Risperidone

Summary

Abstract

The availability of new atypical antipsychotics, such as risperidone, that have higher acquisition costs than conventional treatments has prompted pharmacoeconomic evaluation of their costs and benefits.

Risperidone is reported to have superior efficacy to haloperidol and similar efficacy to other atypical antipsychotics. At dosages ≤8 mg/day, risperidone is generally associated with a lower risk of extrapyramidal symptoms than conventional antipsychotics and may have a more favourable effect on cognitive function and quality of life.

Overall treatment costs during the first year of risperidone treatment were lower than in the previous year in a number of studies in patients with schizophrenia, reflecting a reduction in hospitalisation, although costs slightly increased after risperidone initiation in 2 studies. Total treatment costs were not significantly different with risperidone or conventional antipsychotics in a large, prospective naturalistic study.

The use of risperidone in preference to conventional antipsychotics in patients with chronic schizophrenia has been supported by several modelled studies, including a cost-effectiveness analysis that compared risperidone and haloperidol in chronic schizophrenia and a cost-utility study that compared the drug with oral haloperidol, depot haloperidol decanoate and depot fluphenazine decanoate for 1 year’s treatment of an initially hospitalised chronic schizophrenic patient with moderate symptoms. In another study, the cost-utility ratio for risperidone versus haloperidol was 24 250 Canadian dollars per quality-adjusted life year (year of costing not stated), but only drug costs were considered. Risperidone had favourable cost-benefit ratios relative to conventional antipsychotic treatment in a study that investigated a scenario in which all patients hospitalised with newly diagnosed schizophrenia received conventional antipsychotic therapy for 6 months, and then those who did not respond received a 6-month trial of risperidone or clozapine.

The results of 2 limited decision-analytical models did not favour risperidone. One study compared risperidone with oral haloperidol or depot haloperidol decanoate for the outpatient treatment of a schizophrenic patient with a history of relapse and rehospitalisation. The other compared risperidone, olanzapine and oral haloperidol for the treatment of schizophrenia.

Conclusions: Despite its high acquisition cost, risperidone does not increase, and may even reduce, overall treatment costs of schizophrenia by reducing hospitalisation compared with standard treatment regimens. While further pharmacoeconomic evaluation of risperidone as a first-line agent is required, pharmacoeconomic data overall support its use in patients with chronic schizophrenia.

Overview of Schizophrenia

Schizophrenia is a psychotic disorder that affects approximately 0.5 to 1% of the population worldwide. It is expensive to treat because the age of onset is relatively young (late teens to mid-30s), the disease is often chronic and highly disabling and there is no cure.

Hospitalisation is the greatest contributor to the direct costs of schizophrenia, whereas drug expenditure generally accounts for only about 1 to 6% of costs in developed countries. Indirect costs arising from loss of productivity can be greater than direct costs. Other costs include those related to social welfare administration and criminal justice, the time spent by unpaid caregivers and the intangible costs associated with suffering.

Although the exact cost of schizophrenia is difficult to determine, it has been calculated to account for 1.6 to 2.5% of total healthcare expenditure in various developed countries.

Clinical Efficacy

Risperidone is effective against both the negative and positive symptoms of schizophrenia. About 50 to 75% of risperidone-treated patients were clinically improved (≥20% improvement in the Positive and Negative Syndrome Scale score) in short term comparative trials. The optimally effective dosage for patients with chronic schizophrenia is 4 to 6 mg/day; patients with first-episode schizophrenia appear to respond to lower dosages.

Risperidone (4 to 8 mg/day or flexible dosages) has been reported to have superior clinical efficacy to haloperidol. In short term comparative trials, the efficacy of risperidone was not significantly different from that of zuclopenthixol, amisulpride, clozapine and olanzapine and was superior to perphenazine on some measures. Risperidone may be more efficacious against negative symptoms (e.g. apathy, flattened affect, social or emotional withdrawal and poverty of speech) than conventional antipsychotics. The drug can be efficacious in patients who are resistant to conventional antipsychotics.

Some aspects of the cognitive impairment associated with schizophrenia are improved by risperidone, and it has a more favourable effect on cognitive functioning than conventional antipsychotics such as haloperidol and fluphenazine.

Tolerability

Risperidone is generally well tolerated. At dosages ≤8 mg/day, risperidone is not associated with a significantly greater incidence or severity of extrapyramidal symptoms (EPS) than placebo. At higher dosages, the risk of EPS is greater. Importantly, risperidone ≤8 mg/day is associated with a lower risk of EPS than haloperidol. The incidence of EPS with risperidone is similar to that with perphenazine and amisulpride, and similar to or greater than that with clozapine. Patients treated with risperidone are less likely to require concomitant antiparkinsonian medications than those receiving haloperidol or zuclopenthixol.

Other adverse events that have been reported during risperidone treatment include insomnia, anxiety, headache, orthostatic hypotension, dizziness, tachycardia, bodyweight gain, somnolence/sedation, sexual dysfunction, nausea/vomiting and hyperprolactinaemia. However, the relationship of many of these events to the drug has not been established. Unlike clozapine, risperidone is not associated with significant haematological toxicity and has a low convulsant potential. The tolerability of risperidone is generally similar to or better than that of haloperidol.

Effect on Quality of Life

Risperidone appears to improve quality of life. Scores on the Global Assessment of Functioning or Quality of Life scale improved after the initiation of risperidone in 2 noncomparative studies involving a total of ≈1500 evaluable patients. Quality of Life scale scores improved with both risperidone and olanzapine in another study, with no significant difference in the mean change in total scores between the drugs. In a small and very limited study, the mean score on the Munich Quality of Life Dimensions List was significantly better in patients receiving risperidone than those receiving conventional antipsychotics. In addition, 2 large studies that have not yet been published in full suggest that initiating treatment with risperidone, rather than conventional antipsychotics, after a relapse produces greater improvement in some aspects of quality of life.

Pharmacoeconomic Analyses

Resource utilisation. A number of studies suggest that, compared with standard care, risperidone reduces hospitalisation rates of patients with schizophrenia or related disorders. The mean annual number of days in hospital per patient was 20 to 74% lower in the year after risperidone initiation compared with that during the year before in analyses in patients who completed study treatment, but more variable results were seen in intent-to-treat analyses. In a large naturalistic study, acute care service use was not significantly reduced in patients randomised to receive risperidone after relapse compared with those randomised to conventional antipsychotics according to an intent-to-treat analysis, but a significant difference in favour of risperidone was seen when only patients who remained in their treatment arm were analysed. Fewer hospital admissions were required by risperidone than haloperidol recipients in a retrospective study. In a comparative study, neither risperidone nor olanzapine significantly reduced hospital use compared with the pre-study period.

Cost analyses. Largely as a result of reduced hospitalisation, overall treatment costs were reported to decrease by up to 25% during the first year of risperidone treatment compared with the year before initiation in a number of ‘mirror-image’ studies. Bearing in mind the limitations of such studies, the estimated savings per patient per year were 7925 Canadian dollars ($Can; 1993 values) and $Can2523 (year of costing not stated) in Canada, up to 2854 pounds sterling (1993/1994 values) in the UK, up to 5639 Irish pounds (1996 values) in Ireland and $US308 to $US2659 (1993 to 1997 values) in the US. However, total costs increased by ≈3% after the initiation of risperidone in the primary analyses of 2 US mirrorimage studies. Total treatment costs were not significantly different between patients treated with risperidone and those treated with conventional antipsychotics in a small retrospective and a large prospective, naturalistic study.

In a decision-analytical model, risperidone was associated with higher total direct treatment costs than oral haloperidol or depot haloperidol decanoate for the outpatient treatment of a schizophrenic patient with a history of relapse and rehospitalisation who was about to be discharged. However, this model assumed that each treatment had an equal probability of producing each clinical outcome; this was disadvantageous for risperidone because the drug’s reported potential for reducing hospital use was not accounted for.

Results were not in favour of risperidone in a Dutch decision-analytical comparison with olanzapine. The latter drug was calculated to produce cost savings of 202 Dutch guilders (NLG; year of costing not stated) compared with risperidone and NLG977 compared with haloperidol. However, sensitivity analysis revealed that the results were not robust and the dosages compared were not stated.

Cost-effectiveness and cost-benefit analyses. While subject to some degree of uncertainty inherent to such analyses, cost-effectiveness and cost-benefit analyses have largely supported the use of risperidone rather than conventional agents in the treatment of chronic schizophrenia.

Risperidone was more cost effective than haloperidol in an Australian decision-analytical model of patients with chronic schizophrenia; the expected cost per favourable outcome over 2 years was 19 709 Australian dollars ($A; 1993 values) with risperidone and $A31 104 with oral haloperidol.

Two cost-utility analyses were applied retrospectively to clinical trial data. In the first, the gain in utility from baseline was 0.125 with risperidone treatment and 0.049 with haloperidol treatment. The cost-utility ratio for risperidone versus haloperidol was $Can24 250 per quality-adjusted life year (QALY); however, only drug costs were considered in this analysis and the year of costing was not stated. In the second analysis, risperidone was found to be the dominant strategy for 1 year’s treatment of an initially hospitalised chronic schizophrenic patient with moderate symptoms. Oral risperidone 6 mg/day had a cost-utility ratio of $Can80 293/QALY (1992 to 1996 values), compared with $Can92 006/QALY, $Can93 319/QALY and $Can99 113/QALY for oral haloperidol 20 mg/day, depot haloperidol decanoate 100mg every 3 weeks and depot fluphenazine decanoate 25mg every 3 weeks, respectively.

The health services benefit to cost ratio was 1.32 : 1 for risperidone and 1.87 : 1 for clozapine, and the societal benefit to cost ratios were 1.48 : 1 and 2.04 : 1, respectively, in an Israeli analysis. The modelled scenario was that all hospitalised patients with new-onset schizophrenia would initially receive conventional antipsychotic therapy for 6 months, and the 35% who did not respond would receive a 6-month trial of risperidone or clozapine. It was assumed that hospital use would be reduced by 30% as a result of risperidone or clozapine treatment. For risperidone to produce the same or better benefit to cost ratio as clozapine, it would need to reduce hospital use to a greater extent than clozapine.