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

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

2. Question • What to take away from CATIE

3. Message • One piece of a puzzle

4. Disclosures • Subcontracted site PI • Industry • NIMH • Colleagues

5. Strengths • Design • Sample • Non-industry sponsored • Efficacy • Effectiveness

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

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

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.

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.

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.

11. Primary Outcome Measure:All-Cause Treatment Discontinuation Efficacy Tolerability All-Cause Discontinuation Patient Input Clinician Input

12. Phase I Results

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.

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

15. Phase II-E & T Results

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.

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

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

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.

20. Difficulties in Interpretation • Design • Sample • Dosing • Stratification • Statistical analysis

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.

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.

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.

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.

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

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

27. Findings • Cloz: good • O and R>Q • Z:? • FGA=SGA:?

28. Message • Schizophrenia difficult to treat • Pts/family/MDs switch often • Each med has differential efficacy and side effects

29. Pearls • Monotherapy • Adequate dose and duration • Don’t do polypharmacy • Always combine with individual and family psychosocial intervention

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.

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

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