Investigators faced a dilemma while designing the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). More than 200 enrollees with chronic schizophrenia had pre-existing tardive dyskinesia (TD). Would it be ethical to give them the antipsychotic most likely to worsen their TD? Would exempting them from taking that drug influence the trial’s outcome?
This issue and others had to be resolved before the largest controlled study of “real world” schizophrenia could begin. Now that data are unfolding, groups with diverse agendas are debating CATIE’s methods and surprising results. This article describes how the trial’s design and findings could transform public policy and clinical practice.
poll here
Efficacy vs Effectiveness
The National Institute of Mental Health funded the prospective CATIE schizophrenia study to compare the effectiveness of atypical antipsychotics versus each other and versus a first-generation (typical) antipsychotic.
All approved atypicals have shown similar efficacy compared with placebo in short-term trials (usually 6 weeks).1 The CATIE trial’s rationale is that short-term efficacy studies required for FDA approval may not necessarily reflect the drugs’ effectiveness in long-term schizophrenia management. Effectiveness measures take into account efficacy as well as safety, tolerability, and unpredictable patient behaviors in the real world.
CATIE’s ‘Real World’ Patients
CATIE investigators enrolled a community sample of chronic schizophrenia patients similar to those many psychiatrists see. Very liberal inclusion and exclusion criteria (Table 1) allowed enrollees to have a history of substance abuse, comorbid psychiatric or medical disorders, be receiving other medications, or show evidence of TD. Their schizophrenia ranged from minimal to severe.2,3
The 1,493 patients who completed the study (Table 2) were enrolled at 57 outpatient treatment settings. One site’s 33 patients were eliminated from analysis because of doubts about the integrity of the data, leaving a total of 1,460 subjects.4
Table 1
Criteria for enrolling patients in the CATIE schizophrenia trial
| Inclusion criteria | Ages 18 to 65 yrs |
| DSM-IV diagnosis of schizophrenia | |
| Able to take oral medication | |
| Able to give informed consent | |
| Exclusion criteria | Diagnosis of schizoaffective disorder, mental retardation, or other cognitive disorders |
| History of serious adverse reactions to one of the study medications | |
| Had only one schizophrenic episode | |
| History of treatment resistance, defined as persistence of severe symptoms despite adequate trials of one of the study antipsychotics or prior treatment with clozapine | |
| Pregnant or breast feeding | |
| Serious and unstable medical conditions |
Table 2
CATIE’s 1,460 ‘real world’ schizophrenia patients at trial entry
| Mean age | 40.6±11.1 yrs |
| Mean age of first treatment | 24.0±8.9 yrs |
| Mean duration of treatment | 14.4±10.7 yrs |
| Gender | 74% male |
| Race | 60% white, 35% black, 5% other |
| Mean education | 12.1±2.3 years |
| Marital status | 59% never married |
| 29% previously married | |
| 11% married | |
| Employment status | 85% unemployed |
| Mean PANSS total score | 75.7±17.6 |
| Mean CGI | 4.0±0.9 |
| Psychiatric comorbidities | 29% drug dependence/abuse |
| 28% depression | |
| 25% alcohol dependence/abuse | |
| 14% anxiety disorder | |
| 5% obsessive-compulsive disorder | |
| Illness severity | 4% severe |
| 20% marked | |
| 47% moderate | |
| 23% mild | |
| 6% minimal | |
| PANSS: Positive and Negative Syndrome Scale | |
| CGI: Clinician-rated Clinical Global Impressions severity score | |
| Source: Reference 5. | |
Medications. Before randomization, 28% of enrollees were not receiving antipsychotics. The remainder were receiving:
- olanzapine (22%)
- risperidone (19%)
- quetiapine (7%)
- ziprasidone (0%; approved after the trial began)
- any combination of olanzapine, risperidone, and quetiapine (7%)
- typical antipsychotics (16%).
Metabolic profile. These outpatients had a high rate of metabolic disorders: 42%—twice the rate in the general population—met criteria for metabolic syndrome,5 putting them at high risk to die of cardiovascular causes within 10 years.6 They had relatively poor physical health self-ratings and increased somatic preoccupation.7 Most worrisome, many were receiving no medications for their metabolic disorders, including 45% of those with diabetes, 89% with hyperlipidemia, and 62% with hypertension.8
Substance abuse. At enrollment, 40% of patients were abstinent from substance use, 22% were using substances without abuse or dependence, and 37% had substance abuse or dependence. Compared with nonusers, substance abusers tended to be male with more childhood problems, higher positive symptoms on the Positive and Negative Syndrome Scale (PANSS), and more likely to have had a recent illness exacerbation.9
Tardive dyskinesia. The 231 subjects who met criteria for probable TD10 were older than the overall sample with more years of antipsychotic treatment, especially with conventional neuroleptics and anticholinergics. Substance abuse was associated with TD, as were severity of psychopathology, extrapyramidal 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 negative PANSS symptom scores
- 1.7% of patients with low positive and high negative PANSS symptom scores.
Consent. Patients’ capacity to give consent to participate in the study was assessed with the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR). Psychosis severity (PANSS positive symptom scale) was not found to affect decision-making capacity, but negative symptoms and diminished working memory did.12
CATIE’s Unique Design
Defining effectiveness. CATIE was designed in three phases (Figure). Phase 1—discussed here—was a blinded, controlled comparison of four atypical antipsychotics and perphenazine. Results of phases 2 and 3 have yet to be published. The primary effectiveness endpoint, “all-cause discontinuation,” was defined as: