olanzapine versus risperidone

Olanzapine versus RisperidoneA Prospective Comparison of Clinical and EconomicOutcomes in Schizophrenia

Eric T. Edgell,1 Scott W. Andersen,1 Bryan M. Johnstone,1 Brian Dulisse,1 Dennis Revicki2 and Alan Breier1

1 Eli Lilly and Company, Indianapolis, Indiana, USA2 MEDTAP International, Bethesda, Maryland, USA

Abstract Objective:To compare the clinical and economic outcomes associatedwith olan-zapine and risperidone treatment for schizophrenia.Design and setting: An international, multicentre, double-blind, prospective study.To facilitate economic comparisons, our samplewas restricted to patients enrolledin US sites. 150 patients with a Diagnostic and Statistical Manual of mentaldisorders, 4th edition (DSM-IV) diagnosis of schizophrenia, schizoaffective disorderor schizophreniform disorder were randomised to therapy with either olanzapine10 to 20 mg/day (n = 75) or risperidone 4 to 12 mg/day (n = 75) for a maximumof 28 weeks. In addition to tolerability and efficacy assessments, use of healthservices was assessed at baseline and prospectively, at 8-week intervals and atstudy completion. Clinically important response, defined as a 40% improvementin the Positive andNegative Syndrome Scale total score, maintenance of responseand rates of treatment-emergent extrapyramidal symptoms were compared be-tween groups. Direct medical costs were estimated by assigning standardisedprices to resource units.Median total, inpatient/outpatient service andmedicationacquisition costs were compared between treatment groups.Main outcome measures and results: The mean modal dosages for the olanzapineand risperidone treatment groups were 17.7 ± 3.4 mg/day and 7.9 ± 3.2 mg/day,respectively. Olanzapine-treated patients were more likely to maintain responsecompared with risperidone-treated patients (p = 0.048). In addition, a smallerproportion of olanzapine-treated patients required anticholinergic therapy comparedwith risperidone-treated patients (25.3 vs 45.3%; p = 0.016). Total per patientmedical costs over the study interval were $US2843 (1997 values) [36%] lowerin the olanzapine treatment group than in the risperidone treatment group (p =0.342).Medication costs were significantly higher for olanzapine-treated patients($US2513 vs $US1581; p < 0.001), but this difference was offset by a reductionof $US3774 (52%) in inpatient/outpatient service costs for olanzapine-treatedpatients in comparison with risperidone-treated patients ($US3516 vs $US7291,p = 0.083).Median cost findingswere consistent with results observed using otherrobust measures of central tendency and provide conservative estimates of po-tential savings that may be obtained from olanzapine therapy.Conclusions: In this study, olanzapine-treated patients experienced clinical im-provements that translated into savings in costs of care for both inpatient and

ORIGINAL RESEARCH ARTICLE Pharmacoeconomics 2000 Dec; 18 (6): 567-5791170-7690/00/0012-0567/$20.00/0

© Adis International Limited. All rights reserved.

outpatient services. These savings offset the difference in medication acquisitioncost between olanzapine and risperidone.

Since the introduction of chlorpromazine in the1950s, one class of agents, ‘first-generation’, ‘con-ventional’ or ‘typical’ antipsychotics, has been themainstay of pharmacological management of schi-zophrenia. Although first-generation agents are ef-fective in treating positive symptoms,[1-4] they areineffective in treating negative and cognitive symp-toms.[1] In addition, at least 30% of patients takingfirst-generation agents relapse in the first year oftreatment,[5] as many as 60% experience relapseafter 1 year of therapy,[2] and between 30 and 60%develop extrapyramidal symptoms (EPS).[6] Patientstaking first-generation antipsychotics are also at con-siderable risk for developing tardive dykinesia.[7]‘Second-generation’ or ‘atypical’ antipsychotics

provide similar or improved efficacy in terms ofpositive symptoms, while exhibiting a more favour-able EPS profile, providing efficacy against negativesymptoms, and reducing the risk of tardive dyskin-esia. In 1989, the US Food and Drug Administra-tion approved clozapine, the first second-generationantipsychotic agent, for use in patients with treatment-resistant and treatment-intolerant schizophrenia.[8]Subsequent to the introduction of clozapine, risper-idone was approved in 1994, olanzapine in 1996and quetiapine in 1998.[9-12]The initial focus of studies of second-generation

agentswas on acute efficacy for positive and negativesymptoms and the adverse event profile regardingEPS compared with first-generation antipsychotics.Given their high acquisition costs, subsequent focusturned to the cost effectiveness of these agents.[13-34]Multiple studies have shown that superior outcomescan be achieved with second-generation agents atsimilar or reduced total healthcare costs comparedwith first-generation antipsychotics.[19-34] Questionshave now arisen regarding how individual second-generation agents compare in terms of efficacy, tol-erability and cost effectiveness, with particular fo-cus on olanzapine and risperidone. Indeed, due todifferences in efficacy, tolerability and utilisation,the wisdom of grouping olanzapine and risperidone

into a common ‘second-generation’or ‘atypical’cate-gory has been questioned.[35,36]Tran et al.,[35] conducted the first peer-reviewed,

published, double-blind, randomised study compar-ing olanzapine and risperidone. Although therewasno significant difference between olanzapine andrisperidone in total Positive and Negative Synd-rome Scale (PANSS) score, olanzapine demonstra-ted significantly greater efficacy in negative symp-toms (as measured by the Scale for the Assessmentof Negative Symptoms) and overall response rate(response defined as ≥40% improvement on totalPANSS score). Study participants included an in-ternational sample of 339 patients who met Diag-nostic and Statistical Manual of mental disorders,4th edition (DSM-IV)[37] criteria for schizophre-nia, schizoaffective disorder or schizophreniformdisorder. A greater proportion of olanzapine-treatedpatients maintained their response at 28 weeks com-pared with risperidone-treated patients. The in-cidence of EPS, hyperprolactinaemia and sexualdysfunction was statistically lower in olanzapine-treated patients, and statistically fewer adverse eventswere reported by olanzapine recipients than bytheir risperidone-treated counterparts. Bodyweightgain was reported significantly more frequently byolanzapine-treated patients. Advantages in patients’quality of life and hospitalisation liability associ-ated with olanzapine therapy were also observed.Other randomised, published comparisons of olan-zapine and risperidone have shown similar resultsand additional advantages for olanzapine in cogni-tive functioning.[38,39]There are few comparisons of olanzapine and

risperidone where costs have been fully reported.Of those studies reported in peer-reviewed jour-nals, one was a retrospective assessment conductedin an inpatient setting while the other was based ona decision-analytic model.[20,40] The retrospectiveassessment was criticised for bias associated withpatient selection, lack of statistical rigor and focus-ing on drug costs rather than impact of the medica-

568 Edgell et al.

© Adis International Limited. All rights reserved. Pharmacoeconomics 2000 Dec; 18 (6)

tions on total direct costs of care.[41] The analysisbased on a decision-analytic model was criticisedfor assumptions involving dosage and because afull sensitivity analysis was not conducted.[42]In the context of the trial conducted by Tran et

al.,[35] we compared olanzapine with risperidone interms of both clinical and economic outcomes. Thisanalysis represents the first prospective random-ised comparison of total direct treatment costs as-sociated with olanzapine and risperidone treatmentin patients with schizophrenia.

Methods

Study Design and Patient Sample

Analyses were conducted on data from the ran-domised, double-blind, prospective study of olan-zapine and risperidone conducted by Tran and col-leagues.[35] The study enrolled 339 inpatients oroutpatients from 38 clinical centres in 9 countries.Patients were between the ages of 18 and 65 years,had a documented DSM-IV diagnosis of schizo-phrenia, schizophreniform disorder or schizoaffec-tive disorder, and exhibited a minimum score onthe Brief Psychiatric Rating Scale[43] extracted fromthe PANSS[44] of at least 42 (items scored 1 to 7).Reasons for exclusion included documented treat-ment resistance to antipsychotic agents, presenceof comorbid or other recent major axis I disorder,and/or serious, unstable medical illness.For this analysis the sample was restricted to

patients recruited from 13 clinical centres in theUS(n = 150, 44% of total study sample). Only USpatients were included to minimise variation in men-tal health services delivery and practice patternsacross countries and because of difficulties associ-ated with accurately assigning costs to services de-livered across the other 8 countries.

Treatment Regimen

After a 2- to 9-day antipsychotic washout pe-riod, patients were randomised to olanzapine or ris-peridone for 28-weeks. Olanzapine was initiated ata dosage of 15 mg/day once daily for the first 7days while risperidone was initiated at a dosage of

1mg twice daily on day 1, 2mg twice daily on day2, and 3mg twice daily on days 3 through 7 (con-sistent with risperidone labelling). After the firstweek, investigators could optimise response by ad-justing the daily dose up or down every 7 days.Dosage adjustments could occur in 5 mg/day in-crements for olanzapine-treated patients (10 to 20mg/day) and 2 mg/day increments for risperidone-treated patients (4 to 12 mg/day). With either drug,a wide dosage range was permitted in order to maxi-mise an individual patient’s outcome. Concomitantpsychotropic medications were not allowed duringthe study with the exception of benzodiazepinesfor agitation, chloral hydrate for insomnia, or bi-periden or benzatropine (benztropine mesylate) [upto 6 mg/day] for treatment-emergent EPS. Prophy-lactic use of anticholinergic medications was pro-hibited.

Clinical Outcomes

The primary efficacy measure in this trial wasthe PANSS total score. The Clinical Global Im-pressions – Severity of Illness Scale (CGI-S)[45]was also administered. EPS, akathisia and dyskin-esiawere assessedwith theSimpson-AngusScale,[46]the Barnes Akathisia Scale[47] and the Abnormal In-voluntary Movement Scale (AIMS).[48] These mea-sures were administered at baseline, weekly duringthe first 8 weeks of therapy, and then every 4 weeksfor the remainder of the trial.Visit-wise response rates [last observation car-

ried forward (LOCF)] were evaluated for patientswho achieved reductions in PANSS total scores of20, 30, 40 and 50% from baseline. Time maintainingresponse was also assessed. A significant symptomexacerbationwas defined a priori as a 20%or greaterworsening in the PANSS total score along with aCGI-S score ≥3 after 8 weeks of therapy. Only pa-tients who showed improvement in the PANSS to-tal score of at least 20% from baseline at week 8and who continued past week 8 were included inthe analysis of time maintaining response.To assess treatment-emergent pseudoparkinson-

ism, the proportion of patients with a Simpson-Angus Scale total score ≥4 at any post-baseline

Olanzapine versus Risperidone in Schizophrenia 569


visit was calculated among those with a total scoreless than 4 at baseline. To assess treatment-emergentakathisia, the proportion of patients with a BarnesAkathisia Scale global score ≥2 at any post-baselinevisit was calculated among those with a total scoreless than 2 at baseline. To assess treatment-emergentabnormal dyskinetic movements, the proportion ofpatients with a score of ≥3 on any one of the AIMSitems 1 through 7 or a score of ≥2 on any two ofthe AIMS items 1 through 7 at any post-baselinevisit was calculated among those without either ofthese criteria at baseline. This definition of tardivedyskinesia is consistent with the cross-sectionalresearch diagnostic criteria suggested by Schoolerand Kane.[49] Anticholinergic use during the trialwas also compared between treatment groups as aproxy for treatment-emergent EPS.

Economic Outcomes

This analysis was conducted from the payer orhealthcare system perspective; therefore, only directmedical costs were assessed. Using clinical casereport forms, data were collected on: hospitalis-ations (admission date and length of stay); numberof emergency department visits; number of day hos-pital treatment sessions; number of outpatient visitsto psychiatrists, other physicians or other mentalhealthcare providers (including protocol-related vis-its); and number of home visits by health profes-sionals. Patient reports aboutmedical service use wereverified when psychiatric history, medical recordsor family reports were available. Hospital utilisationdata were verified by hospital records. Resourceuse data were collected at baseline, every 8 weeksup to week 24, and at the final visit.

Table I. Baseline demographic and clinical characteristics by treatment group

Parameter Olanzapine (n = 75) Risperidone (n = 75) p-ValueAge in years [mean (SD)] 39.4 (11.2) 39.6 (11.4) 0.687a

Male (%) 69.3 68.0 0.860b

Caucasian (%) 64.0 64.0 1.000b

Chronic schizophrenia (%) 96.0 94.6 0.699b

Duration of illness in years [mean (SD)] 16.0 (10.2) 16.9 (11.0) 0.788a

Previous hospitalisation duration (%)None 70.3 60.8 0.226c

2 months 24.3 36.52 to <6 months 5.4 2.7

Inpatient at baseline (%) 12.0 10.7 0.797b

PANSS total score [mean (SD)] 90.6 (13.9) 95.1 (15.9) 0.043a

BPRS total score [mean (SD)] 32.9 (7.5) 35.5 (8.6) 0.081a

PANSS positive score [mean (SD)] 21.2 (3.9) 22.7 (4.7) 0.037a

PANSS negative score [mean (SD)] 24.8 (5.5) 25.6 (5.4) 0.209a

Number of emergency room visits (SD)d 0.3 (0.5) 0.3 (0.7) 0.923a

Number of day hospital visits (SD)d 12.8 (36.9) 11.3 (27.2) 0.648a

Number of psychiatrist visits (SD)d 4.2 (5.5) 4.5 (4.5) 0.359a

Number of physician visits (SD)d 1.2 (3.5) 0.7 (1.2) 0.233a

Other mental health visits (SD)d 6.8 (16.1) 7.8 (16.6) 0.270a

Home visits (SD)d 0.2 (1.0) 5.1 (25.0) 0.085a

a ANOVA with numerator df = 1 and denominator df ≥ 140.b χ2 test df = 1.c χ2 test df = 2.d Baseline resource use data assessed in the 6 months prior to randomisation.ANOVA = analysis of variance; BPRS = Brief Psychiatric Rating Scale; df = degrees of freedom; PANSS = Positive and Negative SyndromeScale; SD = standard deviation.

570 Edgell et al.


Costs were estimated by assigning prices froma standard list to units of medical service used dur-ing the study. Medical services were assigned anestimated cost in 1997 US dollars ($US). Althoughit is preferable to use actual accounting costs formedical services[50] in economic studies, obtainingthis information is problematic. Although this maylead to inflation in cost estimates, an acceptablealternative is to estimate costs based on a stand-ardised list of prices for services.[51,52]Several sources were used to develop a price list

because no one source contained complete infor-mation. The prices for outpatient and inpatient phys-ician services were based on Healthcare FinancingAdministration data.[53] Costs for days in the hos-pital were estimated based on cost data for inpatientpsychiatric ($US599 per day) and medical stays($US698per day) from theMonroe-LivingstonMen-tal Health Capitation Program[54,55] and inflated to1997 prices using the medical care component ofthe consumer price index.[56] Cost for outpatientvisits for psychiatrists were estimated at $US50and outpatient visits for physician specialists andgeneral practitioners at $US50 per visit. Costs foroutpatient psychologist visits ($US50 per visit), so-cial work ($US49 per visit), case manager services($US49 per visit), home visits ($US49 per visit),group therapy ($US50 per visit), nurse visits ($US49per visit), day hospital treatments ($US301 per day)and emergency room visits ($US289 per visit) wereestimated from several sources.[55,57,58] Costs perday for concomitant medications were not calcu-lated and were not used in the cost analysis. Anti-psychotic drug costs were based on actual dose andduration recorded, and drug prices were calculatedfrom the 1997 Red Book.[59]

Statistical Methods

Baseline demographic, clinical and resource usecharacteristics were summarised by treatment group.All clinical analyses used a LOCF algorithm; i.e.the last available visit (visits 3 through 15, weeks1 through 28) served as the end-point. Pearson’schi-square test was used to compare treatment groupson categorical variables, and analysis of variance

(ANOVA) was used on continuous variables. Theindependent variables in the ANOVA model weretreatment, geographic region (West, Southwest,Mid-west, Southeast and East regions of the US) andtreatment-by-geographic region interaction. Maineffects were tested at a 2-sided α level of 0.05.The chi-square test was used to evaluate differ-

ences in the proportion of patients in each treat-ment group who had significant clinical improve-ments as measured by percentage change in thePANSS total score from baseline to end-point.Kaplan-Meier survival curves of time maintainingresponse were compared between treatment groupsusing the Wilcoxon test.[60]Resource use data would ideally have been col-

lected over the duration of the trial for all patients.However, resource use data were not collected af-ter withdrawal for patients who did not completethe study. A retrospective chart review was con-ducted to collect resource use data for patients withless than 28 weeks of data. Complete 28-week re-source use data were successfully obtained for anadditional 20 of the 59 US patients who withdrewfrom the trial. For the remaining 39 patients, ordi-nary least squares (OLS) regression was used toimpute the missing cost data based on only the ob-served in-trial costs. Regression models were runon medication, inpatient and outpatient costs. Com-

Sur

viva

l dis

tribu

tion

func

tion

Days since randomisation

1

0.5

0

OlanzapineRisperidone

0 40 80 120 160 200

*

Fig. 1.Maintenance of response. Maintenance of response wasdefined as time not exhibiting a 20% or greater worsening in thePositive and Negative Syndrome Scale (PANSS) total scorealong with a Clinical Global Impressions Severity score ≥3 inpatients who showed improvement in the PANSS total score ofat least 20% after 8 weeks of therapy. * p = 0.048; Wilcoxon test.



plete 28-week costs were then compared betweentreatment groups.Medication, inpatient/outpatient service and total

treatment costs were compared between treatmentgroups. Since the cost distributions were asymmet-rical and included outliers, medians were reportedas measures of location.[61,62] To evaluate the con-sistency of findings using alternative adjustmentsfor non-normality, 10, 15 and 20% trimmed means(for each treatment, 10, 15 and 20% of the datawere removed from each tail of the distribution be-fore calculating the means of each distribution),tri-means (weighted average of the 25th, medianand 75th percentile using weights of 0.25, 0.50 and0.25, respectively) and Gastwirth means (weightedaverage of the 33rd percentile, median and 67thpercentile using weights of 0.30, 0.40 and 0.30,respectively) were also compared between treat-ment groups. Koenker and Bassett[61] showed thesuperiority of these estimators of location comparedwith the mean for non-normal distributions. One-way ANOVA models were run on the ranks of thetotal costs, medication costs and inpatient/outpa-tient service costs in order to calculate between-treatment group p-values.

To confirm the findings of the ANOVAmodels,median regression models were estimated for totalcosts, medication costs and inpatient/outpatient ser-vice costs.[61] Full model predictor variables (notincluding treatment and intercept) with t-statisticswith absolute value less than 1.0 were removed toform the reduced models.[63]Use of median regression models was optimal

due to the asymmetrical cost distributions encoun-tered. The models also allowed for adjustment ofimbalances of covariates at baseline between the 2cohorts (PANSS total and PANSS positive) and forcontrol of baseline hospital status. Median regres-sion results are generally more efficient than thoseproduced by an OLS regression model when theresidual is not normally distributed. It should benoted that interpretation of coefficients is the samein a median regression model and an OLS model.Both estimate the incremental effect on the depend-ent variable of a change in the explanatory vari-able.[61]To determine the sensitivity of cost findings

to the dosage regimen employed, 1-way ANOVAmodels of total, medication and inpatient/outpatientcosts were re-run assuming mean modal doses of13 and 10mg for olanzapine-treated patients, and 5

Table II. Response on Positive and Negative Syndrome Scale (total); last observation carried forward

Observation period (weeks) Response level (%) Number improved (%) p-Valuea

olanzapine (n = 75) risperidone (n = 75)8 20 47 (62.7) 52 (69.3) 0.389

30 31 (41.3) 29 (38.7) 0.73940 12 (16.0) 13 (17.3) 0.82750 1 (1.3) 4 (5.3) 0.172

16 20 48 (64.0) 44 (58.7) 0.50230 33 (44.0) 26 (34.7) 0.24240 19 (25.3) 12 (16.0) 0.15850 5 (6.7) 4 (5.3) 0.731

24 20 47 (62.7) 47 (62.7) 1.00030 38 (50.7) 30 (40.0) 0.18940 25 (33.3) 15 (20.0) 0.06550 6 (8.0) 4 (5.3) 0.513

28 20 44 (58.7) 47 (62.7) 0.61630 38 (50.7) 31 (41.3) 0.25140 21 (28.0) 15 (20.0) 0.25150 7 (9.3) 5 (6.7) 0.547

a χ2 test; df = 1.

572 Edgell et al.


and 6mg for risperidone-treated patients. These as-sumptions were based on the mean and median/modal doses of olanzapine and risperidone obser-ved in usual practice for the treatment of schizo-phrenia.[64,65] These analyses also assumed that treat-ment efficacy and tolerability, and subsequent impactof efficacy and tolerability on cost remain constantat lower doses.Statistical Analysis Software (SAS)[66] and

STATA 6.0[67] were used to perform all statisticalanalyses.

Results

Baseline Characteristics

A total of 150 patients (olanzapine n = 75, ris-peridone n = 75) from US sites were randomisedto one of the 2 treatment groups. The mean modaldosage for the olanzapine treatment group was 17.7±=3.4 mg/day. The mean modal dosage for risperi-done-treated patients was 7.9 ± 3.2 mg/day. Base-line patient demographic, clinical and resource usecharacteristics are summarised in table I. Althoughthe differences were not clinically significant, com-pared with olanzapine-treated patients, risperidonerecipients had significantly greater baseline PANSStotal scores (p = 0.043) and significantly greaterPANSS positive scores (p = 0.037). No differencein rates of discontinuation were found between thetreatment groups.

Clinical Outcomes

Survival analysis assessing maintenance ofresponse revealed that olanzapine-treated patientswere significantly (p = 0.048) more likely to main-tain response throughout the course of the trial com-pared with risperidone-treated patients (fig. 1). Nosignificant treatment group differences were foundin the proportion of patients demonstrating responsebased on PANSS total scores (table II).While more risperidone-treated patients expe-

rienced treatment-emergent pseudoparkinsonism,akathisia and dyskinetic symptoms as assessed bythe Simpson-Angus, Barnes Akathisia and AIMSrating scales, respectively, no significant treatmentgroup differences were found in categorical analy-ses using these scales. However, significantlymore(p = 0.016) risperidone-treated patients required ananticholinergic to control treatment-emergent EPScompared with olanzapine-treated patients (see ta-ble III).

Economic Outcomes

Total, medication and inpatient/outpatient ser-vice costs by treatment group and measure of cen-tral tendency are summarised in table IV. Total perpatient medical costs over the study interval were$US2843 (36%) lower in the olanzapine treatmentgroup than in the risperidone treatment group (p =0.342). Medication costs were significantly higherforolanzapine-treatedpatients ($US2513vs$US1581;p < 0.001), but this difference was offset by a re-

Table III. Treatment-emergent extrapyramidal symptoms (EPS)

Olanzapine Risperidone p-Valuea

n treatment-emergent EPS (%) n treatment-emergent EPS (%)Simpson-Angus Scaleb 67 5 (7.5) 61 8 (13.1) 0.290Barnes Akathisia Scalec 60 17 (28.3) 55 18 (32.7) 0.609AIMSd 66 2 (3.0) 69 9 (13.0) 0.055Any anticholinergic use 75 19 (25.3) 75 34 (45.3) 0.016a χ2 test; df = 1.b The proportion of patients with a Simpson-Angus scale total score ≥4 at any post-baseline visit was calculated among those with a total

score <4 at baseline.c The proportion of patients with a Barnes Akathisia scale score ≥2 at any post-baseline visit was calculated among those with a total

score <2 at baseline.d The proportion of patients with a AIMS score ≥3 at any post-baseline visit was calculated among those with a total score <3 at baseline.AIMS = Abnormal Involuntary Movement Scale; df = degrees of freedom.



duction of $US3774 (52%) in inpatient/outpatientservice costs for olanzapine-treated patients in com-parison with risperidone-treated patients ($US3516vs $US7291, p = 0.083). Median-based findingswere consistent across other robust measures of cen-tral tendency, and in general provide conservativeestimates of observed differences in total cost ofcare in comparison with other measures.Results from analyses using median regression

models confirmed the univariate analyses and aresummarised in table V. While the median regressionmodel estimating medication costs predicted a signi-ficant savings ($US793; p = 0.001) for risperidone-treated patients comparedwith olanzapine recipients,the model estimating inpatient/outpatient servicecost predicted savings for olanzapine-treated pa-tients ($US3644; p = 0.094) that would offset thedifference in medication costs. The median regres-sion model estimating total costs predicted savingsfor olanzapine-treated patients ($US2417; p=0.212),thereby reinforcing the findings of both the univar-iate analysis and the model estimating inpatient/outpatient service costs.Sensitivity analyses were conducted to evaluate

the cost impact of dosage regimens that are morelikely to be seen in clinical practice (table VI). In

comparing 13 mg/day of olanzapine with 5 mg/dayof risperidone, the acquisition cost difference nar-rows from $US932 to $US452 and remains statis-tically significant (p < 0.001). The total cost dif-ference in favour of olanzapine increases from$US2843 to $US3028 (p = 0.342). In the compar-ison of 10 mg/day of olanzapine with 6 mg/day ofrisperidone, the total cost difference in favour ofolanzapine increases to $US3251 (p = 0.104), whilethe acquisition cost difference in favour of risperi-done is $US47 and is no longer statistically signif-icant (p = 0.954). Based on these analyses, it wouldappear that the estimates of potential savings ach-ieved with olanzapine at the dosages used in thetrial are conservative.

Discussion

The objectives of this analysis were to comparethe clinical and economic outcomes associated witholanzapine and risperidone treatment in patients withschizophrenia. To facilitate cost analyses, compar-isons were conducted using the US sample of thefirst large-scale, prospective, double-blind evalua-tion of olanzapine and risperidone published to date(as of this writing).[35] In this study, olanzapine wasfound to have both efficacy and tolerability advan-

Table IV. Medical costs by treatment group (in US dollars; 1997 values)

Costs Median 10% trima 15% trima 20% trima Tri-meanb Gastwirthc p-Valued

MedicationOlanzapine 2513 2272 2271 2127 2393 2464Risperidone 1581 1660 1667 1680 1645 1617Difference (olanzapine minus risperidone) 932 612 604 447 749 848 <0.001

Inpatient/outpatient serviceOlanzapine 3516 7142 4898 4170 4345 3863Risperidone 7291 10 185 9123 8388 9362 8141Difference (olanzapine minus risperidone) –3774 –3043 –4225 –4218 –5017 –4277 0.083

TotalOlanzapine 5141 9414 7169 6297 6262 6198Risperidone 7984 11 845 10 790 10 068 10 728 9601Difference (olanzapine minus risperidone) –2843 –2431 –3621 –3771 –4467 –3403 0.342a Mean with 10, 15 or 20% of the data deleted from each tail of the distribution.b Weighted average of the lower quantile, median and upper quantile using weights of 0.25, 0.50 and 0.25, respectively.c Weighted average of the 33rd percentile, median and 67th percentile using weights of 0.30, 0.40 and 0.30, respectively.d Ranked analysis of variance (n = 150: olanzapine, n = 75; risperidone, n = 75).

574 Edgell et al.


tages compared with risperidone. In addition, thehigher acquisition cost of olanzapine compared withrisperidone was offset by savings in inpatient/outpatient service costs.Trends in clinical outcomes favoured olanzapine-

treated patients. Olanzapine recipients were morelikely to maintain treatment response compared withrisperidone-treated patients. In addition, significantlymore risperidone-treated patients required an anti-cholinergic to control treatment emergentEPS.Thesefindings are consistent with those seen in the inter-national sample.[35] Other differences in clinical out-comes may not have reached statistical significancedue to the loss of statistical power that resultedfrom restriction of the sample to US patients.The differences in clinical outcomes translated

to savings in total and inpatient/outpatient servicecosts for olanzapine-treated patients. Although thedifferences in total and inpatient/outpatient servicecosts between olanzapine- and risperidone-treatedpatients were not statistically significant, the dif-ferences were substantial. It is likely that the morefavourable long term clinical outcomes associatedwith olanzapine treatment in this study (mainte-nance of response) drove the inpatient/outpatientand total cost findings. Olanzapine median inpa-tient/outpatient service costs were $US3774 (52%)lower than risperidone inpatient/outpatient servicecosts. These savings offset significant differencesin medication costs. Olanzapine median total costswere $US2843 (36%) lower than risperidone totalcosts over the 28-week study period.Conclusions drawn from other cost comparisons

of olanzapine and risperidone with differing res-earch designs and a focus on drug acquisition costs

are inconsistent with the present findings. Assess-ments of drug acquisition cost and treatment out-come in inpatient settings have shown olanzapinetreatment to be more costly with no difference orinferior outcomes comparedwith risperidone treat-ment.[40,68-72] Unfortunately, shortcomings in me-thodology and design apparent in these analysesmake it difficult to compare the findings of retro-spective assessmentswith the present findings.Over-all, olanzapine-treated patients included in theseother assessments were likely to be more treatmentrefractory and/or more severely ill than the rispe-ridone-treated patients[36,41,64] and, to date, theseassessments have not included adequate statisticalcontrol for baseline differences between treatmentgroups.[41] Even if there were no design flaws, be-cause these retrospective assessments have inclu-ded patients with a wide range of diagnoses, basedcomparisons on acquisition costs, restricted the sam-ple to inpatients and assessed patients over a re-stricted time period, comparison of findings wouldbe problematic.The current analysis is not without limitations.

Economic analyses based on randomised controlledtrials may be compromised by design character-istics necessary to assess efficacy.[17,73,74] There-fore, the degree to which these results are general-isable to community practice is unclear. Naturalisticeconomic trials comparing olanzapine and risperi-done which more closely reflect usual practice areunderway to confirm cost and outcome findings.[75]Another limitation impacting on generalisability

may be the dosage regimen employed. The parentstudy conducted by Tran et al.[35] has been charac-terised as flawed in design due to the dosage regi-

Table V. Median regression 28-week costs by treatment group

Costs Predicted median cost ($US; 1997 values) Treatment coefficienta p-Valueolanzapine risperidone

Medicationb 2720 1927 –793 0.001Inpatient/outpatient servicec 784 4428 3644 0.094Totalb 3569 5986 2417 0.212a For the treatment dummy variable in the models olanzapine was set equal to 0 and risperidone was set equal to 1.b Geographic region and hospitalisation status at baseline remained with the treatment variable and intercept term in the reduced model.c Geographic region, hospitalisation status, Positive and Negative Syndrome Scale (PANSS) positive score, and PANSS total score at

baseline remained with the treatment variable and intercept term in the reduced model.



men.[76-79] The dosage regimen used has been viewedas biased against risperidone in that the titrationschedule was too rapid and resulted in higher dosesthan those seen in clinical practice. Letters to theeditor[77-79] have stated that this is of concern sinceexperience with risperidone has shown that higherdoses may be associated with more adverse eventsand lower efficacy. The mean modal dosage forrisperidone-treated patients in this analysis was 7.9mg/day. The mean dosage of risperidone in usualpractice for the treatment of schizophrenia has beenreported to be 5.7 mg/day with the median and modebeing 6 mg/day.[64] One should also note that olan-zapine patients were started at 15 mg/day when inusual practice the starting dose is 5 to 10 mg/day.The olanzapine dosage regimen resulted in a meanmodal dosage for olanzapine-treated patients of 17.7mg/day. The mean dosage of olanzapine in usualpractice for the treatment of schizophrenia has beenreported to be 13.5 mg/day with the median andmode being 10 mg/day.[64]When considering the dosage regimens employ-

ed, one should note that the only required risperi-done titration in the study was during the first weekof treatment and that the regimen used was consis-tent with the risperidone US package label.[80]The fact that the study by Tran et al.[35] permitted

investigators to maximise efficacy through dose ti-tration makes the statistically significant differencesfavouring olanzapine on efficacy measures all themore relevant.[81] Whether higher dosages of ris-peridone are less efficacious remains to be seen. In

a naturalistic study of patients with schizophreniaconducted in Spain the average doses of olanzapineand risperidone were 13.0 and 5.4mg, respective-ly.[65] At these doses, risperidone-treated patientswere significantly less likely to respond to treat-ment compared with olanzapine recipients. In ad-dition, risperidone-treated patients were significantlymore likely to require concomitant therapy withanother antipsychotic. These naturalistic findingssupport the findings of this study and indicate that,dose not withstanding, risperidone may not be aseffective as olanzapine for the treatment of patientswith schizophrenia. Had upward titration of risperi-done doses been limited in this study, larger differ-ences in efficacy in favour of olanzapine may havebeen observed.In this present trial, sensitivity analyses were

conducted to test the impact of observed dosageson drug acquisition and total costs compared withdosages observed in usual practice. Comparisonsof 13 and 10 mg/day of olanzapine with 5 and 6mg/day of risperidone, respectively, revealed thatif treatment outcomes remained constant, the acqui-sition cost difference between the 2 agents wouldnarrow and the total cost difference would widencompared with findings under the dosage regimenemployed in this study. Based on these analyses, itwould appear that the estimates of potential sav-ings achieved with olanzapine at the dosages usedin the trial are conservative.Limitations common to economic analyses were

also present in this analysis. Cost distributions were

Table VI. Cost results at dosages typically seen in clinical practice for the treatment of schizophrenia

Costs Median ($US; 1997 values) Difference (olanzapine minusrisperidone) [$US; 1997 values]

p-Valuea

olanzapine risperidone

13 mg/day olanzapine vs 5 mg/day risperidoneMedication 1858 1406 452 <0.001Inpatient/outpatient service 3516 7291 –3775 0.083Total 5048 8076 –3028 0.342

10 mg/day olanzapine vs 6 mg/day risperidoneMedication 1570 1523 47 0.954Inpatient/outpatient service 3516 7291 –3775 0.083Total 4828 8079 –3251 0.104a Ranked analysis of variance (n = 150: olanzapine, n = 75; risperidone, n = 75).

576 Edgell et al.


highly skewed and included outliers. To minimisethe problem of highly skewed cost distributionsand the impact of outliers, cost data were trans-formed using various techniques including loga-rithmic transformation. These techniques did notnormalise the distribution or affect the impact ofoutliers and were not included in the final analysis.Therefore, to accurately represent the centre of thecost distribution, rather than using the mean, it wasnecessary to use more robust measures of centraltendency. Koenker and Bassett[61] go as far as tostate that with distributions such as those encoun-tered in this study ‘only an unshakable a priorifaith in the Gaussian ‘law of errors’would seem tojustify selecting the sample mean.’ In addition, non-parametric approaches were used to determine ifcost differences by treatment group were statisti-cally significant.

Conclusions

The findings of this current study in combina-tion with the findings from the parent study con-ducted by Tran et al.[35] indicate that olanzapine-treated patients may experience superior clinicaloutcomes compared with risperidone-treated pa-tients. These findings indicate that when schizo-phrenia treatment choices are made, olanzapine andrisperidone should not be lumped into a single ‘aty-pical’ category but instead should be consideredseparately based on their distinct clinical profiles.When considering cost in treatment allocation

decisions, the decision-maker should consider theimpact of differences in clinical outcomes on thetotal costs of care. This study indicates that theadvantages in clinical outcomes experienced byolanzapine-treated patients may translate into sav-ings in inpatient and outpatient costs thatmore thanoffset any difference in medication costs relativeto risperidone. As of this writing, this study repre-sents the only prospective randomised assessmentof economic outcomes among patients treated witholanzapine and risperidone. While various retro-spective assessments comparing the 2 agents havebeen presented,[40,68-72] the lack of methodologicalrigor, flawed study design and drug acquisition cost

focus associated with these evaluations limits theirusefulness in drug allocation decisions.[41] This pre-sent study was not without limitations, and the cost-effectiveness question regarding treatmentwith olan-zapine versus risperidone will not be definitivelyanswered until longer term, large, prospective,randomised, naturalistic economic trials compar-ing the 2 agents are completed. However, given theshortcomings associated with the retrospective as-sessments completed to date and the need to maketreatment allocation decisions before results of nat-uralistic economic trials become available, the re-sults of this prospective head-to-head study shouldbe considered in treatment allocation decisions.

Acknowledgements

This study was funded and conducted by Eli Lilly andCompany, Indianapolis, Indiana, USA.

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Correspondence and offprints: Eric T. Edgell, PharmD, MS,Health Outcomes Research Scientist, European Health Out-comes Research, Eli Lilly and Company Ltd, Lilly ResearchCentre, Erl Wood Manor, Windlesham, Surrey, GU20 6PHUK.



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