C 1999 Martin Dunitz Ltd
Zntemational Journal of Psychiatry in Clinical Practice 1999 Volume 3 Pages 3 - 9
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The economic value of atypical antipsychotics: A comparison of risperidone and olanzapine revisited DAMIEN LECOMPTE’ AND RON F COOKSON’ ‘University Hospital Brugmann, Brussels, Belgium; ’Independent Health Economics Consultant, Caversham Park, Reading, UK.
Correspondence Address Professor D Lecompte, Department of Psychiatry, Psychiatric Institute, University Hospital Brugmann, Place A Van Gehuchten 4, 1020 Brussels, Belgium Tel: +32 2 477 27 05 Fax: +32 2 477 21 62
Received 14 January 1999; revised 27 January 1999; accepetd for publication 28 January 1999
Careful analysis of clinical experience to date throws fresh light on the optimal and actual doses used in clinical practice of risperidone and olanzapine. Since launch, the optimal dose for treatment of schizophrenia of risperidone has been established at 4-6 mglday and that of olanzapine at around 15 mglday. We have applied these more realistic dosing assumptions to the published economic comparisons between the various atypical agents and conclude that there are economic and efficacy arguments for risperidone to be considered as the first choice for treatment of patients with schizophrenia. The other atypicals, such as olanzapine and clozapine, should be used as second-line therapy in preference to conventional agents such as haloperidol. Funding arguments support this approach and reinforce the need to reconsider therapy for patients whose current treatment may not be optimal. (Int J Psych Clin Pract 1999; 3: 3-9) Keywords risperidone atypical agent economics
INTRODUCTION chizophrenia a costly illness. Recent estimates in S the United Kingdom suggest that the mean annual cost to society of newly diagnosed patients with is
schizophrenia is €23,000 each.’ Patients in whom a relapsing chronic course develops cost society a great deal more. Costs are similar in other countries and reflect the very large expense associated with hospital care.’ To keep a patient hospitalized for a full year could cost more than €40,000, to which should be added costs relating to lost productivity (indirect Such indirect costs, carried by society but not by the healthcare system, could amount to more than €11,000 per patient per year.’ The high costs are to some extent a reflection of the inadequacies of conventional treatment. Antipsychotic drugs, for example, have been associated in the past with poor efficacy against negative symptoms, significant extrapyramidal symptoms (EPS) and poor patient compliance, often resulting in a vicious cycle of relapse and deteriorating prognosis. In spite of the deficiencies of the older drugs, the adoption of newer, superior therapies has
olawapine schizophrenia funding
been slow as they are often relegated inappropriately to second-line the rap^.^ Following the introduction of the atypical antipsychotics clozapine (1990) and risperidone (1993), increasing evidence has accumulated that hospital stay can be reduced, if not eliminated, quality of life can be improved and patients in many cases can be freed of EPS. More recently olanzapine and other atypical agents have been introduced, although they may not represent a pharmacological advance on either clozapine or ri~peridone.~ The clinical benefit of these newer atypical agents will only be determined with long-term use,5 although much can be deduced from the data already available. To optimize clinical benefit for patients and avoid funding problems for the healthcare system, it is essential to develop a clinical strategy that makes the best use of atypical antipsychotics. To enable such a strategy to be developed, guidelines for patient selection and choice of drug should be clear. In addition the correct dose of drug should be employed. This paper addresses the latter issue and throws light on the consequences for the selection of atypical agents.
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THE DEVELOPMENT OF RECOMMENDED DOSES To place a new drug therapy on the market, the manufacturer has to provide formal evidence of safety, quality and efficacy. Typically randomized controlled clinical trials will have demonstrated efficacy over relatively short periods of a few weeks, with open follow-up studies checking the safety profile of the product for a minimum of 12 months. As regulators require studies against the most common or a standard therapy, early trials on atypical antipsychotics tended to focus on comparison with haloperidol. Such a comparator may not reflect the therapeutic choice faced by psychiatrists in selecting the most suitable atypical for a particular patient. When drugs reach the market, the recommended dose is usually based on clinical trials in less than 1500 patients6 It is only when clinicians have gained experience with much wider ranges of patients and situations than those envisaged in clinical trials, that these doses can be confirmed or modified. Once a drug is used widely, ‘real world’ information allows clinical and economic judgements to be better founded. For example, the safety profile of a drug will only become apparent when many thousands of patients have been treated for long periods. Similarly the most useful clinical dose for a new agent will only emerge when clinicians have had the chance to see how the drug performs in a group of their own patients over a significant period. With modem drugs and their high acquisition costs, relatively small changes in the dose used can have major consequences for pharmacy budgets. The different doses of clozapine employed in early trials and in current clinical practice differ in acquisition costs by $5200 per patient per In schizophrenia it is particularly important to determine the optimum dose of antipsychotics by careful titration. If too low a dose is used patients may relapse, whereas if too high a dose is used, side-effects may reduce compliance and again result in relapse. Similarly, from a health economics and funding perspective, it is vital to determine the appropriate dose to calculate meaningful costs for the pharmacy budget (acquisition costs), as studies can otherwise be very misleading. The availability and analysis of large pharmacy databases are an advantage for those wishing to monitor actual clinical experience of newly introduced drugs and can help in the design of better dosing schedules.’ Analysis of prescription costs in 26 patients treated with clozapine for at least 12 months showed that the cost of medication increased from €211 per annum before clozapine to €2830 once on the drug.’ Although total direct costs decreased from €36,604 to €32,836, this was not statistically significant. A UK model of risperidone experience demonstrated a similar pattern, although the decrease in direct costs was in that case statistically significant.”
THE RISPERIDONE CASE-STUDY
Clinical experience over 5-6 years of general use has confirmed the superiority of risperidone over conventional anti psychotic^.^ This view is supported by published metaanalyses11J2as well as an analysis of the manufacturer’s integrated database of 4228 patients.13-14 Risperidone has superior efficacy to h a l ~ p e r i d o l ” ~ ’ ~ ~ ’ ~ ~ and is comparable to ~lozapine’~-’’and comparable or superior to 01anzapine.~~-~~ One of these studies” was designed to show superiority of olanzapine over risperidone. The study used differences between PANSS scores as the primary measure of efficacy and did not show a statistically significant difference between risperidone and olanzapine for PANSS total score (p=0.413), PANSS positive score (p=0.654) or PANSS negative score (p=0.454). In addition, risperidone has a beneficial effect on cognitive f ~ n c t i o n ~ ~and - * ~ on negative symptoms.Z’ Cognitive impairment is a major contributor to direct and indirect costs of schizophrenia.” The safety profile of risperidone has been reviewed using worldwide experience amounting to more than one million patient-years of exposure.l 4 Other meta-analyses of the major studies in the published literature support the view that risperidone’s safety and side-effect profile is far superior to the conventional antipsychotics and to clozapine.’ Recent major reviews have underlined the clinical and economic superiority (dominance) of risperidone over the conventional antipsychotics, supporting its use in chronic s c h i ~ o p h r e n i a .Health ~ , ~ ~ economic dominance is rare, as usually additional benefit to patients only comes with additional expense as seems to be the case with clozapine and higher doses of olanzapine. The costs of clozapine may be recouped over the longer term ( > 2 years).’ A recent five-year model of olanzapine suggests that at doses used in clinical trials olanzapine, although not cost saving, would improve patient outcome compared to h a l ~ p e r i d o l . ~ ~ An authoritative model from the independent Canadian Co-ordinating Office for Health Technology Assessment (CCOHTA) reaffirmed the dominance of risperidone compared to haloperidol, haloperidol decanoate or fluphenazine decanoate, and suggested that clozapine was dominant over chlorpromazine or haloperidol in treatmentresistant patients.32 Prospective studies with a naturalistic design avoid the difficulties of traditional trials and models33 by attempting to mimic more closely the real world of clinical psychiatry. Two such studies support the clear superiority of risperidone over conventional neur~leptics.~~’~ There are already sufficient data to recommend the use of risperidone as a first-line treatment ahead of conventional agent^.^ Given the therapeutic value of risperidone and its economic profile, a therapeutic trial is justified in all patients requiring either initial treatment or a change to their treatment.3
Economics of risperidone and olanzapine
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Table 1 Optimal daily dose of risperidone (mgfday)
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significant difference in the rate of dose titration. The best response was found if patients were titrated to a maximum dose over six days, double the three days originally used in some studies. They suggested increments during titration Dose Context (patients) Comment of 0.5-2 mg/day rather than the rigid 2 mg/day increments previously used. 4-6 Practice guidelines American Psychiatric The North American dose-finding s t ~ d y ~ concluded ',~~ A~sociation~~ that positive symptoms of schizophrenia were significantly 5 Recommended by WHO3' Defined daily dose lower after haloperidol or fixed doses of risperidone of 3.8 Prescription data World-wide mean* 3 6 mg/day or higher; this study did not include a 4 mg dose 70-80% D2 receptor Theoretical optimum38 occupancy group. Although negative symptoms were reduced after 6 5.7 1072 schizophrenia, or Pharmacy database' or 16 mg risperidone, the higher dose had significant EPS. schizoaffective disorder The optimum dose of those studied was 6 mg/day. Even at 6 513 chronic Dose finding'6v40.41 the lowest dose used (2 mg/day), 35% of patients schizophrenia responded to risperidone. Higher doses (10 and 16 mg/ 4-8 1362 chronic Do~e-finding~~ day) gave a smaller response than was found at 6 mg. schizophrenia These findings suggested that some of the earlier doses 4.8 202 outpatientshew Comparative study" used in trials may have been unnecessarily high. Similarly inpatients the European dose-finding study concluded that 4 mg had 4.89 18 inpatients Database analysis55 the same response rate (63-66%) as 8 m g / d a ~ ~ ~ responding to therapy A three-year survey of doses used in 1057 inpatients on 5.12 449 inpatients initiated Maryland database risperidone showed a steady reduction over time in the (4.3-5.6) in 1996 review43 mean dose used each year (Table 2).43 *De Nijs, personal communication Much of the early economic work on the drug may therefore overstate the acquisition costs of risperidone and As clinical experience has accumulated, it has become underestimate the overall economic benefit of successful use. Thus the average dose in the Lindstrom study during increasingly clear that the optimal dose range of risperthe first year was approximately 9 mg/day, resulting in an idone is 4-6 mg/day (Table 1). Market research data (de annual acquisition cost of €2081 per patient."*44Although Nijs, personal communication) conclude that the mean even such high costs were offset by savings elsewhere in daily dose prescribed worldwide is 3.8 mg. The practice guidelines of the American Psychiatric A s s ~ c i a t i o n ~ ~the health services, lower doses may have benefited patients more and cost the pharmacy less. The average daily recommend that risperidone is most effective at 4-6 mg/ risperidone dose in the UK (de Nijs, personal communicaday with higher doses leading to EPS without greater tion) is 4.9 mg, which would represent a €920 reduction in effectiveness. The World Health Organization has reduced the acquisition cost reported. its Defined Daily Dose to 5 mg/da~.~' These policy and advice statements are in accord with the recent literature and theoretical predictions. Theoretical arguments have been developed to suggest ways to improve THE INTRODUCTION OF OLANZAPINE on the conclusions on optimal dose derived from clinical trial^.^' To minimize side-effects lower doses than those Olanzapine, a chemical analogue of clozapine, was introduced in 1996 and seems to exhibit a clear dose-response suggested by flexible and fixed dose trials may work for relationship in the treatment of acute exacerbations of most patients. For any given patient the pharmacokinetic chronic ~chizophrenia.~~ Interestingly, when some flexand pharmacodynamic issues specific to that individual will ibility of dose was allowed the olanzapine patients tended affect the optimum dose. In general it is wise to titrate doses slowly to therapeutic effect, avoiding the unnecessary risk of EPS. Table 2 PET studies on receptor occupancy show that a steady Reduction of risperidone dose with experience43 state dose of risperidone of 2.9-5.1 mg/day results in 7080% occupancy of the D2 receptor, a range predicted to be Patients antipsychotic with minimal EPS.3'"9*58 discharged Inpatients Total Total Use of pharmacy databases throws light on current Year ( W h y ) hglday) (mglday) patients risperidone doses. For example Luchins and colleagues' examined 1072 patients with schizophrenia or schizoaffective disorder who were treated with risperidone for at least 6.4 263 1994 5.7 6.8 12 months. They showed that the mean dose in these 4.8 5.8 5.4 345 1995 5.1 449 4.3 5.6 1996 patients was 5.7 mg/day. Contrasting risperidone responders with those who did not respond they found a
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D Lecompte and RF Coohson
to be titrated to the upper end of their dose ~ a n g e . ~ ~ . Table ~' 3 Optimal daily dose of olanzapine (mg/day) Doses found to be useful tend to be significantly higher than the lOmg/day originally recommended (Table 3). Dose Context (patients) Comment Sixty-six per cent of olanzapine patients completed a six-week study and the mean modal doses (the most common doses used) in these patients are shown in Table 4. 13.2 Prescription data World-wide mean* Approximately one-third of patients could not continue 15 7040% Dz receptor Theoretical optimum3' on olanzapine for six weeks, one-third required 5 or 10 mg/ occupancy day and one-third required 15 or 20 mg. 12.65 1336 schizophrenia, or Comparative schizoaffective disorder 6 weeks treatment The use of mean modal doses over such a short time only period is difficult to interpret as these data could underUK inpatients 6r Database analysis" 14.4 220 estimate the need for higher doses over a longer period. outpatients Thus to reach 20 mg/day the patient would need to spend (12.4) (patients treated 6 weeks) titration period would be allocated to lower doses. A recent retrospective study of 15 UK National Health *De Nijs. personal communication Service trusts involving 202 patients on olanzapine found Table 4 that the mean dose used in the first six weeks was 12.4 mg/ Patients discontinued and mean modal doses after 6 weeks treatment for day, but this increased in patients treated for longer than 6 remainder4' weeks to 15.8 mg/day.+' The authors concluded that olanzapine was not wholly effective at low doses, thus Dose (mg/day) Olanzupine requiring higher doses than those routinely recommended or the addition of other antipsychotics. Although there are pharmacological similarities be32% Discontinued tween the newer atypicals such as olanzapine and the more 5 19% established drugs such as risperidone and clozapine,5 10 15% clinicians will need to know whether they provide a 15 13% 20 21% therapeutic advance, at least for some patients. Studies on the effectiveness of olanzapine have shown no evidence of superiority over r i s p e r i d ~ n e . ~ Indeed ' - ~ ~ there may be an advantage for risperidone." Relative doses can be clarified by use of other Most early studies used haloperidol as information sources such as analyses of prescription Given that the clinical differences between atypicals are patterns both locally, within units, and nationally using much less than the differences between them and market research data. As evidence accumulates, doseconventional antipsychotics, a robust definition of any related data enable comparison of clinically equivalent differences, for example between risperidone and olanza- doses (Table 5). pine, would require studies involving many thousands of Although the optimal dose of risperidone is 4-6 mg/ patients. In considering the relative profiles of these two day, the data on olanzapine seem to suggest that an drugs, it is necessary to have a clear understanding of what equivalent dose may be towards the top end of the are comparable doses. Unfortunately the only published recommended range of 5-20 mg/day (Table 3). Receptor double-blind comparison of risperidone and olanzapinez' is occupancy studies suggest that olanzapine 10- 20 mg./day flawed in its design and s t a t i s t i ~ s . ~ ~ - ~ ~ is equivalent to risperidone 2-4 mg/da~.~' Sub group analysis, when there were no differences Comparing the various trials which used haloperidol as detected with the primary measures, was used as a way of a control, it can be seen that the effects of risperidone and claiming differences between the products. The dosing olanzapine 16.4 mg are similar and both are superior to regime for selection of maintenance dose seems biased olanzapine 11.3 mg and olanzapine 13.2 mg (Table 6). against risperidone. The employed rapid titration of risperidone would result in too high a dose being used and the different approach to olanzapine would limit the THE ECONOMIC IMPLICATIONS use of higher doses. This is of concern as early experience with risperidone has shown higher doses may be associated All patients are different, and clinical choice is the with more adverse events and lower efficacy. The nonprerogative of the clinician, who must choose the most equivalence of the dose regimes lead Kasper and Kufferle to appropriate therapy for a specific patient. In this context it question the validity of the is necessary to recognize that inappropriate choice can not A more recent double-blind study rectifies some of these only disadvantage the patient but may disadvantage others faults and suggests some additional benefit for risperidone by denying someone else the resource consumed. This is over olanzapine when clinically relevant doses are used." the rationale for examining the economics of therapies.
Economics of risperidone and olanzapine
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Table 5 Comparable daily doses (mglday) of risperidone and olanzapine Source
Risperidone
Ofanzapine
2-4 7.2 4.8 5.98 5.83 (4.89) 4.7
10-20 17.2 12.5 14.02 19.83 (17.19) 13.2
5.3
15.3
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Receptor occupancy3’ Comparative study2’ Comparative study” Database analysis56 Database analysis55 US Market Research57 (di Nijs, personal communication) Mean of above six estimates
Table 6 Incremental change in Positive and Negitive Syndrome Scale PANSS5’ for risperidone and olanzapine compared to haloperidol internal ~ o n t r o l s ’ ~ * ~ ~ , ~ ~ Risperidone 11.3 mglday Patient numbers PANSS total PANSS positive PANSS negative
1056
- 6.6 - 1.6 - 1.3
83 -2.7 +0.3 -0.6
OIanzapine 13.2 mglday 888 -4.3
-0.9 -1.3
16.
85 -6.7 - 1.7 -1.8
Although the acquisition costs of the atypical antipsychotics seem high, this is because they are set against the background of cheap generic drugs whose prices reflect costs in the 1950s. The 30-year gap between haloperidol and risperidone has seen UK prices rise by a factor of 13. Applying this factor to the acquisition cost of haloperidol would result in a product 30% more expensive than risperidone. Two issues need to be considered: the economic and funding issues of selecting an atypical as opposed to conventional antipsychotics, and the choice between the atypicals available. The economic arguments for the use of atypicals are sufficiently strong to argue that they should now be used in preference to the older t h e r a p i e ~ . ~ . ~The . ~ . ~toxicity ’ of clozapine and the consequent mandatory monitoring and restriction on prescription mean that it should be reserved for second-line therapy.’ Models have been developed and will continue to appear to argue the relative economic merits of risperidone and olanzapine. Given the evidence discussed here, it is important that such models allow appropriate doses to be compared - not necessarily those originally chosen by the manufacturer. Olanzapine has been supported by a model published on the basis that 10 mg/day is the appropriate dose.31This
Comment Theoretical Risperidone titration flawedz4 407 outpatients, low initial PANSS scores 113 inpatients, similar outcomes All patients (Responders) Prescription data Dose ratio 1:3
concludes that at that dose over five years a saving relative to haloperidol of $1539 would be achieved, together with an improvement in patient outcome. Sensitivity analysis examines the impact of the more realistic 15 mg/day and concludes that olanzapine would cost $844 - $1477 more than haloperidol to provide the improved patient outcome. These data should provide some reassurance in selecting olanzapine in preference to haloperidol, even though threemonth data are extrapolated to five years to show an effect. A second model has suggested that the choice of olanzapine over haloperidol is cost-neutral, but with greater benefits for olanzapine treated ~atients.~’ An attempt is made by the authors of the model3’ to apply the same arguments to select olanzapine in favour of risperidone, although the economics depend on which doses of risperidone and olanzapine are chosen. Although the model and conclusions have been ~ r i t i c i z e dsufficient ,~~ details are available to compare 15 mg olanzapine and 6 mg risperidone, not far from what may be the correct doses. The drugs differ by 1%in anticipated patient outcome and risperidone would save $7733 relative to olanzapine. At a funding level, five-year economic benefits may be a desirable objective, but difficult to achieve as additional cash might be required to ‘prime the pump’. It may therefore be helpful to look at the impact of both these agents on pharmacy budgets. At current UK prices,*’ olanzapine 15 mg costs €5.65 per day, more than twice the cost of risperidone 4 mg. If risperidone 5 mg53were to be preferred to olanzapine 15 mg in the UK just for the 7500 new patients with schizophrenia each year, it would save pharmacy €6.6 million in the first year. If clinicians, patients and policy-makers can agree that these new agents should replace conventional agents this would free more hospital facilities for previously undertreated patients, such as those to be found among the homeless.’ Such a process would require additional funds or at least significant reallocation of budgets. The CCOHTA model suggested that the use of risperidone in all hospitalized patients with schizophrenia could save the Canadian health care system $662 million.
D Lecompte and RF Cookson
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Even conservative assumptions' would suggest that in the UK a 6%cost saving would be achieved if patients were switched to risperidone. As schizophrenia costs UK society €2.6 billion each year,54this represents an additional €156 million available each year for patient care. On the basis of the published dose and economic data, risperidone seems to be the first-choice antipsychotic with clozapine and the other atypicals available as second-line treatment. Clinicians and their patients are fortunate at last to have such a choice of active and relatively non-toxic drugs. It is no longer ethically acceptable for most patients to use the older, less efficient drugs. The cost of failure with the older therapies is a continuing slide with the patient deteriorating into a life dominated by relapse and expensive care. The hidden costs of patient suffering and the denial of resources to other patients, now make the availability of new therapy not just an opportunity, but a necessity.
ACKNOWLEDGEMENTS
has been brought to bear on their conclusions by the manufacturer of any of the products mentioned.
KEY POINTS 0
0
0
Clinical experience rather than early clinical trials is the best way to select equivalent doses for comparison of new agents This approach suggests the optimal daily dose for risperidone is 4-6 mg and 15 mg or higher for olanzapine At these doses risperidone is more cost-effective than olanzapine
The writing of this paper was funded by the Janssen Research Foundation. The authors assert that no influence
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22. Schooler NR (1998) Comments on article by Tran and Colleagues.J Clin Psychopharmacol 18: 174-6. 23. Gheuens J, Grebb JA (1998) Comments on article by Tran and associates.j Clin Psychopharmacol 18: 176- 7. 24. Kasper S, Kufferle B (1998) Comments on ‘Double-blind comparison of olanzapine and risperidone in the treatment of schizophrenia and other psychotic disorders’ by Tran and associates.j Clin Psychopharmacol, 18: 353-4. 25. Foster Green M, Marshall BD, Wirshing WC et a1 (1997) Does risperidone improve verbal working memory in treatmentresistant schizophrenia? Amer J Psychiatry 154: 799 - 804. 26. Borison RL (1996) The role of cognition in the risk-benefit and safety analysis of antipsychotic medication. Acta Psychiatr Scand 94: 5-11. 27. Stip E, Lussier I (1996) The effect of risperidone on cognition in patients with schizophrenia. Can J Psychiatry 41(2 Suppl): 35s- 40s. 28. Carman J, Peuskens J, Vangeneuden A (1995) Risperidone in the treatment of negative symptoms of schizophrenia: a metaanalysis. Int Clin Psychopharmacol 10: 207- 13. 29. Sevy S, Davidson M (1995) The cost of cognitive impairment in schizophrenia. Schizophrenia Research 17: 1- 3. 30. Foster RH, Goa KL (1998) Risperidone: A pharmacoeconomic review of its use in schizophrenia. Pharmacoeconomics 14: 97133. 31. Palmer CS, Revicki DA, Genduso LA et a1 (1998) A costeffectiveness clinical decision analysis model for schizophrenia. Am J Managed Care 4: 345-55. 32. Glennie JL (1997) Pharmacoeconomic evaluations of clozapine in treatment-resistant Schizophrenia and risperidone in chronic schizophrenia. Canadian Co-ordinating Centre for Health Technology Assessment (CCOHTA). Ottawa, Ontario. 33. Maynard AL, Cookson RF (1998) Computer Modelling: The need for careful evaluation and public audit. Pharmacoeconomics 14(Suppl 2): 67-72. 34. Bouchard R-H, Demers MF, Merette C. Pourcher E (1998) Classical neuroleptics vs risperidone interim 12 months efficacy analysis of a long-term naturalistic study in schizophrenics. In 21st Congress of the Collegium Internationale Neuropsychopharmacologicum (CINP). Glasgow, UK. PT 07104. 35. Mahmoud RA, Engelhart LM, Oster G, Stevens MC et a1 (1997) Risperidone vs conventional antipsychotics: a prospective randomised naturalistic effectiveness trial of outcomes in chronic schizophrenia. In 36th Annual Meeting of the American College of Neuropsychopharmacology. Kamuela, Hawaii. 36. American Psychiatric Association (1997) Practice guidelines for the treatment of schizophrenia. Am j Psychiatry 154(4 suppl): 154. 37. World Health Organization (1998) WHO Drug Information 12: 18-21. 38. Farde L, Nyberg S (1998) Dosing determination for novel antipsychotics. Int j Psychiatry Clin Practice (Suppl 2): S39542. 39. Farde L, Nyberg S, Oxenstierna G et a1 (1995) Positron emission tomography studies on D2- and 5-HT2 receptor binding in risperidone-treated patients. j Clin Psychopharmacol ~ ~ ( S U1): P P19s-23s. ~ 40. Marder SR, Meibach RC (1994) Risperidone in the treatment of schizophrenia. Am j Psychiatry 151: 825-35.
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41. Chouinard G, Jones B, Remington G et a1 (1993) A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 13: 25 - 40. 42. Peuskens J and The Risperidone Study Group (1995) Risperidone in the treatment of patients with chronic schizophrenia: a multi-national, multi-centre, double-blind, parallelgroup study versus haloperidol. Br j Psychiatry 166: 712-26. 43. Love RC, Conley RR, Kelly DL et a1 (1997) Risperidone dosing trends in the Maryland state mental health system. In 36th Annual Meeting of the American College of Neuropsychopharmacology. Kamuela, Hawaii. 44. Lindstrom E, Eriksson B, Hellgren A et a1 (1995) Efficacy and safety of risperidone in the long-term treatment of patients with schizophrenia. Clin Ther 17: 402- 12. 45. Beasley CM, Tollefson G, Tran PV et a1 (1996) Olanzapine versus placebo and haloperidol. Neuropsychopharmacol 14: 111- 23. 46. Beasley CM, Hamilton SH, Crawford AM et a1 (1997) Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol 7: 125-37. 47. Tollefson GD, Beasley CM, Tran PV et a1 (1997) Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am j Psychiatry 154: 457-65. 48. Taylor D, Drummond S, Pendlebury J (1998) Olanzapine in practice. Psychiat Bull 22: 552-4. 49. Hamilton SH, Revicki DA, Genduso LA, Beasley CM (1998) Olanzapine versus placebo and haloperidol: quality of life and efficacy results of the North American double-blind trial. Neuropsychopharmacol 18: 41 -9. 50. Almond S, ODonnell 0 (1998) Cost analysis of the treatment of schizophrenia in the UK: a comparison of olanzapine and haloperidol. Pharmacoeconomics 13: 575 - 88. 51. Mohr P, Neumann P, Claxton K (1998) Letter to the Editor. Am j Managed Care 4 1200-1. 52. Eli Lilly and Company Limited (1996) Olanzapine Product Monograph. Eli Lilly, Basingstoke UK. 53. British Medical Association and Royal Pharmaceutical Society of Great Britain (1998) British National Formulary. 54. Knapp M (1997) Costs of schizophrenia. Br j Psychiatry 171: 509- 18. 55. Procyshyn R, Zerjav S (1998) Drug utilisation patterns and outcomes associated with in-hospital treatment with risperidone and olanzapine. Clin Ther 20: 1203- 17. 56. Chan Y-C, Votolato NA, Nasrallah HA (1998) Pharmacoeconomic comparisons of risperidone and olanzapine during acute inpatient treatment of schizophrenia. In American Psychiatric Association Annual Meeting. Toronto, Canada. 57. Kasper S (1998) Risperidone and olanzapine: optimal dosing for efficacy and tolerability in patients with schizophrenia. Int Clin Psychopharmacol 13: 253 -62. 58. Kufferle B, Brucke T, Topitz-Schratzberger A et a1 (1996) Striatal dopamine-2 receptor occupancy in psychotic patients treated with risperidone. Psych Res - Neuroimaging 68: 23 - 30. 59. Kay SR, Opler LA, Lindenmayer JP (1989) The positive and negative syndrome scale (PANSS) rationale and standardisation. Br j Psychiatry 155: 59-65.
Zntemational Journal of Psychiatry in Clinical Practice 1999 Volume 3 Pages 3 - 9
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The economic value of atypical antipsychotics: A comparison of risperidone and olanzapine revisited DAMIEN LECOMPTE’ AND RON F COOKSON’ ‘University Hospital Brugmann, Brussels, Belgium; ’Independent Health Economics Consultant, Caversham Park, Reading, UK.
Correspondence Address Professor D Lecompte, Department of Psychiatry, Psychiatric Institute, University Hospital Brugmann, Place A Van Gehuchten 4, 1020 Brussels, Belgium Tel: +32 2 477 27 05 Fax: +32 2 477 21 62
Received 14 January 1999; revised 27 January 1999; accepetd for publication 28 January 1999
Careful analysis of clinical experience to date throws fresh light on the optimal and actual doses used in clinical practice of risperidone and olanzapine. Since launch, the optimal dose for treatment of schizophrenia of risperidone has been established at 4-6 mglday and that of olanzapine at around 15 mglday. We have applied these more realistic dosing assumptions to the published economic comparisons between the various atypical agents and conclude that there are economic and efficacy arguments for risperidone to be considered as the first choice for treatment of patients with schizophrenia. The other atypicals, such as olanzapine and clozapine, should be used as second-line therapy in preference to conventional agents such as haloperidol. Funding arguments support this approach and reinforce the need to reconsider therapy for patients whose current treatment may not be optimal. (Int J Psych Clin Pract 1999; 3: 3-9) Keywords risperidone atypical agent economics
INTRODUCTION chizophrenia a costly illness. Recent estimates in S the United Kingdom suggest that the mean annual cost to society of newly diagnosed patients with is
schizophrenia is €23,000 each.’ Patients in whom a relapsing chronic course develops cost society a great deal more. Costs are similar in other countries and reflect the very large expense associated with hospital care.’ To keep a patient hospitalized for a full year could cost more than €40,000, to which should be added costs relating to lost productivity (indirect Such indirect costs, carried by society but not by the healthcare system, could amount to more than €11,000 per patient per year.’ The high costs are to some extent a reflection of the inadequacies of conventional treatment. Antipsychotic drugs, for example, have been associated in the past with poor efficacy against negative symptoms, significant extrapyramidal symptoms (EPS) and poor patient compliance, often resulting in a vicious cycle of relapse and deteriorating prognosis. In spite of the deficiencies of the older drugs, the adoption of newer, superior therapies has
olawapine schizophrenia funding
been slow as they are often relegated inappropriately to second-line the rap^.^ Following the introduction of the atypical antipsychotics clozapine (1990) and risperidone (1993), increasing evidence has accumulated that hospital stay can be reduced, if not eliminated, quality of life can be improved and patients in many cases can be freed of EPS. More recently olanzapine and other atypical agents have been introduced, although they may not represent a pharmacological advance on either clozapine or ri~peridone.~ The clinical benefit of these newer atypical agents will only be determined with long-term use,5 although much can be deduced from the data already available. To optimize clinical benefit for patients and avoid funding problems for the healthcare system, it is essential to develop a clinical strategy that makes the best use of atypical antipsychotics. To enable such a strategy to be developed, guidelines for patient selection and choice of drug should be clear. In addition the correct dose of drug should be employed. This paper addresses the latter issue and throws light on the consequences for the selection of atypical agents.
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THE DEVELOPMENT OF RECOMMENDED DOSES To place a new drug therapy on the market, the manufacturer has to provide formal evidence of safety, quality and efficacy. Typically randomized controlled clinical trials will have demonstrated efficacy over relatively short periods of a few weeks, with open follow-up studies checking the safety profile of the product for a minimum of 12 months. As regulators require studies against the most common or a standard therapy, early trials on atypical antipsychotics tended to focus on comparison with haloperidol. Such a comparator may not reflect the therapeutic choice faced by psychiatrists in selecting the most suitable atypical for a particular patient. When drugs reach the market, the recommended dose is usually based on clinical trials in less than 1500 patients6 It is only when clinicians have gained experience with much wider ranges of patients and situations than those envisaged in clinical trials, that these doses can be confirmed or modified. Once a drug is used widely, ‘real world’ information allows clinical and economic judgements to be better founded. For example, the safety profile of a drug will only become apparent when many thousands of patients have been treated for long periods. Similarly the most useful clinical dose for a new agent will only emerge when clinicians have had the chance to see how the drug performs in a group of their own patients over a significant period. With modem drugs and their high acquisition costs, relatively small changes in the dose used can have major consequences for pharmacy budgets. The different doses of clozapine employed in early trials and in current clinical practice differ in acquisition costs by $5200 per patient per In schizophrenia it is particularly important to determine the optimum dose of antipsychotics by careful titration. If too low a dose is used patients may relapse, whereas if too high a dose is used, side-effects may reduce compliance and again result in relapse. Similarly, from a health economics and funding perspective, it is vital to determine the appropriate dose to calculate meaningful costs for the pharmacy budget (acquisition costs), as studies can otherwise be very misleading. The availability and analysis of large pharmacy databases are an advantage for those wishing to monitor actual clinical experience of newly introduced drugs and can help in the design of better dosing schedules.’ Analysis of prescription costs in 26 patients treated with clozapine for at least 12 months showed that the cost of medication increased from €211 per annum before clozapine to €2830 once on the drug.’ Although total direct costs decreased from €36,604 to €32,836, this was not statistically significant. A UK model of risperidone experience demonstrated a similar pattern, although the decrease in direct costs was in that case statistically significant.”
THE RISPERIDONE CASE-STUDY
Clinical experience over 5-6 years of general use has confirmed the superiority of risperidone over conventional anti psychotic^.^ This view is supported by published metaanalyses11J2as well as an analysis of the manufacturer’s integrated database of 4228 patients.13-14 Risperidone has superior efficacy to h a l ~ p e r i d o l ” ~ ’ ~ ~ ’ ~ ~ and is comparable to ~lozapine’~-’’and comparable or superior to 01anzapine.~~-~~ One of these studies” was designed to show superiority of olanzapine over risperidone. The study used differences between PANSS scores as the primary measure of efficacy and did not show a statistically significant difference between risperidone and olanzapine for PANSS total score (p=0.413), PANSS positive score (p=0.654) or PANSS negative score (p=0.454). In addition, risperidone has a beneficial effect on cognitive f ~ n c t i o n ~ ~and - * ~ on negative symptoms.Z’ Cognitive impairment is a major contributor to direct and indirect costs of schizophrenia.” The safety profile of risperidone has been reviewed using worldwide experience amounting to more than one million patient-years of exposure.l 4 Other meta-analyses of the major studies in the published literature support the view that risperidone’s safety and side-effect profile is far superior to the conventional antipsychotics and to clozapine.’ Recent major reviews have underlined the clinical and economic superiority (dominance) of risperidone over the conventional antipsychotics, supporting its use in chronic s c h i ~ o p h r e n i a .Health ~ , ~ ~ economic dominance is rare, as usually additional benefit to patients only comes with additional expense as seems to be the case with clozapine and higher doses of olanzapine. The costs of clozapine may be recouped over the longer term ( > 2 years).’ A recent five-year model of olanzapine suggests that at doses used in clinical trials olanzapine, although not cost saving, would improve patient outcome compared to h a l ~ p e r i d o l . ~ ~ An authoritative model from the independent Canadian Co-ordinating Office for Health Technology Assessment (CCOHTA) reaffirmed the dominance of risperidone compared to haloperidol, haloperidol decanoate or fluphenazine decanoate, and suggested that clozapine was dominant over chlorpromazine or haloperidol in treatmentresistant patients.32 Prospective studies with a naturalistic design avoid the difficulties of traditional trials and models33 by attempting to mimic more closely the real world of clinical psychiatry. Two such studies support the clear superiority of risperidone over conventional neur~leptics.~~’~ There are already sufficient data to recommend the use of risperidone as a first-line treatment ahead of conventional agent^.^ Given the therapeutic value of risperidone and its economic profile, a therapeutic trial is justified in all patients requiring either initial treatment or a change to their treatment.3
Economics of risperidone and olanzapine
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Table 1 Optimal daily dose of risperidone (mgfday)
5
significant difference in the rate of dose titration. The best response was found if patients were titrated to a maximum dose over six days, double the three days originally used in some studies. They suggested increments during titration Dose Context (patients) Comment of 0.5-2 mg/day rather than the rigid 2 mg/day increments previously used. 4-6 Practice guidelines American Psychiatric The North American dose-finding s t ~ d y ~ concluded ',~~ A~sociation~~ that positive symptoms of schizophrenia were significantly 5 Recommended by WHO3' Defined daily dose lower after haloperidol or fixed doses of risperidone of 3.8 Prescription data World-wide mean* 3 6 mg/day or higher; this study did not include a 4 mg dose 70-80% D2 receptor Theoretical optimum38 occupancy group. Although negative symptoms were reduced after 6 5.7 1072 schizophrenia, or Pharmacy database' or 16 mg risperidone, the higher dose had significant EPS. schizoaffective disorder The optimum dose of those studied was 6 mg/day. Even at 6 513 chronic Dose finding'6v40.41 the lowest dose used (2 mg/day), 35% of patients schizophrenia responded to risperidone. Higher doses (10 and 16 mg/ 4-8 1362 chronic Do~e-finding~~ day) gave a smaller response than was found at 6 mg. schizophrenia These findings suggested that some of the earlier doses 4.8 202 outpatientshew Comparative study" used in trials may have been unnecessarily high. Similarly inpatients the European dose-finding study concluded that 4 mg had 4.89 18 inpatients Database analysis55 the same response rate (63-66%) as 8 m g / d a ~ ~ ~ responding to therapy A three-year survey of doses used in 1057 inpatients on 5.12 449 inpatients initiated Maryland database risperidone showed a steady reduction over time in the (4.3-5.6) in 1996 review43 mean dose used each year (Table 2).43 *De Nijs, personal communication Much of the early economic work on the drug may therefore overstate the acquisition costs of risperidone and As clinical experience has accumulated, it has become underestimate the overall economic benefit of successful use. Thus the average dose in the Lindstrom study during increasingly clear that the optimal dose range of risperthe first year was approximately 9 mg/day, resulting in an idone is 4-6 mg/day (Table 1). Market research data (de annual acquisition cost of €2081 per patient."*44Although Nijs, personal communication) conclude that the mean even such high costs were offset by savings elsewhere in daily dose prescribed worldwide is 3.8 mg. The practice guidelines of the American Psychiatric A s s ~ c i a t i o n ~ ~the health services, lower doses may have benefited patients more and cost the pharmacy less. The average daily recommend that risperidone is most effective at 4-6 mg/ risperidone dose in the UK (de Nijs, personal communicaday with higher doses leading to EPS without greater tion) is 4.9 mg, which would represent a €920 reduction in effectiveness. The World Health Organization has reduced the acquisition cost reported. its Defined Daily Dose to 5 mg/da~.~' These policy and advice statements are in accord with the recent literature and theoretical predictions. Theoretical arguments have been developed to suggest ways to improve THE INTRODUCTION OF OLANZAPINE on the conclusions on optimal dose derived from clinical trial^.^' To minimize side-effects lower doses than those Olanzapine, a chemical analogue of clozapine, was introduced in 1996 and seems to exhibit a clear dose-response suggested by flexible and fixed dose trials may work for relationship in the treatment of acute exacerbations of most patients. For any given patient the pharmacokinetic chronic ~chizophrenia.~~ Interestingly, when some flexand pharmacodynamic issues specific to that individual will ibility of dose was allowed the olanzapine patients tended affect the optimum dose. In general it is wise to titrate doses slowly to therapeutic effect, avoiding the unnecessary risk of EPS. Table 2 PET studies on receptor occupancy show that a steady Reduction of risperidone dose with experience43 state dose of risperidone of 2.9-5.1 mg/day results in 7080% occupancy of the D2 receptor, a range predicted to be Patients antipsychotic with minimal EPS.3'"9*58 discharged Inpatients Total Total Use of pharmacy databases throws light on current Year ( W h y ) hglday) (mglday) patients risperidone doses. For example Luchins and colleagues' examined 1072 patients with schizophrenia or schizoaffective disorder who were treated with risperidone for at least 6.4 263 1994 5.7 6.8 12 months. They showed that the mean dose in these 4.8 5.8 5.4 345 1995 5.1 449 4.3 5.6 1996 patients was 5.7 mg/day. Contrasting risperidone responders with those who did not respond they found a
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D Lecompte and RF Coohson
to be titrated to the upper end of their dose ~ a n g e . ~ ~ . Table ~' 3 Optimal daily dose of olanzapine (mg/day) Doses found to be useful tend to be significantly higher than the lOmg/day originally recommended (Table 3). Dose Context (patients) Comment Sixty-six per cent of olanzapine patients completed a six-week study and the mean modal doses (the most common doses used) in these patients are shown in Table 4. 13.2 Prescription data World-wide mean* Approximately one-third of patients could not continue 15 7040% Dz receptor Theoretical optimum3' on olanzapine for six weeks, one-third required 5 or 10 mg/ occupancy day and one-third required 15 or 20 mg. 12.65 1336 schizophrenia, or Comparative schizoaffective disorder 6 weeks treatment The use of mean modal doses over such a short time only period is difficult to interpret as these data could underUK inpatients 6r Database analysis" 14.4 220 estimate the need for higher doses over a longer period. outpatients Thus to reach 20 mg/day the patient would need to spend (12.4) (patients treated 6 weeks) titration period would be allocated to lower doses. A recent retrospective study of 15 UK National Health *De Nijs. personal communication Service trusts involving 202 patients on olanzapine found Table 4 that the mean dose used in the first six weeks was 12.4 mg/ Patients discontinued and mean modal doses after 6 weeks treatment for day, but this increased in patients treated for longer than 6 remainder4' weeks to 15.8 mg/day.+' The authors concluded that olanzapine was not wholly effective at low doses, thus Dose (mg/day) Olanzupine requiring higher doses than those routinely recommended or the addition of other antipsychotics. Although there are pharmacological similarities be32% Discontinued tween the newer atypicals such as olanzapine and the more 5 19% established drugs such as risperidone and clozapine,5 10 15% clinicians will need to know whether they provide a 15 13% 20 21% therapeutic advance, at least for some patients. Studies on the effectiveness of olanzapine have shown no evidence of superiority over r i s p e r i d ~ n e . ~ Indeed ' - ~ ~ there may be an advantage for risperidone." Relative doses can be clarified by use of other Most early studies used haloperidol as information sources such as analyses of prescription Given that the clinical differences between atypicals are patterns both locally, within units, and nationally using much less than the differences between them and market research data. As evidence accumulates, doseconventional antipsychotics, a robust definition of any related data enable comparison of clinically equivalent differences, for example between risperidone and olanza- doses (Table 5). pine, would require studies involving many thousands of Although the optimal dose of risperidone is 4-6 mg/ patients. In considering the relative profiles of these two day, the data on olanzapine seem to suggest that an drugs, it is necessary to have a clear understanding of what equivalent dose may be towards the top end of the are comparable doses. Unfortunately the only published recommended range of 5-20 mg/day (Table 3). Receptor double-blind comparison of risperidone and olanzapinez' is occupancy studies suggest that olanzapine 10- 20 mg./day flawed in its design and s t a t i s t i ~ s . ~ ~ - ~ ~ is equivalent to risperidone 2-4 mg/da~.~' Sub group analysis, when there were no differences Comparing the various trials which used haloperidol as detected with the primary measures, was used as a way of a control, it can be seen that the effects of risperidone and claiming differences between the products. The dosing olanzapine 16.4 mg are similar and both are superior to regime for selection of maintenance dose seems biased olanzapine 11.3 mg and olanzapine 13.2 mg (Table 6). against risperidone. The employed rapid titration of risperidone would result in too high a dose being used and the different approach to olanzapine would limit the THE ECONOMIC IMPLICATIONS use of higher doses. This is of concern as early experience with risperidone has shown higher doses may be associated All patients are different, and clinical choice is the with more adverse events and lower efficacy. The nonprerogative of the clinician, who must choose the most equivalence of the dose regimes lead Kasper and Kufferle to appropriate therapy for a specific patient. In this context it question the validity of the is necessary to recognize that inappropriate choice can not A more recent double-blind study rectifies some of these only disadvantage the patient but may disadvantage others faults and suggests some additional benefit for risperidone by denying someone else the resource consumed. This is over olanzapine when clinically relevant doses are used." the rationale for examining the economics of therapies.
Economics of risperidone and olanzapine
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Table 5 Comparable daily doses (mglday) of risperidone and olanzapine Source
Risperidone
Ofanzapine
2-4 7.2 4.8 5.98 5.83 (4.89) 4.7
10-20 17.2 12.5 14.02 19.83 (17.19) 13.2
5.3
15.3
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Receptor occupancy3’ Comparative study2’ Comparative study” Database analysis56 Database analysis55 US Market Research57 (di Nijs, personal communication) Mean of above six estimates
Table 6 Incremental change in Positive and Negitive Syndrome Scale PANSS5’ for risperidone and olanzapine compared to haloperidol internal ~ o n t r o l s ’ ~ * ~ ~ , ~ ~ Risperidone 11.3 mglday Patient numbers PANSS total PANSS positive PANSS negative
1056
- 6.6 - 1.6 - 1.3
83 -2.7 +0.3 -0.6
OIanzapine 13.2 mglday 888 -4.3
-0.9 -1.3
16.
85 -6.7 - 1.7 -1.8
Although the acquisition costs of the atypical antipsychotics seem high, this is because they are set against the background of cheap generic drugs whose prices reflect costs in the 1950s. The 30-year gap between haloperidol and risperidone has seen UK prices rise by a factor of 13. Applying this factor to the acquisition cost of haloperidol would result in a product 30% more expensive than risperidone. Two issues need to be considered: the economic and funding issues of selecting an atypical as opposed to conventional antipsychotics, and the choice between the atypicals available. The economic arguments for the use of atypicals are sufficiently strong to argue that they should now be used in preference to the older t h e r a p i e ~ . ~ . ~The . ~ . ~toxicity ’ of clozapine and the consequent mandatory monitoring and restriction on prescription mean that it should be reserved for second-line therapy.’ Models have been developed and will continue to appear to argue the relative economic merits of risperidone and olanzapine. Given the evidence discussed here, it is important that such models allow appropriate doses to be compared - not necessarily those originally chosen by the manufacturer. Olanzapine has been supported by a model published on the basis that 10 mg/day is the appropriate dose.31This
Comment Theoretical Risperidone titration flawedz4 407 outpatients, low initial PANSS scores 113 inpatients, similar outcomes All patients (Responders) Prescription data Dose ratio 1:3
concludes that at that dose over five years a saving relative to haloperidol of $1539 would be achieved, together with an improvement in patient outcome. Sensitivity analysis examines the impact of the more realistic 15 mg/day and concludes that olanzapine would cost $844 - $1477 more than haloperidol to provide the improved patient outcome. These data should provide some reassurance in selecting olanzapine in preference to haloperidol, even though threemonth data are extrapolated to five years to show an effect. A second model has suggested that the choice of olanzapine over haloperidol is cost-neutral, but with greater benefits for olanzapine treated ~atients.~’ An attempt is made by the authors of the model3’ to apply the same arguments to select olanzapine in favour of risperidone, although the economics depend on which doses of risperidone and olanzapine are chosen. Although the model and conclusions have been ~ r i t i c i z e dsufficient ,~~ details are available to compare 15 mg olanzapine and 6 mg risperidone, not far from what may be the correct doses. The drugs differ by 1%in anticipated patient outcome and risperidone would save $7733 relative to olanzapine. At a funding level, five-year economic benefits may be a desirable objective, but difficult to achieve as additional cash might be required to ‘prime the pump’. It may therefore be helpful to look at the impact of both these agents on pharmacy budgets. At current UK prices,*’ olanzapine 15 mg costs €5.65 per day, more than twice the cost of risperidone 4 mg. If risperidone 5 mg53were to be preferred to olanzapine 15 mg in the UK just for the 7500 new patients with schizophrenia each year, it would save pharmacy €6.6 million in the first year. If clinicians, patients and policy-makers can agree that these new agents should replace conventional agents this would free more hospital facilities for previously undertreated patients, such as those to be found among the homeless.’ Such a process would require additional funds or at least significant reallocation of budgets. The CCOHTA model suggested that the use of risperidone in all hospitalized patients with schizophrenia could save the Canadian health care system $662 million.
D Lecompte and RF Cookson
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Even conservative assumptions' would suggest that in the UK a 6%cost saving would be achieved if patients were switched to risperidone. As schizophrenia costs UK society €2.6 billion each year,54this represents an additional €156 million available each year for patient care. On the basis of the published dose and economic data, risperidone seems to be the first-choice antipsychotic with clozapine and the other atypicals available as second-line treatment. Clinicians and their patients are fortunate at last to have such a choice of active and relatively non-toxic drugs. It is no longer ethically acceptable for most patients to use the older, less efficient drugs. The cost of failure with the older therapies is a continuing slide with the patient deteriorating into a life dominated by relapse and expensive care. The hidden costs of patient suffering and the denial of resources to other patients, now make the availability of new therapy not just an opportunity, but a necessity.
ACKNOWLEDGEMENTS
has been brought to bear on their conclusions by the manufacturer of any of the products mentioned.
KEY POINTS 0
0
0
Clinical experience rather than early clinical trials is the best way to select equivalent doses for comparison of new agents This approach suggests the optimal daily dose for risperidone is 4-6 mg and 15 mg or higher for olanzapine At these doses risperidone is more cost-effective than olanzapine
The writing of this paper was funded by the Janssen Research Foundation. The authors assert that no influence
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