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

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

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

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

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 -0.4 -0.3 0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 r (95% CI) *Statistically significant. Modified from Leucht S, et al. Schizophr Res. 1999;35:51-68.

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.

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.

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 3.8 + 3.2 months (median 2.5 months). Crossovers from haloperidol to clozapine occurred at 5.5 + 3.0 months (median 4.8 months). Mixed model analysis: ns

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

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

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;30:193-217.

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.

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

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

CATIE: Broad Inclusion & Minimal Exclusion Criteria DSM-IV schizophrenia, 18-65 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.

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.

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.

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.

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.

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.

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.

Demographic & Clinical Characteristics Insert Edited Table 1

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 = 0.0001 CATIE vs NHANES. McEvoy et al. Schizophrenia Research 2005

Substance Use in CATIE Subjects (Alcohol and Illicit Drugs) Source of data: Marvin Swartz, MD; unpublished data.

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.

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.

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.

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.

Reasons for Discontinuation Due to Intolerability All Randomized Patients Discontinued for Intolerability 15% Weight/Metabolic 4% Extrapyramidal 4% Sedation 2% Other 5%

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.  

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.  

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.  

Hospitalizations for Exacerbation of Schizophrenia

Treatment-Emergent Adverse Events

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

Weight change from Baseline to Last Observation

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.

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.

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.

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.

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.

Some early reactions

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

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”

“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”

Tom Toles Sketch, Washington Post, September 23, 2005

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?

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

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

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

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

Thank you.