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 2

CLOZAPINE

(open-label)

OLANZAPINE, QUETIAPINE or RISPERIDONE

OLANZAPINE, QUETIAPINE or RISPERIDONE

ZIPRASIDONE

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;29:15-31.
        - CLOZAPINE

R

OLANZAPINE

QUETIAPINE

RISPERIDONE

ZIPRASIDONE

PERPHENAZINE

Phase 1*

Double-blind, random treatment assignment.

R

R

Primary Outcome Measure:All-Cause Treatment Discontinuation

All-Cause Discontinuation

Efficacy

Tolerability

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*

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.

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, 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).

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

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).

Perphenazine>risperidone (with Hochberg adjustment for multiple comparisons)

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).

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).

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).

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).

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

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).

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).

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).

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).

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).

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).

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) 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
        - 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:
        - 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
        - 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
        - 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%
        - Akithesia		3.4%
        - Diabetes		14.6%
        - Hyperlipidemia	27.1%
        - Obesity		20.5%
        - Hypertension		34.0%

-  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.