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Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia: Efficacy and Safety Outcomes of the CATIE Trial






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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.
Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia: Efficacy and Safety Outcomes of the CATIE Trial

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Slide 1

Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia: Efficacy and Safety Outcomesof the CATIE Trial

Ira D. Glick, MD

Stanford University School of Medicine

For Jeffrey Lieberman, MD and the CATIE Investigators

Slide 2

Question

  • What to take away from CATIE

Slide 3

Message

  • One piece of a puzzle

Slide 4

Disclosures

  • Subcontracted site PI

  • Industry

  • NIMH

  • Colleagues

Slide 5

Strengths

  • Design

  • Sample

  • Non-industry sponsored

  • Efficacy

  • Effectiveness

Slide 6

Side Effects of Atypical Antipsychotics: Shift in Risk Perception

Prior Safety Concerns

Current Safety Concerns

Diabetes

Neurologic Side Effects

EPS + TD

Weight Gain

Hyper

Glycemia

CVD

Insulin

Resistance

Weight Gain

Insulin

Resistance

EPS

Hyper-

lipidemia

QTc

Dyslipidemia

CVD

QTc

Hyper-

glycemia

Slide 7

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

Slide 8

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 cost-effective?

Stroup TS et al. Schizophr Bull. 2003;29:15-31.

Slide 9

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.

Slide 10

Phase 1*

Double-blind, random treatment assignment.

OLANZAPINE

R

R

R

QUETIAPINE

RISPERIDONE

ZIPRASIDONE

PERPHENAZINE

CATIE Schizophrenia Trial Design

Phase 3

Phase 2

Participants who discontinuePhase 2 choose one of the following open-label treatments

Participants who discontinue Phase 1 choose either the clozapine or the ziprasidone randomization pathways

  • ARIPIPRAZOLE

  • CLOZAPINE

CLOZAPINE

(open-label)

  • FLUPHENAZINE DECANOATE

  • OLANZAPINE

OLANZAPINE, QUETIAPINE or RISPERIDONE

1460 patients with SCZ

Comorbidity

Other meds

  • PERPHENAZINE

ZIPRASIDONE

  • QUETIAPINE

OLANZAPINE, QUETIAPINE or RISPERIDONE

  • RISPERIDONE

  • ZIPRASIDONE

  • 2 of the antipsychotics above

No one assigned to same drug as in Phase 1

*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.

Slide 11

Primary Outcome Measure:All-Cause Treatment Discontinuation

Efficacy

Tolerability

All-Cause Discontinuation

Patient Input

Clinician Input

Slide 12

Phase I Results

Slide 13

1460 Patients

with Schizophrenia

Randomized

CATIE Phase 1: Double-Blinded and Randomized

Olanzapine 7.5–30 mg/day

Perphenazine 8–32 mg/day

Quetiapine 200–800 mg/day

Risperidone 1.5–6 mg/day

Ziprasidone 40–160 mg/day *

Persons with TD not assigned to perphenazine

* Ziprasidone added after 40% sample enrolled

Stroup TS et al. Schizophr Bull. 2003;29:15-31.

Slide 14

Highlights of Phase I

  • High rate of discontinuation (switching) %74

    • Hypothesized 60%

    • Consistent with practice and clinical trials

  • OLZ most effective

    • Best efficacy, worst side effects

  • PER comparably effective to SGAs

    • Very slightly higher EPS

  • No differential effects of SGAs on Sxs including negative Sxs

    • Cognition, substance abuse, violence ?

  • Differences in types and severity of side effects

  • Consistent results across multiple measures within domains

Slide 15

Phase II-E & T Results

Slide 16

CATIE Phase 2: Preference Pathways (for people who discontinue Phase 1)

Clozapine—open-label

Hypothesized CLZ superior

Efficacy

Pathway

Randomized

Olanzapine, Quetiapine, or Risperidone—one of these not taken in Phase 1

Randomized

Tolerability

Pathway

Hypothesized ZIP superior

Ziprasidone

Randomization within chosen pathways

Stroup TS et al. Schizophr Bull. 2003;29:15-31.

Slide 17

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

Slide 18

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

Slide 19

Change in Neurocognitive Composite Score After 18 Months of Treatment

Overall differences between treatments (p<.05)

N above histogram

27

23

21

z-Score Change from Baseline to 18 Months

27

34

Ziprasidone

Perphenazine

Risperidone

Quetiapine

Olanzapine

TD Patients Excluded

Ziprasidone Cohort

Keefe RSE, et al. Presented at: 61st SOBP Annual Meeting; May 18-20, 2006; Toronto, Canada.

Slide 20

Difficulties in Interpretation

  • Design

  • Sample

  • Dosing

  • Stratification

  • Statistical analysis

Slide 21

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.

Slide 22

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.

Slide 23

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.

Slide 24

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.

Slide 25

Summary Findings

  • Perphenazine is significantly less costly than other medications and not significantly or substantially less effective.

Slide 26

Summary Findings

  • The superiority of the SGAs may be most evident in the refractory end of the schizophrenia spectrum.

Slide 27

Findings

  • Cloz: good

  • O and R>Q

  • Z:?

  • FGA=SGA:?

Slide 28

Message

  • Schizophrenia difficult to treat

  • Pts/family/MDs switch often

  • Each med has differential efficacy and side effects

Slide 29

Pearls

  • Monotherapy

  • Adequate dose and duration

  • Don’t do polypharmacy

  • Always combine with individual and family psychosocial intervention

Slide 30

HIGHLIGHTS

  • 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.

Slide 31

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

Slide 32

Principal Investigators

Joe McEvoy

Scott Stroup

Diana Perkins

Marvin Swartz

Richard Keefe

Ed Davis

Bob Rosenheck

Sonia Davis

John Hsaio

Jeffrey Lieberman

57 Site Investigators

Collaborators


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