CATIE

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Lieberman JA, et al. "Effectiveness of antipsychotic drugs in patients with chronic schizophrenia". The New England Journal of Medicine. 2005. 353(12):1209-23.
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Clinical Question

Among patients with schizophrenia, how do the second-generation antipsychotic medications such as olanzapine, quetiapine, risperione and ziprasidone compare to first-generation antipsychotic medications such as perphenazine in terms of relative effectiveness?

Bottom Line

Among patients with schizophrenia, patients receiving olanzapine experienced a longer time to discontinuation compared with the other antipsychotic medications, but they experienced greater weight gain, hyperglycemia and hyperlipidemia.

Major Points

The Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) schizophrenia trial compared the relative effectiveness of the second-generation antipsychotic medications (olanzapine, risperidone, quetiapine, and ziprasidone) to the first-generation antipsychotic perphenazine. The primary outcome was time to discontinuation for any cause, and remarkably, only 26% of patients completed 18 months of the study drug to which they were randomized. Olanzapine was associated with a longer time to discontinuation than quetiapine or risperidone, but was similar to perphenazine and ziprasidone. Olanzapine was associated with greater weight gain, hyperlipidemia, and hyperglycemia, whereas ziprasidone was associated with weight loss and improvement in lipids and in blood glucose.

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=1,432
    • Olanzapine (n=330)
    • Perphenazine (n=257)
    • Quetiapine (n=329)
    • Risperidone (n=333)
    • Ziprasidone (n=183) added in 2002
  • Setting: 57 centers in the US
  • Enrollment: 2001-2004
  • Analysis: Intention-to-treat
  • Follow-up: 18 months
  • Primary outcome: time to discontinuation of treatment for any cause

Population

Inclusion Criteria

  • Age 18-65 years
  • Schizophrenia by DSM-IV
  • Able to take oral antipsychotics

Exclusion Criteria

  • Diagnosis of schizoaffective disorder
  • Had only one psychotic episode
  • Mental retardation or other cognitive disorders
  • Adverse reactions to study drugs
  • Treatment resistance, defined by persistent, severe symptoms despite adequate treatment with study drugs
  • Pregnancy or breast-feeding
  • Serious and unstable medical condition

Baseline Demographics

  • Age: 40.6 yrs
  • Male: 74%
  • White: 60%
  • Black: 35%
  • Latino: 12%
  • Education: 12 years
  • Married: 11%
  • Unemployed: 85%
  • Exacerbation in prior 3 mos: 28%
  • Psychiatric history
    • PANSS score: 75.7
    • Clinician-rated CGI severity score: 4.0
    • Age at 1st treatment for any behavioral or emotional problem: 24 yrs
    • Years since 1st antipsychotic medication prescribed: 14.4
  • Structured Clinical Interview for DMS-IV diagnosis in past 5 yrs
    • Depression: 28%
    • Alcohol dependence or alcohol abuse: 25%
    • Drug dependence or drug abuse: 29%
    • Obsessive-compulsive disorder: 5%
    • Other anxiety disorder: 14%
  • Medical comorbidities:
    • DM: 9-12%
    • HL: 12-17%
    • HTN: 17-23%

Baseline Medications

  • Olanzapine alone: 22%
  • Quetiapine alone: 7%
  • Risperidone alone: 19%
  • Any combination including olanzapine, quetiapine, risperidone: 7%
  • All others: 16%
  • None: 28%

Interventions

  • Randomized to olanzapine 7.5-30 mg/day, perphenazine 8-32 mg/day, quetiapine 200-800 mg/day, risperidone 1.5-6 mg/day for up to 18 mos. Ziprasidone 40-120 mg/day was approved for use by the FDA and added to trial in January 2002 after ~40% patients enrolled.
  • Gradual 4-wk transition from pre-trial therapy to study agents
  • Monthly visits with study doctors
  • Patients with tardive dyskinesia could not be assigned to perphenazine
  • Successful treatment time defined as months of treatment with CGI scale of ≥3 or 4 with an improvement of ≥2 points from baseline

Outcomes

Comparisons are olanzapine vs. quetiapine vs. risperidone vs. perphenazine vs. ziprasidone.

Primary Outcome

Discontinuation of treatment for any cause
64% vs. 82% vs. 74% vs. 75% vs. 79%
Time to discontinuation
9.2 vs. 4.6 vs. 4.8 vs. 5.6 vs. 3.5 mos (P=0.004)
Olanzapine vs. quetiapine: HR 0.63; 95% CI 0.52-0.76; P<0.001
Olanzapine vs. risperidone: HR 0.75; 95% CI 0.62-0.90; P=0.002
Olanzapine vs. perphenazine: HR 0.78; 95% CI 0.63-0.96; P=0.021; NS after adjustment for multiple comparisons, required P≤0.017
Olanzapine vs. ziprasidone: HR 0.76; 95% CI 0.60-0.97; P=0.028; NS after adjustment for multiple comparisons, required P≤0.013

Secondary Outcomes

Discontinuation of treatment for lack of efficacy
15% vs. 28% vs. 27% vs. 25% vs. 24%
Time to discontinuation
NA vs. 6.0 vs. 6.0 vs. 6.1 vs. 6.9 mos (P<0.001)
NA -- olanzapine could not be estimated because of low event rates.
Olanzapine vs. quetiapine: HR 0.41; 95% CI 0.29-0.57; P<0.001
Olanzapine vs. risperidone: HR 0.45; 95% CI 0.32-0.64; P<0.001
Olanzapine vs. perphenazine: HR 0.47; 95% CI 0.31-0.70; P<0.001
Olanzapine vs. ziprasidone: HR 0.59; 95% CI 0.37-0.93; P=0.026; NS after adjustment for multiple comparisons, required P≤0.013
Patient's decision to stop treatment
24% vs. 33% vs. 30% vs. 30% vs. 34%
Time to discontinuation
12.3 vs. 4.9 vs. 4.5 vs. 6.2 vs. 3.4 mos (P=0.034)
Duration of successful treatment time
3 vs. 1 vs. 1 vs. 1 mos (P<0.001)
Hospitalization for exacerbation of schizophrenia
11% vs. 20% vs. 15% vs. 16% vs. 18% (P<0.001)
0.17 vs. 0.44 vs. 0.30 vs. 0.33 vs. 0.40 hospitalizations per person-year of treatment

Adverse Events

Insomnia
16% vs. 18% vs. 24% vs. 25% vs. 30% (P<0.001)
Urinary hesitancy, dry mouth, constipation
24% vs. 31% vs. 25% vs. 22% vs. 20% (P<0.001)
Discontinuation due to intolerable side effects
18% vs. 15% vs. 10% vs. 15% vs. 15% (P=0.04)
Discontinuation due to weight gain or metabolic effects
9% vs. 4% vs. 2% vs. 1% vs. 3% (P<0.001)
Weight change
30% vs. 16% vs. 14% vs. 12% vs. 7% gained >7% weight (P<0.001)
+2.0 vs. +0.5 vs. +0.4 vs. -0.2 vs. -0.3 lb/mo of treatment (P<0.001)
Discontinuation due to extrapyramidal effects
2% vs. 3% vs. 3% vs. 8% vs. 4% (P=0.002)
Exposure-adjusted mean change in HbA1c
+0.40 vs. +0.04 vs. +0.07 vs. +0.09 vs. +0.11% (P=0.01)
Exposure-adjusted mean change in cholesterol
+9.4 vs. +6.6 vs. -1.3 vs. +1.5 vs. -8.2 mg/dl (P<0.001)
Exposure-adjusted mean change in triglycerides
+40.5 vs. +21.2 vs. -2.4 vs. +9.2 vs. -16.5 mg/dl (P<0.001)
Exposure-adjusted mean change in prolactin
-8.1 vs. -10.6 vs. +13.8 vs. -1.2 vs. -5.6 (P<0.001)
Mean change in corrected QT interval from baseline to last observation
1.2 vs. 5.9 vs. 0.2 vs. 1.4 vs. 1.3 msec (P=0.25)
Prolonged corrected QT interval
0% vs. 3% vs. 3% vs. 1% vs. 1% (P=0.03)
Use of additional anxiolytics
9% vs. 14% vs. 10% vs. 15% vs. 15% (P<0.001)
Use of additional antidepressants
12% vs. 8% vs. 16% vs. 11% vs. 14% (P=0.03)
Use of additional hypnotics, sedatives
7% vs. 4% vs. 9% vs. 9% vs. 9% (P=0.03)

Criticisms

  • Doses were given based upon recommendations by the manufacturer rather than by the FDA
  • 74% patients in intention-to-treat analysis discontinued their assigned treatment in phase 1 before 18 months (median 6 months)

Funding

Funded by National Institute of Mental Illness (NIMH) and by Foundation of Hope of Raleigh, NC. AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Forest Pharmaceuticals, Janssen Pharmaceutica, Eli Lilly, Otsuka Pharmaceutical, Pfizer, Zenit Goldline Pharmaceuticals, Schering-Plough, and Novartis provided study drugs. Multiple authors with disclosures.