The CATIE Schizophrenia Trial is part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Project. The schizophrenia trial is being conducted to determine the long-term effects and usefulness of antipsychotic medications in persons with schizophrenia. It is designed for people with schizophrenia who may benefit from a medication change. The study involves the newer atypical antipsychotics (olanzapine, quetiapine, risperidone, clozapine, and ziprasidone)and the typical antipsychotics (perphenazine and fluphenazine decanoate). All participants will receive an initial comprehensive medical and psychiatric evaluation and will be closely followed throughout the study. For most participants the study will last up to 18 months. Everyone in the study will be offered an educational program about schizophrenia and family members will be encouraged to participate.

This trial will consist of 1600 patients with schizophrenia for whom a medication change may be indicated for reasons of limited efficacy or tolerability. All patients will receive some psychosocial treatment through study participation. Research participants and their family members will be offered psychosocial interventions directed at improving patient and family understanding of the illness, decreasing the burden of illness in the family, maximizing treatment adherence, minimizing relapse, enhancing access to a range of community-based rehabilitative services and improving study retention.

Phase I: Patients will be randomly assigned to one of five treatment conditions for up to 18 months:

1. 320 begin double-blind treatment with perphenazine (PER)
2. 320 begin double-blind treatment with olanzapine (OLZ)
3. 320 begin double-blind treatment with quetiapine (QUET)
4. 320 begin double-blind treatment with risperidone (RIS)
5. 220 begin double-blind treatment with ziprasidone (ZIP)

Phase IA: 100 patients screened and found to have tardive dyskinesia who would otherwise be eligible for the study will be randomly assigned to one of the four atypical drugs in Phase IA.

Phase IB: Patients who fail treatment with perphenazine in Phase I will be randomly assigned to olanzapine, quetiapine, or risperidone in Phase IB.

Phase II: Patients who discontinue their initial assigned atypical antipsychotic treatment in Phase I, IA, or IB for any non-administrative reason will proceed to their second assigned treatment (third for Phase IB patients) and will be followed for up to the remainder of their 18-month participation, as follows:

1. Patients originally assigned to one of the newer atypical antipsychotics who discontinue due to efficacy failure will be randomly assigned to double-blind treatment with one of the other two newer atypical antipsychotics (OLZ, RIS, QUET) which they had not previously received (50%) or with open label clozapine (50%).
2. Patients originally assigned to one of the newer atypical antipsychotics who discontinue due to tolerability failure will be randomly assigned to double-blind treatment with one of the other newer atypical antipsychotics (OLZ, RIS, QUET) which they had not previously received (50%), or with ziprasidone (50%). Until ziprasidone is activated, all patients will be assigned to one of the other atypical antipsychotics.

Phase II will last at least 6 months, even if that means participants stay in the study for more than 18 months

Phase III: Patients who discontinue Phase II will be recommended open treatment with the preferred regimen based on their treatment history in the study.

The treatment options include clozapine, newer atypical antipsychotic (olanzapine, risperidone, quetiapine, ziprazidone, and aripiprazole), fluphenazine decanoate, perphenazine, and dual antipsychotic therapy using two of these drugs.

Note: All treatments will be double-blinded in treatment Phases I and II except for clozapine.

• Drug: perphenazine
• Drug: olanzapine
• Drug: quetiapine
• Drug: risperidone
• Drug: ziprasidone
• Drug: clozapine
• Drug: fluphenazine decanoate

• Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005 Sep 22;353(12):1209-23. Epub 2005 Sep 19.
• McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006 Apr;163(4):600-10.
• Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM, Rosenheck RA, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry. 2006 Apr;163(4):611-22.
• Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, Lebowitz BD, Lyketsos CG, Ryan JM, Stroup TS, Sultzer DL, Weintraub D, Lieberman JA; CATIE-AD Study Group. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med. 2006 Oct 12;355(15):1525-38.
• Rosenheck RA, Leslie DL, Sindelar J, Miller EA, Lin H, Stroup TS, McEvoy J, Davis SM, Keefe RS, Swartz M, Perkins DO, Hsiao JK, Lieberman J. Cost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia. Am J Psychiatry. 2006 Dec;163(12):2080-9.
• Essock SM, Covell NH, Davis SM, Stroup TS, Rosenheck RA, Lieberman JA. Effectiveness of switching antipsychotic medications. Am J Psychiatry. 2006 Dec;163(12):2090-5.
• Davis SM, Koch GG, Davis CE, LaVange LM. Statistical approaches to effectiveness measurement and outcome-driven re-randomizations in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) studies. Schizophr Bull. 2003;29(1):73-80.
• Keefe RS, Mohs RC, Bilder RM, Harvey PD, Green MF, Meltzer HY, Gold JM, Sano M. Neurocognitive assessment in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project schizophrenia trial: development, methodology, and rationale. Schizophr Bull. 2003;29(1):45-55.
• Lieberman JA, Stroup TS. Guest editors' introduction: what can large pragmatic clinical trials do for public mental health care? Schizophr Bull. 2003;29(1):1-6. No abstract available.
• Rosenheck R, Doyle J, Leslie D, Fontana A. Changing environments and alternative perspectives in evaluating the cost-effectiveness of new antipsychotic drugs. Schizophr Bull. 2003;29(1):81-93.
• Schneider LS, Ismail MS, Dagerman K, Davis S, Olin J, McManus D, Pfeiffer E, Ryan JM, Sultzer DL, Tariot PN. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer's disease trial. Schizophr Bull. 2003;29(1):57-72.
• Sernyak MJ, Leslie D, Rosenheck R. Use of system-wide outcomes monitoring data to compare the effectiveness of atypical neuroleptic medications. Am J Psychiatry. 2003 Feb;160(2):310-5.
• Stroup TS, McEvoy JP, Swartz MS, Byerly MJ, Glick ID, Canive JM, McGee MF, Simpson GM, Stevens MC, Lieberman JA. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull. 2003;29(1):15-31.
• Swartz MS, Perkins DO, Stroup TS, McEvoy JP, Nieri JM, Haak DC. Assessing clinical and functional outcomes in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. Schizophr Bull. 2003;29(1):33-43.
• Stroup TS, Appelbaum PS. Evaluation of "subject advocate" procedures in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study. Schizophr Bull. 2006 Jan;32(1):147-52. Epub 2005 Nov 10.

Inclusion

• 18-65 years old
• DSM-IV diagnosis of schizophrenia
• adequate capacity to consent

Exclusion

• Intolerance or failure to respond to one of the treatments
• Diagnoses of schizoaffective disorder, mental retardation, pervasive developmental disorder, delirium, dementia, amnesia
• First episode of schizophrenia
• Women currently pregnant or breast-feeding