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 Subcontracted site PI Industry NIMH Colleagues

Strengths 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 Hyper Glycemia CVD Insulin Resistance Side Effects of Atypical Antipsychotics: Shift in Risk Perception Weight Gain Insulin Resistance Hyper- lipidemia EPS QTc Dyslipidemia CVD QTc Hyper- glycemia

“real-world” settings 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 cost-effective? 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 In order to enroll a broad array of patients representing those who are actually seen in clinics, we developed minimal inclusion and exclusion criteria: Stroup TS et al. Schizophr Bull. 2003;29:15-31.

CATIE Schizophrenia Trial Design Phase 1* R OLANZAPINE QUETIAPINE RISPERIDONE ZIPRASIDONE PERPHENAZINE Double-blind, random treatment assignment. Phase 2 Phase 3 Participants who discontinue Phase 1 choose either the clozapine or the ziprasidone randomization pathways Participants who discontinue Phase 2 choose one of the following open-label treatments ARIPIPRAZOLE CLOZAPINE CLOZAPINE (open-label) FLUPHENAZINE DECANOATE 1460 patients with SCZ Comorbidity Other meds R OLANZAPINE, QUETIAPINE or RISPERIDONE OLANZAPINE PERPHENAZINE ZIPRASIDONE QUETIAPINE R OLANZAPINE, QUETIAPINE or RISPERIDONE RISPERIDONE ZIPRASIDONE 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 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.

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

Phase II-E & T Results

Hypothesized ZIP superior Randomization within chosen pathways 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 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

Change in Neurocognitive Composite Score After 18 Months of Treatment Overall differences between treatments (p<.05) N above histogram 27 23 z-Score Change from Baseline to 18 Months 21 27 Neurocog improved for all treatments Second generation not better than older drug May want to drop neurocog results entirely 34 Perphenazine Risperidone Quetiapine Olanzapine Ziprasidone Ziprasidone Cohort TD Patients Excluded Keefe RSE, et al. Presented at: 61st SOBP Annual Meeting; May 18-20, 2006; Toronto, Canada.

Difficulties in Interpretation 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 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

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.

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 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