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Effectiveness and Cost of Olanzapine and Haloperidol in the
Treatment of Schizophrenia
A
Randomized Controlled Trial
Robert
Rosenheck, MD; Deborah Perlick, PhD; Stephen Bingham, PhD; Wen Liu-Mares,
PhD; Joseph Collins, ScD; Stuart Warren, JD, PharmD; Douglas Leslie, PhD;
Edward Allan, MD; E. Cabrina Campbell, MD; Stanley Caroff, MD; June Corwin,
PhD; Lori Davis, MD; Richard Douyon, MD; Lawrence Dunn, MD; Denise Evans,
MD; Ede Frecska, MD; John Grabowski, MD; David Graeber, MD; Lawrence Herz,
MD; Kong Kwon, MD; William Lawson, MD; Felicitas Mena, MD; Javaid Sheikh,
MD; David Smelson, PhD; Valerie Smith-Gamble, MD; for the Department of
Veterans Affairs Cooperative Study Group on the Cost-Effectiveness of
Olanzapine
JAMA. 2003;290:2693-2702.
ABSTRACT
Context Although olanzapine has been
widely adopted as a treatment of choice for schizophrenia, its
long-term effectiveness and costs have not been evaluated in a
controlled trial in comparison with a standard antipsychotic
drug.
Objective To evaluate the effectiveness
and cost impact of olanzapine compared with haloperidol in the
treatment of schizophrenia.
Design and
Setting
Double-blind, randomized controlled trial with randomization
conducted between June 1998 and June 2000 at 17 US Department of
Veterans Affairs medical centers.
Participants Three hundred nine patients
with a Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition diagnosis of schizophrenia or schizoaffective
disorder, serious symptoms, and serious dysfunction for the
previous 2 years. Fifty-nine percent fully completed and 36%
partially completed follow-up assessments.
Interventions Patients were randomly
assigned to receive flexibly dosed olanzapine, 5 to 20 mg/d,
with prophylactic benztropine, 1 to 4 mg/d (n = 159); or haloperidol,
5 to 20 mg/d (n = 150), for 12 months.
Main Outcome
Measures
Standardized measures of symptoms, quality of life,
neurocognitive status, and adverse effects of medication.
Veterans Affairs administrative data and interviews concerning
non-VA service use were used to estimate costs from the
perspective of the VA health care system and society as a whole
(ie, consumption of all resources on behalf of these patients).
Results There were no significant
differences between groups in study retention; positive,
negative, or total symptoms of schizophrenia; quality of life;
or extrapyramidal symptoms. Olanzapine was associated with
reduced akathisia in the intention-to-treat analysis (P<.001)
and with lower symptoms of tardive dyskinesia in a secondary
analysis including only observations during blinded treatment
with study drug. Small but significant advantages were also
observed on measures of memory and motor function. Olanzapine
was also associated with more frequent reports of weight gain
and significantly greater VA costs, ranging from $3000 to $9000
annually. Differences in societal costs were somewhat smaller
and were not significant.
Conclusion Olanzapine does not
demonstrate advantages compared with haloperidol (in combination
with prophylactic benztropine) in compliance, symptoms,
extrapyramidal symptoms, or overall quality of life, and its
benefits in reducing akathisia and improving cognition must be
balanced with the problems of weight gain and higher cost.
INTRODUCTION
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Schizophrenia is a disabling mental illness that affects more than
2 million persons in the United States1 and was estimated to
consume $16 billion of US health care services in 1990.2
In recent years, a new series of antipsychotic medications has been
released, referred to as "atypical" because they have fewer extrapyramidal
adverse effects than older agents do.3-5
The most widely used of these medications in the treatment of
schizophrenia is olanzapine,6
with $3.7 billion in 2002 worldwide annual sales.7
In a series of randomized trials, olanzapine had fewer extrapyramidal
adverse effects than haloperidol8-10
and, in some studies8,
10-13
but not others,9,
14-15
was associated with greater improvement in symptoms and quality
of life and lower total health care costs.15
However, a recent review of 20 olanzapine trials by the Cochrane
Collaboration5
concluded that "the large proportions of participants
leaving the studies early . . . make it difficult to draw
conclusions on clinical effects. Large long-term randomized trials
. . . are long overdue."
Olanzapine, like
other atypical antipsychotic agents, can cause serious weight
gain16
and may also be associated with hyperglycemia,17
diabetes,18
and hyperlipidemia,19-20
increasing the importance of evaluating its benefits. No
long-term effectiveness study has compared olanzapine or any of
the other atypical antipsychotics except clozapine,21-22
whose use is quite restricted, with a conventional drug.
Although olanzapine is more expensive than conventional agents
(costing >$4000 more annually at wholesale prices6),
if it yields equivalent savings in other health costs, these
expenditures would be justified. To further evaluate the effectiveness
and cost of olanzapine, we conducted a 12-month clinical trial
comparing olanzapine with haloperidol, a widely used
conventional antipsychotic agent. We hypothesized that olanzapine
would outperform haloperidol on 3 primary outcomes, as
demonstrated by fewer symptoms, better quality of life, and lower
costs in patients with schizophrenia.
METHODS
Between June 1998 and June 2000, patients at 17 Department of Veterans
Affairs (VA) medical centers were randomly assigned to
olanzapine or haloperidol. Medication kits were prepared in sets
of 4 (2 olanzapine and 2 haloperidol) and each was labeled with
a random sequence number. Patients were assigned a kit at the
end of a telephone conversation with the coordinating center.
Human rights committees at each participating medical center approved
the protocol and all patients provided written informed consent.
Data from an 18th site were excluded because of problems with a
local institutional review board unrelated to this study.
Entry
Criteria
The study was
initially targeted to patients currently hospitalized for
schizophrenia for less than 365 days, but the criteria were expanded
after 9 months to include patients with schizoaffective disorder
and outpatients with any history of psychiatric hospitalization during
the previous 2 years.
Eligibility criteria
included (1) a Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition (DSM-IV) diagnosis of
schizophrenia or schizoaffective disorder on the Structured Clinical
Interview for DSM-IV Disorders23;
(2) serious symptoms (ie, score of  36
on the Brief Psychiatric Rating Scale24);
and (3) serious dysfunction for the previous 2 years with
inability to work or social constriction. Patients were excluded
if they or their clinicians were unable or unwilling to
cooperate; if they had a serious medical illness, unexplained seizures,
or severe medication allergies; or if they had previously participated
in olanzapine research.
The medical records
of 4386 patients were reviewed (Figure
1). Only 2141 (49%) were eligible for further assessment;
1530 (35%) either refused participation themselves or their
clinicians refused participation; 7% could not participate for
other reasons; and 309 (7%) provided informed consent and were
randomized.
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Figure
1.
Enrollment, Allocation, Follow-up, and Analysis
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Pharmacotherapy
After completing
baseline assessments, patients were assigned to receive
double-blind treatment with oral olanzapine, 5 to 20 mg/d, or
haloperidol, 5 to 20 mg/d. Dose adjustments were made as
clinically indicated, using 4 fixed dosage levels at 5-mg
intervals. Patients assigned to receive haloperidol also received
prophylactic benztropine mesylate, 1 to 4 mg/d, for extrapyramidal
symptoms (EPS). The olanzapine group received matching placebo
benztropine, and both groups could increase the dose with active
benztropine. The protocol did not allow concomitant use of other
antipsychotic medications, although other psychotropic
medications were permitted.
Psychosocial
Treatment
A predefined program
of psychosocial treatment was offered to both drug treatment
groups through a structured treatment planning process.25
Outcome
Measures
Symptom outcomes were
assessed at baseline, 6 weeks, and 3, 6, 9, and 12 months with
the Positive and Negative Syndrome Scale (PANSS),26
in which high scores reflect worse symptoms and a 20% reduction
represents clinically important improvement (possible range of
scores, 30-210).27
The Heinrichs-Carpenter Quality of Life Scale (QOLS), a
clinician-rated scale, was used to assess social functioning and
severe behavioral deficits, in which higher scores indicate
improvement (possible range, 0-126).28
Secondary outcomes
included adverse effects, assessed with the Barnes scale for
akathisia (ie, restlessness and agitation; possible range, 0-5
[ie, none, questionable, mild, moderate, marked, or severe]),29
the Abnormal Involuntary Movement Scale (AIMS) for tardive
dyskinesia (possible range, 0-42),30
the Simpson-Angus scale for EPS (possible range, 0-4),31
and a checklist of adverse reactions. Further assessment of
clinical status was measured with the Clinical Global Impression
scale32
and quality of life with the Short Form 36-Item Health Survey
(SF-36).33
Neurocognitive status
was assessed at baseline and at 3, 6, and 12 months using the
list learning, recall, recognition, and coding subtests from the
Repeatable Battery for the Assessment of Neuropsychological
Status,34
along with the Grooved Pegboard,35
Wisconsin Card Sorting Test–64 Card Version,36
Trail-Making Test Part B,35
and the Controlled Oral Word Association Test.37
The Wide Range Achievement Test–Revised reading subtest was
used to assess premorbid intellectual functioning.38
Principal components factor analysis with varimax rotation
identified 3 orthogonal factors: motor function, memory, and the
Wisconsin Card Sorting Test. These factors were moderately
intercorrelated (Pearson r range, 0.42-0.58) and together
explained 71% of the variance. They were significantly
correlated with age, sex, education, the Simpson-Angus scale for
EPS, and the Wide Range Achievement Test, which were included as
covariates in analyses of these measures.
Assessment of
Health Care Costs
Health care costs
were calculated by multiplying the number of units of service
for each patient by estimated 1998 unit costs and were estimated
from the perspective of the VA and society as a whole, ie,
consumption of all resources on behalf of these patients.
Societal costs include not only health care costs and criminal
justice costs, for example, but all costs related to these
patients for all payors in society.
Service
Utilization.
Health service data from the VA were derived from national
workload data systems: the patient treatment file (inpatient
care), the extended care file (nursing home and domiciliary care),
and the outpatient care file. The Service Use and Resource Form
recorded patient reports of non-VA medical and mental health inpatient,
residential, and nursing home care and 19 types of medicosurgical
and mental health outpatient care.
VA Unit Costs. Unit costs for VA inpatient
and residential care were estimated on the basis of files
created by the VA's Health Economic Resource Center39-40 using data from the VA's Cost
Distribution Report (CDR). The VA medical and mental health outpatient
unit cost estimates were also derived from the CDR. Group
therapy unit costs were weighted at 20% of the cost of an
individual visit, psychosocial rehabilitation at one third, and
day treatment at half. Costs of intensive case management were
based on cost data from each facility.41
Non–VA Unit Costs. Non-VA costs were derived
from (1) analysis of costs in the 1998 MarketScan data set,42
a compilation of all insurance claims from more than
500 000 private-sector mental health service users; (2) VA
contract payments for private nursing home care available in the
CDR; (3) VA payments for contract residential treatment43;
and (4) published literature presenting unit costs from large
non-VA health care systems.44-45
Medication Costs. The cost of olanzapine was
estimated in a sensitivity analysis using both 1999 discounted
VA pharmacy cost levels of $2.83 per 5 mg6
and wholesale community costs of $4.84 per 5 mg.46
The cost of haloperidol was estimated at $0.02 per 5 mg on the
basis of both VA pharmacy data and community prices.46
Nonstudy medication costs were also estimated using VA and
wholesale prices.
Non–Health Care
Costs.
Non–health care costs were derived from individual interview
data on use of services and from published literature.47-50
These costs included the administrative costs of transfer
payments (eg, disability, welfare),47-48
criminal justice system costs (eg, police contacts, arrests),49-50
and productivity (estimated by employment earnings, included as
a negative cost). For transfer payments, only administrative costs
were included because they alone represent consumed societal resources.47
Statistical
Analyses
The primary analyses
for this study are based on intention-to-treat principles
including all patients as randomized. Power calculations targeted
randomizing 600 patients to yield an 80% chance of detecting a
difference of $8700 in VA inpatient costs. However, only 309
patients were recruited, yielding an 80% chance of detecting a
5-point (6%) difference in symptoms on the PANSS26
or a 5-point (11%) difference in the Heinrichs-Carpenter QOLS.28
Primary clinical
outcomes were analyzed using random-effects repeated-measures
models,51
conducted with PROC MIXED from SAS statistical software, version
8 (SAS Institute Inc, Cary, NC). These models
accommodate correlations among the repeated observations and
therefore allow the inclusion of available data from individuals with
missing observations. Missing data in these models were assumed
to be missing at random. In these models, both group assignment
and time are modeled as class variables, which allows assessment
of both main effects for group assignment (the overall difference
between treatment groups across all time points) and group x time interactions (the difference in slopes).
All models included adjustment for baseline values of the
dependent measures and site effects.
Because cost data
were skewed, both mean and median values of aggregated cost data
are presented, and analyses of statistical significance were
conducted with analysis of covariance of log-transformed measures
and of ranks, controlling for baseline symptoms and service use.
Although 177 patients
(57.3%) discontinued the assigned study medication because of
lack of efficacy, adverse effects, or other reasons (54.1% in
the olanzapine group and 60.7% in the haloperidol group;  21
= 1.37; P = .24), efforts were made to follow up all
patients for a full 12 months and to record nonstudy medications;
26.7% of olanzapine discontinuers and 32.1% of haloperidol
discontinuers were successfully followed up for the entire 12
months (21
= 0.35; P = .55). Outcomes were compared first as
randomized (intention-to-treat analysis, for which 63% of all
follow-up data were available) and second after excluding all
data from time points after the first interruption of study drug
use (for which only 49% of all follow-up data were available). An
 value
of .05 was used for all statistical tests.
RESULTS
Sample and Treatment
Patients randomized
to olanzapine (n = 159) and to haloperidol (n = 150) were
significantly different with regard to only 1 measure at
baseline: the PANSS negative subscale (P = .02) (Table
1).
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Table
1.
Baseline Characteristics of Patients Assigned to Receive Olanzapine
or Haloperidol*
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Treatment
During the first 6
weeks of the trial, the mean (SD) dosages were 11.4 (2.2) mg/d
for olanzapine and 11.2 (2.2) mg/d for haloperidol. During the
remainder of the first 6 months, they were 14.7 (3.9) mg/d for
olanzapine and 13.5 (4.4) mg/d for haloperidol and during the
last 6 months were 15.8 (3.9) mg/d for olanzapine and 14.3 (4.6)
mg/d for haloperidol.
Retention
Survival analysis of
participation in the double-blind drug treatment showed no
significant difference between groups (P = .25 by
log-rank test) (Figure
2). There were no significant differences in the proportion
of patients who completed the entire trial while blinded and
receiving study drug (39.3% of patients assigned to haloperidol
vs 45.9% assigned to olanzapine; P = .25) or in the
reasons for discontinuation among those who did not. Patients
assigned to haloperidol were only marginally significantly more
likely to discontinue because of adverse effects (10.0% vs 4%; P
= .08) and there were no significant differences in the
proportion of haloperidol vs olanzapine patients, respectively,
who discontinued because of lack of efficacy or worsening of
symptoms (12.7% vs 17.6%; P = .27); who were lost to
follow-up, missed appointments, or moved (15.3% vs 11.9%; P
= .41); who withdrew consent or were unhappy with blinded treatment
(10.7% vs 8.8%; P = .70); or who discontinued for other
reasons (12.0% vs 11.3%; P = .85). Nor were there significant differences
in the use of concomitant medications at any time, including
conventional antipsychotics (range, 5%-16% for all patients
across time points), nonstudy atypical antipsychotics (5%-17%),
antidepressants (18%-25%), and anticholinergics (6%-11%). On
average, 7.7% of the olanzapine group and 8.6% of the haloperidol group
took open-label anticholinergics.
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Figure
2.
Retention in Trial
Analyzed by
intention to treat (F = 0.871,204; P = .35).
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Outcomes
Fifty-nine percent of
patients fully completed and 36% partially completed follow-up
assessments. Intention-to-treat analysis showed no significant
overall differences during the 12 months of treatment on the
PANSS total symptom score (F1,204 = 0.87; P =
.35) (average difference, -1.1 points; -1.3% favoring olanzapine; Figure
3) or on either the positive (F = 0.221,206; P = .64)
or negative (F1,208 = 1.05; P = .31) subscales.
There were no significant differences at any time point in the
proportion of patients who showed a 20% improvement in PANSS
scores. There was also no significant difference between the
groups on the QOLS (F = 0.141,211; P = .71)
(average difference, 0.1 points; 0.2% favoring olanzapine). Nor
were there any significant differences on specific subscales of
the QOLS that address intrapsychic foundations (F = 0.281,207;
P = .59), interpersonal relationships (F = 0.001,213;
P = .97), or instrumental role functioning (F = 0.01,199;
P = .94); on either the physical (F = 1.941,220; P
= .16) or mental (F = 1.441,216; P = .23) component
scales of a secondary measure of quality of life, the SF-36; or
on a global measure, the Clinical Global Outcomes scale (F =
0.021,196; P = .89). Olanzapine was associated
with significantly lower scores overall on the Barnes scale for
akathisia (F = 14.981,217; P<.001) but not
on the AIMS measure of tardive dyskinesia (F = 1.871,225;
P = .17) or on the Simpson-Angus scale for EPS (F = 0.901,203;
P = .34). Although a smaller proportion of olanzapine patients
had moderate or marked akathisia (5.8% vs 9.6% across all
assessments, with no patient in either group having a severe rating)
(Figure
4), this difference was modest in magnitude.
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Figure
3.
PANSS Total Scores
PANSS indicates
Positive and Negative Syndrome Subscale. Error bars indicate SDs.
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Figure
4.
Percentage of Patients With Moderate or Marked Symptoms on Barnes
Akathisia Global Scale
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Secondary analysis
excluding observations after the first discontinuation of study
drug also showed no differences on either PANSS symptoms scores
or the QOLS but somewhat more robust overall differences on the
Barnes scale for akathisia (F = 21.01,164; P<.001)
and significant differences on the AIMS (F = 3.951,162; P
= .048).
Because of the
substantial amount of missing data in the later months of the
trial, analysis of variance was used to compare least-square
means at the 6-week and 3-month assessments, controlling for
baseline values. These analyses confirmed the overall analysis, showing
no significant differences on the PANSS (or any of its subscales),
the Simpson-Angus scale for EPS, or the AIMS. The haloperidol
group, however, had significantly higher QOLS scores at 6 weeks
(P = .04) and the olanzapine group had significantly lower
Barnes scale for akathisia scores at both 6 weeks (P = .007)
and 3 months (P<.001).
Intention-to-treat
analysis of neurocognitive test results showed significantly
greater improvement among patients assigned to olanzapine on
tests of motor functioning (F = 6.31,176; P = .02)
and memory (F = 5.21,189; P = .03) but not on the
Wisconsin Card Sorting Test (F = 0.011,186; P
= .93). When observations following interruption of blind study
medication were excluded, these effects were somewhat more
robust for motor functioning (F = 8.31,153; P
= .005) and memory (F = 9.41,163; P = .003), but
the Wisconsin Card Sorting Test remained unimproved (F = 1.091,160;
P = .30). These differences were modest in magnitude, reaching
a maximum of 0.16 SD on motor function and 0.22 SD on memory at
9 months (Figure
5) but were evidently not of sufficient magnitude to improve
overall quality of life, interpersonal relationships, or
instrumental role functioning.
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Figure
5.
Neurocognitive Assessment
Analyzed by
intention to treat for motor (F = 6.31,176; P =
.02) and memory (F = 5.21,189; P = .03) factors.
Error bars indicate SDs.
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Further examination
of adverse events shows that among patients assigned to
olanzapine, there were more frequent reports of weight gain
attributed by the patient as possibly or probably related to
study drug that were marginally significant at 3 months (P
= .07 by Fisher exact test), and significant at 6 months (P
= .002) and 12 months (P = .01) (Table
2). There were fewer reports of restlessness with
olanzapine, reflecting lower levels of akathisia.
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Table
2.
Adverse Effects Possibly or Probably Attributable to Study Drug*
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Service Use
and Cost
There were no
significant differences between treatment groups on any measure
of service use or VA costs, exclusive of medications (Table
3). Total medication costs were 4 to 5 times greater for the
olanzapine group than for the haloperidol group, using VA and wholesale
prices. With the cost of medications included, both total VA
mental health costs and total VA health costs were significantly
greater for patients assigned to olanzapine. The magnitude of
the differences in cost is reduced when medians rather than
means were examined, but nonparametric analysis of ranked cost
data still showed statistically significant differences, with
higher VA costs for olanzapine ranging from $3000 to $9000 across
measures (Table
3).
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Table
3.
Comparison of 1-Year VA Service Use and Cost Data by
Intention-to-Treat Analysis (n = 309)
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Non-VA health costs
and nonhealth costs showed no significant differences, and
differences in societal costs (including both VA and non-VA
costs) were slightly smaller than differences in VA costs and
were not statistically significant. (VA plus non-VA costs were
nonsignificant because while VA costs were significantly
different between groups, non-VA costs were not; when combined,
these costs were less different between groups.) While the costs
of antipsychotic drugs were very different between the groups,
the costs of other psychotropic drugs were the same, which
tended to neutralize the cost difference for antipsychotic agents,
leaving less difference in cost between the 2 groups.
COMMENT
This 12-month double-blind study found no statistically or clinically significant
advantages of olanzapine for schizophrenia on measures of
compliance, symptoms, or overall quality of life, nor did it
find evidence of reduced inpatient use or total cost. Olanzapine treatment
did result in modestly reduced symptoms of akathisia, in less
tardive dyskinesia in one secondary analysis, and in small but
significant improvements in measures of memory and motor
function. Although verbal memory has been reported to be
associated with functional capacity,
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