De-diffusion of medical treatments: Atypical antipsychotics the treatment of mental illness Robert Rosenheck MD Yale Medical School

Global Antipsychotic Market Achieved $10.2B In Sales in 2003 Source: IMS Global Antipsychotic Market Sales (MAT Q1 by Yr)

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 Design 1460 patients with SCZ Comorbidity Other meds Participants who discontinue Phase 2 choose one of the following open-label treatments ARIPIPRAZOLE FLUPHENAZINE DECANOATE PERPHENAZINE RISPERIDONE OLANZAPINE ZIPRASIDONE QUETIAPINE 2 of the antipsychotics above Phase 3 Phase 1* R OLANZAPINE QUETIAPINE RISPERIDONE ZIPRASIDONE PERPHENAZINE Double-blind, random treatment assignment. Phase 2 CLOZAPINE (open-label) OLANZAPINE, QUETIAPINE or RISPERIDONE ZIPRASIDONE R R No one assigned to same drug as in Phase 1 Participants who discontinue Phase 1 choose either the clozapine or the ziprasidone randomization pathways *Phase 1A: participants with TD do not get randomized to perphenazine; phase 1B: participants who fail perphenazine will be randomized to an atypical (olanzapine, quetiapine, or risperidone) before they are eligible for phase 2. Stroup TS et al. Schizophr Bull. 2003;29: CLOZAPINE

Primary Outcome Measure: All-Cause Treatment Discontinuation All-Cause Discontinuation EfficacyTolerability Clinician Input Patient Input

Time to Discontinuation for Any Reason P<0.001 for olanzapine vs quetiapine P=0.002 for olanzapine vs risperidone Overall p-value = 0.004*

Treatment-Emergent Adverse Events

Treatment-Emergent Neurologic Effects

Weight change from Baseline to Last Observation

CATIE Cost Effectiveness Analysis (CEA) Study Design Comparison of Initiation Strategies (Intent-to-Treat including all follow-up data) Comparison of “fail first” strategies with different starting agents. Secondary analysis “on initially assigned treatment” excluded observations after first medication change (as in NEJM paper). CATIE multi-phase algorithm assured balanced treatment after first discontinuation. 98% received atypicals Balance across atypicals.

CATIE Cost-Effectiveness (2) EFFECTIVENESS

Methods: Measuring Effectiveness 1) PANSS Total Score: “Gold standard” for symptom comparison: paired comparisons between groups. 2) Primary Outcome Measure: Health State Utility Assessment in Quality Adjusted Life Years [QALYs]: following Gold, Measurement is based on the PANSS-based health states and measures of side effects using methods developed by Lenert et al (societal preferences) ; 3) An aggregate health status measure weighted by patient importance ratings (patient preferences); 4) Visual Analogue Scale: subjective patient global rating of overall health from 0 (worst possible health) to 100 (perfect health) 5) Lehman QOL question (How would you rate your life overall (1-7, delighted to terrible).

Olanzapine<risperidone, quetiapine (with Hochberg adjustment for multiple comparisons)

Perphenazine>risperidone (with Hochberg adjustment for multiple comparisons)

CATIE Cost-Effectiveness Results (1) COST

Service Use and Cost Measures Service Use (Service Use and Resources Form [SURF]) Outpatient Mental health Medical Inpatient Mental Health Substance Abuse Medical Nursing home Residential Medication records Criminal justice, public support, productivity Cost Outpatient All residential Inpatient All health care Experimental medications 2003 Medicaid Discount rates and mandated company rebates VA discount (40%) Sensitivity analysis of price discounts (as funded vs Medicaid vs. VA). Ancillary medication (discounted cost to privately insured Market Scan ® patients).

$200/mo $2,400/yr

Other “no difference” findings Neurocognitive functioning Quality of Life Violent behavior Family burden Employment

Critiques 1) low follow-up rates, 2) “short” study duration to address TD risk, 3) sample characteristics (“too chronic”), 4) the choice of outcome measures (QALYs), 5) exclusion of patients with tardive dyskinesia from assignment to perphenazine, 6) choice of study drugs and doses, 7) reliance on intention-to-treat analysis, and 8) differences in pre-study treatment 9) doesn’t address latest entrants to the market.

Tardive Dyskinesia (TD) Risk Incidence vs Health Outcomes Six Dimensions of Sensitivity analysis i) severity, ii)duration, iii)treatment with SGAs, iv)QOL, iv)QALYs v) Annual cost

ICERs for TD If,as per CATIE cost difference is $2,400- $3,600- $6,000 cost/case of TD yields the following matrix:

Antipsychotic Formulary Policy Revisited Virtual current policy: only use SGAs Greater cost No greater effectiveness Greater risk of weight gain/metabolic syndrome/ diabetes Less risk of EPS/TD than moderate/high dose haloperidol, but not intermediate or high potency FGAs (perphenazine, loxitane, thiothixene) Risperidone, least expensive SGA will be coming off patent and will be even less expensive.

Two Aspects of Formulary Policy What is the most cost effective sequence of treatments? How do we create incentives to follow it? No marketing for generics even if they are SGAs.

Four groups of APS drugs Risperidone or any FGA Clozapine (2 or 3 failures) Generic available Weight gain risk is of concern and some patients may not tolerate the required blood monitoring Aripiprazole, ziprasidone or quetiapine Olanzapine: greatest weight gain

Monitoring Form Data (N=609): Diagnosis and Treatment Treatment of: Schizophrenia19.2% Bipolar disorder27.6% Other affective22.8% PTSD19.7% Other31.9% Treatment proposed: Aripirazole14.6% Olanzapine19.9% Quetiapine56.0% Ziprasidone 6.7% Consta 2.6%

Monitoring Form Data (N=609): Reason for new medication Patient preference28.9% Efficacy34.8% Sleep29.7% Less EPS 13.8% Less TD risk 9.7% Less sedation 5.1% Treatment of TD 0.8% Other24.8%

Monitoring Form Data (N=609): Previous Drugs, Health Status Failed previous drugs due to lack of efficacy Risp (4.3%), Perph 0.7%) Haloperidol (2.4%),Aripip (1.3%), Quet (1.6%), Zip (1.3%), Cloz (0.3) Don’t know (26.8) Failed previous drugs due to intolerability Risp (6.9%), Perph (1.8%), Halop. (2.5%) Aripip (1.1%), Quet (3.4%), Cloz (0.5%) Age=54.2 Wt=196, Ht = 5’9”, BMI=31.0 AIMS = 0.8 (possible TD=1)

Monitoring Form Data (N=609): Co-Morbidity TD 4.6% EPS 4.4% Akithesia3.4% Diabetes14.6% Hyperlipidemia27.1% Obesity20.5% Hypertension34.0% - ASCVD 9.5%

Conclusion The results of the CATIE schizophrenia trial provide no support for the hypothesis that any second generation antipsychotic is more cost-effective than perphenazine in chronic schizophrenia. This study has important implications for practice and policy.