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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. Global Antipsychotic Market Sales (MAT Q1 by Yr). Source: IMS.

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de diffusion of medical treatments atypical antipsychotics the treatment of mental illness

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
Global Antipsychotic Market Achieved $10.2B In Sales in 2003

Global Antipsychotic Market Sales

(MAT Q1 by Yr)

Source: IMS

primary questions addressed by catie schizophrenia trial
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

Phase 1*

Double-blind, random treatment assignment.









CATIE Schizophrenia Trial Design

Phase 3

Phase 2

Participants who discontinuePhase 2 choose one of the following open-label treatments

Participants who discontinue Phase 1 choose either the clozapine or the ziprasidone randomization pathways






1460 patients with SCZ


Other meds





  • 2 of the antipsychotics above

No one assigned to same drug as in Phase 1

*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;29:15-31.

primary outcome measure all cause treatment discontinuation
Primary Outcome Measure:All-Cause Treatment Discontinuation



All-Cause Discontinuation

Patient Input

Clinician Input


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

catie cost effectiveness analysis cea study design
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.
methods measuring 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, 1996.
    • Measurement is based on the PANSS-based health states and measures of side effects using methods developed by Lenert et al. 2004 (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).
service use and cost measures
Service Use (Service Use and Resources Form [SURF])


Mental health



Mental Health

Substance Abuse


Nursing home


Medication records

Criminal justice, public support, productivity



All residential


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).

Service Use and Cost Measures
other no difference findings
Other “no difference” findings
  • Neurocognitive functioning
  • Quality of Life
  • Violent behavior
  • Family burden
  • Employment
  • 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
Tardive Dyskinesia (TD) RiskIncidence 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
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
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
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
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
Monitoring Form Data (N=609): Diagnosis and Treatment
  • Treatment of:
    • Schizophrenia 19.2%
    • Bipolar disorder 27.6%
    • Other affective 22.8%
    • PTSD 19.7%
    • Other 31.9%
  • Treatment proposed:
    • Aripirazole 14.6%
    • Olanzapine 19.9%
    • Quetiapine 56.0%
    • Ziprasidone 6.7%
    • Consta 2.6%
monitoring form data n 609 reason for new medication
Monitoring Form Data (N=609): Reason for new medication
  • Patient preference 28.9%
  • Efficacy 34.8%
  • Sleep 29.7%
  • Less EPS 13.8%
  • Less TD risk 9.7%
  • Less sedation 5.1%
  • Treatment of TD 0.8%
  • Other 24.8%
monitoring form data n 609 previous drugs health status
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
Monitoring Form Data (N=609):Co-Morbidity
  • TD 4.6%
  • EPS 4.4%
  • Akithesia 3.4%
  • Diabetes 14.6%
  • Hyperlipidemia 27.1%
  • Obesity 20.5%
  • Hypertension 34.0%

- ASCVD 9.5%

  • 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.