1. The Clinical Antipsychotic Trials of Intervention Effectiveness Trial
An overview of The “catie” trial
ALBREKA HUDSON, PHARMd candidate
Preceptor:
soheyla Mahdavian, 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
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 pharmacotherapies for schizophrenia
Participants:
14943 in Phase 1
543 in Phase 2
270 in Phase 3
CATIE was conducted at many different treatment sites—
including private clinics, academic centers, Veterans
Administration hospitals, and public mental health centers—in an
attempt to be broadly representative of the real-life settings where
consumers receive care.

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.

5. Demographics Male 74% Female 26% Caucasian 60% African American 35%
Spanish, Hispanic, Latino
12%
Asian 2%
American Indian or Alaska Native
<1%
Native Hawaiian or other Pacific Islander
“Two or more races”

6. Co-Morbidities and Mental Health Conditions
Depression
28%
Anxiety
14%
Drug Dependence/Abuse
29%
Diabetes
11%
Hypertension
20%

7. CATIE Trial Design, 3 phases comparing 4 atypicals to 1 conventional/typical in the first phase. Phase 2 only compares atypicals to each other after failing to respond or to tolerate another drug in the first phase, and then phase 3 is an open label.

8. Outcome Measures
Phase 1

9. Phase 1 Primary: Secondary:
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 Primary: Secondary: Primary: Secondary: Efficacy Tolerability
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.
* The original hypothesis that ziprasidone would be the most effective was not confirmed!

16. Outcome Measures
Phase 3

17. Phase 3 (Open- Label) Primary:
Time until discontinuation for any reason
Phase 3: patients were free to select one among antipsychotic regimens

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
Extrapyramidal symptoms were the most common reason for discontinuation with perphenazine.
No superior efficacy of atypical over conventional antipsychotic ( Ex. perphenazine)
All-cause discontinuation rate of 74% at 18 months.
Olanzapine fared better than quetiapine, risperidone and also with other medications.
In terms of discontinuation of medication due to any cause before the completion of the study
The discontinuation due to intolerable side effects was similar among all the groups, with more individuals discontinuing Olanzapine due to weight gain (07 percent or more of the baseline body weight) and increase in glycosylated haemoglobin, cholesterol and triglyceride leading to metabolic syndrome. In case of perphenazine Extrapyramidal symptoms were the most common reason for discontinuation (08 percent vs. 02 percent to 04 percent, P=0.002). No superior efficacy of Atypical over conventional AP, i.e. Perphenazine.
Perphenazine was however most cost-effective when compared with newer atypical APs.
Clozapine was 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.
Among all, Ziprasiodne 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 (Fluphenazine decanoate, n=09 or Perphenazine, n=04)

20. Phase 3
Clozapine was 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. A reflective review of the trial
Journal Critique
A reflective review of the trial

22. Critique Phase 1 & 2, double-blinded randomized
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
Pros:
Cons:
Open-label trials can lead to significant bias and misrepresentation of outcomes measured. However, clozapine was open label due to the weekly blood monitoring.
Use of pherphenazine only is not representative of the whole class and may lead to inaccurate assumptions of the entire class.
Inability to pinpoint the specific cause of treatment discontinuation and this poses a major problem in the treatment of schizophrenia.

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
Cons:
Risperidone 6 mg was chosen to reduce symptoms of EPS, but maximum effective target dose to treat schizophrenia is 8mg/day PO.
Comorbidities/illnesses can greatlt distort outcomes
Inclusion criteria may confound results, treatment allocation=bias

24. Critique Use of Kaplan-Meier (KM) Curve
Pros
Cons
Use of Kaplan-Meier (KM) Curve
Patients had to have an adequate decisional capacity
Cons:
Adequate decisional capacity: is this representative of the schizophrenic population? Probably not, because most of them need a guardaina advocate, because they have a lower cognitive function, lower adherence to medications, and therefore a lower likelihood to continue treatment.

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:
Ericksen, Jennifer, Sheri A. Strite, and Craig Stern. "CATIE Trial Review of Phases 1 and 2." EBM REVIEW. June Web. 18 Jan
Stroup TS, McEvoy JP, Swartz MS, et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. N Engl J Med. 2005:353:
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  (2008):
Stroup TS, McEvoy JP, Swartz MS, et al. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull 2003;29:15-31.