The C linical A ntipsychotic T rials of I ntervention E ffectiveness Trial

1. The Clinical Antipsychotic Trials of Intervention Effectiveness Trial An overview of The “catie” trial ALBREKA HUDSON, PHARMd candidate Preceptor: soheylaMahdavian, pharmd

2. The CATIE Trial • A nation-wide 3-phase clinical trial • Compared the effectiveness of older and newer antipsychotic medications used to treat schizophrenia • Funded by the National Institute of Mental Health (NIMH)

3. Study Participants and Sites 1,460 participants 57 clinical sites across the U.S. Between January 2001 and December 2004 (over a span of 18 months) Largest, longest, and most comprehensive trial ever conducted to study pharmacotherapiesfor schizophrenia

4. Objective To compare the effectiveness of several newer (atypical) antipsychotic drugs and one older (conventional/typical) antipsychotic drug for schizophrenia in real-world settings over 18 months.

8. Outcome Measures Phase 1

9. Phase 1 • Primary: • Rate of treatment discontinuation for any reason • Secondary: • Measures for clinical and functional outcomes, safety and neurocognition

10. Results and Conclusions Phase 1

11. Phase 1 • Olanzapine was the most effective in terms of rate of discontinuation • Disadvantages: • Greater weight gain • Increases in measures of glucose and lipid metabolism • Efficacy of the conventional antipsychotic perphenazine appeared similar to that of the atypical antipsychotics.

12. Outcome Measures Phase 2

13. Phase 2 Efficacy Tolerability • Primary: • Time until discontinuation for any reason • Secondary: • Time to discontinuation for inadequate therapeutic benefit, intolerable side effects, or patient decision. • Primary: • Time until discontinuation for any reason • Secondary: • Reason for treatment discontinuation

14. Results and Conclusions Phase 2

15. Phase 2 Efficacy Tolerability Treatment with clozapine was significantly more effective than switching to another of the newer atypicals. Olanzapine and risperidone were more effective than quetiapine and ziprasidone* as reflected by longer time until discontinuation for any reason. Olanzapine was the most effective medication for those patients who discontinued their previous treatment due to inefficacy, although not for those who discontinued due to intolerability.

16. Outcome Measures Phase 3

17. Phase 3(Open- Label) • Primary: • Time until discontinuation for any reason

18. Results and Conclusions Phase 3

19. Phase 3 • All-cause discontinuation rate of 74% at 18 months. • Olanzapine better efficacy than quetiapine, risperidone and also with other medications. • More individuals discontinued olanzapine • Weight gain • Increase in hemoglobin • Increase in cholesterol and triglyceride leading to metabolic syndrome • Extrapyramidalsymptoms were the most common reason for discontinuation with perphenazine. • No superior efficacy of atypical over conventional antipsychotic ( Ex. perphenazine)

20. Phase 3 Clozapinewas the most effective compound compared with all the other antipsychotics used in this study. Irrespective of the class of antipsychotics, there was improvement in neuro-cognitive functioning. However this effect remained significant only for two months. Ziprasiodone was most weight neutral and did not come up with any metabolic side-effects. In the last phase which was open label, very few patients selected conventional antipsychotics.

21. JournalCritique A reflective review of the trial

22. Critique Pros Cons Phase 1 & 2, double-blinded randomized Broad inclusion and few exclusion criteria “Real-world” efficacy trial Phase 3, open-label Use of only ONE first generation antipsychotic All-cause treatment discontinuation

23. Critique Pros Cons Broad inclusion and few exclusion criteria Patients representative of the “real-world” Counseling and patient education was offered to increase medication adherence Suboptimal dosing for quetiapine, ziprasidone, and risperidone may have resulted in “better” outcomes for olanzapine which was more optimally dosed. Inclusion of comorbid diseases and substance abuse Details of randomization could not be evaluated Treatment allocation based on patient choice

24. Critique Pros Cons Use of Kaplan-Meier (KM) Curve Patients had to have an adequate decisional capacity

25. Clinical Pearls All antipsychotic medications are effective but have substantial limitations reflected by high discontinuation rates. Olanzapine and clozapine best efficacy but worst side effects. Perphenazine is surprisingly comparable to atypicals in terms of efficacy and effectiveness. Noted differences in types and severity of side effects. Ziprasidone has least weight gain 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 atypicals may be most evident in the refractory end of the schizophrenia spectrum.

26. References • Davis JM, Chen N, Glick ID. A metaanalysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003; 60:553-64. • Ericksen, Jennifer, Sheri A. Strite, and Craig Stern. "CATIE Trial Review of Phases 1 and 2." EBM REVIEW. June 2008. Web. 18 Jan. 2013. • Stroup TS, McEvoy JP, Swartz MS, et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. N Engl J Med. 2005:353:1209-23. • Stroup, S., J. Lieberman, J. Mcevoy, M. Swartz, S. Davis, R. Rosenheck, and R. Keefe. "Findings Of Phase 3 Of The Catie Schizophrenia Trial."Schizophrenia Research 102.1-3 (2008): 34-35. • Stroup TS, McEvoy JP, Swartz MS, et al. TheNational Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull 2003;29:15-31.