CP_02.06_CATIE.Final 1/17/06 4:50 PM Page 48 Copyright® Dowden Health Media For personal use only For mass reproduction, content licensing and permissions contact Dowden Health Media. CP_02.06_CATIE.Final 1/17/06 4:51 PM Page 49 Current p SYCHIATRY In antipsychotics’ square-off, were there winners or losers? nvestigators faced a dilemma while designing the Clinical Antipsychotic Trials of Inter- I vention Effectiveness (CATIE). More than 200 enrollees with chronic schizophrenia had pre-exist- Henry A. Nasrallah, MD ing tardive dyskinesia (TD). Would it be ethical to Professor of psychiatry, neurology, and neuroscience give them the antipsychotic most likely to worsen Department of psychiatry their TD? Would exempting them from taking that University of Cincinnati College of Medicine Member, CATIE Study Investigators Group drug influence the trial’s outcome? This issue and others had to be resolved before the largest controlled study of “real world” schizo- phrenia could begin. Now that data are unfolding, Perphenazine was as effective groups with diverse agendas are debating CATIE’s as the atypical antipsychotics, methods and surprising results. This article des- but could the study’s design cribes how the trial’s design and findings could have swayed the outcome? transform public policy and clinical practice. EFFICACY VS EFFECTIVENESS The National Institute of Mental Health funded the prospective CATIE schizophrenia study to compare the effectiveness of atypical antipsy- ispot chotics versus each other and versus a first-gener- the ation (typical) antipsychotic. c/o Yeo All approved atypicals have shown similar effi- Brad cacy compared with placebo in short-term trials © VOL. 5, NO. 2 / FEBRUARY 2006 49 CP_02.06_CATIE.FinalREV 1/18/06 2:17 PM Page 50 CATIE Table 1 medications, or show evidence of Criteria for enrolling patients TD. Their schizophrenia ranged in the CATIE schizophrenia trial from minimal to severe.2,3 The 1,493 patients who complet- Inclusion criteria Ages 18 to 65 yrs ed the study (Table 2) were enrolled DSM-IV diagnosis of schizophrenia at 57 outpatient treatment settings. One site’s 33 patients were eliminat- Able to take oral medication ed from analysis because of doubts Able to give informed consent about the integrity of the data, leav- 4 Exclusion criteria Diagnosis of schizoaffective ing a total of 1,460 subjects. disorder, mental retardation, Medications. Before randomization, or other cognitive disorders 28% of enrollees were not receiving History of serious adverse reactions antipsychotics. The remainder were to one of the study medications receiving: • olanzapine (22%) Had only one schizophrenic episode • risperidone (19%) History of treatment resistance, • quetiapine (7%) defined as persistence of severe • ziprasidone (0%; approved symptoms despite adequate trials after the trial began) of one of the study antipsychotics • any combination of olanzap- or prior treatment with clozapine ine, risperidone, and quetia- Pregnant or breast feeding pine (7%) Serious and unstable medical • typical antipsychotics (16%). conditions Metabolic profile. These outpatients had a high rate of metabolic disor- ders: 42%—twice the rate in the gen- eral population—met criteria for (usually 6 weeks).1 The CATIE trial’s rationale is metabolic syndrome,5 putting them at high risk to that short-term efficacy studies required for FDA die of cardiovascular causes within 10 years.6 approval may not necessarily reflect the drugs’ effectiveness in long-term schizophrenia manage- ment. Effectiveness measures take into account efficacy as well as safety, tolerability, and unpre- What do you think? dictable patient behaviors in the real world. Go to the Instant Poll www.currentpsychiatry.com CATIE'S 'REAL WORLD' PATIENTS CATIE investigators enrolled a community sample Will the CATIE findings of chronic schizophrenia patients similar to those change the way you treat many psychiatrists see. Very liberal inclusion and patients with schizophrenia? exclusion criteria (Table 1) allowed enrollees to have a history of substance abuse, comorbid psy- chiatric or medical disorders, be receiving other continued on page 53 50 Current VOL. 5, NO. 2 / FEBRUARY 2006 p SYCHIATRY CP_02.06_CATIE.Final 1/17/06 4:51 PM Page 53 Current p SYCHIATRY continued from page 50 They had relatively poor physical Table 2 health self-ratings and increased CATIE’s 1,460 ‘real world’ somatic preoccupation.7 Most worri- schizophrenia patients at trial entry some, many were receiving no med- Mean age 40.6 ± 11.1 yrs ications for their metabolic disor- ders, including 45% of those with Mean age of first treatment 24.0 ± 8.9 yrs diabetes, 89% with hyperlipidemia, Mean duration of treatment 14.4 ± 10.7 yrs and 62% with hypertension.8 Substance abuse. At enrollment, 40% Gender 74% male of patients were abstinent from sub- Race 60% white, 35% black, 5% other stance use, 22% were using sub- Mean education 12.1 ± 2.3 years stances without abuse or depen- dence, and 37% had substance abuse Marital status 59% never married, or dependence. Compared with 29% previously married, nonusers, substance abusers tended 11% married to be male with more childhood Employment status 85% unemployed problems, higher positive symptoms Mean PANSS total score 75.7 ± 17.6 on the Positive and Negative Syndrome Scale (PANSS), and Mean CGI 4.0 ± 0.9 more likely to have had a recent ill- Psychiatric comorbidities 29% drug dependence/abuse ness exacerbation.9 28% depression Tardive dyskinesia. The 231 subjects 25% alcohol dependence/abuse who met criteria for probable TD10 14% anxiety disorder were older than the overall sample 5% obsessive-compulsive with more years of antipsychotic disorder treatment, especially with conven- Illness severity 4% severe, 20% marked, tional neuroleptics and anticholin- 47% moderate, 23% mild, ergics. Substance abuse was associ- 6% minimal ated with TD, as were severity of PANSS: Positive and Negative Syndrome Scale CGI: Clinician-rated Clinical Global Impressions severity score psychopathology, extrapyramidal Source: Reference 5. symptoms (EPS), and akathisia.11 Violent behavior. A history of serious violent behavior was reported in: • 5.4% of patients with high positive and low found to affect decision-making capacity, but negative PANSS symptom scores negative symptoms and diminished working • 1.7% of patients with low positive and high memory did.12 negative PANSS symptom scores. Consent. Patients’ capacity to give consent to par- CATIE’S UNIQUE DESIGN ticipate in the study was assessed with the Defining effectiveness. CATIE was designed in MacArthur Competence Assessment Tool for three phases (Figure, page 54). Phase 1—dis- Clinical Research (MacCAT-CR). Psychosis cussed here—was a blinded, controlled compari- severity (PANSS positive symptom scale) was not son of four atypical antipsychotics and per- VOL. 5, NO. 2 / FEBRUARY 2006 53 CP_02.06_CATIE.Final 1/17/06 4:51 PM Page 54 CATIE Figure CATIE schizophrenia trial design Phase 1* Phase 2 Phase 3 Double-blind random Participants who discontinue Participants who discontinue treatment assignments phase 1 choose either the phase 2 choose one of the clozapine or ziprasidone following open-label randomization pathways treatments ▼ Olanzapine Clozapine • Aripiprazole 1,460 patients ▼ (open-label) • Clozapine with ▼ Quetiapine schizophrenia R Olazapine, • Fluphenazine decanoate (could have ▼ quetiapine, • Olanzapine psychiatric R or risperidone ▼ Risperidone or medical • Perphenazine comorbidities and be taking ▼ Ziprasidone • Quetiapine ▼ Ziprasidone other R Olazapine, • Risperidone medications) ▼ quetiapine, • Ziprasidone or risperidone ▼ Perphenazine • 2 of the antipsychotics No one assigned to same above drug as in phase 1 R = randomization * Phase 1A: participants with tardive dyskinesia (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. Source: Reference 2. phenazine. Results of phases 2 and 3 have yet to 18-month trial in December 2004, and data analy- be published. The primary effectiveness endpoint, sis began in January 2005. Ziprasidone was added “all-cause discontinuation,” was defined as: to phase 1 after 40% of the sample had been • lack of efficacy (patient was switched to enrolled, and aripiprazole was included as an another drug assigned at random) option in the unblinded phase 3. • lack of tolerability (patient requested a Perphenazine was chosen to represent typical drug change) antipsychotics because it has medium potency • safety problem (investigator initiated a and less risk of EPS than high-potency drugs such switch) as haloperidol and is associated with less weight • patient’s decision for any reason (often gain than low-potency drugs such as thioridazine. dropping out of the study). Dosing. Pharmaceutical manufacturers donated The longer subjects stayed on the first anti- the antipsychotics and were invited to recommend psychotic they received, the more effective that their respective drugs’ starting dosages, dose incre- drug was considered to be. ments, and maximum dosages. Olanzapine’s Medications. Three atypicals—risperidone, olanza- maker requested a higher starting dosage (7.5 pine, and quetiapine—were approved for schizo- mg/d instead of 5.0 mg/d) and a maximum dosage phrenia when the trial began in 1999. Recruitment 50% higher than the FDA-approved range (30 ended in June 2003, the last subject completed the mg/d instead of 20 mg/d). The others recom- 54 Current VOL. 5, NO. 2 / FEBRUARY 2006 p SYCHIATRY CP_02.06_CATIE.FinalREV 1/18/06 2:17 PM Page 55 Current p SYCHIATRY mended the FDA-approved Table 3 dosage ranges or less: All-cause discontinuation rates in the CATIE trial • quetiapine, 200 to 800 mg/d Percent Duration on Dosage Antipsychotic discontinued antipsychotic (months)* (mg/d)* • risperidone, 1.5 to 6 mg/d Olanzapine 64% 9.2 20.1 • ziprasidone, 40 to 160 mg/d Perphenazine 75% 4.6 20.8 • perphenazine, 8 to Quetiapine 82% 4.8 543.4 32 mg/d. The study team accepted Risperidone 74% 5.6 3.9 their recommendations. The medications were Ziprasidone 79% 3.5 112.8 packaged in identical cap- Overall 74% Median 6.0; mean 8.3 sules.