1. Scott Stroup, MD, MPH University of North Carolina at Chapel Hill
Comparative Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia: Findings to Date from the NIMH-CATIE Schizophrenia Trial
Scott Stroup, MD, MPH
University of North Carolina at Chapel Hill

2. Research program to evaluate the effectiveness of antipsychotic medications for schizophrenia and Alzheimer’s disease in “real-world” settings

3. Determinants of drug effectiveness Staying on the drug is critical
Efficacy
Tolerability
Decision to stay on the drug
Clinician Input
Patient Input

4. The approach to extrapyramidal side effects is a key methodologic issue in comparative studies of first- and second-generation antipsychotic drugs.

5. New Antipsychotics vs Haloperidol ‘Pooled’ Data on use of anticholinergics Use of Anticholinergic Medication
Olanzapine pooled
r=.35*; n=2694
(3 studies)
Quetiapine pooled
r=.38*; n=758
Risperidone pooled
r=.12*; n=1938
(7 studies)
Greater Use
Lesser Use
The newer atypicals are associated with less EPS than haloperidol
r (95% CI)
*Statistically significant.
Modified from Leucht S, et al. Schizophr Res. 1999;35:51-68.

6. Atypical antipsychotics in the treatment of schizophrenia: meta­regression analysis (Geddes et al for the National Schizophrenia National (UK) Schizophrenia Guideline Development Group 2000)
Result: When the dose was <12 mg/day of haloperidol (or equivalent), atypical antipsychotics had no benefits in terms of efficacy or overall tolerability, but they still caused fewer extrapyramidal side effects.
Conclusion: There is no clear evidence that atypicals are more effective or better tolerated than conventional antipsychotics. Therefore, conventional antipsychotics should usually be used in the initial treatment of schizophrenia
Geddes and colleagues looked at symptoms, side effects, and rate of drop out and came up with the conclusions on the slide.
Of course, this conclusion is drawn in the UK, which has a very different health system than the U.S. But when stewardship of public dollars are concerned people seem to take a different view of whether the marginal benefits of atypicals justify the costs and trade-offs required due to potentially huge expenditures.
An accompanying editorial from Canada, in a setting where the costs of drugs are paid for through public funds, reported that patients almost always choose atypicals when given the opportunity.
Geddes was highly criticized by the drug companies and by some consumer advocates.

7. Effectiveness and cost of olanzapine and haloperidol: A randomized clinical trial
Rosenheck et al. JAMA 2003
All patients assigned haloperidol also received benztropine to minimize EPS.

8. Olanzapine vs. Haloperidol; Rosenheck et al, 2003
Figure 2. Symptom outcomes (PANSS total scores) among patients assigned to clozapine or standard antipsychotic treatment , stratified by whether they continued to take clozapine or a standard medication (completers), or crossed over to the other treatment (crossovers).
Note: Crossovers from clozapine to standard treatment occurred at months (median 2.5 months). Crossovers from haloperidol to clozapine occurred at months (median 4.8 months).
Mixed model analysis: ns

9. Mixed model analysis: ns
Olz. N:
159
121
108 93 90 92
Hal. N:
150
115
105 94 83 85

10. Side Effects of Atypical Antipsychotics: Shift in Risk Perception
Prior Safety Concerns
Current Safety Concerns
Diabetes
Neurologic Side Effects
Weight Gain
EPS + TD
Hyper
Glycemia
CVD
Insulin
Resistance
Side Effects of Atypical Antipsychotics: Shift in Risk Perception
Weight Gain
Insulin
Resistance
Hyper-
lipidemia
EPS
QTc
Dyslipidemia
CVD
QTc
Hyper-
glycemia

11. Chronic Schizophrenia: Key Recommendations of the Schizophrenia Patient Outcomes Research Team (PORT)
No clear statement of preference of SGAs over FGAs in acute or maintenance treatment
Clozapine the treatment of choice for treatment-refractory positive symptoms; clozapine also recommended for hostility and suicidality
Lehman AF et al. Schizophr Bull. 2004;30:

12. Rationale for CATIE Published studies have significant limitations:
Predominantly short-term studies designed for regulatory approval and labeling language
Comparators are either placebo or a single active agent (usually haloperidol)
Results have limited generalizability because they lack representative patient samples, clinical settings and treatment conditions
Existing studies do not address critical clinical and policy questions
Sponsored by pharmaceutical companies
Clinical experience and case reports are not an adequate substitute for data
Existing data largely from studies sponsored by drug companies for regulatory and marketing purposes- these typically focus on short-term efficacy and involve carefully selected patients who have no concurrent medical illnesses or substance use disorders and are conducted in rarified settings, like inpatient research units where medication compliance is ensured, that do not resemble usual practice. In other words, there is little data to inform us about the real-world effectiveness of these trials.

13. Practical Clinical Trials
Designed to answer questions faced by clinicians and policy makers
Compare clinically relevant alternative interventions
Include a representative population of study participants
Conduct studies at representative practice settings
Simulate actual treatment conditions
Collect data on a broad range of health outcomes that are clinically meaningful
Tunis et al JAMA 2003, March et al AJP 2005

14. How Does a Practical Clinical Trial Differ from a Traditional Clinical Trial?
Traditional Clinical Trials
Practical Clinical Trials
Population
Exclusive
Inclusive
Setting
Recruitment relies on patients coming to academic health centers.
Recruitment relies on community practice settings, including private practices and state facilities.
Design
Treatment vs. Placebo
Treatment vs. Treatment
Duration
Weeks
Months
Outcome
Symptoms (efficacy)
Symptoms and Function (effectiveness)
Courtesy Tom Insel, MD

16. CATIE: Broad Inclusion & Minimal Exclusion Criteria
DSM-IV schizophrenia, years old
Not first-episode or treatment resistant
Concomitant medications, medical illnesses, substance use disorders allowed
Conducted at 57 geographically, demographically and organizationally diverse sites
In order to enroll a broad array of patients representing those who are actually seen in clinics, we developed minimal inclusion and exclusion criteria:
Stroup TS et al. Schizophr Bull. 2003;29:15-31.

17. Primary Questions Addressed by CATIE Schizophrenia Trial
How do the second generation antipsychotics compare with a representative first generation antipsychotic?
What is the comparative effectiveness of the second generation antipsychotic drugs?
Are the second generation antipsychotics cost-effective?
Stroup TS et al. Schizophr Bull. 2003;29:15-31.

18. CATIE Schizophrenia Trial: Overview
Participants
1460 people with schizophrenia
Trial duration
Subjects participate for 18 months
Design
Practical trial that is a hybrid of efficacy and effectiveness trial designs
Stroup TS et al. Schizophr Bull. 2003;29:15-31.

19. CATIE Schizophrenia Trial Design
Phase 1* R
OLANZAPINE
QUETIAPINE
RISPERIDONE
ZIPRASIDONE
PERPHENAZINE
Double-blind, random treatment assignment.
Phase 2
Phase 3
Participants who discontinue Phase 1 choose either the clozapine or the ziprasidone randomization pathways
Participants who discontinue Phase 2 choose one of the following open-label treatments
ARIPIPRAZOLE
CLOZAPINE
CLOZAPINE
(open-label)
FLUPHENAZINE DECANOATE
1460 patients with SCZ
Comorbidity
Other meds R
OLANZAPINE, QUETIAPINE or RISPERIDONE
OLANZAPINE
PERPHENAZINE
ZIPRASIDONE
QUETIAPINE R
OLANZAPINE, QUETIAPINE or RISPERIDONE
RISPERIDONE
ZIPRASIDONE
No one assigned to same drug as in Phase 1
2 of the antipsychotics above
*Phase 1A: participants with TD (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.
Stroup TS et al. Schizophr Bull. 2003;29:15-31.

20. Primary Effectiveness Measure: All-Cause Treatment Discontinuation
Efficacy
Tolerability
All-Cause Discontinuation
Clinician Input
Patient Input
Stroup TS et al. Schizophr Bull. 2003;29:15-31.

21. Stroup TS et al. Schizophr Bull. 2003;29:15-31.
Secondary Outcomes
Symptom measures
Safety
Service use and costs
Neurocognition
Treatment adherence
Comorbidity
Quality of Life
Substance use
Violence
Psychiatric studies usually have “cumbersome and lengthy follow-up interviews.” We are doing perhaps more of these than is desirable because of our and our funding agency’s desire to use this effort to obtain lots of data and to have available some evidence of our primary outcome’s validity. For efficacy we are using the usual rating scales. We have familiar monthly ratings of side effects and questions about other possible adverse events. We have a neurocognitive battery. We have multiple measures of treatment adherence. And we have a monthly interview about service use that will be used in cost-effectiveness and cost-benefit analyses.
Stroup TS et al. Schizophr Bull. 2003;29:15-31.

22. CATIE Phase 1: Double-Blinded and Randomized
Olanzapine 7.5–30 mg/day
Perphenazine 8–32 mg/day
1460 Patients
with Schizophrenia
Randomized
Quetiapine 200–800 mg/day
Risperidone 1.5–6 mg/day
Ziprasidone 40–160 mg/day *
Persons with TD not assigned to perphenazine
* Ziprasidone added after 40% sample enrolled
Stroup TS et al. Schizophr Bull. 2003;29:15-31.

23. Demographic & Clinical Characteristics
Insert Edited Table 1

24. Prevalence of Metabolic Syndrome in CATIE Schizophrenia Study Participants at Baseline vs. the General Adult Population (NHANES Data)
CATIE (N = 689) *
NHANES (N = 687) *
CATIE = Clinical Antipsychotic Trials in Intervention Effectiveness; NHANES = National Health and Nutrition Examination Survey *P = CATIE vs NHANES.
McEvoy et al. Schizophrenia Research 2005

25. Substance Use in CATIE Subjects (Alcohol and Illicit Drugs)
Source of data: Marvin Swartz, MD; unpublished data.

26. Phase I Randomization and Treatment
Intent-to-treat (ITT) patients received at least one dose of study medication.
Dose and efficacy assessments are reported for the ITT patients. Safety assessments are reported for all randomized patients.

27. Time to Discontinuation for Any Reason
Overall p-value = 0.004*
P<0.001 for olanzapine vs quetiapine
P=0.002 for olanzapine vs risperidone
The Kaplan Meier median is the time by which half of the patients have discontinued
The hazard ratio for olanzapine vs. quetiapine is 0.63: at any given time, patients on olanzapine are 63% less likely to discontinue treatment compared to patients on quetiapine.
The Hazard ratio is from Cox proportional hazards regression, and is the ratio of the probability of discontinuing the phase at any timepoint for one treatment group vs. another.

28. Time to Discontinuation for Lack of Efficacy
Overall p-value < 0.001*
P<0.001 for olanzapine vs quetiapine, risperidone and perphenazine
The Kaplan Meier 25th %ile is the time by which 25% of the patients have discontinued. The median can not be estimated due to low event rates.
The hazard ratio for olanzapine vs. quetiapine is 0.41: at any given time, patients on olanzapine are 41% less likely to discontinue treatment for lack of efficacy compared to patients on quetiapine.
The Hazard ratio is from Cox proportional hazards regression, and is the ratio of the probability of discontinuing the phase at any timepoint for one treatment group vs. another.

29. Time to Discontinuation for Intolerability
Overall p-value = 0.054
Kaplan Meier medians and 25th %ile can not be estimated due to low event rates
The hazard ratio for risperidone vs. olanzapine is 0.62: at any given time, patients on risperidone are 62% less likely to discontinue treatment for intolerability compared to patients on olanzapine. This difference is not significant since the overall p-value was not less than 0.05.
The Hazard ratio is from Cox proportional hazards regression, and is the ratio of the probability of discontinuing the phase at any timepoint for one treatment group vs. another.

30. Reasons for Discontinuation Due to Intolerability All Randomized Patients
Discontinued for Intolerability 15% Weight/Metabolic 4% Extrapyramidal 4% Sedation 2% Other %

31. PANSS Total Score
P=0.001 for time-by-treatment interaction
P=0.065 for ziprasidone cohort
Interaction of time × treatment indicates significant variation in treatment effects over time. Improvement was initially greatest with olanzapine but its advantage diminished over time. The number of patients declines over assessment times. Least -square mean estimates are from a mixed model, which assumes that data are missing at random. Values at later time points are based on the observed data for continuing patients as well as  estimated data for discontinued patients.  

32. PANSS Positive Score
P=0.004 for time-by-treatment interaction
P=0.346 for ziprasidone cohort
Interaction of time × treatment indicates significant variation in treatment effects over time. The number of patients declines over assessment times. Least -square mean estimates are from a mixed model, which assumes that data are missing at random. Values at later time points are based on the observed data for continuing patients as well as  estimated data for discontinued patients.  

33. PANSS Negative Score
P=0.177 for time-by-treatment interaction
P=0.019 for ziprasidone cohort
The number of patients declines over assessment times. Least -square mean estimates are from a mixed model, which assumes that data are missing at random. Values at later time points are based on the observed data for continuing patients as well as  estimated data for discontinued patients.  

34. Hospitalizations for Exacerbation of Schizophrenia

35. Treatment-Emergent Adverse Events

36. Treatment-Emergent Neurologic Effects
AIMS percentages exclude TD patients.
Barnes and Simpson-Angus percentages in NEJM did not exclude TD patients

37. Weight change from Baseline to Last Observation

38. Laboratory Chemistry: Change from Baseline to Average of Two Highest Values
patients were instructed to fast, nonfasting results were not excluded
Exposure-adjusted means are the estimated mean values that we would see at the average treatment duration across all groups (8.3 months). They are least squares means from an ANCOVA model adjusting for treatment duration.

39. Reasons for Discontinuation Due to Intolerability All Randomized Patients
FYI: the percentages of patients discontinued for intolerability differ slightly between this slide and the previous one because this slide is based on all randomized patients, and the previous slide is limited to ITT patients who took at least one dose of study medication.

40. Key Messages
CATIE provides important new information on antipsychotic drugs that should greatly assist doctors and patients in making individualized treatment choices.
Overall, all the medications were comparably effective but were associated with high rates of discontinuation due to intolerable side effects, failure to adequately control symptoms, or other reasons.

41. Key Messages
Olanzapine was somewhat more efficacious than the other drugs but also was associated with significant weight gain and metabolic changes.
The older medication perphenazine generally performed as well as the newer medications. The older medication was as well tolerated as the newer drugs and was as effective as three of the newer medications. Contrary to expectations, EPS was not seen more frequently with perphenazine than with the newer drugs.

42. Key Messages
Treatments for persons with schizophrenia must be individualized. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects in choosing an appropriate medication. What works for one person may not work for another.

43. Some early reactions

44. Washington Post New Antipsychotic Drugs Criticized Federal Study Finds No Benefit Over Older, Cheaper Drug September 20, 2005; A01
New York Times Study Finds Little Advantage in New Schizophrenia Drugs September 20, 2005 F-1
The Wall Street Journal Generic Fares Well in Big Psychiatry Study: Newer Costlier Drugs Have Little Advantage for Schizophrenia September 20, 2005 D-1

45. Alliance for Human Research Protection
29 July 2005:
“Next Phase in Psychiatry? Or, NIMH Effort to Rescue Bad Drugs”
20 September 2005:
“Federal Study Finds No Benefit of New Antipsychotic Drugs”

46. “Psychiatry hasn’t advanced in thirty years!”
Schizophrenia Anonymous-Durham is going retro to celebrate Halloween
On 9/20, the researchers got their treat: the psychiatric patients got the trick.
…while saving Medicaid money and adjusting to those vintage neuroleptics, here’s some music to get you in the mood: “Let’s twist again”

47. Tom Toles Sketch, Washington Post, September 23, 2005

48. FAQs Are the newer medications better than the older ones?
Are the newer drugs all the same?
Are the older drugs all the same? Do the results with perphenazine apply to the others?

49. FAQs Why were the discontinuation rates so high?
Were the doses comparable?
Was the study long enough to make comparisons regarding tardive dyskinesia?

50. FAQs Should everyone be switched to a cheaper drug?
Should we keep everything on the formulary?
Why not start with the cheapest drugs?

51. FAQs
Do we know what to do when someone doesn’t do well on one medication?

52. CATIE results still to come
Cost-effectiveness evaluation
Phase 2 studies:
Efficacy pathway: clozapine vs. a second atypical
Tolerability pathway: ziprasidone vs. a second
Neurocognition
Substance use, violence

53. Thank you.