Effectiveness of Antipsychotic Drugs in Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia: Patients with Chronic Schizophrenia:

Efficacy and Safety OutcomesEfficacy and Safety Outcomesof the CATIE Trialof 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

• Subcontracted site PI

• Industry

• NIMH

• Colleagues

Strengths

• Design

• Sample

• Non-industry sponsored

• Efficacy

• Effectiveness

EPS + TDEPS + TD

Weight Gain

Weight Gain

Insulin Resistance

Insulin Resistance

Hyper-glycemiaHyper-

glycemia

CVDCVD

Hyper-lipidemiaHyper-

lipidemia

Weight GainWeight Gain

DiabetesDiabetes

Hyper Glycemia

Hyper Glycemia

Insulin Resistance

Insulin Resistance

QTcQTc

CVDCVD

DyslipidemiaDyslipidemia

Prior Safety Concerns

Current Safety Concerns

Side Effects of Atypical Antipsychotics: Side Effects of Atypical Antipsychotics: Shift in Risk Perception Shift in Risk Perception

QTc

EPS

Neurologic Side Effects

NIMH-sponsored research program to NIMH-sponsored research program to evaluate the effectiveness of antipsychotic evaluate the effectiveness of antipsychotic

medications for schizophrenia and Alzheimer’s medications for schizophrenia and Alzheimer’s disease in broad patient populations and disease in broad patient populations and

““real-world” settingsreal-world” settings

Primary Questions Addressed Primary Questions Addressed by CATIE Schizophrenia Trialby 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.

CATIE: CATIE: Broad Inclusion & Broad Inclusion & Minimal Exclusion CriteriaMinimal 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 DesignCATIE Schizophrenia Trial Design

1460 patients with SCZ

ComorbidityOther meds

Participants who discontinue Phase 2 choose one of the

following open-label treatments

•ARIPIPRAZOLE

•FLUPHENAZINE DECANOATE

•PERPHENAZINE

•RISPERIDONE

•OLANZAPINE

•ZIPRASIDONE

•QUETIAPINE

•2 of the antipsychotics above

Phase 3Phase 1*

R

OLANZAPINE

QUETIAPINE

RISPERIDONE

ZIPRASIDONE

PERPHENAZINE

Double-blind, random treatment assignment.

Phase 2

CLOZAPINE(open-label)

OLANZAPINE, QUETIAPINE or RISPERIDONE

OLANZAPINE, QUETIAPINE or RISPERIDONE

ZIPRASIDONE

R

R

No one assigned to same drug as in Phase 1

Participants who discontinue Phase 1 choose either the

clozapine or the ziprasidone randomization pathways

*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.

•CLOZAPINE

Primary Outcome Measure:Primary Outcome Measure:All-Cause Treatment DiscontinuationAll-Cause Treatment Discontinuation

All-Cause Discontinuation

Efficacy Tolerability

Clinician Input Patient Input

Phase I ResultsPhase I Results

CATIE Phase 1: CATIE Phase 1: Double-Blinded and RandomizedDouble-Blinded and Randomized

Persons with TD not assigned to perphenazine

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

1460 Patientswith

SchizophreniaRandomized

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 *

* Ziprasidone added after 40% sample enrolled

Highlights of Phase IHighlights 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

Phase II-E & T Phase II-E & T ResultsResults

CATIE Phase 2: CATIE Phase 2: Preference Pathways Preference Pathways

(for people who discontinue Phase 1)(for people who discontinue Phase 1)

Randomization within chosen pathways

EfficacyPathway

TolerabilityPathway

Clozapine—open-label

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

Ziprasidone

Randomized

Randomized

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

Hypothesized CLZ

superior

Hypothesized ZIP superior

Highlights of Phase 2EHighlights 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 2THighlights 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

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Change in Neurocognitive Composite Score After 18 Months of Treatment

Ziprasidone Cohort

z-Sc

ore

Cha

nge

from

Bas

elin

e to

18

Mon

ths

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

27

27

21

34

23

N above histogram

Overall differences between treatments

(p<.05)

Perphenazine Risperidone Quetiapine Olanzapine

TD Patients Excluded

Ziprasidone

Difficulties in Interpretation

• Design

• Sample

• Dosing

• Stratification

• Statistical analysis

• 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 FindingsSummary 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 FindingsSummary 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 FindingsSummary 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 FindingsSummary Findings

Summary FindingsSummary Findings

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

Summary FindingsSummary Findings

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

Findings

• 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

• Monotherapy

• Adequate dose and duration

• Don’t do polypharmacy

• Always combine with individual and family psychosocial intervention

HIGHLIGHTSHIGHLIGHTS All antipsychotic medications are effective but have All antipsychotic medications are effective but have

substantial limitations reflected by high discontinuation substantial limitations reflected by high discontinuation ratesrates

Olanzapine and Clozapine best efficacy but worst side Olanzapine and Clozapine best efficacy but worst side effectseffects

Perphenazine surprisingly comparable to atypicalsPerphenazine surprisingly comparable to atypicals Differences in types & severity of side effectsDifferences in types & severity of side effects Ziprasidone has least weight and metabolic side effectsZiprasidone has least weight and metabolic side effects What drug you should switch to depends on what What drug you should switch to depends on what

treatment you have received and why you stopped it.treatment you have received and why you stopped it. The superiority of the SGAs may be most evident in the The superiority of the SGAs may be most evident in the

refractory end of the schizophrenia spectrum.refractory end of the schizophrenia spectrum.

Principles from CATIE Results Principles from CATIE Results 1. Antipsychotic medications are not equivalent or interchangeable1. Antipsychotic medications are not equivalent or interchangeable

2. Individual history, symptoms, side effects and circumstances 2. Individual history, symptoms, side effects and circumstances must guide medication choicesmust guide medication choices

3. Choice of medication is vital given the complexity and3. Choice of medication is vital given the complexity andheterogeneity of schizophreniaheterogeneity of schizophrenia

4. CATIE does not support a blanket "fail first" policy4. CATIE does not support a blanket "fail first" policy

5. CATIE does not support severe restrictions in formularies;5. CATIE does not support severe restrictions in formularies;algorithms may be helpful, based on individual needsalgorithms may be helpful, based on individual needs

6. CATIE does not mean people doing well on newer medications 6. CATIE does not mean people doing well on newer medications should be switched on older drugsshould be switched on older drugs

7. CATIE does not mean it is always best for the patient to stay with7. CATIE does not mean it is always best for the patient to stay withthe current treatmentthe current treatment

Collaborators 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