Transcript (Title of Presentation) - Oregon Psychiatric Association

Effectiveness of Antipsychotic Drugs in
Patients with Chronic Schizophrenia:
Efficacy and Safety Outcomes
of the CATIE Trial
Ira D. Glick, MD
Stanford University School of Medicine
For Jeffrey Lieberman, MD and the CATIE Investigators
Question
• What to take away from CATIE
Message
• One piece of a puzzle
Disclosures
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Subcontracted site PI
Industry
NIMH
Colleagues
Strengths
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Design
Sample
Non-industry sponsored
Efficacy
Effectiveness
Side Effects of Atypical Antipsychotics:
Shift in Risk Perception
Prior Safety Concerns
Current Safety Concerns
Diabetes
Neurologic Side Effects
EPS + TD
Weight
Gain
QTc
Weight GainHyper
Glycemia
CVD
Insulin
Resistance
Insulin
Resistance
Hyperglycemia
CVD
Hyperlipidemia
EPS
QTc
Dyslipidemia
NIMH-sponsored research program to
evaluate the effectiveness of antipsychotic
medications for schizophrenia and Alzheimer’s
disease in broad patient populations and
“real-world” settings
Primary Questions Addressed
by CATIE Schizophrenia Trial
• How do the second generation antipsychotics
compare with a representative first generation
antipsychotic?
• What is the comparative effectiveness of the
second generation antipsychotic drugs?
• Are the second generation antipsychotics costeffective?
Stroup TS et al. Schizophr Bull. 2003;29:15-31.
CATIE: Broad Inclusion &
Minimal Exclusion Criteria
• DSM-IV schizophrenia, 18-65 years old
• Not first-episode or treatment resistant
• Concomitant medications, medical
illnesses, substance use disorders allowed
• No adjunctive antipsychotic after
randomization
Stroup TS et al. Schizophr Bull. 2003;29:15-31.
CATIE Schizophrenia Trial Design
Phase 2
Phase 1*
Double-blind, random
treatment assignment.
Participants who discontinue
Phase 1 choose either the
clozapine or the ziprasidone
randomization pathways
OLANZAPINE
CLOZAPINE
(open-label)
QUETIAPINE
1460 patients
with SCZ
Comorbidity
Other meds
R
R
OLANZAPINE,
QUETIAPINE or
RISPERIDONE
RISPERIDONE
Phase 3
Participants who discontinue
Phase 2 choose one of the
following open-label
treatments
•ARIPIPRAZOLE
•CLOZAPINE
•FLUPHENAZINE
DECANOATE
•OLANZAPINE
•PERPHENAZINE
ZIPRASIDONE
•QUETIAPINE
ZIPRASIDONE
R
OLANZAPINE,
QUETIAPINE or
RISPERIDONE
•RISPERIDONE
•ZIPRASIDONE
PERPHENAZINE
No one assigned to same
drug as in Phase 1
•2 of the antipsychotics
above
*Phase 1A: participants with TD (N=231) do not get randomized to perphenazine; phase 1B: participants
who fail perphenazine will be randomized to an atypical (olanzapine, quetiapine, or risperidone) before
eligibility for phase 2.
Stroup TS et al. Schizophr Bull. 2003;29:15-31.
Primary Outcome Measure:
All-Cause Treatment Discontinuation
Efficacy
Tolerability
All-Cause
Discontinuation
Clinician Input
Patient Input
Phase I Results
CATIE Phase 1:
Double-Blinded and Randomized
Olanzapine
7.5–30 mg/day
Perphenazine
8–32 mg/day
1460 Patients
with
Schizophrenia
Randomized
Quetiapine
200–800 mg/day
Risperidone
1.5–6 mg/day
Persons with TD not assigned to perphenazine
Ziprasidone
40–160 mg/day *
* Ziprasidone added after 40% sample enrolled
Stroup TS et al. Schizophr Bull. 2003;29:15-31.
Highlights of Phase I
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High rate of discontinuation (switching) %74
– Hypothesized 60%
– Consistent with practice and clinical trials
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OLZ most effective
– Best efficacy, worst side effects
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PER comparably effective to SGAs
– Very slightly higher EPS
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No differential effects of SGAs on Sxs including negative Sxs
– Cognition, substance abuse, violence ?
•
Differences in types and severity of side effects
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Consistent results across multiple measures within domains
Phase II-E & T
Results
CATIE Phase 2:
Preference Pathways
(for people who discontinue Phase 1)
Clozapine—open-label
Efficacy
Pathway
Hypothesized CLZ superior
Randomized
Olanzapine, Quetiapine, or
Risperidone—one of these
not taken in Phase 1
Tolerability
Pathway
Randomized
Hypothesized ZIP superior
Ziprasidone
Randomization within chosen pathways
Stroup TS et al. Schizophr Bull. 2003;29:15-31.
Highlights of Phase 2E
• High rate of discontinuation (switching) %65
• CLZ most effective and OLZ next most
effective
– Best efficacy, worst side effects (1 agranulocytosis)
• Differences in types and severity of side effects
• Consistent results across multiple measures
within domains
Highlights of Phase 2T
• High rates of discontinuation (switching) %70
• Overall RIS and OLZ more effective than QUET and
ZIP
– RIS most effective in patients Phase 1 who switched for
tolerability
– OLZ most effective in patients Phase 1 who switched for
efficacy
• Differences in types and severity of side effects
• Consistent results across multiple measures within
domains
z-Score Change from Baseline to 18 Months
Change in Neurocognitive Composite
Score After 18 Months of Treatment
0.7
0.6
0.5
0.4
Overall differences
between treatments
(p<.05)
N above
histogram
27
0.3
0.2
27
0.1
0
23
21
34
Perphenazine Risperidone
Ziprasidone Cohort
Quetiapine Olanzapine
Ziprasidone
TD Patients Excluded
Keefe RSE, et al. Presented at: 61st SOBP Annual Meeting; May 18-20, 2006; Toronto, Canada.
Difficulties in Interpretation
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Design
Sample
Dosing
Stratification
Statistical analysis
Summary Findings
• All APDs are generally effective but have various limitations
as reflected by high rates of discontinuation, intolerable side
effects and failure to adequately control symptoms.
• In non-refractory patients olanzapine is more efficacious than
the other SGAs (other than clozapine) but also was
associated with significant weight gain and metabolic
changes.
• Intermediate potency FGAs (e.g. perphenazine, loxapine,
molindone, thiothixene) are likely comparably effective to the
SGAs and, in moderate doses, as well tolerated as the
newer drugs.
Summary Findings
• There is variation in the side effects of the
antipsychotic drugs which for individual
patients can be substantial.
• Clozapine and olanzapine produced the
most weight and metabolic effects followed
by quetiapine and risperidone.
• Ziprasidone has the least weight and
metabolic effects.
Summary Findings
• Treatments for persons with
schizophrenia must be individualized.
Doctors and patients must carefully
evaluate the tradeoffs between
efficacy and side effects in choosing
an appropriate medication.
Summary Findings
• For patients whose symptoms don’t
improve with initial treatment
clozapine is most effective followed
by olanzapine.
• For patients who must switch
medications due to side effects the
best alternative depends on the
individual side effects.
Summary Findings
• Perphenazine is significantly less
costly than other medications and not
significantly or substantially less
effective.
Summary Findings
• The superiority of the SGAs may be
most evident in the refractory end of
the schizophrenia spectrum.
Findings
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Cloz: good
O and R>Q
Z:?
FGA=SGA:?
Message
• Schizophrenia difficult to treat
• Pts/family/MDs switch often
• Each med has differential efficacy and side
effects
Pearls
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Monotherapy
Adequate dose and duration
Don’t do polypharmacy
Always combine with individual and family
psychosocial intervention
HIGHLIGHTS
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All antipsychotic medications are effective but have
substantial limitations reflected by high discontinuation
rates
Olanzapine and Clozapine best efficacy but worst side
effects
Perphenazine surprisingly comparable to atypicals
Differences in types & severity of side effects
Ziprasidone has least weight and metabolic side effects
What drug you should switch to depends on what
treatment you have received and why you stopped it.
The superiority of the SGAs may be most evident in the
refractory end of the schizophrenia spectrum.
Principles from CATIE Results
1.
Antipsychotic medications are not equivalent or interchangeable
2.
Individual history, symptoms, side effects and circumstances
must guide medication choices
3.
Choice of medication is vital given the complexity and
heterogeneity of schizophrenia
4.
CATIE does not support a blanket "fail first" policy
5.
CATIE does not support severe restrictions in formularies;
algorithms may be helpful, based on individual needs
6.
CATIE does not mean people doing well on newer medications
should be switched on older drugs
7.
CATIE does not mean it is always best for the patient to stay with
the current treatment
Collaborators
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Principal Investigators
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Joe McEvoy
Scott Stroup
Diana Perkins
Marvin Swartz
Richard Keefe
Ed Davis
Bob Rosenheck
Sonia Davis
John Hsaio
Jeffrey Lieberman
57 Site Investigators