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.
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.
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.
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.
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.
A predefined program of psychosocial treatment was offered to both drug
treatment groups through a structured treatment planning process.25
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
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 × 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; χ21 = 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 (χ21 = 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 α
value of .05 was used for all statistical tests.
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).
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.
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.
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.
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.
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.
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).
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.
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,52 cognitive gains with olanzapine
were insufficient to improve QOLS functioning or employment earnings. Olanzapine
was also associated with more frequent reports of weight gain and with significantly
greater total VA costs, ranging from $3000 to $9000 per patient annually.
These results are substantially less favorable for olanzapine than those
reported in previous trials.8-13,15 Perhaps
the most unexpected difference was the lack of any significant advantage for
olanzapine on measures of retention, termination due to adverse effects, or
EPS other than akathisia. These differences are most likely explained by 2
major differences between this study and others: (1) prophylactic benztropine
was prescribed for the haloperidol group (as recommended in a recent treatment
overview53 and as used in typical clinical
practice54) and (2) outcome data were collected
for all patients, even after interruptions of protocol treatment. Studies
more favorable to olanzapine,8-11,13,15 in
contrast, allowed use of antiparkinsonian agents only after symptoms arose,
increasing the risk of EPS (which is greater for haloperidol than any other
antipsychotic and is especially high for men55).
Rating biases also may have been introduced in those studies because without
prophylaxis, haloperidol patients can readily be identified. In addition,
since no data were collected after protocol interruptions due to EPS, there
could be no documentation of eventual recovery from this highly treatable
syndrome.
Apparent differences in symptom and functional outcomes may also reflect
these methodological differences. Clinical descriptions from the pre-atypical
era suggest that even in the absence of frank pseudoparkinsonian symptoms,
patients taking conventional medications may have akinesia and, as a result,
manifest a poor response to conventional antipsychotics until prescribed anticholinergic
agents.56 In the International Collaborative
Trial (ICT), one of the manufacturer's US Food and Drug Administration registration
trials and the basis for most published comparisons of olanzapine and haloperidol,10-13 66.5%
of olanzapine patients but only 46.8% of haloperidol patients (P<.001) completed 6 weeks of treatment—a substantial difference
that was attributed to lack of efficacy.10 The
high failure rate with haloperidol in the ICT, however, may actually reflect
the lack of prophylactic antiparkinsonian medication. In contrast with the
46.8% retention rate among haloperidol patients in the ICT, the present study
found that 71% of prophylactically treated haloperidol patients were retained
during the first 6 weeks of the trial. Thus, the main difference between the
2 studies is the far superior performance of haloperidol in the current trial.
Once properly treated for EPS, haloperidol patients in the ICT would most
likely have shown further clinical improvement, but such improvement was not
documented because data collection was halted. Furthermore, in the absence
of prophylactic treatment, haloperidol patients, like their raters, could
have recognized which treatment they were receiving, further undoing the double
blind.
While the present study relied on mixed models that used all available
data and associated each observation with the actual time point at which it
was obtained, the ICT relied on a last-observation-carried-forward analysis
in which the last rating during assigned study drug treatment was used as
the single end point, regardless of when it was obtained. Since patients assigned
to olanzapine discontinued later than haloperidol patients, their last observation
was likely to have been biased by having more time for either improvement
or regression to the mean.
After 6 weeks, the ICT conducted follow-up assessments only on treatment
responders.10 Reports of reduced long-term
health costs13 and improved quality of life11 with olanzapine in the ICT are thus based on seriously
biased last-observation-carried-forward rather than intention-to-treat analyses
and follow-up rates of only 28% over the year for the olanzapine group and
15% for haloperidol.13
One final difference is that, unlike the ICT, the current trial did
not exclude patients with current addictive disorders. However, reanalysis
of major outcomes excluding these patients did not reveal any additional differences
in symptoms, adverse effects, or quality of life.
The major limitations of this study are the loss of follow-up data,
especially in the later phases of the trial, and the use of concomitant nonstudy
atypical and conventional antipsychotic agents. However, there were no significant
differences between groups in the duration of adherence to the study protocol,
reasons for discontinuing study drug, or use of any concomitant medications,
including anticholinergic agents. Furthermore, the results based on all data
do not differ from those that exclude data collected after treatment protocol
violations or from analyses limited to the first 3 months of the trial, when
protocol adherence was high.
Also, because the study sample was overwhelmingly male, all treatment
was provided in VA facilities, and less than 10% of patients considered for
recruitment were enrolled, the generalizability of these findings to other
populations and health care systems is unknown. The hospitals involved in
this trial had somewhat higher per diem psychiatric inpatient costs than other
VA facilities40 but lower per diem costs than
non-VA hospitals.44,45
Another possible limitation is that a strict upper limit of 20 mg/d
was placed on the dosages of both haloperidol and olanzapine. However, the
average dosage of olanzapine used in this study was similar to the average
dosages of 14.1 mg/d nationally in the VA57,58 and
to both 12.2 mg/d in a large private sector sample57,58 and
dosages reported in the ICT.10 Haloperidol
dosages averaged 13.6 mg/d in the current trial compared with only 11.8 mg/d
in the ICT.
Although we did not meet our power target of 600 patients, we still
had 80% power to detect a 6% difference between groups on the PANSS and an
11% difference on the QOLS, both notably smaller than generally accepted difference
of 20% needed for clinical significance. Average differences on both measures
were, in fact, less than 2%.
A final limitation is that this study did not determine whether the
benefits of olanzapine are worth the additional costs and adverse consequences.
It is clear that olanzapine is not a dominant choice (ie, it does not have
both superior outcomes and lower cost).59 Our
analyses did not indicate, however, whether the clinically modest reduction
in akathisia and the improvements on neurocognitive measures are valuable
enough to offset the increased cost of olanzapine and the risk of weight gain
and, possibly, diabetes.18 Although methods
have been developed to address this kind of question,59-61 they
are not readily applicable to this study because of the discrepant positive
and negative findings across measures and because data from a global health
utility measure59,60,62 were
not collected. However, in view of the very small average differences between
groups in quality of life and the significantly higher quality-of-life scores
in the haloperidol group at 6 weeks, when adherence to the research protocol
was best, it seems unlikely that olanzapine would have shown significantly
higher scores than haloperidol on such measures.
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