Risperidone versus other atypical antipsychotic medication for schizophrenia (Review)

Transcription

1 Risperidone versus other atypical antipsychotic medication for schizophrenia (Review) Gilbody S, Bagnall AM, Duggan L, Tuunainen A This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 3

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 1 Death Analysis 1.2. Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 2 Leaving the study early Analysis 1.3. Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 3 Service use: Not discharged from hospital Analysis 1.4. Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 4 Global impression: 1. CGI endpoint score (short term) Analysis 1.5. Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 5 Global impression: 2. GAF score (short term) Analysis 1.6. Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 6 Mental state: 1. Clinically not improved (<20% decrease in PANSS) Analysis 1.7. Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 7 Mental state: 2. PANSS endpoint score (high=poor) Analysis 1.8. Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 8 Mental state: 3. Positive symptom score (PANSS, BPRS subscale endpoint score, high=poor) Analysis 1.9. Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 9 Mental state: 4. Negative symptom scores (PANSS, BPRS subscale endpoint score, high=poor) Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 10 Mental state: 5. SFS total endpoint score (high=poor) Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 11 Mental state: 6. DAI total endpoint score (high=poor) Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 12 Cognitive functioning: 1. Concentration difficulties Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 13 Cognitive functioning: 2. Memory problems Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 14 Side effects: 1. Arousal Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 15 Side effects: 2. Cardiovascular - dizziness (orthostatic) Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 16 Side effects: 3. Gastrointestinal - nausea/ vomiting Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 17 Side effects: 4. Haematological problems - important drop in white cell count Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 18 Side effects: 5. Libido - decrease.. 39 Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 19 Side effects: 6. Movement disorders. 40 Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 20 Side effects: 7. Weight gain Analysis Comparison 1 RISPERIDONE versus CLOZAPINE, Outcome 21 Quality of life: Not feeling even a little better (PGI) Analysis 2.1. Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 1 Leaving the study early - any reason. 42 i

3 Analysis 2.2. Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 2 Global Impressiion: CGI endpoint score (high=poor) - medium term (18-28 weeks) Analysis 2.3. Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 3 Mental state: 1. No important clinical response (<40% reduction in PANSS) - medium term (18-28 weeks) Analysis 2.5. Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 5 Mental state: 3. PANSS endpoint score (high=poor) Analysis 2.6. Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 6 Mental state: 4. PANSS Positive subscale endpoint score (high=poor) Analysis 2.8. Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 8 Mental state: 6. PANSS negative subscale endpoint score Analysis Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 10 Side-effects: 1. Movement disorders. 47 Analysis Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 12 Side effects: 3. Weight gain Analysis Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 13 Quality of life: Endpoint scale scores - medium term (18-28 weeks) Analysis 3.1. Comparison 3 RISPERIDONE versus AMISULPRIDE, Outcome 1 Leaving the study early - any reason. 49 Analysis 3.2. Comparison 3 RISPERIDONE versus AMISULPRIDE, Outcome 2 Mental state: 1. BPRS total endpoint scores Analysis 3.3. Comparison 3 RISPERIDONE versus AMISULPRIDE, Outcome 3 Mental state: 2. PANSS Positive subscale endpoint scores Analysis 3.4. Comparison 3 RISPERIDONE versus AMISULPRIDE, Outcome 4 Mental state: 3. PANSS Negative subscale endpoint scores Analysis 3.5. Comparison 3 RISPERIDONE versus AMISULPRIDE, Outcome 5 Side-effects: 1. Endocrine symptoms (at least one) Analysis 3.6. Comparison 3 RISPERIDONE versus AMISULPRIDE, Outcome 6 Side-effects: 2. Gastrointestinal symptoms Analysis 3.7. Comparison 3 RISPERIDONE versus AMISULPRIDE, Outcome 7 Side-effects: 3. Movement disorders. 53 Analysis 3.8. Comparison 3 RISPERIDONE versus AMISULPRIDE, Outcome 8 Side-effects: 4. Psychiatric symptoms. 54 Analysis 3.9. Comparison 3 RISPERIDONE versus AMISULPRIDE, Outcome 9 Side-effects: 5. Weight gain FEEDBACK WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT NOTES INDEX TERMS ii

4 [Intervention Review] Risperidone versus other atypical antipsychotic medication for schizophrenia Simon Gilbody 1, Anne-Marie Bagnall 2, Lorna Duggan 3, Arja Tuunainen 4 1 Department of Health Sciences, University of York, York, UK. 2 Faculty of Health, Leeds Metropolitan University, Leeds, UK. 3 Care Principles Ltd, Newmarket, UK. 4 Department of Psychiatry, University of Helsinki, Hus, Finland Contact address: Simon Gilbody, Department of Health Sciences, University of York, Seebohm Rowntree Building, York, YO10 5DD, UK. sg519@york.ac.uk. Editorial group: Cochrane Schizophrenia Group. Publication status and date: Edited (no change to conclusions), published in Issue 3, Review content assessed as up-to-date: 23 May Citation: Gilbody S, Bagnall AM, Duggan L, Tuunainen A. Risperidone versus other atypical antipsychotic medication for schizophrenia. Cochrane Database of Systematic Reviews 2000, Issue 3. Art. No.: CD DOI: / CD Background A B S T R A C T Risperidone is one of a number of atypical antipsychotics which are currently being marketed for the treatment of those with schizophrenia, largely on the basis of claims of improved tolerability and effectiveness compared to much cheaper conventional antipsychotics. The efficacy of risperidone has already been compared to conventional drugs, but it remains unclear how risperidone compares with other atypical antipsychotic drugs such as clozapine. Objectives To determine the effects of risperidone compared with other atypical antipsychotic drugs for schizophrenia. Search methods Electronic searches of Biological Abstracts ( ), The Cochrane Library (Issue 1, 2000), The Cochrane Schizophrenia Group s Register (January 1999), EMBASE ( ), MEDLINE ( ), LILACS ( ), PSYNDEX ( ) and PsycLIT ( ) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. Pharmaceutical companies and authors of trials were contacted. Selection criteria All randomised controlled clinical trials that compared risperidone to other atypical antipsychotic treatments for schizophrenia and schizophrenia-like psychoses were included by independent assessment. Data collection and analysis Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, standardised and weighted mean differences were calculated (SMD, WMD). All data were inspected for heterogeneity. 1

5 Main results Nine studies were obtained, comparing risperidone with clozapine (five studies - largely amongst treatment resistant patients); olanzapine (three studies); and amisulpiride (one study). The research was beset by problems of high attrition rates and short term follow up. Clozapine does seem equally acceptable to risperidone in the short term (leaving the study early, n=466, RR 1.00 CI ). For most other outcomes wide confidence intervals were obtained, which meant that it was impossible to judge whether the two compounds were equally effective, or whether one was in fact superior to the other. Olanzapine and risperidone seem broadly similar according to numbers of patients responding to treatment (40% reduction in PANSS scores: n=339, RR 1.14, CI ). Olanzapine caused fewer people to leave the study early (n=404, RR 1.31 CI ; NNT 8 CI 4-32) and fewer extrapyramidal side effects (n=339, RR 1.67 CI ; NNH 8 CI 5-33), although comparative doses of risperidone were higher than those recommended in practice. In one single study (n=228) amisulpiride seemed broadly similar to risperidone in most respects. There were no useful data presented relating to service use and costs. Very few data relating to quality of life were presented. Authors conclusions The equivalence of clozapine and risperidone for treatment resistant schizophrenia cannot yet be assumed and there seems to be little to chose between risperidone and both olanzapine and amisulpiride. The research is limited in many respects, and longer term studies measuring clinically important outcomes, including service use and quality of life are needed to judge the comparative value of the various atypical drugs. P L A I N L A N G U A G E S U M M A R Y Risperidone versus other atypical antipsychotic medication for schizophrenia Synopsis pending. B A C K G R O U N D Drug treatments form the mainstay of treatment for those with schizophrenia, and conventional antipsychotic drugs, such as haloperidol and chlorpromazine, are frequently used as the first line treatment (Kane 1990, Kane 1993). However, about 5-25% of these people show poor response to conventional treatments (Davis 1977, Christison 1991, Meltzer 1992). In addition, side effects such as the movement disorders (that is, distressing restlessness, stiffness, potentially disfiguring repetitive movements of the mouth and face) and sedation often make compliance with the older generation of drug treatments problematic (Kane 1990). The efficacy of these medications with respect to positive symptoms, such as fixed, false beliefs (delusions) and perceptions with no cause (hallucinations) is well described. It has been suggested, however, that conventional antipsychotic treatment has less effect on the negative symptoms of schizophrenia, that is symptoms such as poverty of speech, lack of motivation and apathy, and impoverished ability to express emotion (Crow 1980, Andreasen 1985). Risperidone is one of the new generation antipsychotic compounds introduced in recent years. These compounds are claimed to offer significant advances over older conventional drugs in terms of their side effects, tolerability and (in some cases) ability to treat negative symptoms and those positive symptoms which fail to respond to conventional drugs (i.e. efficacy in treatment resistant schizophrenia ). These drugs have also been labelled atypical in that they do not induce catalepsy in laboratory animals. Examples of atypical antipsychotics include clozapine, olanzapine, sertindole, zotepine and amisulpiride. Claims are made that these drugs should now form the first line treatment for schizophrenia or should be introduced at the first opportunity, once side effects with conventional drugs are experienced. One atypical drug, clozapine, is useful for treatment resistant schizophrenia, but is associated with a potentially fatal blood disorder in 1% of cases (see Wahlbeck 2000 in this library for review), and has more recently 2

6 been associated with fatal cardiomyopathies and sudden cardiac death (Kilian 1999). Technical background Risperidone has a well-described mechanism of action in the brain (a high ratio of serotonin to D2 receptor blockade) (Gupta 1994, Curtis 1995), and was first made available for the care of those with schizophrenia in Since then clinical trials have been conducted to evaluate its efficacy and safety (e.g. He 1995, Chouinard 1993). As well as its reputed tendency to cause fewer movement disorders it is claimed that risperidone may improve negative symptoms (Livingston 1994, Edwards 1994). Unlike many antipsychotic drugs, both conventional and atypical, risperidone does not bind to the sites in the brain (cholinergic/muscarinic receptors) that cause the dry mouth, blurred vision, constipation and urinary retention commonly seen with the conventional class of drugs (Edwards 1994, He 1995, Keltner 1995). It is also claimed that risperidone may reduce the decline in memory, attention and concentration associated with schizophrenia which conventional neuroleptics fail to reverse or prevent (Meltzer 1992, Stip 1996). Side effects commonly associated with risperidone include anxiety, agitation, insomnia, headache, movement disorders and weight gain (Remington 1993, Janssen-Cilag 1996, Kennedy 1999). Atypical antipsychotics are currently being heavily marketed by the pharmaceutical industry on the basis of their purported advantage over conventional drugs and benefits for treatment resistant schizophrenia. They are however more expensive than conventional drugs (Wood Mackenzie 1998), but it has been suggested that if they do indeed reduce a person s need for inpatient services their use would result in a net reduction of costs (Buckley 1997, Glazer 1997) - thus proving to be clinically and cost effective. Risperidone is a relatively expensive neuroleptic, being around ten times the cost of conventional antipsychotics, but is similar in cost to other atypical anti-psychotics. Clozapine, due to the necessity of blood monitoring, remains the most expensive antipsychotic in most health care systems. Risperidone has been compared to older typical antipsychotics in a separate Cochrane review (Kennedy 1999) but not to other new atypical antipsychotics. The purpose of this review is to compare the clinical and cost effectiveness of risperidone to that of other atypical antipsychotics. O B J E C T I V E S 1. whether people with schizophrenia described as treatment resistant differed in their response from those whose illness was not designated as such; 2. whether people having predominantly positive or negative symptoms of schizophrenia were more responsive to risperidone than those without this designation; and 3. whether people experiencing their first episode of schizophrenia differed in their response from those at a later stage of their illness. M E T H O D S Criteria for considering studies for this review Types of studies All relevant randomised controlled trials (quasi-randomised studies were excluded). Types of participants People with the diagnosis of schizophrenia and related psychoses (schizophreniform-, delusional- and schizoaffective disorder), however diagnosed, were included. If possible, children, people with dementing illnesses, depression and primary problems associated with substance misuse were excluded. Types of interventions 1. Risperidone, any dose 2. Any other atypical antipsychotic: amisulpiride, clozapine, olanzapine, quetiapine, sertindole, ziprasidone, zotepine. Types of outcome measures All outcomes were reported for the short term (up to six weeks), medium term (7-28 weeks) and longer term (more than 28 weeks). Primary Objective 1. To determine the clinical effects, safety and cost effectiveness of risperidone compared with other atypical antipsychotics, for treating schizophrenia. As secondary objectives, it was proposed to investigate: Primary outcomes 1. Clinical response: 1.1 clinically significant response in global state - as defined by each of the studies 3

7 Secondary outcomes 1. Death - suicide or natural causes. 2. Leaving the study early. 3. Clinical response: 3.1 average score/change in global state; 3.2 clinically significant response in mental state - as defined by each of the studies; 3.3 average score/change in mental state; 3.4 clinically significant response on positive symptoms - as defined by each of the studies; 3.5 average score/change in positive symptoms; 3.6 clinically significant response on negative symptoms- as defined by each of the studies; 3.7 average score/change in negative symptoms. 4. Extrapyramidal side effects: 4.1 incidence of use of antiparkinsonian drugs; 4.2 clinically significant extrapyramidal side effects- as defined by each of the studies; 4.3 average score/change in extrapyramidal side effects. 5. Other adverse effects, general and specific. 6. Service utilisation outcomes: 6.1 hospital admission; 6.2 days in hospital; 6.3 change in hospital status. 7. Economic outcomes. 8. Quality of life/satisfaction with care for either recipients or carers measured by directly asking participants: 8.1 significant change as defined by each of the studies; 8.2 average score/change in quality of life/ satisfaction. Search methods for identification of studies Electronic searches 1. Biological Abstracts (January February 1999) was searched using the Cochrane Schizophrenia Group s phrase for both randomised controlled trials and schizophrenia (see Group search strategy) combined with the phrase: [and (risperidone or R or risperdal or rispolin or belivon or risperin)] 2. The Cochrane Library (Issue 1, 2000) was searched using the phrase: [risperidone or R or risperdal or rispolin or belivon or risperin] 3. The Cochrane Schizophrenia Group s Register (January 1999) was searched using the phrase: [risperidone or R or risperdal or rispolin or belivon or risperin or #42=142] (#42 is the field within this register that contains the intervention code and 142 is risperidone.) 4. EMBASE (January February 1999) was searched using the Cochrane Schizophrenia Group s phrase for both randomised controlled trials and schizophrenia (see Group search strategy) combined with the phrase: [and risperidone or R or risperdal or rispolin or belivon or risperin or explode RISPERIDONE / all subheadings)] 5. MEDLINE (January February 1999) was searched using the Cochrane Schizophrenia Group s phrase for both randomised controlled trials and schizophrenia (see Group search strategy) combined with the phrase: [and risperidone or R or risperdal or rispolin or belivon or risperin] 6. PsycLIT (January February 1999) was searched using the Cochrane Schizophrenia Group s phrase for both randomised controlled trials and schizophrenia (see Group search strategy) combined with the phrase: [and (risperidone or R or risperdal or rispolin or belivon or risperin)] 7. LILACS (January February 1999) was searched using the Cochrane Schizophrenia Group s phrase for both randomised controlled trials and schizophrenia (see Group search strategy) combined with the phrase: [and (risperidone or R or risperdal or rispolin or belivon or risperin)] 8. PSYNDEX (January February 1999) was searched using the Cochrane Schizophrenia Group s phrase for both randomised controlled trials and schizophrenia (see Group search strategy) combined with the phrase: [and (risperidone or R or risperdal or rispolin or belivon or risperin)] 9. CINAHL ( ) was searched using the following phrase: [(explode Psychotic-Disorders / all topical subheadings / all age subheadings or schizo* or schizo* in ti,ab or psychoti* or psychoti* in ti,ab or psychosis or psychosis in ti,ab or psychoses or psychoses in ti,ab or ((chronic* or sever*) with mental* with (ill or illness* or disorder*))) and (risperidone or R or risperdal or rispolin or belivon or risperin)] 10. Specific searches for trials of risperidone were undertaken in the following data services, and using the following search strategy: ((schizo$ or psychotic$ or psychoses or psychosis or ((chronic$ or sever$) near2 mental$ near2 (ill$ or disorder$)) and (trial$ or random$ or (singl$ or doubl$ or trebl$ or tripl$) near (blind$ or mask$) or ((placebo or standard) adj treatment) or study or studies or rct$ or crossover$ or control or controlled or controls) and (risperidone or R or risperdal or rispolin or belivon or risperin) 10.1 Datastar service (February 1999) Pharmaceutical databases available within this system: ADIS Inpharma (indexes 2000 international medical & biomedical journals); ADIS LMS drug alerts (indexes 2,300 international medical & 4

8 biomedical journals ); IDIS Drug File (indexes 140 English language medical journals); PharmLine (indexes 100 journals in drugs and professional pharmacy ); Pharma Marketing Service (indexes 200 international journals and other non-journal publications) Dialog service Pharmaceutical databases available within this system: CAB Health (international coverage of health journal and nonjournal material); Conference Papers Index; Derwent Drug File; Dissertation Abstracts; Extramed; Federal Research in Progress (US federally funded research); International Pharmaceutical Abstracts (indexes 800 pharmaceutical and medical journals); JICST-EPLus (Japanese Science and Technology); Mental Health Abstracts; NTIS (national Technical Information Service); Pascal; Pharmaprojects; USP-DI - Drug information for the health care professional. Searching other resources 1. Citation searches were carried out on first authors of all identified RCTs. 2. Reference lists All references of articles selected were searched for further relevant trials. 3. Authors of studies The reviewers contacted authors of studies when necessary to clarify data, and asked for additional studies. 4. Pharmaceutical company The reviewers contacted Janssen-Cilag Pharmaceuticals and Eli- Lilly to obtain data on unpublished trials. Data collection and analysis 1. Selection of trials The inspection of the citations identified in the search outlined above was performed independently by SG and AMB - who were not blinded in any way regarding any trial details. Potentially relevant abstracts were identified and full papers ordered and reassessed for inclusion and methodological quality. Any disagreement was discussed and resolved. 2. Assessment of quality Trials were allocated to three quality categories, as described in the Cochrane Collaboration Handbook (Mulrow 1999) by each reviewer, again, working independently. When disputes arose as to which category a trial was allocated, again, resolution was attempted by discussion. When this was not possible, and further information was necessary, data were not entered into the analyses and the study was allocated to the list of those awaiting assessment. Only trials in Category A or B were included in the review. 3. Data management 3.1 Data extraction This was performed independently by reviewers (AMB, SMG, LD & AT) and, where further clarification was needed the authors of trials were (where possible) contacted to provide missing data. 3.2 Intention to treat analysis In studies with less than 50% dropout rate, people leaving early were considered to have had the negative outcome, except for the event of death. The impact of including studies with high attrition rates (25-50%) was analysed in a sensitivity analysis. If inclusion of data from this latter group did result in a substantive change in the estimate of effect their data were not added to trials with less attrition, but presented separately. Data were excluded from studies where more than 50% of participants in any group were lost to follow up, but were included in a sensitivity analysis. 4. Data analysis 4.1 Binary data For binary outcomes a standard estimation of the risk ratio (RR) and its 95% confidence interval (CI) was calculated. The number needed to treat statistic (NNT) was also calculated for significant results. If heterogeneity was found (see section 5), sources of potential heterogeneity were sought. For unexplained heterogeneity, statistical pooling was not attempted. 4.2 Continuous data Skewed data: continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non-parametric data the following standards are applied to all data before inclusion: (i) standard deviations and means were reported in the paper or were obtainable from the authors; (ii) when a scale starts from a finite number (such as zero), the standard deviation, when multiplied by two, was less than the mean (as otherwise the mean was unlikely to be an appropriate measure of the centre of the distribution) (Altman 1996) Endpoint versus change data: unfortunately, change data are often distributed around zero and the tests of normality outlined above cannot be applied. We therefore used endpoint data only. Subsequent versions of this review will endeavour to seek endpoint data from authors, where only change data are currently reported. Unfortunately, at this stage, the inability to check for normality amongst change data may mean that potentially useful information cannot be included Summary statistic: for continuous outcomes a weighted mean difference (WMD) between groups was estimated where there was a common metric and a standardised mean difference (SMD) was estimated where different scales were employed to measure the same construct. 5

9 4.2.4 Valid scales: continuous data from rating scales were included only if the measuring instrument had been described in a peerreviewed journal. Data obtained by self report or completed by an independent rater or relative were judged to be more valid than data obtained from clinicians who were also responsible for the care of the patient. Where it was clear that clinician rated outcomes were employed, then this was highlighted in the body of the review. 5. Test for heterogeneity A Chi-square test was used, as well as visual inspection of graphs, to investigate the possibility of heterogeneity. A significance level less than 0.10 was interpreted as evidence of heterogeneity. If this was found, the data were reanalysed using a random effects model to see if this made a substantial difference. If it did, the studies responsible for the heterogeneity were summated and presented separately, and possible reasons for the heterogeneity were explored. 6. Addressing publication bias Data from all included studies were entered into a funnel graph (trial effect against trial size or precision) in an attempt to investigate the likelihood of overt publication bias (Egger 1997). However, this form of sensitivity analysis is only possible when there are a sufficient number of individual studies and a range of sample sizes. In cases where funnel plots could not be constructed, then the possibility of publication bias cannot be explored in any detail. 7. Sensitivity analyses The effect of including studies with high attrition rates was analysed in a sensitivity analysis. It also was hoped to investigate whether there were differences between: 7.1 people with schizophrenia described as treatment resistant and those whose illness was not designated as such; 7.2 people having predominantly positive or negative symptoms of schizophrenia and those without this designation; and 7.3 people experiencing their first episode of schizophrenia and those at a later stage of their illness. 8. General Where possible, reviewers entered data in such a way that the area to the left of the line of no effect indicated a favourable outcome for risperidone. R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies. For substantive descriptions of studies please see Included and Excluded Studies tables. 1. Excluded studies We excluded nine studies, eight of which were non-randomised or crossover studies. One study (Conley 1999) was withdrawn by the manufacturers of risperidone. 2. Awaiting assessment These reports are mostly conference abstracts that do not report their data in sufficient detail to include, or are preliminary reports. 3. Ongoing studies Naber 1997 and Hagger 1997 report ongoing studies with risperidone. 4. Included studies We identified nine studies for inclusion in this review. All were randomised and, with the exception of Clozapine 2000, all were double blind. 4.1 Length of trials Schizophrenia is a lifelong illness. Five studies, however, were less than ten weeks in duration, with two longer term studies of olanzapine (Olanzapine six months; Olanzapine 1998a - one year) 4.2 Participants All participants met operationalised diagnoses of schizophrenia by Diagnostic Statistical Manual (American Psychiatric Association) criteria, with more males being randomised. Most studies were on patients with chronic (long term) schizophrenia, however three explicitly included patient with treatment resistant schizophrenia (Clozapine 1998a, Clozapine 1998b, Clozapine 2000). Treatment-resistant schizophrenia was defined as follows: Clozapine 1998a - failure to respond to or intolerance of more than two classes of antipsychotics in appropriate doses for >4 weeks. Clozapine 1998b - severe chronic disease and poor response to previous antipsychotics (no period of good functioning for at least 24 months despite the use of two antipsychotics. Current episode without significant improvement for at least six months despite the use of an antipsychotic equivalent to haloperidol 20mg for at least six months (total BPRS>45, CGI>4). Clozapine failure to respond to >2 classes of antipsychotics (equivalent to 1000mg chlorpromazine), plus a six-week trial of haloperidol for those not treated with this compound in the past. 4.3 Setting Trials took place in a mixture of inpatient and outpatient settings, although setting was often not explicitly stated. 4.4 Study size Studies ranged from 21 (Clozapine 2000) to 339 (Olanzapine 1997), with a median of 86 people. 4.5 Interventions Patients received doses of risperidone in various doses either fixed (Clozapine 1998a - 6mg, Clozapine and 8mg) or flexible doses determined by physician (Clozapine 2000, Olanzapine 1997, Olanzapine 1998a). The comparators were amisulpiride, remoxipride, zotepine, clozapine and olanzapine, although insufficient data were presented to allow comparisons relating to remoxipride and zotepine. 4.6 Outcomes (Dichotomous) Improvement was most often defined by experimenters as 20% reduction in BPRS or PANSS scores (see below for details of these 6

10 scales), although these data were often not useable due to inadequate reporting of data (unclear/imprecise graphical representations of these changes) Adverse effects Experience of individual adverse effects was reported for several trials and was available for pooling. Leaving the study early due to adverse events were also specified in Amisulp 1997 and Clozapine Adverse effects were also recorded using continuous scales, which are outlined below Outcomes - scales Global state - Clinical Global Impression Scale - CGI Scale (Guy 1976). This is used to assess both severity of illness and clinical improvement, by comparing the conditions of the person standardised against other people with the same diagnosis. A seven-point scoring system is usually used with low scores showing decreased severity and/or overall improvement Mental state Brief Psychiatric Rating Scale - BPRS (Overall 1962). This is used to assess the severity of abnormal mental state. The original scale has 16 items, but a revised 18-item scale is commonly used. Each item is defined on a seven-point scale varying from not present to extremely severe, scoring from 0-6 or 1-7. Scores can range from 0-126, with high scores indicating more severe symptoms. Positive and negative syndrome scale - PANSS (Kay 1986). This schizophrenia scale has 30 items, each of which can be defined on a seven-point scoring system varying from one - absent to seven - extreme. This scale can be divided into three subscales for measuring the severity of general psychopathology, positive symptoms (PANSS-P), and negative symptoms (PANSS-N). A low score indicates lesser severity. Scale for the Assessment of Negative Symptoms - SANS ( Andreasen 1982). This six-point scale gives a global rating of the following negative symptoms; alogia, affective blunting, avolition-apathy, anhedoniaasociality and attention impairment. Higher scores indicate more symptoms Adverse effects: extrapyramidal Abnormal Involuntary Movement Scale - AIMS (Guy 1976) This has been used to assess tardive dyskinesia, a long-term, druginduced movement disorder. The AIMS can be used to assess some short-term movement disorders such as tremor. Simpson Angus Scale (Simpson 1970) This ten-item scale, with a scoring system of 0-4 for each item, measures drug-induced parkinsonism, a short-term drug-induced movement disorder. A low score indicates low levels of parkinsonism Quality of life Quality of Life Interview (Lehman 1983) This standardised assessment includes areas such as living situation, leisure activities, relationships and finances. Rated on a sevenpoint scale, with higher scores indicating a better quality of life. Quality of Life Scale (QLS, Carpenter 1984) This semi-structured interview is administered and rated by trained clinicians. It contains 21 items rated on a seven-point scale based on the interviewers judgement of patient functioning. A total QLS and four sub-scale scores are calculated, with higher scores indicating less impairment Missing outcomes Hospital admission data are absent. No useful data about daily functioning, such as employed or trouble with the police, or satisfaction with care, or costs were reported. No study reassured the reader as regards mortality. Risk of bias in included studies 1. Randomisation Only one study (Clozapine 2000) reported adequate randomisation and concealment of allocation. Eli Lilly provided unpublished methodological data relating to olanzapine studies, each of which had adequate concealment of allocation. The remaining studies reported that they were randomised but fell into quality category B. For these studies, it was not clear exactly how randomisation had occurred and the reader was not assured that biases could not have been introduced. Studies have shown that poor reporting of randomisation increases the odds of presenting significant outcomes (Schulz 1995; Chalmers 1983). 2. Blinding to interventions and outcomes One trial (Clozapine 1998a) clearly described adequate precautions for blinding of treatment, and another eschewed double blind conditions due to a pragmatic design, but clearly described blinded assessment of outcome (Clozapine 2000). The remainder were described as double blind but no further details were given and blindness does not seem to have been tested. 3. Follow-up The numbers leaving the study early were high, albeit comparable to trials of other atypical antipsychotics (Fabre 1995, Thornley 1998). They ranged from 0% (Clozapine 1999) to 55% (Olanzapine 1998a, Olanzapine 1998b). Most studies stated that they analysed their data on an intentionto-treat basis using the last observation carried forward and this practice may well overestimate any treatment effect. Once participants leave a study, unless the trialists continue to follow and collect data, assumptions have to be made about outcome. In this review those leaving the studies early were classified as a bad outcome and analysed accordingly (except for the outcome of death). Only one study (Clozapine 2000) actually conducted this form of analysis within their published report. Whatever the management of lost data, interpretation of results with large degrees of attrition must be undertaken with caution. 7

11 Effects of interventions The studies included in this review generally compare risperidone with two important drugs - olanzapine and clozapine. The two drugs are known to show dissimilar side effect profiles (see Tuunainen 2000 and Duggan 2000 in this library) and the clinical indications for their routine use are essentially different. Clozapine is generally restricted to those with treatment resistant schizophrenia, and olanzapine is widely advocated as a first line drug therapy or acceptable alternative to conventional drugs. For these reasons, we decided to make separate comparisons between risperidone and either olanzapine or clozapine. These are outlined below. Further versions of this review will also include comparisons of risperidone with all other atypical drugs (other than clozapine) as a group - in line with emerging evidence. A single study comparing risperidone and amisulpiride is also reported separately. 1. RISPERIDONE versus CLOZAPINE All studies were twelve weeks and under in duration and are combined together. 1.1 Death Two studies (n=50) explicitly reported that no deaths had occurred in either treatment group. 1.2 Leaving the study early For the four studies which compared risperidone with clozapine, there was no significant difference in terms of the numbers of patients leaving the study early (n=466, RR 1.00 CI ) 1.3 Service use Only Clozapine 2000 reported any aspect of service use, by describing which patients were able to leave hospital, although the study was insufficiently powered to give precise estimates of this outcome (n=19, relative risk of not leaving hospital 0.56 CI ) 1.4 Clinical response There were no significant differences demonstrated between either compound for most of the reported endpoints of clinical response. However, wide confidence intervals (due to small sample size) and insufficient data prevent any assumptions of the clinical equivalence of these two compounds being made. The specific endpoints relating to clinical response which were reported and were suitable for analysis are outlined below. Trialists generally report mental state as change and endpoint scores on the PANSS and BPRS, and dichotomised this into a 20% reduction from baseline. Where clinical response is operationally defined as a 20% reduction in PANSS endpoint score, at six weeks, there is no between group difference shown in this respect (n=134, RR 0.99 CI ). Total PANSS endpoint scores are non-significantly different (n= 134, WMD 2.0 CI ) at six weeks, and those studies that present sufficient data to allow positive and negative subscales to be pooled separately are also non-significant (PANSS positive scale, n=134, WMD CI ; PANSS and BPRS negative sub scale n =1 34, SMD CI ). Wide confidence intervals do not allow the equivalence of the two compounds nor the superiority of either compound to be assumed for these outcomes. Global scores as measured by the CGI scale show no between group differences (n=105 WMD 0.00 CI ) A non-significant trend in favour of risperidone was found for measures of cognitive functioning (concentration difficulties (n= 86, RR 6.64 CI ). 1.5 Adverse effects Extrapyramidal side effects There were no significant differences between the two compounds in terms of either the numbers of patients who reported either movement disorders (N=86, RR 1.00 CI ) or received antiparkinsonian medication (n=19, RR 2.22 CI ) in the short term. Wide confidence intervals do not allow the equivalence of the two compounds nor the superiority of either compound to be assumed for these outcomes Other side effects There was a non-significant trend for risperidone to cause less weight gain than clozapine (n=43, RR CI ), and to cause less drowsiness (n=86, RR 0.65 CI ). Other side effects were either not reported in sufficient detail, or presented such wide confidence intervals to preclude interpretation. 1.6 No economic data were reported. 1.7 Quality of life Quality of life was not generally examined in the included studies, although Clozapine 2000 asked a simple question of patients by inquiring if they felt a little better. There were no significant differences in this respect, although the study was not sufficiently powered to answer this question (n=19, RR 1.11 CI ). 1.8 Subgroup and sensitivity analyses Excluding high attrition studies Two studies (Clozapine 1998b, Clozapine 2000) reported high attrition rates. The exclusion of these studies prevented several outcomes from being estimated with any level of statistical power. Hence, the following results were based upon studies with high attrition rates and should be interpreted with caution: received antiparkinson medication and quality of life Treatment resistant people Most of the data presented above relate to treatment resistant patients (Clozapine 1998a, Clozapine 1998b, Clozapine 2000), and exclusion of non-treatment resistant patients does not materially alter the results Patients with negative or first episode schizophrenia. No studies present these data or focus exclusively on these populations. 2. RISPERIDONE VERSUS OLANZAPINE Outcomes for the three studies which compared these two drugs are presented below. Studies are either medium term (Olanzapine 1997; Olanzapine 1998b) or longer term (Olanzapine 1998a), and all show high levels of attrition (47% to 55%), and should therefore be interpreted with caution. 2.1 Death 8

12 No trials report mortality data. 2.2 Leaving the study early Medium term Olanzapine seemed more acceptable than risperidone when numbers of patients leaving the study early due to any reason were compared (n=404, pooled relative risk 1.31 CI ; NNT= 8 CI 4-32) Long term There was a non-significant trend for an increased acceptability of olanzapine in the longer term when all patient discontinuations were considered (RR 1.56 CI ). 2.3 Clinical response When clinical response was dichotomised into a 40% reduction in PANSS score for one medium term study (Olanzapine 1997), there was a benefit for olanzapine, which was of borderline significance (n=339, RR 1.14 CI ). Of the several comparisons made using continuous parameters, there was only one important significant difference demonstrated between the two compounds - total endpoint scores on the PANSS. There was a statistically significant benefit for olanzapine amongst medium term studies of 7.5 points (n=392, CI ) on this 210 point scale. This difference was not replicated in the longer term study (Olanzapine 1998a; n=42, WMD -1.9 CI ), nor were there any significant differences noted in positive and negative subscale PANSS scores in either the medium term (positive PANSS n=62, WMD 0.1 CI ; negative PANSS n=392, WMD 0.8 CI ); or in the longer term (positive PANSS n=42, WMD 0.6 CI ; negative PANSS n=42, WMD 0.2 CI ). Global sores were essentially similar for both compounds, indicating that there was little difference between risperidone and olanzapine with respect to this outcome (n=394, WMD 0.03 CI= ). BPRS scores, when recorded, were skewed and were not entered into RevMan. 2.4 Adverse effects Extrapyramidal side effects Those taking olanzapine reported fewer extrapyramidal side effects in the medium term (n=339, RR=1.67 CI ; NNH 8 CI 5-33), reported fewer new episodes of Parkinsonism (n=339, RR 1.73 CI ), and received less antiparkinsonian medication (n=339, RR 1.67 CI ; NNH 8 CI 5-25). All these results are based on evidence from one trial only (Olanzapine 1997) Other side effects There was a non-significant trend for risperidone to cause less weight gain than olanzapine in both the medium term (n=395, WMD -2.96Kg CI -6.4Kg to 0.7Kg), and longer term (n=44, WMD -10.1Kg CI -20.9Kg to 0.7Kg). 2.5 Service use No studies reported service use 2.6 No economic data were reported. 2.7 Quality of life Quality of life was examined in two studies (Olanzapine 1997 & Olanzapine 1998a), but no difference was found between the two compounds in this respect (n=339, SMD CI ). 2.8 Subgroup and sensitivity analyses Excluding high attrition studies All studies had a high level of attrition, either approaching or above 50%. No subgroup analyses were felt to be justified, since the results of all studies must be interpreted with caution and none can be singled out as being of greater quality or more robust Treatment resistant patients. No studies included exclusively treatment resistant patients Patients with negative or first episode schizophrenia. No studies present these data or focus exclusively on these populations. 3. RISPERIDONE versus AMISULPRIDE (AND OTHER ATYPICAL DRUGS) One study was found which compared risperidone and amisulpiride (Amisulp 1997), and this is reported separately. One study (Clozapine 1996) also included comparisons with zotepine and remoxipride, but we were unable to present comparisons with these two drugs for two reasons. Firstly, continuous outcomes could not be compared due to the fact that two risperidone treatment arms were used, and insufficient data were available to combine these treatment arms. Secondly, important dichotomous outcomes (such as discontinuation) were not presented by the authors. Further versions of this review will seek to present these data as and when they become available. 3.1 Death Was not explicitly reported by the authors. 3.2 Leaving the study early There was no significant difference in terms of the numbers of patients leaving the study early (n=228, RR 0.88 CI ). 3.3 Clinical response There were no significant differences demonstrated between either compound for the reported endpoints of clinical response. BPRS Total scores and PANSS positive subscale scores were essentially broadly similar (BPRS: n=228, WMD 1.5 CI ; PANSSpositive: n=228, WMD 0.00 CI= ). There was a non-significant trend in favour of amisulpiride when endpoint PANSS negative scale scores were considered separately (n=228, WMD 1.8 CI ). Insufficient data were presented to obtain dichotomised treatment responses (40% reductions in BPRS score) and social functioning outcomes. 3.4 Adverse effects Extrapyramidal side effects There were no significant differences between the two compounds in terms of either the numbers of patients who reported either movement disorders (N=228, RR 0.78 CI ) or received antiparkinsonian medication (n=228, RR 0.76 CI ) Other side effects Risperidone showed a greater tendency to cause agitation (n=228, 9

13 RR 0.29 CI ), and constipation (n=228, RR 0.13 CI ) than amisulpiride. There were no differences shown between the two compounds with respect to anxiety, insomnia, other endocrine problems and weight gain. 3.5 Service use No aspect of service use was reported. 3.6 Economic data Were not reported. 3.7 Quality of life Was not reported 3.8 Subgroup and sensitivity analyses Were not possible or appropriate, given only one study was available. D I S C U S S I O N 1. General comments Surprisingly few studies were found and the studies we included were generally of short duration, small (under-powered) and failed to report many outcomes in sufficient detail to allow pooling of all possible data. When this was possible, for the vast majority of outcomes of interest, wide confidence intervals were obtained, making it difficult to know whether there was in fact any real difference between risperidone and other atypical drugs or whether they were the same in these respects. There was a poor consideration of statistical power on the part of the authors. It was difficult to know whether the studies had been designed to demonstrate equivalence between the two compounds or whether the authors set out to demonstrate a real difference on many clinically important outcomes. It is clear that most of the studies are efficacy studies that allow us to say little about the comparative effectiveness of these drugs as they might be used in routine clinical practice. Clinically important outcomes were not collected and the general absence of information on the quality of life and service use amongst patients is unfortunate. We had aimed to test for the presence of publication bias in this data set, but unfortunately were unable to do this, since there were insufficient studies of only a limited range of sample sizes. This prevented the construction of funnel plots. It should be noted that a probable publication bias has been detected in studies comparing risperidone with conventional neuroleptics (Kennedy 1999). Further versions of this review will continue to attempt to detect publication bias, and the existence of publication bias cannot be excluded at present. Some more specific comments regarding clozapine, olanzapine and amisulpiride will now be outlined in turn. 2. RISPERIDONE versus CLOZAPINE Given the side effects, need for blood tests and non-drug costs associated with clozapine, it would be useful for clinicians, patients and decision makers to know if a more acceptable alternative were to exist. Risperidone represents one potential alternative. Unfortunately there are few trials to inform this question, and the research is limited in many respects. Most of the studies relate to treatmentresistant schizophrenia, and it is particularly disappointing that follow-up was not longer in this important group, where benefit would need to be judged over a longer time period, given the chronicity and severity of illness amongst participants. More studies, including greater numbers of patients, will be needed to judge the comparative effectiveness of these two compounds. 2.1 Death Few studies explicitly reported this outcome and greater numbers of patients, followed up over a longer period, will be required to show that risperidone is safer than clozapine in this respect. 2.2 Leaving the study early Risperidone and clozapine seemed to be equally acceptable, as evidenced by the overall drop out rates from the study. 2.3 Clinical response Unnecessarily wide confidence intervals for many of the outcomes relating to clinical response means that the equivalence of the two compounds cannot be assumed. 2.4 Extrapyramidal side effects Unnecessarily wide confidence intervals for many of the outcomes relating to extrapyramidal side effects means that the equivalence of the two compounds cannot be assumed. 2.5 Other adverse effects There was a non-significant trend to suggest that risperidone caused fewer patients to gain weight or to experience significant sedation. More research is needed to confirm or refute this trend. 2.6 Service utilisation, economic outcomes and quality of life Important outcomes relating to overall quality of life, patient satisfaction or preference with treatment, service use and costs were not reported or recorded. Similarly, the brevity of the available studies make it impossible to judge the comparative longer term impact of these two important drugs in those with treatment resistant schizophrenia. 3. RISPERIDONE versus OLANZAPINE Risperidone and olanzapine are important drug treatment options for those with schizophrenia. The question as to whether they, rather than cheaper conventional drugs, should form the first line treatment for schizophrenia has important clinical and economic implications, and is addressed in two reviews which should be read in conjunction with the present review (Duggan 2000; Kennedy 10

14 1999). Olanzapine currently holds global market dominance ( Wood Mackenzie 1998) and the comparative evidence upon which this dominance is based is summarised below. Available studies have many limitations - the most obvious of which is the high attrition rates which are observed and which exceed 50% in most cases. Consequently all the results outlined in this review are based upon assumptions about missing data which may be true, but are difficult to justify. The data included in this review are also largely based upon studies conducted by Eli Lilly (the manufacturers of olanzapine), since one important large scale study (Conley 1999) conducted by the manufacturers of risperidone has been withdrawn for reasons which are not as yet clear. Subsequent versions of this review will include this and other studies, in line with emerging data. The comparative research is also dominated by one single study (Olanzapine 1997), which uses comparative doses of risperidone which are in excess of those used in routine clinical practice (2-12mg), and the results of which are difficult to generalise to routine care. Studies ensure internal validity by employing strict entry criteria and double blind conditions, and they measure outcome using multiple rating scales which are sensitive to change, rather than collecting simple dichotomous outcomes. These conditions make it difficult to judge the degree to which results can be extrapolated to real world patients in real world settings (Wells 1999). With these limitations in mind, the current review highlights the following comparative similarities and differences between risperidone and olanzapine. 3.1 Death No studies explicitly reported this outcome, and the equivalence of these compounds cannot be assumed. 3.2 Leaving the study early Olanzapine seemed to be more acceptable in the medium term, as evidenced by slightly fewer patients leaving the study early, although discontinuations were unduly high, irrespective of which medication was allocated. However, any benefit of increased acceptability was not seen in the longer term studies. 3.3 Clinical response The clinical response amongst patients allocated to olanzapine and risperidone did seem broadly similar, especially when global scores were pooled. A significant difference between olanzapine and risperidone was noted for the total PANSS score in the medium term, although the clinical meaning of a 7.5 point difference on a 210-point scale is difficult to judge. Longer term studies failed to show any difference in this outcome. 3.4 Extrapyramidal side effects Olanzapine tended to cause fewer extrapyramidal side effects than risperidone, however this result is largely based on one study where the dose of risperidone was higher than that used in routine practice. The statistically significantly fewer extrapyramidal side effects are of questionable clinical significance, when NNTs are considered. Eight patients need be treated with olanzapine, rather than risperidone in order to prevent one incidence of extrapyramidal side effects - with a relatively wide confidence interval between five and 25. These results are also based upon a high comparative dose of risperidone, and the difference may therefore be an artefact of the design of the trial, rather than one which might be important in routine care. 3.5 Other adverse effects The possible benefits of olanzapine over risperidone in terms of fewer EPS need to be balanced by the fact that risperidone showed a reduced tendency to cause weight gain when compared to olanzapine. 3.6 Service utilisation, economic outcomes and quality of life It was welcome that data relating to quality of life were reported, although unduly wide confidence intervals prevent us knowing whether the two compounds produced any real or differential benefit in terms of this construct. It is regrettable that no service utilisation or economic data were presented. 4. RISPERIDONE versus AMISULPRIDE One important study was available with attrition rates of 30%, which were certainly lower than those in other studies presented in this review. The two compounds seemed broadly similar in most respects, and the specific comparative effects are discussed below. 4.1 Death No studies explicitly reported this outcome, and the equivalence of these compounds cannot be assumed. 4.2 Leaving the study early The two compounds seem to be equally acceptable. 4.3 Clinical response The two compounds seem to produce equivalent clinical response, although there is a suggestion that amisulpiride may be superior in alleviating negative symptoms. This trend was non-significant, and more research will be needed to confirm or refute this finding. 4.4 Extrapyramidal side effects The two compounds seem to be equivalent in their propensity to cause extrapyramidal side effects. 4.5 Other adverse effects Amisulpiride caused more agitation and constipation than risperidone. Both compounds cause weight gain, and there was little differential propensity for either compound to cause the other adverse effects which were measured. 11

15 4.6 Service utilisation, economic outcomes and quality of life It was regrettable that no data were presented for these important domains. A U T H O R S C O N C L U S I O N S Implications for practice 1. For clinicians The very great losses to follow-up make recommendations difficult. In these trials most people, when given either risperidone or another atypical antipsychotic, stop it within six months to one year. Clozapine has (rightly or wrongly) come to be seen as a gold standard for those whose schizophrenia has failed to respond to conventional anti-psychotics. The value of clozapine in this respect is reviewed in this library (Wahlbeck 2000). The limited data presented in this review make it difficult to draw strong conclusions regarding the equivalence of risperidone in the management of treatment resistant schizophrenia. More research is needed in this respect, since if a less toxic alternative to clozapine were to emerge, then this would be an important advance. Olanzapine has become the market leader amongst the atypical antipsychotics in the management of schizophrenia. The data summarised in this review suggest that there is little to chose between risperidone and olanzapine when the short and medium term outcomes measured in the available studies are compared. More research is needed to establish the true value of and comparative differences between the atypical antipsychotics with respect to those outcomes which clinicians (rather than researchers) might value. In summary, the evidence base to support the choice of antipsychotic for first line and first episode treatment of schizophrenia is limited. More robust data are presented elsewhere to support the value of clozapine in treatment resistant schizophrenia - albeit that this drug has important side effects (Wahlbeck 2000). The present review does not yet present sufficient data to guide clinical practice when considering risperidone as an alternative to clozapine for treatment resistant patients. 2. For people with schizophrenia For people with less severe schizophrenia, risperidone is an effective antipsychotic, but may cause slightly more movement disorder side effects than other new drugs, such as olanzapine - although this is only based on one trial which used higher doses of risperidone than that used in routine practice. Olanzapine, clozapine and risperidone all tend to cause weight gain, although risperidone may be preferable - more research is needed to confirm this finding. For people whose schizophrenia has failed to respond to older drugs or who cannot tolerate older drugs due to their side effects, clozapine is often offered, but has important side effects which require weekly blood tests. Risperidone does seem to be equally acceptable as clozapine in terms of distressing movement disorders, and if this is the only reason why clozapine is offered, then risperidone might be an acceptable alternative. However, there is as yet insufficient evidence to suggest that risperidone is as good as clozapine for symptoms which have not been helped by older drugs. 3. For managers/policy makers Risperidone is a relatively expensive antipsychotic, but is broadly similar to olanzapine in many respects. An important policy question remains whether atypical antipsychotics, rather than conventional antipsychotics should form the first line treatment of schizophrenia, and the current review can provide little guidance in this respect. Managers may be interested to know that risperidone is generally cheaper (in terms of direct acquisition costs) than olanzapine. The real world cost effectiveness (encompassing all costs and consequences of drug choice) remains to be established for risperidone in comparison with other atypical antipsychotics. Whilst risperidone is a cheaper alternative to clozapine, there are insufficient data to suggest that risperidone is as effective as clozapine for those with treatment resistance. Implications for research Larger, longer term trials are urgently needed. Better reporting of randomisation, allocation concealment and blinding procedures would lend extra value to the results of these trials. The inclusion of clinically and socially relevant outcomes should be a matter of high priority. Trials which focus on people experiencing their first episode of schizophrenia or those with predominantly positive or negative symptoms are also needed. A C K N O W L E D G E M E N T S We are grateful for the assistance of Dr Clive Adams, Dr Stefan Leucht and the team at the Cochrane Schizophrenia Group editorial base in Oxford for their patience and assistance. We are also grateful to Julie Glanville and her colleagues in the information service of NHS CRD for their assistance in searching and retrieving data for this review. Eli Lilly and their contact person, Anne-Marie Crawford, have been exceedingly helpful in identifying and supplying extra data from unpublished trials, and clarifying any questions we have had about data. We also thank Jo Wood of Janssen-Cilag for her assistance in locating research relating to risperidone. 12

16 R E F E R E N C E S References to studies included in this review Amisulp 1997 {published data only} Fleurot O, Bech P, Turjanski S. Amisulpride versus risperidone in the treatment of acute schizophrenia. Biol Psychiatry. 1997; Vol. 42:1S 297S. Peushkins, J. Bech, P. Moller, HJ. Bale, R, Fleurot, O. Rien, W. Amisulpride versus risperidone in the treatment of acute exacerbations of schizophrenia. Psychiatry Research 1999;88: Clozapine 1996 {published data only} Heinrich K. Risperidone versus clozapine in acute schizophrenia. 1st International Risperidone Investigators Meeting, Conference Review, Paris, France March Heinrich K. Risperidone versus clozapine in acute schizophrenia. 1st International Risperidone Investigators Meeting, Conference Review, Paris, France. 1992:27 8. Heinrich K, Klieser E, Lechmann E, Kinzler E. Experimental comparison of the efficacy and compatibility of clozapine and risperidone in acute schizophrenia. Clinical Neuropharmacology. 18th Collegium Internationale Neuro-Psychopharmacologicum Congress, Nice, France. 1992; Vol. 15 Suppl 1(Part B):375B. Heinrich K, Klieser E, Lehmann E, Kinzler E. Experimental comparison of the efficacy and compatibility of clozapine and risperidone in acute schizophrenia. 17th Congress of Collegium Internationale Neuro-Psychopharmacologicum, Kyoto, Japan Sept Heinrich K, Klieser E, Lehmann E, Kinzler E. Experimental comparison of the efficacy and compatibility of risperidone and clozapine in acute schizophrenia. Risperidone - major progress in antipsychotic treatment. Proceddings of a satellite symposium at the 17th Congress of Collegium Internationale Neuro-Psychopharmacologicum, Kyoto, Japan. Sept 10 13, 1991:37 9. Heinrich K, Klieser E, Lehmann E, Kinzler E, Hruschka H. Risperidone versus clozapine in the treatment of schizophrenic patients with acute symptoms: a double-blind, randomised trial. Progressive Neuro- Psychopharmacology and Biological Psychiatry 1994;18: Kleiser E, Lehmann E, Kinzler E, Wurthmann C, Heinrich K. Randomised double-blind controlled trial of risperidone versus clozapine in patients with chronic schizophrenia. Journal of Clinical Psychopharmacology 1995;15(Suppl 1): 45S 51S. Klieser E, Kinzler E. Risperidone versus clozapine in the treatment of schizophrenic patients with acute symptoms: a double-blind, randomised trial. Clinical research Report on R64766 Ris-FRG-9005 Aug Klieser E, Lehmann E, Heinrich K. Risperidone in comparison with various treatments of schizophrenia. In: Kane JM, Moller HJ, Awouters F editor(s). Medicine Psychiatry. Serotonin in antipsychotic treatment: Mechanisms and clinical practice. Vol. 3, New York: Marcel Dekker, 1996: Klieser E, Rappard F. Randomised, double-blind, controlled trial of risperidone versus clozapine in patients with acute exacerbations of schizophrenia. 7th Congress of the Association of European Psychiatrists, Copenhagen, Denmark. 1994; Vol. 9, suppl 1:154S. Klieser E, Strauss WH, Burtscheid W. Double-blind comparative study of haloperidol, remoxipride and clozapine in schizophrenia. 15th Collegium Internationale Neuro-Psychopharmacologicum Congress, San Juan, Puerto Rico. 1986:111. Clozapine 1998a {published data only} Bondolfi G, Baumann P, Dufour H. Treatment-resistant schizophrenia: clinical experience with new antipsychotics. European Neuropsychopharmacology 1996;6:S Bondolfi G, Baumann P, Patris M, May JP, Billeter U, Dufour H. A randomised double-blind trial of risperidone versus clozapine for treatment-resistant chronic schizophrenia (abstract). American Psychiatric Association 148th Annual Meeting, Miami, USA. 1995, May 20 25: 185. Bondolfi G, Baumann P, Patris M, May JP, Billeter U, Dufour H. A randomised double-blind trial of risperidone versus clozapine for treatment-resistant chronic schizophrenia [abstract]. 8th European College of Neuropsychopharmacology Congress, Venice, Italy. Sep 30 Oct 4. Bondolfi G, Baumann P, Patris M, May JP, Billeter U, Dufour H. A randomised double-blind trial of risperidone versus clozapine for treatment-resistant chronic schizophrenia [abstract]. 8th European College of Neuropsychopharmacology Congress, Venice, Italy Sep 30 Oct 4; Vol. 5:349. Bondolfi G, Dufour H, Patris M, May JP, Billeter U, Eap CB. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomised double-blind study. American Journal of Psychiatry 1998;155: Clozapine 1998b {published data only} Anand R, Alphs L, Azorin JM, Remington G, Péré JJ, Bourdeix I. Superior efficacy of clozapine in chronic, severe schizophrenia: comparison with risperidone. Highlights. Treatment-resistant schizophrenia and beyond. Current concepts and future prospects; London, UK 1998 July 8 9. Clozapine 1999 {published data only} Breier AF, Malhotra AK, Su TP, Pinals DA, Elman E, Adler CM, et al.clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine responses. American Journal of Psychiatry 1999;156: Clozapine 2000 {published data only} Cheine MV, Wahlbeck K, Tuisku K, Joffe G. Risperidone versus clozapine in the treatment of neuroleptic-refractory/ intolerant schizophrenia patients: a single-blind randomized 13

17 trial. Preliminary report of an on-going study. Proceedings of the 38th Annual Meeting of the Scandinavian Society for Psychopharmacology; Copenhagen, Denmark. Nordic Journal of Psychiatry Apr 9 11,1997;51:99. Wahlbeck K, Cheine M, Tuisku K, Ahokas A, Joffe G, Rimon R. Risperidone versus clozapine in treatmentresistant schizophrenia: a randomised pilot study. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2000; 24(6): Olanzapine 1997 {published data only} Edgell ET, Andersen SW, Grainger D, Wang J. Resource use and quality of life of olanzapine compared with risperidone: results from an international randomized clinical trial. Proceedings of XXIst Collegium Internationale Neuropsychopharmacologicum. Glasgow, Scotland, UK, 1998, July Kinon B, Basson B, Tollefson GD. Gender-specific prolactin response to treatment with olanzapine versus risperidone in schizophrenia. 151st Annual Meeting of American Psychiatric Association. Toronto, Ontario, Canada, 1998, May 30 June 4. Tollefson GD, Tran PV, Hamilton S, Kuntz A. Olanzapine versus risperidone in the treatment of psychosis. Preliminary report. Schizophrenia Research (Special Issue) - The VIth International Congress on Schizophrenia Research, Colorado Springs, CO, USA. 1997, April 12 16; Vol. 24: 191. Tran PV, Hamilton SH, Kuntz AJ, Potvin JH, Andersen SW, Beasley C Jr, Tollefson GD. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. Journal of Clinical Psychopharmacology 1997;17: Tran PV, Tollefson GD, Andersen SW, Kuntz AJ, Hamilton SH. [Olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders]. 10th European College of Neuropsychopharmacology Congress. Vienna, Austria, 1997, Sep Tran PV, Tollefson GD, Hamilton S. Olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. American Psychiatric Association, 150th Annual Meeting. San Diego, Tran PV, Tollefson GD, Hamilton S, Kuntz A. Olanzapine vs. risperidone in the treatment of psychosis. Sixth World Congress of Biological Psychiatry. Nice, France, 1997, June Olanzapine 1998a {published data only} Canadain Cognition and Outcome Study Group. Neuropsychological change in early phase schizophrenia over twelve months of treatment with olanzapine, risperidone or haloperidol. Schizophrenia Research 1998;29: Jones, B. Olanzapine versus risperidone and haloperidol in the treatment of schizophrenia. 151st Annual Meeting of American Psychiatric Association. Toronto, Canada, 1998, May 30 June 4. Jones B, Tollefson G. Olanzapine versus risperidone and haloperidol in the treatment of schizophrenia. Schizophrenia Research 1998;29: Purdon SE, Jones BDW, Stip E, Labelle A, Addington D, Breier A, Tollefson GD, the Canadian Collaborative Group for Research on Cognition in Schizophrenia. Olanzapine versus haloperidol versus risperidone in early illness schizophrenia. Data on file 2001: Olanzapine 1998b {published data only} Gregor K, Gureje O, Lambert T, Grainger D, Tran PV, Andersen SW, and the Australasian Olanzapine Study Group. Olanzapine versus risperidone in the management of schizophrenia: a randomized, double-blind study in Australia and New Zealand. World Psychiatric Association. Hamburg, Germany. 1999, August. Gureje O, Catts S, Fraser A, Hustig H, Keks N, Lambert Y, McGrath J, Miles W, Thomas A, Grainger D, Andersen S, Tollefson G. Olanzapine versus risperidone in the treatment of schizophrenia and related psychotic disorders. XXIst Collegium Internationale Neuro-psychopharmacologicum. Glasgow, Scotland, UK. July 12 16, Gureje O, Lambert T, Grainger D, Tran PV, Andersen SW, and the Australasian Olanzapine Study Group. Olanzapine versus risperidone in the management of schizophrenia: a randomized, double-blind study in Australia and New Zealand. XXIst Collegium Internationale Neuropsychopharmacologicum. Glasgow, Scotland, UK. 1998, July Thomas A, Grainger D, Andersen S, Tollefson G. Olanzapine versus risperidone in the treatment of schizophrenia and related psychotic disorders. Schizophrenia Research 1998;29(1-2):47. References to studies excluded from this review Chouinard 1994 {published data only} Chouinard G, Beaudry P, Vainer J, Turnier L, Roy JY, Miller R. Risperidone and clozapine in the treatment of neuroleptic-induced supersensitivity psychosis. Proceedings of the 48th Annual Convention & Scientific Program of the Society of Biological Psychiatry. Biological Psychiatry. San Francisco, USA, 1993, May 19 23; Vol. 33:130A. Conley 1999 {published data only} Conley RR, Mahmoud R, and the Risperidone Study Group. Risperidone versus olanzapine in patients with schizophrenia and schizoaffective disorder. US Psychiatric and Mental Health Congress. Atlanta, GA, Konrad 1996 {published data only} Konrad C, Schormair C, Eikelmann B, Berger K, Rottmann P. Clozapine and risperidone in the treatment of therapy-resistant schizophrenia: a preliminary report on two ongoing clinical trials. 8th Congress of the Association of European Psychiatrists, London, UK. 1996, July [: NNT174, CSG1538] Konrad 1997 {published data only} Konrad C, Schormair C, Knickelbein U, Ophaus P, Eikelmann B. Risperidone and clozapine in pharmacoresistant schizophrenia. Pharmacopsychiatry 1997;30:

18 Kumra 1998 {published data only} Kumra S, Jacobsen LK, Lenane M, Karp BI, Frazier JA, Smith AK. Childhood-onset schizophrenia: an open-label study of olanzapine in adolescents. Journal of American Academy of Child and Adolescent Psychiatry 1998;37: Lindenmayer 1998 {published data only} Lindenmayer JP, Iskander A, Park M, Apergi FS, Czobor P, Smith R. Clinical and neurocognitive effects of clozapine and risperidone in treatment-refractory schizophrenic patients: a prospective study. Journal of Clinical Psychiatry 1998;59: Lindenmayer J-P, Iskander A, Park M, Smith R, Apergi F- S, Czobor P. Psychopathological and neuropsychological profile of clozapine vs. risperidone in refractory schizophrenics. Proceedings of the 6th International Congress on Schizophrenia Research, Colorado Springs; 1997 Apr 12-16; Colorado, USA. Schizophrenia Research 1997;24:195. Lindenmayer J-P, Park M, Iskander A, Bark NM, Smith RM, Cooper TB. Clozapine versus risperidone in treatment refractory state psychiatric inpatients. Proceedings of the 149th Annual Meeting of the American Psychiatric Association; New York, USA May 4 9. Sharif 1998 {published data only} Sharif ZA, Raza A, Ratakonda S, Kirschner T, Miller CE, Gorman JM. Comparative efficacy of clozapine and risperidone in treatment refractory schizophrenia. Schizophrenia Research 1998;29:147. Su 1996 {published data only} Su TP, Elman I, Malhotra AK, Adler CM, Pickar D, Breier AF. Comparison of weight gain during risperidone and clozapine treatment in chronic schizophrenia. Proceedings of the 149th Annual Meeting of the American Psychiatric Association; New York, USA May 4 9. Tauscher 1999 {published data only} Tauscher J, Kufferle B, Barnas C, Asenbaum S, Bruecke T, Kasper S. 123I IBZM SPECT imaging of dopamine- 2 receptors in psychotic patients treated with olanzapine, risperidone, clozapine and haloperidol. Pharmacopsychiatry 1997;30:228. References to studies awaiting assessment Nicolini 1997 {published data only} Nicolini H, Cruz C, Kanarena B, Ortega H. 5HT2A and DRD4 molecular genotypes in a clinical trial of olanzapine versus risperidone in schizophrenic patients. 10th ECNP Congress, Sep Vienna, Austria, Olanzapine 1998c {published data only} Brecher M. Risperidone versus olanzapine in the treatment of patients with schizophrenia or schizoaffective disorder. Proceedings of XXIst Collegium Internationale Neuropsychopharmacologicum. Glasgow, Scotland, 1998, July References to ongoing studies Hagger 1997 {published data only} Hagger C, Mitchell D, Wise AL, Schulz SC. Effects of oral ziprasidone and risperidone on cognitive functioning in patients with schizophrenia or schizoaffective disorder: preliminary data. 10th European College of Neuropsychopharmacology Congress Naber 1997 {unpublished data only} Naber D. Evidence of efficacy of neuroleptics in affective versus negative symptoms. 10th European College of Neuropsychopharmacology Congress (ECNP ). Vienna, Austria, Additional references Altman 1996 Altman DG, Bland M. Detecting skewness from summary information. BMJ 1996;313:1200. [: RSPA020600] Andreasen 1982 Andreasen NC. Negative symptoms in schizophrenia. Archives of General Psychiatry 1982;39: Andreasen 1985 Andreasen NC. Negative syndrome in schizophrenia: strategies for long-term management. Advances in Biochemical Psychopharmacology 1985;40:1 7. Buckley 1997 Buckley PF. New dimensions in the pharmacologic treatment of schizophrenia and related psychoses. Journal of Clinical Pharmacology 1997;37: Carpenter 1984 Heinrichs DW, Hanlon ET, Carpenter WT Jr. The quality of life scale: an instrument for rating the schizophrenic deficit syndrome. Schizophrenia Bulletin 1984;10: Chalmers 1983 Chalmers TC, Celano P, Sacks HS, Smith H Jr. Bias in treatment assignment in controlled clinical trials. New England Journal of Medicine 1983;309: Chouinard 1993 Chouinard G, Arnott W. Clinical review of risperidone. Canadian Journal of Psychiatry 1993;38(suppl 3): Christison 1991 Christison GW, Kirch DG, Wyatt RJ. When symptoms persist choosing among alternative somatic symptoms for schizophrenia. Schizophrenia Bulletin 1991;17: Crow 1980 Crow TJ. Positve and negative schizophrenic symptoms and the role of dopamine. British Journal of Psychiatry 1980; 137: Curtis 1995 Curtis V, Kerwin R. A risk benefit assessment of risperidone in schizophrenia. Drug Safety 1995;12: Davis 1977 Davis JM, Casper R. Antipsycotic drugs: clinical pharmacology and therapeutic use. Drugs 1977;14:

19 Duggan 2000 Duggan L, Fenton M, Dardennes RM, El-Dosoky A, Indran S. Olanzapine for schizophrenia. Cochrane Database of Systematic Reviews 2000, Issue 1. [DOI: / CD pub2] Edwards 1994 Edwards JG. Risperidone for schizophrenia. BMJ 1994; 308: Egger 1997 Egger M, Davey-Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: Fabre 1995 Fabre LF, Arvanitis L, Pultz J, Jones VM, Malick JB, Slotnick VB. ICI 204,636, a novel, atypical antipsychotic - early indication of safety and efficacy in patients with chronic and subchronic schizophrenia. Clinical Therapeutics 1995;17: Glazer 1997 Glazer WM, Johnstone BM. Pharmacoeconomic evaluation of antipsychotic therapy for schizophrenia. Journal of Clinical Psychiatry 1997;58(10):50 4. Gupta 1994 Gupta S, Black D, Smith D. Risperidone: review of its pharmacology and therapeutic use in schizophrenia. Annals of Clinical Psychiatry 1994;6: Guy 1976 Guy W. Early clinical drug evaluation (ECDEU) assessment manual for psychopharmacology. Washington, DC: National Institute of Mental Health Publication No , 1976: He 1995 He H, Richardson JS. A pharmacological, pharmacokinetic and clinical overview of risperidone, a new antipsychotic that blocks serotonin 5-HT2 and dopamine D2 Receptors. International Clinical Psychopharmacology 1995;10: Janssen-Cilag 1996 Janssen-Cilag Ltd. Risperidal (risperidone) summary of product characteristics. UK Kane 1990 Kane JM. Treatment programme and long term outcome in chronic schizophrenia. Acta Psychiatrica Scandinavica Supplementum 1990;358: Kane 1993 Kane JM. Newer antipsychotic drugs. A review of their pharmacology and therapeutic potential. Drugs 1993;46: Kay 1986 Kay SR, Opler LA, Fiszbein A. Positive and negative syndrome scale (PANSS) manual. North Tonawanda, NY: Multi-Health Systems, Keltner 1995 Keltner Nl. Risperidone the search for a better antipsychotic. Perspectives in Psychiatric Care 1995;31:30 3. Kennedy 1999 Kennedy E, Song F, Hunter R, Clarke A, Gilbody S. Risperidone versus typical antipsychotic medication for schizophrenia. Cochrane Database of Systematic Reviews 1999, Issue 3. [DOI: / CD002306] Kilian 1999 Kilian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354(November 27): Lehman 1983 Lehman A. The well being of chronic mental patients: assessing their quality of life. Archives of General Psychiatry 1983;40: Livingston 1994 Livingston MG. Risperidone. Lancet 1994;343: Meltzer 1992 Meltzer HY. Treatment of the neuroleptic-nonresponsive schizophrenic patient. Schizophrenia Bulletin 1992;18: Mulrow 1999 Murow, CD, Oxman. AD. The Cochrane Handbook. Cochrane Database of Systematic Reviews. Oxford: Update Software, 1999; Vol. Issue 3. Overall 1962 Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychological Reports 1962;10: Remington 1993 Remington GJ. Clinical considerations in the use of risperidone. Canadian Journal of Psychiatry 1993;38: Schulz 1995 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273: Simpson 1970 Simpson GM, Angus JWS. A rating scale for extrpyramidal side-effects. Acta Psychiatrica Scandinavica Suppl 1970;212: Stip 1996 Stip E, Lussier I. The effect of risperidone on cognition in patients with schizophrenia. Canadian Journal of Psychiatry 1996;41: Thornley 1998 Thornley B, Adams CE. Content and quality of 2000 controlled trials in schizophrenia over 50 years. BMJ 1998; 317: Tuunainen 2000 Tuunainen, A. Wahlbeck, K. Gilbody, S. Newer atypical antipsychotic medication versus clozapine for schizophrenia. Cochrane Database of Systematic Reviews 2000, Issue 1. [DOI: / CD000966] Wahlbeck 2000 Wahlbeck K, Cheine M, Essali MA. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane 16

20 Database of Systematic Reviews 2000, Issue 1. [DOI: / CD000059] Wells 1999 Wells, K. Treatment research at the crossroads: the scientific interface of clinical trials and effectiveness research. American Journal of Psychiatry 1999;156:5 10. Wood Mackenzie 1998 Wood Mackenzie. Review of the Global Schizophrenia Market. PharmaForum 1998;39:9. Indicates the major publication for the study 17