NIMH Practical Trials:
Implications for Practice
and Policy
Matthew V. Rudorfer, M.D.
Division of Services & Intervention Research
National Institute of Mental Health
June 5, 2007
Two Kinds of
Translational Research
Bench
Bedside
Pathophysiology
Diagnostic tests
Biomarkers
New treatments
Practice
Practical Trials
Clinical Trials Networks
Services Research
Dissemination & Implementation
Utility of Large Studies –
“Practical Clinical Trials”
• Public health perspective on clinical issues
– Big questions and community effect
– Chronic diseases require long term look
• Longitudinal follow-up and link intermediate change
to long term outcomes
• Linkage of biological (biomarker, genetics – Perlis et
al, STAR*D, Arch Gen Psychiatry June 2007) and
clinical data; potential for targeted interventions
• Identification of subgroups (differential response -“personalized treatment”)
Personalized Treatment
Optimizing the Benefit:Risk Ratio
Practical Clinical Trials:
NIMH Approach
• 1999 – 2006: Multiple large clinical trials
launched under contract mechanism
• 2006 – onward: With completion of practical
trials, infrastructure for disorder-focused
clinical trials networks formed from nucleus
of high-performing sites + coordinating center
Clinical Trial Design
Patients
Phase
N
Settings
Masked Treatment
Masked Raters
Outcome
Measures
Efficacy
Effectiveness
Narrow dx; few
comorbidities or
concurrent meds
II, III
Few exclusion
criteria
10s – 100s
Health care
100s – 1,000s
Various
Yes (Protocol)
No (Clinician /
Algorithm)
Yes
Yes
Symptomatic only
III, IV
Functional, Cost/
Utilization as well
Methodology Designed for High
Generalizability in Practical Trials
• Equipoise design, in some cases using patient preference,
reflects practice, increasing generalizability of findings
• Real-world patients enrolled (comorbidities OK)
• Use of cutting-edge technology, e.g. Web-based quality
control of treatment, ratings entry via IVR
• Advances in valid and reliable clinical ratings, e.g. QIDSC or QIDS-SR instead of traditional Hamilton score; “allcause discontinuation” as a measure of effectiveness
• Outcomes beyond symptomatic ratings, e.g. quality of life,
functional measures
NIMH Contracts:
Practical Clinical Trials
• STEP-BD (Bipolar Disorder)
– 4,360 / 13 sites
– Standard care and random pathways
• CATIE (Schizophrenia / Alzheimer’s Disease)
– 1,914 / 57 sites
– 1,493 in Schizophrenia; 421 in Alzheimer’s Disease
– Randomized comparison
• STAR*D (Refractory Depression)
– 4,041 / 41 sites
– Sequential pathways
Less than 1/3 of symptomatic bipolar patients reach
recovery and remain well over 2 years in STEP-BD
• Achieved recovery
58.5%
– (< 2 mood symptoms for at least 8 weeks)
• Relapse into depression
34.7%
• Relapse into mood elevation
13.8%
• Total relapse rate
48.5%
• Total that stayed recovered over 2 years
(100%-48.5%)
51.5%
• Total who recovered and remained free of depressive and
mood elevation recurrences over 2 years
(51.5% out of 58.5% who achieved remission)
30.1%
N=1469 who entered symptomatic
Perlis et al, STEP-BD, Am J Psychiatry 2006 Feb;163:217-24.
Anxiety comorbid conditions with higher risk of
relapse in bipolar disorder in STEP-BD
without anxiety
with anxiety
N=489
Overall relapse rate = 41.4%
Overall Hazard Ratio (HR)= 1.764
( 2=10.9, P=0.001)
HR=1.55 for one disorder
HR=2.17 for two or more disorders
HR=2.07 for social anxiety disorder
HR=2.45 for PTSD
Otto et al., STEP-BD, Br J Psychiatry 2006 Jul;189:20-5.
April 26,
2007
Effectiveness of Adjunctive Antidepressant Treatment
for Bipolar Depression
Gary S. Sachs, M.D., Andrew A. Nierenberg, M.D., Joseph R. Calabrese, M.D.,
Lauren B. Marangell, M.D., Stephen R. Wisniewski, Ph.D., Laszlo Gyulai, M.D.,
Edward S. Friedman, M.D., Charles L. Bowden, M.D., Mark D. Fossey, M.D.,
Michael J. Ostacher, M.D., M.P.H., Terence A. Ketter, M.D., Jayendra Patel, M.D.,
Peter Hauser, M.D., Daniel Rapport, M.D., James M. Martinez, M.D., Michael H.
Allen, M.D., David J. Miklowitz, Ph.D., Michael W. Otto, Ph.D., Ellen B. Dennehy,
Ph.D., and Michael E. Thase, M.D.
Intensive psychosocial interventions for bipolar
depression better than collaborative care, but over
a third never reach recovery
80
Intensive Treatment
Collaborative Care
70
60
50
% Well
40
30
20
10
0
1
2
3
4
5
6
7
Month
8
9
10
11
1-year recovery rate for intensive group, 105/163 [64.4%]; for CC, 67/130 [51.5%];
log-rank 2(1) = 6.20, p = 0.013; hazard ratio (HR) = 1.47; 95% CI = 1.08-2.00
Miklowitz et al., STEP-BD, Arch Gen Psychiatry, April 2007
12
Am J Psychiatry 164:201-204, February 2007
© 2007 American Psychiatric Association
Special Article
STAR*D: What Have We Learned?
A. John Rush, M.D.
STAR*D represents a 7-year effort by literally hundreds of people and thousands of
patients. Future reports will 1) compare longer-term outcomes of the various
randomized treatments (e.g., does cognitive therapy prevent relapse better than
medication as either a switch or augmentation strategy?); 2) identify which patients
benefit from which treatments (e.g., do different patients [defined by different clinical
features or genetic polymorphisms] respond differently to different treatments?); and
3) determine whether different treatment sequences (in steps 1 to 4) are preferred for
some but not other patients.
Volume 353:1209-1223 September 22, 2005 Number 12
Effectiveness of Antipsychotic Drugs in
Patients with Chronic Schizophrenia
Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D.,
M.P.H., et al. for the Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) Investigators
CATIE:
Primary Questions Addressed
• How do the atypical antipsychotic medications
compare with an older, less expensive
conventional antipsychotic?
• How do the atypical antipsychotics compare to
one another?
• Are the atypical antipsychotics cost-effective?
Stroup TS et al. Schizophr Bull. 2003;29:15-31.
Use of Atypical Antipsychotic Medications in U.S.
TRx (000s)
50,000
40,000
30,000
20,000
10,000
0
1993
1994
1995
Conventionals
1996
Clozaril
1997
1998
Risperdal
1999
2000
Zyprexa
2001
2002
Seroquel
2003
Geodon
2004
2005
Abilify
Source: IMS NPA Plus, Dec 05. Lieberman – Presentation to NIMH Advisory Council, Sept 2006
CATIE Schizophrenia Trial Design
Phase 1*
Double-blind, random
treatment assignment.
Phase 3
Phase 2
Participants who discontinue
Phase 1 choose either the
clozapine or the ziprasidone
randomization pathways
CLOZAPINE
OLANZAPINE
(open-label)
1500
participants
with schizophrenia
QUETIAPINE
R
R
•ARIPIPRAZOLE
•CLOZAPINE
•FLUPHENAZINE
DECANOATE
•OLANZAPINE
•PERPHENAZINE
RISPERIDONE
ZIPRASIDONE
R
ZIPRASIDONE
OLANZAPINE,
QUETIAPINE or
RISPERIDONE
Participants who discontinue
Phase 2 choose one of the
following open-label
treatments
•QUETIAPINE
OLANZAPINE,
QUETIAPINE or
RISPERIDONE
•RISPERIDONE
•ZIPRASIDONE
PERPHENAZINE
No one assigned to same
drug as in Phase 1
•2 of the antipsychotics
above
Responders stay on assigned medication for duration of 18-month treatment period
* Phase 1A: participants with tardive dyskinesia do not get randomized to perphenazine
Phase 1B: participants who fail perphenazine will be randomized to an atypical (olanzapine, quetiapine, or
risperidone) before they are eligible for Phase 2
Stroup et al 2003
Proportion of Patients without Event
PHASE 1: Time to Discontinuation for Any
Reason
1
0.8
0.6
0.4
36%
26% 25%
21 %
18%
0.2
0
0
3
15
12
9
6
Time to Discontinuation for Any Cause (mo)
Olanzapine (n=330)
▬▬▬ Olanzapine (n=330)
Perphenazine (n=257)
Quetiapine (n=329)
▬▬▬ Risperidone (n=333)
Risperidone (n=333)
▬▬▬ Ziprasidone (n=183)
▬▬▬ Quetiapine (n=329)
18
Ziprasidone (n=183)
▬▬▬ Perphenazine (n=257)
Problems with Movement During the Trial
Percent (%)
15%
10%
5%
0%
Perphenazine Risperidone
Quetiapine
Olanzapine
Ziprasidone
Exposure-adjusted Mean
(ng/mL)
Prolactin: Change from Baseline
20.0
15.0
10.0
5.0
0.0
-5.0
-10.0
-15.0
Perphenazine Risperidone
Quetiapine
Olanzapine
Ziprasidone
Body Weight: Change from Baseline
Weight Gain >7%
40%
30%
20%
10%
Exposure-adjusted Mean
(mg/dL)
Exposure-adjusted Mean
(mg/dL)
0%
Perphenazine
Risperidone
Quetiapine
Olanzapine
Ziprasidone
Fasting Glucose: Change from Baseline
15.0
10.0
5.0
0.0
Perphenazine
Risperidone
Quetiapine
Olanzapine
Ziprasidone
Fasting Triglycerides: Change from Baseline
40.0
25.0
10.0
-5.0
-20.0
Perphenazine
Risperidone
Quetiapine
Olanzapine
Ziprasidone
American Journal of Psychiatry 163:600-610, April 2006
Effectiveness of Clozapine Versus Olanzapine,
Quetiapine, and Risperidone in Patients With
Chronic Schizophrenia Who Did Not Respond to
Prior Atypical Antipsychotic Treatment
Joseph P. McEvoy, M.D., Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H.,
Sonia M. Davis, Dr.P.H., Herbert Y. Meltzer, M.D., Robert A. Rosenheck, M.D., Marvin
S. Swartz, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Clarence
E. Davis, Ph.D., Joanne Severe, M.S., John K. Hsiao, M.D. for the CATIE Investigators
CATIE Phase 2:
Preference Pathways
(for people who discontinue Phase 1)
Clozapine—open-label
Efficacy
Pathway
Randomized
Olanzapine, Quetiapine, or
Risperidone—drug not
taken in Phase 1
Tolerability
Pathway
Randomized
Ziprasidone
Stroup TS et al. Schizophr Bull. 2003;29:15-31.
Proportion of Patients without Event
PHASE 2E: Time to Discontinuation
for Any Reason
1
0.8
0.6
0.4
44%
29%
14%
7%
0.2
0
0
3
6
9
12
15
Time to Discontinuation for Any Cause (mo)
Clozapine (N=45)
Olanzapine (N=17)
18
Quetiapine (N=14)
Risperidone (N=14)
Proportion of Patients without Event
PHASE 2T: Time to Discontinuation
for Any Reason
1
0.8
0.6
0.4
36%
33%
23%
16%
0.2
0
0
4
8
12
Time to Discontinuation for Any Cause (mo)
Olanzapine
Quetiapine
16
Risperidone
Ziprasidone
Negative Symptoms and
Cognitive Function
• No differences between
atypical antipsychotics and a
conventional antipsychotic
(perphenazine) on negative
symptoms and cognitive
functions
December 1, 2006
Older Medication May Be More Cost-Effective for
Some Patients with Schizophrenia
A new study analyzing the economic implications of CATIE concludes
that the older (first generation) antipsychotic medication perphenazine
was less expensive and no less effective than the newer (second
generation) medications used in the trial during initial treatment,
suggesting that older antipsychotics still have a role in treating
schizophrenia. Total monthly health costs, a figure that includes both
average medication costs and inpatient and outpatient costs, were up to
30 percent lower for those taking perphenazine than for those taking the
second generation medications.
-- NIMH Press Release Re: Rosenheck et al, Am J Psychiatry, December 2006
Study May Boost Use of Cheaper
Antipsychotic Drug
By Avery Johnson, The Wall Street Journal,
December 1, 2006
For the cost-effectiveness portion of the Catie study, a team of
researchers led by Yale Medical School's Robert Rosenheck found that
patients taking the generic antipsychotic paid $960 in average health
costs per month, including the $50 price of the drug. The average
monthly cost of treatment with Eli Lilly & Co.'s Zyprexa, for instance,
was $1,404 -- the lowest of the branded drugs -- after accounting for the
$545 per month cost of the antipsychotic, plus additional medications
and hospital costs. Average health costs for patients on Johnson &
Johnson's Risperdal were $1,533 a month, including $474 for the drug.
Two other branded drugs were also analyzed
CATIE HIGHLIGHTS
– All antipsychotic medications studied are
effective but have substantial limitations reflected
by high discontinuation rates
– Olanzapine and Clozapine show the best
efficacy but the worst side effects
– Perphenazine was surprisingly comparable to
atypicals
– Differences in types and severity of side effects
– Ziprasidone has least weight and metabolic side
effects (Aripiprazole was released later)
“CATIE has opened the door to more choice in
treatment options."
-- Robert Rosenheck, M.D.
Treatments for persons with schizophrenia must
be individualized. Doctors and patients must
carefully evaluate the tradeoffs between
efficacy and side effects and past treatment
history in choosing an appropriate medication.
Lieberman – Presentation to NIMH Advisory Council, Sept 2006
Issues in Schizophrenia Treatment
Research Still Needing Attention
• Need for strategies beyond clozapine or alternatives to
clozapine for patients with refractory symptoms
• Rational antipsychotic polypharmacy?
• What are optimal strategies for first-episode psychosis?
• How to enhance treatment adherence ?
Lieberman – Presentation to NIMH Advisory Council, Sept 2006
355:1525-1538
October 12, 2006
Number 15
Effectiveness of Atypical Antipsychotic Drugs in
Patients with Alzheimer's Disease
Lon S. Schneider, M.D., Pierre N. Tariot, M.D., Karen S. Dagerman, M.S., Sonia M.
Davis, Dr.P.H., John K. Hsiao, M.D., M. Saleem Ismail, M.D., Barry D. Lebowitz,
Ph.D., Constantine G. Lyketsos, M.D., M.H.S., J. Michael Ryan, M.D., T. Scott Stroup,
M.D., David L. Sultzer, M.D., Daniel Weintraub, M.D., Jeffrey A. Lieberman, M.D., for
the CATIE-AD Study Group
"The antipsychotic
medications may
be effective
against some
symptoms in
Alzheimer's
patients compared
to placebo, but
their tendency to
cause intolerable
adverse side
effects in this
vulnerable
population offsets
their benefits."
Lon Schneider, MD
Schneider et al,
CATIE-AD,
N Engl J Med,
Oct 2006
Psychotherapy in NIMH
Effectiveness Trials – completed
• STEP-BD (Bipolar Depression)
– 3 types of structured psychotherapy are effective
adjuncts to pharmacotherapy
(Miklowitz et al, Arch Gen Psychiatry, April 2007)
• STAR*D (Refractory Depression)
– Only 26% of patients agreed to treatment with
cognitive therapy (CT) as a second-line treatment after
inadequate response to citalopram. Responses to CT,
as monotherapy or augmenting citalopram, were
equivalent to medication-only groups. Time to remission
was slower with CT but with fewer side effects
(Thase et al, & Wisniewski et al, Am J Psychiatry, May 2007)
Psychotherapy in NIMH
Effectiveness Trials – in progress
• Research Evaluating the Value of
Augmenting Medication with Psychotherapy
(REVAMP / Chronic Major Depression)
–
Does CBASP or supportive psychotherapy add to
pharmacotherapy in the treatment of chronic forms
of major depression? (Kocsis et al)
• Coordinated Anxiety Learning and
Management (CALM / Anxiety Disorders)
–
Does computer-based individualized CBT add to
pharmacotherapy for anxiety disorders in primary
care? (Roy-Byrne et al)
What Questions Should Be Pursued Next?
• Widely used treatments and treatment
combinations that are untested?
• New molecules ready for wider testing?
• Patient attrition?
• Longer-term outcomes?
• Tailoring treatment to individuals?
• Enhancing cost efficiency?
• Practice procedures that are controlled by payor
costs without regard to patient outcomes?
Rush – Presentation to NIMH Advisory Council, Sept 2006
What’s Next at NIMH
• Three new clinical trials networks (Depression,
Bipolar Disorder, Schizophrenia), building upon
completed Practical Clinical Trials
• Platform funding
• Central data management
• Collaboration with new partners
• Identify challenging public mental health
questions suitable for study on Networks
• Continue regular grant support of non-Network
services and interventions research
www.nimh.nih.gov/ncdeu/index.cfm
For complete details of NIMH-supported Clinical Trials, please see
http://www.nimh.nih.gov/studies/index.cfm