College
> College
Insurance
Private
Public
None
% Primary Care
Household Income ($ mo.)
Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006
%
12.6
62.2
25.2
51.1
14.2
34.7
37.9
Mean (SD)
2358 (3030)
Social Baseline Features
(N=2876)
Marital Status
Never Married
Married
Divorced
Widowed
Employment Status
Employed
Unemployed
Retired
Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006
%
28.7
41.7
26.5
3.1
56.2
38.2
5.6
Clinical Baseline Features
(N=2876)
%
Recurrent Depression
75.7
Onset age < 18 yrs.
37.8
Positive Family History of Depression 55.5
History of Attempted Suicide
17.9
Current MDE > 24 months
25.3
Anxious Depression
53.2
Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006
Clinical Baseline Features
(N=2876)
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
Majority Had Concurrent Axis I
Disorders at Baseline
(N=2876)
40
35
34.8
30
%
26.6
25
20
16.5
15
12.9
9.2
10
5
0
0
1
2
3
# Concurrent Axis I Disorders
Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006
> or = 4
Concurrent Baseline Axis I
Disordersa (N=2876)
Generalized Anxiety Dis.
Obsessive Compulsive Dis.
Panic Disorder
Social Phobia
Posttraumatic Stress Dis.
Agoraphobia
Alcohol Abuse/Dependence
Drug Abuse/Dependence
Somatoform Dis.
Hypochondriasis
Bulimia
Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006
a
%
23.6
14.3
13.1
31.3
20.6
11.8
12.1
7.4
2.4
4.4
13.0
Defined by PDSQ.
Treatment and Symptom
Outcomes (n=2876)

Response (without remission)
• 50% decrease in baseline QIDS-SR16


Remission
• HAMD17
<7
• QIDS-SR16
<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 2006;163:28-40
Treatment Outcome: Level 1
(N=2876)
100
90
80
70
60
%
50
47
40
HRSD-17
QIDS-SR-16
27.5
30
20
32.9
10
0
Response
Remission
HAMD-17=17-item Hamilton Rating Scale for Depression
QIDS-SR-16=16-item Quick Inventory of Depressive Symptomatology – Self-Report
Trivedi et al., Am J Psychiatry 2006;163:28-40
Similar Outcomes in Primary and
Psychiatric Care Settings
(N=2876)
100
90
%
80
QIDS-SR-16 Response
70
HRSD-17 Remission
60
50
40
30
48
46
26.6
28
20
10
0
Primary Care
Trivedi et al., Am J Psychiatry 2006;163:28-40
Psychiatric Care
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
Of Ultimate Remitters,
1/2 Remitted by Week 6
52.9%
25.0
22.1
Percent
20.0
n=2,876
19.4
Remission= QIDS-SR16 < 5
14.5
15.0
12.9
12.9
11.4
10.0
10.0
5.0
0.0
2
4
Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006
6
8
Weeks
10
12
>13
Remission vs. Non-Remission:
Significant Baseline Differences






Female gender
Being employed
Caucasian (vs. AfricanAmerican)
Being married or cohabitating
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
Summary: Level 1

Over one-third of patients have been depressed
for >2 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
Level 2 Findings
Level 2
Randomize
SER
BUP-SR VEN-XR
Switch
Options
CT
CIT +
CIT + CIT +
CT
BUP-SR BUS
Augmentation
Options
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
Level 2 Medication Switch
Treatment Outcomes: Level 2 Switch
(% remission)
30
HRSD-17
QIDS-SR-16
26.6
25.5
24.8
25.0
21.3
20
17.6
Percent
10
0
BUP-SR
SERT
(N-239)
(N = 238)
Rush et al., N Engl J Med 2006;354(12):1231-42
VEN-XR
(N = 250)
Level 2 Medication
Augmentation
Treatment Outcomes: Level 2
Augmentation
(% remission)
50
HRSD-17
39.0
40
30
QIDS-SR-16
29.7
32.9
30.1
Percent
20
10
0
BUP-SR
(N = 279)
Trivedi et al., N Engl J Med 2006;354(12):1243-52
BUS
(N = 286)
Summary: Level 2 (switch)





Mean doses/day: bupropion=282.7mg;
sertraline=135mg; venlafaxine=193mg
~ 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
Summary: Level 2 (augment)




Mean doses/day: bupropion=267mg;
buspirone=41mg
~ 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
Level 2 Cognitive Therapy
Findings
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
Treatment Outcomes
(% Remission)
(L-2 CT vs. Med Switch)
40
HRSD-17
QIDS-SR-16
30.6
30
27.9
26.7
25.0
Percent 20
10
0
CT
(N = 36)
Thase et al., in preparation
MED
(N = 86)
Treatment Outcomes
(% Remission)
(L-2 CT vs. Med Augment)
40
HRSD-17
QIDS-SR-16
30.8
33.3
33.3
30
23.1
Percent 20
10
0
CT
(N = 65)
Thase et al., in preparation
MED
(N = 117)
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
Level 3
Randomize
MRT
Switch
NTP
L-2 Tx +
Li
L-2 Tx +
THY
Augmentation
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
Treatment Outcomes: Level 3 Switch
(% Remission)
30
HRSD-17
QIDS-SR-16
19.8
20
Percent
12.4
12.3
10
8.0
0
MIRT
(N = 114)
Fava et al., Am J Psychiatry, in press
NTP
(N = 121)
Treatment Outcomes: Level 3
Augmentation (% remission)
30
HRSD-17
QIDS-SR-16
24.7
24.7
20
15.9
Percent
13.2
10
0
Nierenberg et al., Am J Psychiatry, submitted
Lithium
Thyroid
(N = 69)
(N = 73)
Summary: Level 3 (switch)

Remission rates (<20%) 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
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
Level 4
Randomize
TCP
VEN-XR +
MRT
Switch
Treatment Outcomes: Level 4
(% Remission)
20
HRSD-17
QIDS-SR-16
15.7
13.8
13.7
Percent 10
6.9
0
TCP
(N = 58)
McGrath et al., Am J Psychiatry, submitted
VEN + MIRT
(N = 51)
Summary: Level 4

Mean doses/day:Tranylcypromine=37mg;
Venlafaxine=210mg; Mirtazapine=36mg

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
Remission Rates by Levelsa
a
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
By QIDS-SR16 <5 at level exit
Follow-up Findings
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 > 11 (~ equal to HAM-D of 14)
Level 1 Follow-Up
1
0.75
Cumulative
0.5
Probability
0.25
Yes
Remission
No
0
0
p < 0.0001
Relapse = QIDS-IVR16 > 11
3
6
Months in Follow-Up
9
12
Level 2 Follow-Up
1
0.75
Cumulative
0.5
Probability
0.25
Yes
Remission
No
0
0
p < 0.0001
Relapse = QIDS-IVR16 > 11
3
6
Months in Follow-Up
9
12
Level 3 Follow-Up
1
0.75
Cumulative
0.5
Probability
0.25
Yes
Remission
No
0
0
p < 0.0132
Relapse = QIDS-IVR16 > 11
3
6
Months in Follow-Up
9
12
Level 4 Follow-Up
1
0.75
Cumulative
0.5
Probability
0.25
Yes
Remission
No
0
0
p < 0.1387
Relapse = QIDS-IVR16 > 11
3
6
Months in Follow-Up
9
12
Relapse in Follow-up for Participants
Remitting with Different Numbers of
Acute Treatment Steps
p<.0001
1 Step
2 Steps
(N=1085) (N=383)
Relapse = QIDS-IVR16 > 11.
3 Steps
4 Steps
(N=35)
(N=15)
Relapse in Follow-up for Participants
Not remitting to Different Numbers
of Acute Treatment Steps
1 Step
2 Steps
3 Steps
4 Steps
(N=388)
(N=237)
(N=66)
(N=34)
p<.0001
Relapse = QIDS-IVR16 > 11.
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 >2 steps
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
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
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?
The STAR*D Study Investigators
National Coordinating Center University of California, Los
Angeles
A. John Rush, MD
Andrew Leuchter, MD
Madhukar H. Trivedi, MD
Ira Lesser, MD
Diane Warden, PhD, MBA
Ian Cook, MD
Melanie M. Biggs, PhD
Daniel Castro, MD
Kathy Shores-Wilson, PhD
University of California, San
Diane Stegman, RNC
Diego
Michael Kashner, PhD, JD
Sidney Zisook, MD
Data Coordinating Center
Ari Albala, MD
Stephen R. Wisniewski, PhD
Timothy Dresselhous, MD
G.K. Balasubramani, PhD
Steven Shuchter, MD
James F. Luther, MA
Terry Schwartz, MD
Heather Eng, BA.
Northwestern University
University of Alabama
Medical School, Chicago
Lori Davis, MD
William T. McKinney, MD
William S. Gilmer, MD
The STAR*D Study Investigators
University of Kansas, Wichita New York State Psychiatric
and Clinical Research
Institute and Columbia
Institute
College of Physicians and
Sheldon H. Preskorn, MD
Surgeons, New York
Ahsan Khan, MD
Frederic M. Quitkin, MD
Massachusetts General
Patrick J. McGrath, MD
Hospital, Boston
Jonathan W. Stewart, MD
Jonathan Alpert, MD
Harold Sackeim, PhD
Maurizio Fava, MD
University of North Carolina,
Andrew A. Nierenberg, MD
Chapel Hill
University of Michigan, Ann
Arbor
Robert N. Golden, MD
Elizabeth Young, MD
Bradley N. Gaynes, MD
Michael Klinkman, MD
Sheila Marcus, MD
The STAR*D Study Investigators
Laureate Healthcare System, The University of Texas
Tulsa
Southwestern Medical
Jeffrey Mitchell, MD
Center, Dallas
William Yates, MD
Mustafa M. Husain, MD
University of Pittsburgh
Michael Downing, MD
Medical Center, Pittsburgh
Diane Stegman, RNC
Michael E. Thase, MD
Laurie MacLeod, RN
Edward S. Friedman, MD
Vanderbilt University Medical Virginia Commonwealth
University, Richmond
Center, Nashville
Susan G. Kornstein, MD
Steven Hollon, PhD
Richard Shelton, MD
Robert K. Schneider, MD
Pharmaceutical Industry Support
STAR*D medications were provided
gratis by Bristol-Myers Squibb
Company, Forest Pharmaceuticals Inc.,
GlaxoSmithKline, King
Pharmaceuticals, Organon Inc., Pfizer
Inc., and Wyeth-Ayerst Laboratories.
References
Rush AJ, Fava M, Wisniewski SR et al: Sequenced Treatment
Alternatives to Treat Depression (STAR*D): rationale and design.
Control Clin Trials 2004; 25:119-142
Trivedi MH, Rush AJ, Wisniewski SR et al: Evaluation of outcomes
with citaloprram for depression using measurement-based care in
STAR*D: Implications for clinical practice. Am J Psychiatry 2006;
163:1-13
Rush AJ, Trivedi M, Wisniewski SR et al: Bupropion-SR, sertraline,
or Venlafaxine-XR after failure of SSRIs for depression. N Engl J
Med 2006;354:1231-42
Trivedi MH, Rush AJ, Wisniewski SR et al: Medication
augmentation after the failure of SSRIs for depression. N Engl J
Med 2006;354:1243-1252
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 STAR*D report.
Am J Psychiatry 2006;163:1161-1172
Insel T: Beyond efficacy: the STAR*D Trial. Am J Psychiatry
2006; 163:5-7
Nierenberg AA, Fava M, Trivedi MH et al: A comparison of
lithium and T3 augmentation following two failed medication
treatments for depression: a STAR*D report. Am J Psychiatry
2006;163:1519-1530
McGrath PJ, Stewart JW, Fava M et al: Tranylcypromine versus
venlafaxine plus mirtazapine following three failed antidepressant
medication trials for depression: A STAR*D report. Am J Psychiatry
2006:163:1531-1541
References
Rush AJ, Trivedi MH Wisniewski SR et al: Acute and longer-term
outcomes in depressed outpatients requiring one or several
treatment steps: a STAR*D report. Am J Psychiatry
2006;163:1905-1917
Rubinow DR: Treatment strategies after SSRI failure—good
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