Risperidone versus placebo for schizophrenia
Abstract
Background
Risperidone is the first new‐generation antipsychotic drug made available in the market in its generic form.
Objectives
To determine the clinical effects, safety and cost‐effectiveness of risperidone compared with placebo for treating schizophrenia.
Search methods
On 19th October 2015, we searched the Cochrane Schizophrenia Group Trials Register, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. We checked the references of all included studies and contacted industry and authors of included studies for relevant studies and data.
Selection criteria
Randomised clinical trials (RCTs) comparing oral risperidone with placebo treatments for people with schizophrenia and/or schizophrenia‐like psychoses.
Data collection and analysis
Two review authors independently screened studies, assessed the risk of bias of included studies and extracted data. For dichotomous data, we calculated the risk ratio (RR), and the 95% confidence interval (CI) on an intention‐to‐treat basis. For continuous data, we calculated mean differences (MD) and the 95% CI. We created a 'Summary of findings table' using GRADE (Grading of Recommendations Assessment, Development and Evaluation).
Main results
The review includes 15 studies (N = 2428). Risk of selection bias is unclear in most of the studies, especially concerning allocation concealment. Other areas of risk such as missing data and selective reporting also caused some concern, although not affected on the direction of effect of our primary outcome, as demonstrated by sensitivity analysis. Many of the included trials have industry sponsorship of involvement. Nonetheless, generally people in the risperidone group are more likely to achieve a significant clinical improvement in mental state (6 RCTs, N = 864, RR 0.64, CI 0.52 to 0.78, very low‐quality evidence). The effect withstood, even when three studies with >50% attrition rate were removed from the analysis (3 RCTs, N = 589, RR 0.77, CI 0.67 to 0.88). Participants receiving placebo were less likely to have a clinically significant improvement on Clinical Global Impression scale (CGI) than those receiving risperidone (4 RCTs, N = 594, RR 0.69, CI 0.57 to 0.83, very low‐quality evidence). Overall, the risperidone group was 31% less likely to leave early compared to placebo group (12 RCTs, N = 2261, RR 0.69, 95% CI 0.62 to 0.78, low‐quality evidence), but Incidence of significant extrapyramidal side effect was more likely to occur in the risperidone group (7 RCTs, N = 1511, RR 1.56, 95% CI 1.13 to 2.15, very low‐quality evidence).
When risperidone and placebo were augmented with clozapine, there is no significant differences between groups for clinical response as defined by a less than 20% reduction in PANSS/BPRS scores (2 RCTs, N = 98, RR 1.15, 95% CI 0.93 to 1.42, low‐quality evidence) and attrition (leaving the study early for any reason) (3 RCTs, N = 167, RR 1.13, 95% CI 0.53 to 2.42, low quality evidence). One study measured clinically significant responses using the CGI, no effect was evident (1 RCT, N = 68, RR 1.12 95% CI 0.87 to 1.44, low quality evidence). No data were available for extrapyramidal adverse effects.
Authors' conclusions
Based on low quality evidence, risperidone appears to be benefitial in improving mental state compared with placebo, but it also causes more adverse events. Eight out of the 15 included trials were funded by pharmaceutical companies. The currently available evidence isvery low to low quality.
PICOs
Plain language summary
Risperidone versus placebo for schizophrenia
Review question
Is risperidone (tablet form) more effective than placebo in treating the symptoms of schizophrenia or schizophrenia‐like illnesses?
Background
People with schizophrenia often hear voices and see things (hallucinations) and have strange beliefs (delusions). These are called ‘positive symptoms’. Mental illness also causes tiredness, apathy, emotional numbness, and withdrawal. These are called ‘negative symptoms’. The main treatment for the symptoms of schizophrenia are antipsychotic drugs. Antipsychotic drugs can be classified into typical (older) and atypical (newer) drugs. Typical antipsychotics such as chlorpromazine and haloperidol have been the mainstay of treatment for decades, and have been effective in reducing the positive symptoms of schizophrenia. Negative symptoms, however, have been fairly resistant to treatment. In addition, drug treatments are associated with unpleasant side effects that cause people to stop taking medication, which may lead to relapse. It is thought that newer atypical antipsychotics, such as risperidone, are more effective than the older antipsychotics as they reduce the positive symptoms but cause fewer side effects.
Study characteristics
Searches for high‐quality randomised trials were carried out in 2008, 2013 and 2015. The review now includes 15 studies with 2428 participants. The studies randomised participants (in‐ and outpatients) with schizophrenia or schizophrenia‐like illnesses into treatment groups that received oral risperidone or placebo.
Key results
Results from limited data suggest that risperidone is more effective than placebo for reducing the overall symptoms of schizophrenia, and participants receiving risperidone were more likely to comply with treatment. However, like the older typical antipsychotics, risperidone was also associated with serious side effects, such as parkinsonism.
Quality of the evidence
The evidence available was very low quality. Information and data were limited, poorly reported, and probably biased in favour of risperidone . Nearly half of the included trials were funded by drug companies. Firm conclusions are difficult to make based on the results of this review. Better conduct and reporting of trials could increase confidence in the results.
Ben Gray, Senior Peer Researcher, McPin Foundation. http://mcpin.org/
Authors' conclusions
Summary of findings
| RISPERIDONE compared to PLACEBO for schizophrenia | ||||||
| Patient or population: patients with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| PLACEBO | RISPERIDONE | |||||
| Mental state: no clinically significant response in psychotic symptoms (defined by various scale total score change) ‐ short term (up to 12 weeks) ‐ defined by PANSS/BPRS <20% decline | Study population | RR 0.64 | 864 | ⊕⊝⊝⊝ | ||
| 692 per 1000 | 443 per 1000 | |||||
| Moderate | ||||||
| 733 per 1000 | 469 per 1000 | |||||
| Leaving the study early ‐ short term (up to 12 weeks) ‐ any reason | Study population | RR 0.69 | 2261 | ⊕⊕⊝⊝ | ||
| 495 per 1000 | 342 per 1000 | |||||
| Moderate | ||||||
| 486 per 1000 | 335 per 1000 | |||||
| Global state: 2. no significant clinical improvement ‐ CGI, short term (up to 12 weeks) | Study population | RR 0.69 | 594 | ⊕⊝⊝⊝ | ||
| 744 per 1000 | 513 per 1000 | |||||
| Moderate | ||||||
| 732 per 1000 | 505 per 1000 | |||||
| Adverse effects: 1a. extrapyramidal ‐ various effects ‐ short term (up to 12 weeks) ‐ general ‐ any significant EPS | Study population | RR 1.56 | 1511 | ⊕⊕⊝⊝ | ||
| 73 per 1000 | 113 per 1000 | |||||
| Moderate | ||||||
| 106 per 1000 | 165 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to risk of bias: studies contributing data to this body of evidence have unclear or high risk of bias in one or more domains, some were also sponsored by pharmaceutical companies. | ||||||
| RISPERIDONE + CLOZAPINE compared to PLACEBO + CLOZAPINE for schizophrenia | ||||||
| Patient or population: people with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| PLACEBO + CLOZAPINE | RISPERIDONE + CLOZAPINE | |||||
| Mental state: no clinically significant response in psychotic symptoms ‐ short term | Moderate1 | RR 1.15 | 98 | ⊕⊕⊝⊝ | ||
| 725 per 1000 | 834 per 1000 | |||||
| Leaving the study early due to any reason ‐ short term Follow‐up: 12 weeks | 119 per 1000 | 135 per 1000 (63 to 288) | RR1.13 (0.53 to 2.42) | 167 | ⊕⊝⊝⊝ | |
| Global state: no significant clinical improvement ‐ CGI short term | 735 per 10003 | 824 per 1000 | RR 1.12 | 68 | ⊕⊕⊝⊝ | |
| Adverse effects: extrapyramidal ‐ short term Follow‐up: 12 weeks | See comment | See comment | Not estimable | ‐ | See comment | No study reported this outcome |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to risk of bias: studies contributing data to this body of evidence have unclear risk of bias in one or more domains. | ||||||
Background
Risperidone (Figure 1) is the first new‐generation antipsychotic drug made available in the market in its generic form. It has been used in the treatment of schizophrenia and related psychotic disorders for over a decade.
Risperidone
Description of the condition
Schizophrenia is a serious, chronic, and relapsing mental illness with a worldwide lifetime prevalence of about 1%. It is characterised by positive symptoms such as hallucinations and delusions, and negative symptoms such as emotional numbness and withdrawal. One‐third of those who experience an episode of schizophrenia recover and the illness does not recur. Another 30% experience an unremitting illness. The remainder have a recurrent illness but with long episodes of considerable recovery from the positive symptoms. The overall cost of the illness to the individuals, their families, and the community is considerable.
Description of the intervention
Conventional antipsychotic drugs were introduced into widespread use in the 1950s, and have since formed the mainstay of drug treatment for schizophrenia. Although these drugs were indeed a revolution, their early promise of complete recovery was unfulfilled. Continued interests in further developments led to the formulation of clozapine in the early 1960s, which, in turn, paved the way for a series of new atypical antipsychotic drugs. This disparate grouping was said to be 'atypical' because they did not seem to cause movement disorders to the same extent as the older generation of drugs.
This series of newer drugs appeared on the market in the early 1990s, risperidone being one of the first. Initially, risperidone was compared with placebo and then with the older‐generation antipsychotic drugs, especially haloperidol (Hunter 2003). More recently, risperidone has been used as the control compound when other new antipsychotic drugs are compared with a 'standard atypical'. In 2007 risperidone became off‐licence, and it seems likely that this drug will emerge as the new standard care comparator, replacing the older and more problematic haloperidol (Joy 2006).
The absolute effects of a drug are often less well investigated when a standard treatment is widely used, and it is seen as unethical not to treat with drug therapy. With almost everyone having access to older drug treatments for schizophrenia, placebo‐controlled trials in this area are now difficult to justify (Carpenter 2003; Laughren 2001). Yet in many physical diseases, such as angina pectoris, bronchial asthma, herpes simplex, and duodenal ulcers, placebo effects can account for up to 33% of clinical improvement (Benson 1996). When it comes to new drugs such as risperidone, clinicians and the public are often provided the evidence for the comparative effects, but the newer drug has been compared with a less‐than‐ideal drug (Hunter 2003). We argue that knowledge of the effects of a drug compared with placebo assists development of a rational therapeutic approach (Vallance 2006).
How the intervention might work
Risperidone (4‐[2‐[4‐(6‐fluorobenzo[d]isoxazol‐3‐yl)‐1‐piperidyl]ethyl]‐3‐methyl‐2,6‐diazabicyclo[4.4.0]deca‐1,3‐dien‐5‐one) is a strong postsynaptic dopamine receptor antagonist, but also acts as a 5‐HT2A antagonist and is called a serotonin/dopamine antagonist (Leysen 1994). Risperidone is rapidly and very well absorbed after administration orally, and less than 1% is excreted unchanged in the faeces (Heykants 1994). It reaches peak plasma levels quickly regardless of whether it is administered as a liquid or pill. It is 90% plasma protein bound (Darby 1997). Risperidone binds to D2 and D3 receptors with 50 and 20 times greater affinity than clozapine and is only 2 to 3 times less potent than haloperidol. Also, its affinity for D1 receptors is 100 times lower than for D4 receptors (Leysen 1994).
Why it is important to do this review
Comparing any drug with a placebo has always been an intriguing aspect of drug trials, and some authors, such as Vallance 2006, feel that outcome measures are best measured when compared with a placebo as it partly accounts for the philosophical obstacles such as the mind/body dichotomy, which are inherent in conceptualising these effects. In 60% to 90% of diseases, including angina pectoris, bronchial asthma, herpes simples, and duodenal ulcers, placebo effects can account for up to 33% of clinical improvement and yield clinical results (Benson 1996). The placebo effect ultimately allows a rationalised therapeutic approach to be developed to maximise the clinical benefit of the therapeutic encounter and evaluate various outcome measures (Vallance 2006).
Cochrane reviews to date have evaluated the efficacy of risperidone for schizophrenia by comparing it with typical and other atypical antipsychotics. This comparison of risperidone versus placebo is one of a set of reviews on risperidone (Table 1).
| Comparison | Reference | |
| Oral risperidone | vs other atypical drugs | |
| vs olanzapine | ||
| vs typical drugs | ||
| Depot risperidone | ||
| Risperidone dose | ||
| Risperidone for acute aggression | ||
Objectives
To determine the clinical effects, safety, and cost‐effectiveness of risperidone compared with placebo for treating schizophrenia.
Methods
Criteria for considering studies for this review
Types of studies
We included all relevant RCTs. If a trial was described as 'double‐blind', but only implied that the study is randomised, then we included it in a sensitivity analysis. If in such a trial there was no implied randomisation, we contacted the authors to clarify the randomisation. We excluded trials where randomisation did not occur. If there was no substantive difference within primary outcomes (see Types of outcome measures) when these 'implied randomisation' studies were added, then we included these in the final analysis. If there was a substantive difference, we only used clearly randomised trials and described the results of the sensitivity analysis in the text. We excluded quasi‐randomised studies, such as those allocated by using alternate days of the week.
Types of participants
We included people (above 17 years of age) with schizophrenia and other types of schizophrenia‐like psychoses (schizophreniform and schizoaffective disorders), as evidence suggests that they are fundamentally not too dissimilar (Carpenter 1994).
Types of interventions
1. Oral risperidone: any dose or form
2. Placebo
Types of outcome measures
We grouped outcomes into short term (up to 12 weeks), medium term (13 to 26 weeks), and long term (over 26 weeks).
Primary outcomes
1. Mental state
1.1 Clinical response: no clinically significant response in psychotic symptoms, as defined by each of the studies (short term)
2. Service utilisation
2.1 Hospital admission and/or re‐admission
Secondary outcomes
1. Leaving the study early
2. Global state
2.1 Average score/change in global state
2.2 No clinically significant response on global state, as defined by each of the studies
3. Mental state
3.1 Average score/change on psychotic symptoms
3.2 No clinically significant response on positive symptoms, as defined by each of the studies
3.3 Average score/change in positive symptoms
3.4 No clinically significant response on negative symptoms, as defined by each of the studies
3.5 Average score/change in negative symptoms
3.6 Use of additional medication (other than anticholinergics) for psychiatric symptoms
4. Extrapyramidal adverse effects
4.1 Use of antiparkinson drugs
4.2 No clinically significant extrapyramidal adverse effects, as defined by each of the studies
4.3 Average score/change in extrapyramidal adverse effects
5. Other adverse effects
5.1 General and specific (including deaths by suicide or natural causes)
6. Service utilisation outcomes
6.1 Days in hospital
7. Economic outcomes
8. Quality of life/satisfaction with care for either recipients of care or carers
8.1 Significant change in quality of life/satisfaction, as defined by each of the studies
8.2 Average score/change in quality of life/satisfaction
9. 'Summary of findings' table
We used the GRADE approach to interpret findings and used GRADEpro to import data from RevMan 5.1 to create 'Summary of findings' tables (Schünemann 2008). These tables provide outcome‐specific information concerning the overall quality of evidence from each included study in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on all outcomes we rated as important to patient‐care and decision making. We selected the following main outcomes for inclusion in the 'Summary of findings' table:
-
Mental state ‐ no clinically significant response
-
Leaving the study early ‐ for any reason
-
Global state ‐ no significant clinical improvement
-
Adverse events ‐ extrapyramidal effects
Search methods for identification of studies
Electronic searches
1. Cochrane Schizophrenia Group Trials Register
On 19th October 2015, the Trials Search Co‐ordinator searched the Cochrane Schizophrenia Group Trials Register using the following search strategy:
((risperidone* or Risperdal*) AND placebo*):ti,ab of REFERENCES or ((risperidone* or Risperdal*) AND placebo*):sin of STUDIES
The Cochrane Schizophrenia Group Trials Register is compiled by systematic searches of major resources (including AMED, BIOSIS, CINAHL, EMBASE, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings (see Group Module). There are no language, date, document type, or publication status limitations for inclusion of records into the register.
For details of the previous search, please see Appendix 1.
Searching other resources
1. Reference lists
We searched all references of the reports of included trials for further relevant studies.
2. Authors of studies
When necessary, we contacted authors of studies to clarify data and request additional studies, but received no response. We also contacted authors for information on any published or unpublished additional studies that they were aware of, but again, received no response.
3. Pharmaceutical companies
We contacted relevant pharmaceutical companies for additional studies and to clarify study data. However, we did not receive any further information.
Data collection and analysis
We have updated some text of the methods to reflect changes and updates in Cochrane methodology; please see Appendix 2 for details of methods used in original version.
Selection of studies
Two review authors (RR, MJ) independently inspected all reports of studies identified for the original search. Any disagreements were resolved by consensus; where doubt remained, we acquired the full article. Review authors (RR, BL and JX) independently decided whether these studies met the review criteria. We did not intend to blind the names of authors, institutions, and journal of publication. Again, any disagreements were resolved by consensus. When this was not possible, we sought further information and, in the interim, added these trials to the Studies awaiting classification list.
SS screended results from 2013 search and review authors SZ and BL independently inspected citations from the subsequent updated search (19th October 2015) to identify relevant abstracts. We obtained and inspected full reports of the abstracts meeting the review criteria.
Data extraction and management
1. Extraction
Review authors RR, MJ (original search), SS (2013 search), SZ, BL (2015 search) independently extracted data from all included studies. In addition, to ensure reliability, JX independently extracted data from a random sample of these studies comprising 10% of the total. Again, we discussed any disagreements and documented decisions. The need did not arise, but we had planned to extract data presented only in graphs and figures whenever possible, while only including the data if two review authors independently reached the same result. We also attempted to contact authors through an open‐ended request in order to obtain missing information or for clarification whenever necessary.
2. Management
2.1 Forms
We extracted data on to standard, simple forms.
2.2 Scale‐derived data
We included continuous data from rating scales only if:
a. the psychometric properties of the measuring instrument have been described in a peer‐reviewed journal (Marshall 2000); and
b. the measuring instrument was not written or modified by one of the trialists for that particular trial.
2.3 Endpoint versus change data
Both endpoint and change data have advantages. Change data can remove a component of between‐person variability from the analysis. On the other hand, calculation of change needs two assessments (baseline and endpoint), which can be difficult in unstable and hard‐to‐measure conditions such as schizophrenia. We decided to primarily use endpoint data, and only use change data if the former were not available. We combined endpoint and change data in the analysis, as we used mean differences (MD) rather than standardised mean differences (SMD) throughout (Higgins 2011, Chapter 9.4.5.2).
2.4 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, we aimed to apply the following standards to all data before inclusion: a) standard deviations and means are reported in the paper or obtainable from the authors; b) when a scale starts from the finite number 0, the standard deviation, when multiplied by 2, is less than the mean (as otherwise the mean is unlikely to be an appropriate measure of the centre of the distribution (Altman 1996)); c) if a scale started from a positive value (such as the Positive and Negative Syndrome Scale (PANSS), which can have values from 30 to 210), we modified the calculation described above to take the scale starting point into account. In these cases, skew is present if 2 SD > (S ‐ S min), where S is the mean score and S min is the minimum score. Endpoint scores on scales often have a finite start and endpoint, and these rules can be applied. We entered skewed endpoint data from studies of fewer than 200 participants in 'other tables' within the Data and analyses section rather than into a statistical analysis. Skewed data pose less of a problem when looking at mean if the sample size is large; we entered such data from studies with over 200 participants into syntheses. When continuous data are presented on a scale that includes a possibility of negative values (such as change data), it is difficult to tell whether data are skewed or not, we entered skewed change data into analyses.
2.5 Common measure
Had we identified such data, we intended to convert variables that can be reported in different metrics, such as days in hospital (mean days per year, per week, or per month) to a common metric (for example mean days per month) to facilitate comparison between trials. However, we did not identify such data.
2.6 Conversion of continuous to binary
Where possible, we made efforts to convert outcome measures to dichotomous data. This can be done by identifying cutoff points on rating scales and dividing participants accordingly into 'clinically improved' or 'not clinically improved'. It is generally assumed that if there is a 50% reduction in a scale‐derived score such as the Brief Psychiatric Rating Scale, Overall 1962, or the PANSS, Kay 1986, this could be considered as a clinically significant response (Leucht 2005a; Leucht 2005b). If data based on these thresholds were not available, we used the primary cutoff the original authors presented. Some included studies provided a definition of response as a reduction in PANSS or Clinical Global Impression scores, in which case we employed the dichotomous data provided from the primary study report.
2.7 Direction of graphs
Where possible, we entered data in such a way that the area to the left of the line of no effect indicated a favourable outcome for risperidone.
Assessment of risk of bias in included studies
For the update, two review authors (SZ, BL) independently used the criteria described in the Cochrane Handbook for Systematic Reviews of InterventionsHiggins 2011to assess trial quality (Higgins 2011). This new set of criteria is based on evidence of associations between overestimate of effect and high risk of bias of the article such as sequence generation, allocation concealment, blinding, incomplete outcome data, and selective reporting.
Where details of randomisation and other characteristics of trials were inadequate, we contacted authors of the studies to obtain additional information.
We have noted the level of risk of bias in both the text of the review and in Summary of findings table 1 and summary of findings Table 2.
Measures of treatment effect
1. Binary data
For binary outcomes, we calculated a standard estimation of the risk ratio (RR) and its 95% confidence interval (CI). It has been shown that RR is more intuitive than odds ratios and that clinicians tend to interpret odds ratios as RR (Boissel 1999; Deeks 2000). The number needed to treat to harm statistic with its CIs is intuitively attractive to clinicians but is problematic both in its accurate calculation in meta‐analyses and in its interpretation (Hutton 2009). For binary data presented in the 'Summary of findings' table/s, where possible, we calculated illustrative comparative risks.
2. Continuous data
For continuous outcomes, we estimated MD between groups. We preferred not to calculate effect size measures (SMD). However, if scales of very considerable similarity were used, we presumed there was a small difference in measurement, and we calculated effect size and transformed the effect back to the units of one or more of the specific instruments.
Unit of analysis issues
To facilitate comparison between trials, we intended to convert variables (such as days in hospital) that can be reported in different metrics (mean days per year, per week, or per month) to a common metric (for example mean days per month), but no studies reported data for these types of outcomes.
Dealing with missing data
1. Overall loss of credibility
At some degree of loss of follow‐up, data loses credibility (Xia 2009). For outcomes where more than 50% of data were unaccounted for, we intended to not reproduce these data or use them within analyses. If more than 50% of data in one arm of a study were lost, but the total loss was less than 50%, we intended to mark data with (*) to indicate that such a result may well be prone to bias.
2. Binary
In cases where attrition for a binary outcome was between 0% and 50% and where these data were not clearly described, we presented data on a 'once‐randomised‐always‐analyse' basis wherever possible (an intention‐to‐treat (ITT) analysis). For every outcome with the exception of the outcome of death, we had planned to assume those participants leaving the study early to have the same rates of negative outcome as those who completed. However, doing this drastically changed the significance of many outcomes and sometimes the direction of significant results, so we only presented data that was already available from the studies to reduce the risk of making incorrect assumptions.
3. Continuous
3.1 Attrition
In cases where attrition for a continuous outcome was between 0% and 50% and completer‐only data were reported, we reproduced these.
3.2 Standard deviations
We didn't need to calculate any standard deviations (SD) in this review, but our protocol stated that we would first try to obtain missing values from the authors. If not available, where measures of variance for continuous data were missing but an exact standard error (SE) and CI were available for group means, and either the P value or t value was available for differences in means, we calculated SDs according to the rules described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). When only the SE was reported, we would calculate SDs using the formula SD = SE * square root (n). Sections 7.7.3 and 16.1.3 of the Cochrane Handbook for Systematic Reviews of InterventionsHiggins 2011present detailed formulae for estimating SDs from P values, t or F values, CIs, or other statistics (Higgins 2011). If these formulae did not apply, we would calculate the SDs according to a validated imputation method that is based on the SDs of the other included studies (Furukawa 2006). Although some of these imputation strategies can introduce error, the alternative would be to exclude a given study’s outcome and thus to lose information. We would nevertheless examine the validity of the imputations in a sensitivity analysis excluding imputed values.
3.3 Last observation carried forward
We anticipated that some studies would employ the method of last observation carried forward (LOCF). As with all methods of imputation to deal with missing data, LOCF introduces uncertainty about the reliability of the results. Therefore, where a trial used LOCF data, if less than 50% of the data were assumed, we reproduced these data and indicated that they were the product of LOCF assumptions.
Assessment of heterogeneity
Firstly, we considered all the included studies within any comparison to judge clinical heterogeneity. We then visually inspected the graphs in order to investigate the possibility of statistical heterogeneity; to supplement this we used, primarily, the I2 statistic, which provides an estimate of the percentage of variability due to heterogeneity rather than due to chance alone. Where the I2 estimate was greater than or equal to 75%, we interpreted this as indicating the presence of high levels of heterogeneity (Higgins 2003). If inconsistency became high, we did not summate data, but presented it separately, and we investigated the reasons for heterogeneity.
Assessment of reporting biases
In order to investigate the likelihood of overt publication bias, we entered all data from all identified and selected trials into a funnel graph (trial effect against trial size) (Egger 1997).
Data synthesis
We understand that there is no closed argument for preference for use of fixed‐effect or random‐effects models. We used the random‐effects model for all analyses due to the potential for heterogeneity between studies. The random‐effects method incorporates an assumption that the different studies are estimating different, yet related, intervention effects. This often seems to be true to us, and the random‐effects model takes into account differences between studies even if there is no statistically significant heterogeneity. However, there is a disadvantage to the random‐effects model. It puts added weight on to small studies, which are often the most biased ones. Depending on the direction of effect, these studies can either inflate or deflate the effect size.
Subgroup analysis and investigation of heterogeneity
If data were clearly heterogeneous, we checked that they had been extracted and entered correctly, and that we had made no unit of analysis errors. If the high levels of heterogeneity remained, we did not undertake a meta‐analysis at this point, because if there is considerable variation in results, and particularly if there is inconsistency in the direction of effect, it may be misleading to quote an average value for the intervention effect. We prespecified no characteristics of studies that may be associated with heterogeneity except quality of trial method.
Sensitivity analysis
If studies had high attrition rates, we analysed the effect of including these studies in a sensitivity analysis, but we did not include any figures with more than 50% attrition in the analysis of efficacy. Where a trial was described as 'double‐blind', but it was implied that the study was randomised, we had intended to include such studies in the sensitivity analysis, but we did not come across any such studies.
Results
Description of studies
For a substantial description of each study, please refer to the relevant tables:Characteristics of included studies, Characteristics of excluded studies, Characteristics of ongoing studies.
Results of the search
The initial search resulted in 815 citations. We were able to include 42 references, relating to only 10 studies from which we could extract useable data. We used information regarding unpublished data from trials on risperidone available to the Cochrane Schizophrenia Group from drug companies. The update searches run in 2013 and 2015 yielded 94 citations, of which 5 new studies were included.
In total up to the current update, 909 citations were identified from the search process in total. After removing duplicates, 763 unique records were screened by viewing titles and abstracts. A total number of 116 studies with 406 full‐text articles were screened for eligibility. Finally, 86 studies with 337 references were excluded, 14 studies with 24 references are awaiting assessment due to lack of full‐texts and one study was onging trial, which resulted in 15 studies with 56 references being included in the data and analysis (see Figure 2 for study flow diagram).
Study flow diagram.
Included studies
1. Length of trials
Fourteen studies reported data on short‐term follow‐up, and only 1 study reported medium‐term outcomes (Bachmann 2003), but even that was only at 16 weeks. Two studies were of 4 weeks duration (Potkin 1997; Potkin 2003), 6 studies were 6‐weeks long (Borison 1992; Geffen 2010; Heisterberg 2007; Potkin 2006; Potkin 2007; Yagcioglu 2005), 3 studies were 8 weeks from start to finish (Chouinard 1992; Honer 2006; Marder 1994a), 2 studies were 9 weeks from start to finish (Downing 2014; Durgam 2014) and 1 study was 12 weeks in duration (Pai 2002).
2. Participants
Amongst our included studies, two included participants with no clear operational diagnostic criteria and simply stated "schizophrenia" (Potkin 1997; Potkin 2007). Nine studies included people with a sole diagnosis of schizophrenia as per Diagnostic Statistical Manual of Mental Disorders (DSM) criteria (Borison 1992; Chouinard 1992; Downing 2014; Durgam 2014; Geffen 2010; Heisterberg 2007; Marder 1994a; Pai 2002; Yagcioglu 2005), and the remaining four studies included participants with a diagnosis of schizophrenia or schizoaffective disorder as per DSM criteria (Bachmann 2003; Honer 2006; Potkin 2003; Potkin 2006).
Potkin 2007 did not report the sex of participants in the study. All other studies included both men and women, but the majority of participants were male. Most participants were aged between late 30s and early 40s.
Two studies did not have definitive exclusion criteria (Heisterberg 2007; Potkin 1997). The remaining studies excluded people with alcohol and substance misuse, as well as pregnant or breastfeeding women. Yagcioglu 2005 excluded people who were intolerant to risperidone in the past, Potkin 2003 excluded people being treated with risperidone at baseline, and Potkin 2006 excluded people who had received risperidone within the last seven days. Marder 1994a excluded people with schizoaffective disorder, and Potkin 2006 excluded people with borderline personality disorder. Potkin 2007 excluded people who had made a recent suicide attempt and who had serious suicidal thoughts.
3. Setting
Eight of the included studies took place in the inpatient setting (Borison 1992; Chouinard 1992; Downing 2014; Durgam 2014; Geffen 2010; Marder 1994a; Potkin 2003; Potkin 2006). Three studies involved both inpatients and outpatients (Bachmann 2003; Honer 2006; Yagcioglu 2005). We could not find any explicit information on setting for the remaining four studies (Heisterberg 2007; Pai 2002; Potkin 1997; Potkin 2007).
Studies were conducted in the USA (Bachmann 2003; Borison 1992; Geffen 2010; Marder 1994a; Potkin 1997; Potkin 2003; Potkin 2006; Potkin 2007), Canada (Chouinard 1992; Honer 2006), India (Geffen 2010), Romania (Geffen 2010), Denmark (Heisterberg 2007), and Turkey (Yagcioglu 2005). One studies recruited participants internationally from 65 study centres in the United States, India, Russia, Ukraine, and Malaysia.
4. Study size
The largest study was Downing 2014, which randmised 1009 people to four groups, among which, 437 participants were assigned to either resperidone or placebo group. Heisterberg 2007 randomised 303 people to receive either risperidone or placebo. Durgam 2014 randomised 729 people to five groups, however, only 291 participants were assigned to either resperidone or placebo group. Where a study randomised different doses of risperidone in different arms, as well as having a separate placebo arm, we tried to take data from the risperidone arm that best fitted with the average doses across studies. For example, as the mean dose of risperidone for all the other trials was 5.5 mg per day, we took the 6 mg arm from the Marder 1994a and Chouinard 1992 trials for efficacy measures in the meta‐analysis. In Potkin 1997, which had two risperidone arms of 4 mg and 8 mg, we took the 4 mg arm for efficacy measures in the meta‐analysis, as this was closer than the 8 mg arm to the mean of 5.5 mg. Potkin 2006 randomised 226 people, Potkin 2003 202, Marder 1994a 130, Chouinard 1992 44, and Potkin 1997 168. The rest of the studies ranged between 24 and 121 participants.
5. Interventions
5.1 Risperidone
The dose of risperidone administered by the trialists varied from 2 mg up to 10 mg per day.
5.2 Placebo
All studies had a placebo arm, and most had another arm with an active treatment in addition to risperidone. Borison 1992, Marder 1994a, and Chouinard 1992 had an arm for haloperidol. Downing 2014 had two arms for LY2140023 with low dosage or high dosage. Durgam 2014 had three arms of cariprazine with low, medium or high dosage. Geffen 2010 had two additional arms for a low dose and a high dose of BL‐1020. Marder 1994a and Chouinard 1992 also had four different risperidone arms with daily doses of 2 mg, 6 mg, 10 mg, and 16 mg. We used the 6 mg arm from the Marder 1994a and Chouinard 1992 trials for efficacy measures in the meta‐analysis and the 4 mg arm data from Potkin 1997. Heisterberg 2007 used bifeprunox as the other arm, Potkin 2003 aripiprazole, Potkin 2006 quetiapine, and Potkin 2007 asenapine.
5.3 Augmentation
In three studies the risperidone and placebo arms were combined with clozapine (Bachmann 2003; Honer 2006; Yagcioglu 2005).
6. Outcomes
Our primary outcome measures were mental state and service utilisation; no data were available for service utilisation. Other outcomes of interest were leaving the study early, global state, adverse effects, and quality of life.
6.1 Mental state
The trials used several different rating scales to report on mental state. Heisterberg 2007 did not report useable data on mental state, and we could not use the Positive and Negative Symptom Scale (PANSS) data from Potkin 2007 as this trial had more than 50% attrition. Downing 2014 only reported means of PANSS score in each group, therefore we are unable to use the data. All other trials used either the PANSS or the Brief Psychiatric Rating Scale to measure this outcome. Wherever possible, we used the binary data from these measures, but the validity of dichotomising these measures, although widely accepted, is, nevertheless, unclear.
6.2 Leaving the study early
All included trials provided useable data on the number of participants leaving the study early.
6.3 Global state
Five of the included studies reported global change using the Clinical Global Impression (CGI) scale (Durgam 2014, Honer 2006, Marder 1994a, Potkin 2003, Potkin 2006). Yagcioglu 2005 used both the CGI and the Global Assessment of Functioning Scale.
6.4 Adverse effects
Adverse effects are an important outcome measure from any trial. We were able to pool data on adverse effects from the majority of trials; some data was skewed and is presented in additional tables.
6.5 Quality of life
were only presented by Only Yagcioglu 2005 presented quality of life data.
6.6 Missing outcomes
No data were available for service utilisation or economic outcomes.
6.7 Outcome scales
6.7.1 Global state scales
6.7.1.1 Clinical Global Impression (Guy 1976)
The CGI scale was 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. It is a seven‐point scoring system with low scores showing decreased severity or overall improvement, or both.
6.7.1.2 Global Assessment of Functioning Scale (DSM‐IV‐TR)
The GAF scale is a numeric scale (0 through 100) used by mental‐health clinicians and doctors to rate the social, occupational, and psychological functioning of adults. The scale is presented and described in the DSM‐IV‐TR on page 32 (Table 2).
| Score | Judgement |
| 91‐100 | Superior functioning in a wide range of activities, life's problems never seem to get out of hand, is sought out by others because of his or her many qualities. No symptoms. |
| 81‐90 | Absent or minimal symptoms, good functioning in all areas, interested and involved in a wide range of activities, socially effective, generally satisfied with life, no more than everyday problems or concerns. |
| 71‐80 | If symptoms are present they are transient and expectable reactions to psychosocial stresses; no more than slight impairment in social, occupational, or school functioning. |
| 61‐70 | Some mild symptoms OR some difficulty in social, occupational, or school functioning, but generally functioning pretty well, has some meaningful interpersonal relationships. |
| 51‐60 | Moderate symptoms OR any moderate difficulty in social, occupational, or school functioning. |
| 41‐50 | Serious symptoms OR any serious impairment in social, occupational, or school functioning. |
| 31‐40 | Some impairment in reality testing or communication OR major impairment in several areas, such as work or school, family relations, judgement, thinking, or mood. |
| 21‐30 | Behavior is considerably influenced by delusions or hallucinations OR serious impairment in communications or judgment OR inability to function in all areas. |
| 11‐20 | Some danger of hurting self or others OR occasionally fails to maintain minimal personal hygiene OR gross impairment in communication. |
| 1‐10 | Persistent danger of severely hurting self or others OR persistent inability to maintain minimum personal hygiene OR serious suicidal act with clear expectation of death. |
| 0 | Not enough information available to provide GAF. |
6.7.2 Mental state scales
6.7.2.1 Positive and Negative Syndrome Scale (Kay 1986)
The PANSS is used for measuring symptom severity of people with schizophrenia. It is widely used in the study of antipsychotic therapy. The name refers to the two types of symptoms in schizophrenia, as defined by the American Psychiatric Association: positive symptoms, which refer to an excess or distortion of normal functions, and negative symptoms, which represent a diminution or loss of normal functions.
6.7.2.2 Brief Psychiatric Rating Scale (Overall 1962)
The BPRS consists of 18 items on a 7‐point severity scale. Initially published as a 16‐item scale in 1962, the standard 18‐item version has been used since 1967 to successfully demonstrate efficacy of antidepressants, anti‐anxiety drugs, and antipsychotics, including the newer 'atypical' antipsychotics. The BPRS has also been used in epidemiological studies, geropsychiatric research, and to compare diagnostic concepts between countries. It is most frequently used in schizophrenia. When using BPRS, rater training is a must and the use of a standardised interview is highly recommended in order to ascertain consistent results.
6.7.2.3 Calgary Depression Scale for Schizophrenia (Addington 1993)
Developed at the University of Calgary, the CDSS specifically assesses the level of depression in schizophrenia. It has been extensively evaluated in both relapsed and remitted patients and appears sensitive to change.
6.7.2.4 Scale for the Assessment of Negative Symptoms (Andreasen 1981)
The SANS assesses affective blunting, alogia, avolition/apathy, anhedonia/asociality, and disturbance of attention to measure negative symptoms in schizophrenia.
6.7.3 Adverse effects scales
6.7.3.1 Barnes Akathisia Scale (Barnes 1989)
The Barnes Akathisia Scale (commonly known as BAS or BARS) is a four‐item rating scale administered by physicians to assess the severity of drug‐induced akathisia. The most widely used scale for akathisia, it includes both objective items (e.g. observed restlessness) and subjective items (e.g. patient's awareness of restlessness and related distress), together with a global clinical assessment of akathisia. Global assessment is made on a scale of 0 to 5, with comprehensive definitions provided for each anchor point on the scale: 0 = absent; 1 = questionable; 2 = mild akathisia; 3 = moderate akathisia; 4 = marked akathisia; 5 = severe akathisia.
6.7.3.2 Extrapyramidal Symptom Rating Scale (Chouinard 1993)
The ESRS is a physician‐rated scale for measuring extrapyramidal adverse effects from antipsychotic medication. It takes approximately 10 minutes and involves 6 questions about the person’s subjective experience of extrapyramidal features (slowness, stiffness, and tremor); a standardised procedure for physical examination; and 7 rater‐assessed items that address parkinsonian features (rigidity and tremor). The instrument may not differentiate effectively between dyskinesia and dystonia.
6.7.3.3 Simpson Angus Scale (Simpson 1970)
The SAS is a 10‐item instrument used to evaluate the presence and severity of parkinsonian symptomatology specifically in patients who may be experiencing drug‐induced parkinsonism and other extrapyramidal effects. For the past 25 years it has been the most commonly used rating scale for parkinsonism in clinical trials. The 10 items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0 to 4 scale, with definitions given for each anchor point.
6.7.3.4 Abnormal Involuntary Movement Scale (Guy 1976)
The AIMS is a 12‐item clinician‐rated scale to assess severity of dyskinesias including orofacial movements, extremity and truncal movements in patients taking neuroleptic medications.
6.7.3.5 The UKU side effect rating scale (Lingjaerde 1987)
UKU is a 48 item clinician‐rated scale to assess the side effects of psychopharmacological medications. The interview takes anywhere from 10‐30 minutes depending on the number of symptoms reported, the complexity of the symptoms, and the patient’s ability to provide good report.
6.7.4 Quality of life scales
6.7.4.1 Quality of Life Scale (Carpenter 1994)
The QLS is a 21‐item scale rated from a semistructured interview providing information on symptoms and functioning during the preceding 4 weeks. It is intended to be administered by a trained clinician and requires about 45 minutes to complete. Each item is rated on a 7‐point scale and, in all but 2 cases, requires a judgement by the clinician/interviewer. Each item is comprised of 3 parts: (1) a brief descriptive statement to focus the interviewer on the judgement to be made; (2) a set of suggested probes; and (3) the 7‐point scale with descriptive anchors for every other point. The specific descriptions vary among items, but the high end of the scales (scores 5 and 6) reflects normal or unimpaired functioning, and the low end of the scales (scores 0 and 1) reflects severe impairment of the function in question. The interviewer is instructed to probe around each item until he or she has an adequate basis for making the required judgement, and is encouraged to go beyond the suggested probes with questions tailored for the individual patient. Thus the experience of both the patient and interviewer is similar to a careful clinical interview.
6.7.5 Cognitive function scales
6.7.5.1 Groton Maze Learning Test (Pietrzak 2008) (used in an ongoing study)
The GMLT assesses processing speed, working memory, and aspects of executive function in healthy adults. Performance on GMLT outcome measures can be compared to performance on tests of psychomotor speed, working memory, and learning from the Cogstate computerized cognitive test battery. Studies suggest that the GMLT measures of spatial learning efficiency and error monitoring correlate with Cogstate measures of attention, working memory, and learning. Exploratory factor analyses have yielded a two‐factor solution of error monitoring and learning efficiency, which have been stable across repeated assessments.
6.8 Of note
Borison 1992: In 1997 the first author and his colleague, Diamond, were convicted in the US courts (AHRP 2006; CBS News 2000CBS News 2000AHRP 2006). For example, one website states: “Diamond, a Ph.D. pharmacologist who had performed more than 300 trials over the course of his career on patients who assumed he was an M.D., was convicted in 1997 on 53 criminal counts, including practicing medicine without a license, theft, prescribing medications without a license, fraud, false statements, tax evasion and bribery. Although he admitted to a growing greed that led to some of his illegal practices, Diamond maintained that the pair had never fabricated research data.” We have continued to include data from this small study.
Excluded studies
We excluded 86 studies, 7 of which were not randomised (David 2000; Davis 2001; Baker 2012; Castle 2015; Kinon 2015; Marder 1991; Pikalov 2012). We excluded seven studies due to their populations not including people with schizophrenia (Anwunah 1999; Ayd 2001; NCT00088075; NCT00305474; Siever 2002; Anwunah 1999; Schmechtig 2010). The remaining excluded studies did not directly compare oral risperidone with placebo.
Ongoing studies
We identified one ongoing study. NCT00174200 is assessing the effects of risperidone (2 mg daily) on the differential sensitivity of two spatial working memory tests in non‐agitated, drug‐naive people suffering from first‐episode schizophrenia or schizophreniform disorder. They intend to enrol 20 patients for the trial. Pfizer is sponsoring the study.
Awaiting assessment
Fourteen studies are awaiting assessment as sufficient information is not currently available (Anon 2010; Litman 2014; NCT 00694707; Vanover 2014; Nisenbaum 2013; Xu 2009; Bose 2010a; Cavazzoni 2002; DeMartinis 2012; GlaxoSmithKline 2006; NCT01086748; NCT01175135; NCT01363349; Rujescu 2009).
Risk of bias in included studies
Pharmaceutical companies funded 8 out of the 15 included trials. We did our best to collect as much information as possible from different sources about the types of biases that could have occurred during these trials, and have presented the results of our investigations in the following paragraphs. Figure 3 and Figure 4 presents the summary of risk of bias in included studies.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Allocation
All included studies were said to be randomised, but many did not explicitly describe the method by which this was undertaken. Bachmann 2003 utilised randomisation that was stratified by inpatient status; no further details were provided. Honer 2006 used a computer‐generated schedule with a permuted‐block design to generate sequences. Marder 1994a and Chouinard 1992 undertook randomisation in blocks of 12. Geffen 2010 and Potkin 2006 both used a centralised interactive voice response system for allocation concealment. Although Yagcioglu 2005 used a pre‐assigned random sequence for each of their study sites that was developed before the start of their study no further details were provided. The rest of the studies provided no information about the process of randomisation (Borison 1992; Downing 2014; Durgam 2014; Heisterberg 2007; Pai 2002; Potkin 1997; Potkin 2003; Potkin 2007; Potkin 2003; Potkin 1997; Pai 2002; Heisterberg 2007; Borison 1992), despite this having been repeatedly shown to be of key importance in excluding selection biases (Juni 2001).
Blinding
All the included studies were described as double blind, with some describing how this was achieved. Blinding is important for minimising observation bias and, because many of the outcomes were subjective.
Incomplete outcome data
Bachmann 2003, Downing 2014, Durgam 2014, Geffen 2010, Heisterberg 2007, Marder 1994a, Chouinard 1992, and Potkin 2006 used an intention‐to‐treat (ITT) analysis. Honer 2006, Yagcioglu 2005 and Durgam 2014 used the ITT principle in a mixed‐model analysis. Potkin 2007 used ITT for the efficacy data and last observation carried forward (LOCF) for safety data.
We judged Pai 2002 and Borison 1992 to have a high risk of bias, as they did not consider in their analysis the data of participants who left early. We judged Potkin 1997 to be at unclear risk of bias, as no information about loss to follow‐up was provided. Potkin 2003 used the LOCF method to manage their loss to follow‐up, but as they had over 40% loss, we downgraded this category because such a high attrition rate makes data prone to bias. None of the trials attempted to validate assumptions by following up participants who did leave early.
Selective reporting
We were unable to obtain original study protocol, however, the included studies appear to have reported the results for all the outcomes listed in their methods sections. Based on the information available, we did not detect any obvious act of selective reporting.
Other potential sources of bias
1. Poor reporting
We could not use much data because of poor reporting. Findings that are presented as graphs, in percentiles, or simply reported as inexact P values were of little use to us as review authors. Many studies failed to provide standard deviations (SDs) when reporting mean changes. We are seeking further data from the first authors of relevant trials.
2. Industry
Pharmaceutical companies funded 8 out of the 13 included trials, with the majority of these funded by a company that would profit from finding beneficial effects of risperidone.
Effects of interventions
See: Summary of findings for the main comparison RISPERIDONE compared to PLACEBO for schizophrenia; Summary of findings 2 RISPERIDONE + CLOZAPINE compared to PLACEBO + CLOZAPINE for schizophrenia
Studies relevant to this review fall into three comparisons. We identified 15 randomised trials from which it is possible to extract numerical data.
1. COMPARISON 1: RISPERIDONE versus PLACEBO
This comparison has 20 outcomes.
1.1 Mental state: no clinically significant response in psychotic symptoms (defined by various scale total score change) ‐ short term (up to 12 weeks)
1.1.1 defined by PANSS < 30% decline
Three trials with a total of 707 participants provided data for this subset . We did find evidence that 'risperidone' was clearly different in its effects compared with 'placebo' (RR 0.74, 95% CI 0.67 to 0.83) (Analysis 1.1).
1.1.2 defined by PANSS/BPRS < 20% decline
Six trials with a total of 864 participants provided data for this subset. We did find evidence that 'risperidone' was clearly different in its effects compared with 'placebo' (RR 0.64, 95% CI 0.52 to 0.78). This subgroup had important levels of heterogeneity (Chi2 = 12.27; df = 5.0; P = 0.03; I2 = 59%) (Analysis 1.1).
1.2 Leaving the study early ‐ short term (up to 12 weeks)
1.2.1 any reason
There were 12 relevant trials, with a total of 2261 participants providing data for numbers leaving the study early for any reason. We did find evidence that 'risperidone' was clearly different in its effects compared with 'placebo' (RR 0.69, 95% CI 0.62 to 0.78). There are moderate levels of heterogeneity (Chi2 = 14.73; df = 11; P = 0.20; I2 = 25%) (Analysis 1.2).
1.2.2 due to adverse events
There were 10 relevant trials, with a total of 2081 participants, providing data for this subset. There was not a clear difference between 'risperidone' and 'placebo' (RR 0.78, 95% CI 0.59 to 1.03) (Analysis 1.2).
1.2.3 due to lack of efficacy
Eleven trials, with a total of 2211 participants provided data for this subset We found evidence of a clear difference between 'risperidone' and 'placebo' (RR 0.39, 95% CI 0.29 to 0.51). There are moderate levels of heterogeneity (Chi2 = 14.70; df = 10; P = 0.14; I2 = 32%) (Analysis 1.2).
1.2.4 due to non‐compliance
We found 4 trials to be relevant to this subset, with a total of 534 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.15, 95% CI 0.33 to 4.05) (Analysis 1.2).
1.2.5 lost to follow‐up
We found 6 trials to be relevant to this subset, with a total of 1545 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 0.79, 95% CI 0.25 to 2.56). This subset had important levels of heterogeneity (Chi2 = 11.97; df = 4.0; P = 0.02; I2 = 67%) (Analysis 1.2).
1.2.6 protocol violation
We found 4 trials to be relevant to this subset, with a total of 1257 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 0.79, 95% CI 0.39 to 1.62) (Analysis 1.2).
1.2.7 reported death
There were 10 relevant trials in this subset, with a total of 1532 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 3.07, 95% CI 0.13 to 74.28) (Analysis 1.2).
1.2.8 withdrawal of consent
We found 7 trials to be relevant to this subset, with a total of 1589 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.12, 95% CI 0.80 to 1.56) (Analysis 1.2).
1.2.9 other
There were 3 relevant trials in this subset, with a total of 615 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.03, 95% CI 0.68 to 1.57) (Analysis 1.2).
1.3 Global state: 1. average endpoint scores of CGI severity scale (high = poor) ‐ short term (up to 12 weeks)
We identified 3 studies relevant to this outcome, with a total of 457 participants. This outcome had no subsets. We found evidence of a clear difference between 'risperidone' and 'placebo' (MD ‐0.81, 95% CI ‐0.89 to ‐0.73) (Analysis 1.3).
1.4 Global state: 2. no significant clinical improvement ‐ short term (up to 12 weeks)
For this outcome we found 4 relevant studies involving 594 participants. There were no subsets in this outcome. We found evidence of a clear difference between 'risperidone' and 'placebo' (RR 0.69, 95% CI 0.57 to 0.83). For this outcome heterogeneity was moderately high (Chi2 = 5.43; df = 3.0; P = 0.14; I2 = 44%) (Analysis 1.4).
1.5 Global state: 3. needing additional medication ‐ short term (up to 12 weeks)
For this outcome we found six relevant studies, the data from which we divided into seven subsets.
1.5.1 benzodiazepine
There was a single trial in this subset, with a total of 42 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.96, 95% CI 0.77 to 1.2) (Analysis 1.5).
1.5.2 benzodiazepine derivatives ‐ lorazepam
There were 2 relevant trials in this subset, with a total of 228 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 0.93, 95% CI 0.68 to 1.27) (Analysis 1.5).
1.5.3 benzodiazepine derivatives ‐ Nitrazepam
There was a single trial in this subset, with a total of 184 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.51, 95% CI 0.10 to 2.72) (Analysis 1.5).
1.5.4 benzodiazepine related drugs ‐ Zolpidem
We found 1 trial to be relevant to this subset, with a total of 184 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.81, 95% CI 0.53 to 1.23) (Analysis 1.5).
1.5.5 sedative/hypnotic
We found 2 trials to be relevant to this subset, with a total of 230 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.86, 95% CI 0.69 to 1.06) (Analysis 1.5).
1.5.6 antiparkinsonian
There were 2 relevant trials in this subset, with a total of 172 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.21, 95% CI 0.79 to 1.86) (Analysis 1.5).
1.5.7 psychotropics
We found 1 trial to be relevant to this subset, with a total of 186 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (RR 0.62, 95% CI 0.45 to 0.85) (Analysis 1.5).
1.6 Mental state: 1. average endpoint scores on various scales on psychotic symptoms (high = poor) ‐ short term (up to 12 weeks)
We identified three studies relevant to this outcome, the data from which we divided into five subsets.
1.6.1 BPRS total
We found 2 trials to be relevant to this subset, with a total of 171 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (MD ‐12.69, 95% CI ‐17.06 to ‐8.32) (Analysis 1.6).
1.6.2 PANSS total
We found 3 trials to be relevant to this subset, with a total of 457 participants. For this outcome, within this subset, we did find evidence that 'risperidone' was clearly different in its effects compared with 'placebo' (MD ‐17.81, 95% CI ‐18.17 to ‐17.45) (Analysis 1.6).
1.6.3 PANSS general pathology
There was a single trial in this subset, with a total of 44 participants. For this outcome, within this subset, we did find evidence that 'risperidone' was clearly different in its effects compared with 'placebo' (MD ‐13.20, 95% CI ‐20.15 to ‐6.25) (Analysis 1.6).
1.6.4 PANSS negative symptom
There were 3 relevant trials in this subset, with a total of 457 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (MD ‐3.10, 95% CI ‐3.19 to ‐3.01) (Analysis 1.6).
1.6.5 PANSS positive symptom
We found 3 trials to be relevant to this subset, with a total of 457 participants. For this outcome, within this subset, we did find evidence that 'risperidone' was clearly different in its effects compared with 'placebo' (MD ‐5.49, 95% CI ‐6.18 to ‐4.80) (Analysis 1.6).
1.7 Mental state: 2. skewed data ‐ short term (up to 12 weeks)
These continuous data, from two trials were skewed. Therefore we have reported these data in a separate data table (Analysis 1.7) .
1.8 Adverse effects: 1a. extrapyramidal ‐ various effects ‐ short term (up to 12 weeks)
We identified 11 studies relevant to this outcome, the data from which we divided into 12 subsets.
1.8.1 general ‐ any significant extrapyramidal symptom
We found 7 trials to be relevant to this subset, with a total of 1511 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.56, 95% CI 1.13 to 2.15) (Analysis 1.8).
1.8.2 general ‐ no improvement on AIMS score
There was a single trial in this subset, with a total of 42 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (RR 0.30, 95% CI 0.15 to 0.61) (Analysis 1.8).
1.8.3 general ‐ no improvement on BAS score
There was a single trial in this subset, with a total of 226 participants. For this outcome, within this subset, we did find evidence that 'risperidone' was clearly different in its effects compared with 'placebo' (RR 1.14, 95% CI 1.01 to 1.28) (Analysis 1.8).
1.8.4 general ‐ needing medication for EPS
We found 2 trials to be relevant to this subset, with a total of 94 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.14, 95% CI 0.78 to 1.67) (Analysis 1.8).
1.8.5 specific ‐ akathisia
We found 5 trials to be relevant to this subset, with a total of 1204 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (RR 2.58, 95% CI 1.41 to 4.72). For this subset heterogeneity was moderately high (Chi2 = 5.63; df = 4.0; P = 0.23; I2 = 29%). (Analysis 1.8).
1.8.6 specific ‐ bradykinesia
We found 2 trials to be relevant to this subset, with a total of 485 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.87, 95% CI 0.6 to 1.24) (Analysis 1.8).
1.8.7 specific ‐ dyskinesia
We found 1 trial to be relevant to this subset, with a total of 303 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 0.32, 95% CI 0.01 to 7.86) (Analysis 1.8).
1.8.8 specific ‐ dystonia
There were 3 relevant trials in this subset, with a total of 687 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 3.40, 95% CI 0.26 to 44.46). This subset had important levels of heterogeneity (Chi2 = 13.09; df = 2.0; P = 0.001; I2 = 84%) (Analysis 1.8).
1.8.9 specific ‐ hypertonia
There were 3 relevant trials in this subset, with a total of 505 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (RR 2.98, 95% CI 1.35 to 6.59). For this subset heterogeneity was moderately high (Chi2 = 2.87; df = 2.0; P = 0.24; I2 = 30%) (Analysis 1.8).
1.8.10 specific ‐ parkinsonism
We found 2 trials to be relevant to this subset, with a total of 485 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (RR 7.64, 95% CI 1.4 to 41.59) (Analysis 1.8).
1.8.11 specific ‐ tardive dyskinesia
There was a single trial in this subset, with a total of 303 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 6.77, 95% CI 0.35 to 130.03) (Analysis 1.8).
1.8.12 specific ‐ tremor
We found 5 trials to be relevant to this subset, with a total of 1204 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.60, 95% CI 0.89 to 2.88). This subset had moderate levels of heterogeneity (Chi2 = 5.86; df = 4.0; P = 0.21; I2 = 32%) (Analysis 1.8).
1.9 Adverse effects: 1b. extrapyramidal ‐ AIMS average endpoint score ‐ short term (up to 12 weeks)
For this outcome we found a single study. A greater reduction in AIMS scores were seen for people in the risperidone arm compared to the placebo arm (1 RCT, N=42, MD ‐5.50 95% CI ‐8.60 to ‐2.40) (Analysis 1.9).
1.10 Adverse effects: 1c. extrapyramidal ‐ skewed data (various scales) ‐ short term (up to 12 weeks)
These continuous data (four RCTs) had such large SDs as to suggest that analysis within RevMan would be inadvisable. Therefore, we have reported these data in a separate table (Analysis 1.10).
1.11 Adverse effects: 2. any adverse event ‐ short term (up to 12 weeks)
For this outcome we found 9 relevant studies and categorised data into 16 subsets.
1.11.1 any adverse event
There were 7 relevant trials in this subset, with a total of 1610 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.05, 95% CI 0.96 to 1.15). This subset had important levels of heterogeneity (Chi2 = 14.46; df = 6.0; P = 0.02; I2 = 58%) (Analysis 1.11).
1.11.2 asthenia
There were 2 trials in this subset, with a total of 639 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.93, 95% CI 0.62 to 6.02) (Analysis 1.11).
1.11.3 back pain
There was a single trial in this subset, with a total of 202 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.04, 95% CI 0.38 to 2.86) (Analysis 1.11).
1.11.4 blurred vision
There was a single trial in this subset, with a total of 202 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 4.16, 95% CI 0.47 to 36.59) (Analysis 1.11).
1.11.5 cogwheel rigidity
We found 1 trial to be relevant to this subset, with a total of 226 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 5.25, 95% CI 0.69 to 39.88) (Analysis 1.11).
1.11.6 death
We found 1 trial to be relevant to this subset, with a total of 182 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 3.13, 95% CI 0.13 to 75.92) (Analysis 1.11).
1.11.7 dental disorder
There was a single trial in this subset, with a total of 202 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 3.64, 95% CI 0.78 to 17.11) (Analysis 1.11).
1.11.8 dysmenorrhoea
There were two trials in this subset, with a total of 495 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.10, 95% CI 0.04 to 30.00) (Analysis 1.11).
1.11.9 fatigue
There were two trial in this subset, with a total of 558 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 2.23, 95% CI 0.69 to 7.22) (Analysis 1.11).
1.11.10 fever
We found 1 trial to be relevant to this subset, with a total of 130 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 9.28, 95% CI 0.51 to 168.9) (Analysis 1.11).
1.11.11 infection
We found 1 trial to be relevant to this subset, with a total of 202 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 0.52, 95% CI 0.10 to 2.78) (Analysis 1.11).
1.11.12 salivation ‐ increased
There was a single trial in this subset, with a total of 202 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 7.28, 95% CI 0.38 to 139.15) (Analysis 1.11).
1.11.13 pyrexia
We found 1 trial to be relevant to this subset, with a total of 182 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.19, 95% CI 0.45 to 3.16) (Analysis 1.11).
1.11.14 pain
There was a single trial in this subset, with a total of 121 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.58, 95% CI 0.47 to 5.31) (Analysis 1.11).
1.11.15 rash (skin)
There was a single trial in this subset, with a total of 202 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.19, 95% CI 0.45 to 3.16) (Analysis 1.11).
1.11.16 vaginitis
There was a single trial in this subset, with a total of 58 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.07, 95% CI 0.07 to 16.32) (Analysis 1.11).
1.12 Adverse effects: 3. cardiovascular ‐ short term (up to 12 weeks)
For this outcome we found four relevant studies and categorised data into seven subsets.
1.12.1 dizziness ‐ orthostatic
There was a single trial in this subset, with a total of 44 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 3.0, 95% CI 0.13 to 69.87) (Analysis 1.12).
1.12.2 ECG abnormal
We found 1 trial to be relevant to this subset, with a total of 182 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 9.40, 95% CI 0.51 to 172.11) (Analysis 1.12).
1.12.3 heart rate decreased
We found 1 trial to be relevant to this subset, with a total of 182 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 0.52, 95% CI 0.05 to 5.66) (Analysis 1.12).
1.12.4 heart rate increased
There was a single trial in this subset, with a total of 182 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 0.85, 95% CI 0.37 to 1.96) (Analysis 1.12).
1.12.5 hypotension ‐ postural
There was a single trial in this subset, with a total of 44 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 3.00, 95% CI 0.13 to 69.87) (Analysis 1.12).
1.12.6 corrected QT interval > 450 milliseconds or > 10% increase from baseline
We found 2 trials to be relevant to this subset, with a total of 380 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (RR 8.46, 95% CI 1.07 to 67.07) (Analysis 1.12).
1.12.7 tachycardia
We found 2 trials to be relevant to this subset, with a total of 332 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (RR 12.22, 95% CI 2.33 to 64.1) (Analysis 1.12).
1.13 Adverse effects: 4. central nervous system ‐ short term (up to 12 weeks)
We identified ten studies relevant to this outcome, the data from which we divided into eight subsets.
1.13.1 agitation
There were 8 relevant trials in this subset, with a total of 1388 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.93, 95% CI 0.75 to 1.17) (Analysis 1.13).
1.13.2 anxiety
We found 6 trials to be relevant to this subset, with a total of 1225 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.04, 95% CI 0.73 to 1.48) (Analysis 1.13).
1.13.3 dizziness
There were 5 relevant trials in this subset, with a total of 970 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.41, 95% CI 0.65 to 3.05). This subset had moderate levels of heterogeneity (Chi2 = 7.37; df = 4.0; P = 0.12; I2 = 46%) (Analysis 1.13).
1.13.4 headache
We found 10 trials to be relevant to this subset, with a total of 1905 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.99, 95% CI 0.81 to 1.21) (Analysis 1.13).
1.13.5 insomnia
We found 10 trials to be relevant to this subset, with a total of 1905 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.16, 95% CI 0.97 to 1.39) (Analysis 1.13).
1.13.6 sedation
There were two trials in this subset, with a total of 517 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.84, 95% CI 0.52 to 6.50) (Analysis 1.13).
1.13.7 somnolence
We found 6 trials to be relevant to this subset, with a total of 951 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.61, 95% CI 1.06 to 2.45) (Analysis 1.13).
1.13.8 restlessness
There were two trials in this subset, with a total of 619 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.16, 95% CI 0.49 to 2.74) (Analysis 1.13).
1.14 Adverse effects: 5. endocrine ‐ serum prolactin increase above reference range (23 ng/ml) ‐ short term (up to 12 weeks)
For this outcome we found 2 relevant studies, with a total of 323 participants. There were no subsets in this outcome. We found evidence of a clear difference between 'risperidone' and 'placebo' (RR 12.14, 95% CI 4.38 to 33.68). For this outcome heterogeneity was high (Chi2 = 2.14; df = 1.0; P = 0.14; I2 = 53%).
1.15 Adverse effects: 6. gastrointestinal system ‐ short term (up to 12 weeks)
For this outcome we found ten relevant studies and categorised data into six subsets.
1.15.1 constipation
We found 8 trials to be relevant to this subset, with a total of 1695 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.88, 95% CI 1.19 to 2.96) (Analysis 1.15).
1.15.2 diarrhoea
There was a single trial in this subset, with a total of 202 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.92, 95% CI 0.37 to 2.3) (Analysis 1.15).
1.15.3 dry mouth
We found 1 trial to be relevant to this subset, with a total of 202 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 2.43, 95% CI 0.65 to 9.12) (Analysis 1.15).
1.15.4 dyspepsia
There were 5 relevant trials in this subset, with a total of 1058 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.24, 95% CI 0.64 to 2.40) (Analysis 1.15).
1.15.5 nausea
There were 6 relevant trials in this subset, with a total of 1225 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.18, 95% CI 0.75 to 1.86) (Analysis 1.15).
1.15.6 vomiting
There were 5 relevant trials in this subset, with a total of 1181 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.16, 95% CI 0.65 to 2.07) (Analysis 1.15).
1.16 Adverse effects: 7a. metabolic ‐ weight gain ‐ short term (up to 12 weeks)
For this outcome we found six relevant studies, the data from which we divided into two subsets.
1.16.1 any gain
We found 3 trials to be relevant to this subset, with a total of 910 participants. For this outcome, within this subset, we did find evidence that 'risperidone' was clearly different in its effects compared with 'placebo' (RR 3.77, 95% CI 1.34 to 10.63) (Analysis 1.16).
1.16.2 > 7% increase from baseline
We found 3 trials to be relevant to this subset, with a total of 606 participants. For this outcome, within this subset, we did find evidence that 'risperidone' was clearly different in its effects compared with 'placebo' (RR 3.47, 95% CI 1.64 to 7.33) (Analysis 1.16).
1.17 Adverse effects: 7b. metabolic ‐ skewed data ‐ average change value on lipid profile ‐ short term (up to 12 weeks)
These continuous data (two RCTs) had such large SDs as to suggest that analysis within RevMan would be inadvisable. Therefore, we presented them in an separate table (Analysis 1.17).
1.18 Adverse effects: 8. musculoskeletal system ‐ short term (up to 12 weeks)
We identified one study relevant to this outcome and categorised data into two subsets.
1.18.1 myalgia
We found 1 trial to be relevant to this subset, with a total of 202 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 0.69, 95% CI 0.12 to 4.06). (Analysis 1.18).
1.18.2 joint disorder
We found 1 trial to be relevant to this subset, with a total of 202 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 2.6, 95% CI 0.52 to 13.1) (Analysis 1.18).
1.19 Adverse effects: 9. physiology ‐ short term (up to 12 weeks)
For this outcome we found two studies and categorised data into four subsets.
1.19.1 alanine aminotransferase increased
There was a single trial in this subset, with a total of 182 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.04, 95% CI 0.07 to 16.45) (Analysis 1.19).
1.19.2 aspartate aminotransferase increased
There was a single trial in this subset, with a total of 182 participants. No increase occured in either group. (Analysis 1.19).
1.19.3 blood creatine phosphokinase increased
We found 2 trials to be relevant to this subset, with a total of 619 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.67, 95% CI 0.23 to 1.95) (Analysis 1.19).
1.19.4 blood pressure increased
There was a single trial in this subset, with a total of 182 participants. There was not a clear difference between 'risperidone' and 'placebo' within this subset (RR 1.04, 95% CI 0.15 to 7.26) (Analysis 1.19).
1.20 Adverse effects: 10. respiratory system ‐ short term (up to 12 weeks)
For this outcome we found four relevant studies and categorised data into three subsets.
1.20.1 upper respiratory infection
There were 2 relevant trials in this subset, with a total of 323 participants. We found evidence of a clear difference between 'risperidone' and 'placebo' within this subset (RR 2.83, 95% CI 1.03 to 7.74) (Analysis 1.20).
1.20.2 pharyngitis
There was a single trial in this subset, with a total of 202 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.42, 95% CI 0.08 to 2.1) (Analysis 1.20).
1.20.3 rhinitis
There were 2 relevant trials in this subset, with a total of 306 participants. For this outcome, within this subset, we found evidence that 'risperidone' was clearly different in its effects compared with 'placebo' (RR 10.81, 95% CI 2.58 to 45.29) (Analysis 1.20).
1.20.4 Sinusitis
There were 1 relevant trial in this subset, with a total of 437 participants. For this outcome, we did not find evidence of a clear difference between the two treatments (RR 1.04, 95% CI 0.09 to 11.36) (Analysis 1.20).
2. COMPARISON 2: RISPERIDONE plus CLOZAPINE versus PLACEBO plus CLOZAPINE
This particular comparison had 23 outcomes.
2.1 Mental state: no clinically significant response in psychotic symptoms (defined by PANSS/BPRS < 20% decline) ‐ short term (up to 12 weeks)
For this outcome two relevant studies found no clear difference between treatments (2 RCTS, N = 98, RR 1.15, 95% CI 0.93 to 1.42 Analysis 2.1 )
2.2 Leaving the study early ‐ short term (up to 12 weeks)
For this outcome we found three relevant studies and categorised data into nine subsets.
2.2.1 any reason
We found 3 trials to be relevant to this subset, with a total of 167 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.13, 95% CI 0.53 to 2.42) (Analysis 2.2).
2.2.2 due to adverse events
There were 2 relevant trials in this subset, with a total of 137 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (RR 4.11, 95% CI 0.47 to 36.24) (Analysis 2.2).
2.2.3 due to lack of efficacy
We found 1 trial to be relevant to this subset, with a total of 69 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (RR 0.55, 95% CI 0.11 to 2.78) (Analysis 2.2).
2.2.4 due to noncompliance
We found 1 trial to be relevant to this subset, with a total of 69 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.36, 95% CI 0.02 to 8.61) (Analysis 2.2).
2.2.5 lost to follow‐up
We found 1 trial to be relevant to this subset, with a total of 69 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.36, 95% CI 0.02 to 8.61) (Analysis 2.2).
2.2.6 reported death
There was a single trial in this subset, with a total of 68 participants. No deaths were reported. (Analysis 2.2).
2.2.7 withdrawal of consent
There were 3 relevant trials in this subset, with a total of 167 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.41, 95% CI 0.28 to 7.09) (Analysis 2.2).
2.2.8 administrative reasons
We found 1 trial to be relevant to this subset, with a total of 69 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 5.44, 95% CI 0.27 to 109.34) (Analysis 2.2).
2.2.9 abnormal lab results
We found 1 trial to be relevant to this subset, with a total of 69 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.36, 95% CI 0.02 to 8.61) (Analysis 2.2).
2.3 Global state: 1. average endpoint scores of CGI severity scale (high = poor) ‐ short term (up to 12 weeks)
We identified 1 study relevant to this outcome involving 65 participants. This outcome had no subsets. We did not find evidence of a clear difference between the two treatments in this comparison (MD 0.51, 95% CI 0.02 to 1.00).
2.4 Global state: 2. no significant clinical improvement ‐ short term (up to 12 weeks)
We identified 1 study relevant to this outcome, with a total of 68 participants. There were no subsets in this outcome. We did not find evidence of a clear difference between the two treatments in this comparison (RR 1.12, 95% CI 0.87 to 1.44) (Analysis 2.4).
2.5 Global state: 3. general functioning ‐ average endpoint GAF score (high = good) ‐ short term (up to 12 weeks)
We identified 1 study relevant to this outcome involving 30 participants. This outcome had no subsets. We found evidence of a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' (MD ‐4.50, 95% CI ‐8.38 to ‐0.62) (Analysis 2.5).
2.6 Mental state: 1. average endpoint scores on various scales on psychotic symptoms (high = poor) ‐ short term (up to 12 weeks)
For this outcome we found two relevant studies and categorised data into five subsets.
2.6.1 PANSS total
We found 2 trials to be relevant to this subset, with a total of 95 participants. We found evidence of a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD 5.56, 95% CI 1.59 to 9.53) (Analysis 2.6).
2.6.2 PANSS general pathology
There was a single trial in this subset, with a total of 30 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD 2.50, 95% CI 0.03 to 4.97) (Analysis 2.6).
2.6.3 PANSS delusion
We found 1 trial to be relevant to this subset, with a total of 30 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD 0.70, 95% CI 0.09 to 1.31) (Analysis 2.6).
2.6.4 PANSS negative symptom
We found 2 trials to be relevant to this subset, with a total of 95 participants. For this subset, we did not find evidence of a clear difference between the two treatments (MD 0.69, 95% CI ‐0.68 to 2.05) (Analysis 2.6).
2.6.5 PANSS positive symptom
We found 2 trials to be relevant to this subset, with a total of 95 participants. For this subset, we did not find evidence of a clear difference between the two treatments (MD 2.30, 95% CI 0.98 to 3.62) (Analysis 2.6).
2.7 Mental state: 2. average endpoint scores on various scales on psychotic symptoms (high = poor) ‐ medium term (up to 26 weeks)
For this outcome we found a single study, the data from which we divided into four subsets.
2.7.1 BPRS total
We found 1 trial to be relevant to this subset, with a total of 53 participants. We found evidence of a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD ‐4.60, 95% CI ‐9.88 to 0.68) (Analysis 2.7).
2.7.2 BPRS positive symptom
There was a single trial in this subset, with a total of 53 participants. For this subset, we did not find evidence of a clear difference between the two treatments (MD ‐0.90, 95% CI ‐2.81 to 1.01) (Analysis 2.7).
2.7.3 BPRS anxiety/depression factor
There was a single trial in this subset, with a total of 53 participants. We found evidence of a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD ‐1.00, 95% CI ‐2.80 to 0.80) (Analysis 2.7).
2.7.4 SANS total
We found 1 trial to be relevant to this subset, with a total of 53 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD ‐3.10, 95% CI ‐10.30 to 4.10) (Analysis 2.7).
2.8 Mental state: 3. skewed data ‐ short term (up to 12 weeks)
These continuous data (two RCTs) had such large SDs as to suggest that analysis within RevMan would be inadvisable. Therefore, we have presented them in a separate data table (Analysis 2.8).
2.9 Adverse effects: 1a. extrapyramidal ‐ average endpoint SAS score ‐ short term (up to 12 weeks)
For this outcome we found a single study. People in the risperidone + clozapine arm were less likely to experience extrapyramidal adverse events as reported on the SAS than those in the placebo + clozapine arm (1 RCT, N=30, MD ‐0.90 95% CI ‐1.97 to 0.17) (Analysis 2.9).
2.10 Adverse effects: 1b. extrapyramidal ‐ skewed data (various scales) ‐ short term (up to 12 weeks)
These continuous data (two RCTs) had such large SDs as to suggest that analysis within RevMan would be inadvisable. Therefore, we have presented them in a separate data table (Analysis 2.10).
2.11 Adverse effects: 1c. extrapyramidal ‐ skewed data (various scales) ‐ medium term (up to 26 weeks)
These continuous data (one RCT) were too skewed to report in a graphic. Therefore, we have reported these data in a separate data table (Analysis 2.11).
2.12 Adverse effects: 2. any adverse event ‐ short term (up to 12 weeks)
We identified one study relevant to this outcome and categorised data into nine subsets.
2.12.1 any adverse event
We found 1 trial to be relevant to this subset, with a total of 64 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.14, 95% CI 0.83 to 1.58) (Analysis 2.12).
2.12.2 amenorrhoea
There was a single trial in this subset, with a total of 64 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 3.00, 95% CI 0.13 to 71.0) (Analysis 2.12).
2.12.3 asthenia
There was a single trial in this subset, with a total of 64 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (RR 1.08, 95% CI 0.61 to 1.91) (Analysis 2.12).
2.12.4 depression
We found 1 trial to be relevant to this subset, with a total of 64 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (RR 1.20, 95% CI 0.61 to 2.37) (Analysis 2.12).
2.12.5 emotional indifference
We found 1 trial to be relevant to this subset, with a total of 64 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (RR 1.11, 95% CI 0.52 to 2.37) (Analysis 2.12).
2.12.6 fatigue
We found 1 trial to be relevant to this subset, with a total of 64 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.08, 95% CI 0.61 to 1.91) (Analysis 2.12).
2.12.7 failing memory
There was a single trial in this subset, with a total of 64 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (RR 0.67, 95% CI 0.32 to 1.41) (Analysis 2.12).
2.12.8 increased duration of sleep
We found 1 trial to be relevant to this subset, with a total of 64 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (RR 1.00, 95% CI 0.51 to 1.97) (Analysis 2.12).
2.12.9 salivation ‐ increased
We found 1 trial to be relevant to this subset, with a total of 64 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.25, 95% CI 0.81 to 1.94) (Analysis 2.12).
2.13 Adverse effects: 3a. cardiovascular ‐ short term (up to 12 weeks)
For this outcome we found a single study and categorised data into three subsets (in keeping with our protocol).
2.13.1 dizziness ‐ orthostatic
We found 1 trial to be relevant to this subset, with a total of 64 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (RR 1.00, 95% CI 0.43 to 2.34) (Analysis 2.13).
2.13.2 palpitation
There was a single trial in this subset, with a total of 64 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.00, 95% CI 0.27 to 3.66) (Analysis 2.13).
2.13.3 tachycardia
We found 1 trial to be relevant to this subset, with a total of 64 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (RR 1.00, 95% CI 0.27 to 3.66) (Analysis 2.13).
2.14 Adverse effects: 3b. cardiovascular ‐ corrected QT interval ‐ short term (up to 12 weeks)
For this outcome we found a single study, with a total of 30 participants. There were no subsets in this outcome. We did not find evidence of a clear difference between the two treatments in this comparison (MD ‐19.70, 95% CI ‐42.08 to 2.68).
2.15 Adverse effects: 4. central nervous system ‐ short term (up to 12 weeks)
For this outcome we found a single study and categorised data into three subsets.
2.15.1 sedation
There was a single trial in this subset, with a total of 64 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (RR 1.46, 95% CI 0.88 to 2.43) (Analysis 2.15).
2.15.2 somnolence
We found 1 trial to be relevant to this subset, with a total of 64 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.00, 95% CI 0.51 to 1.97) (Analysis 2.15).
2.15.3 tension
We found 1 trial to be relevant to this subset, with a total of 64 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.23, 95% CI 0.71 to 2.12) (Analysis 2.15).
2.16 Adverse effects: 5. gastrointestinal system ‐ short term (up to 12 weeks)
For this outcome we found a single study and categorised data into one subset.
2.16.1 constipation
We found 1 trial to be relevant to this subset, with a total of 64 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 0.71, 95% CI 0.25 to 2.02) (Analysis 2.16).
2.17 Adverse effects: 6a. haematological ‐ short term (up to 12 weeks)
We identified two studies relevant to this outcome and categorised data into three subsets.
2.17.1 neutrophil count
There was a single trial in this subset, with a total of 57 participants. For this subset, we did not find evidence of a clear difference between the two treatments (MD 0.37, 95% CI ‐0.42 to 1.16) (Analysis 2.17).
2.17.2 prolactin level, ng/mL
We found 1 trial to be relevant to this subset, with a total of 30 participants. For this outcome, within this subset, we did find evidence that 'risperidone plus clozapine' was clearly different in its effects compared with 'placebo plus clozapine' (MD 60.1, 95% CI 46.52 to 73.68) (Analysis 2.17).
2.17.3 white cell count
There was a single trial in this subset, with a total of 61 participants. For this subset, we did not find evidence of a clear difference between the two treatments (MD 0.66, 95% CI ‐0.20 to 1.52) (Analysis 2.17).
2.18 Adverse effects: 6b. haematological ‐ medium term (up to 26 weeks)
For this outcome we found a single study, the data from which we divided into two subsets.
2.18.1 prolactin level ng/mL
There was a single trial in this subset, with a total of 44 participants. We found evidence of a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD 34.1, 95% CI 17.63 to 50.57) (Analysis 2.18).
2.18.2 fasting glucose
There was a single trial in this subset, with a total of 40 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD ‐4.60, 95% CI ‐17.09 to 7.89) (Analysis 2.18).
2.19 Adverse effects: 7a. metabolic ‐ weight gain ‐ short term (up to 12 weeks)
There was a single trial in this subset, with a total of 64 participants. For this subset, we did not find evidence of a clear difference between the two treatments (RR 1.00, 95% CI 0.40 to 2.52) (Analysis 2.19).
2.20 Adverse effects: 7a. metabolic ‐ weight gain ‐ medium term (up to 26 weeks)
We found 1 trial to be relevant to this subset, with a total of 48 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (RR 0.20, 95% CI 0.01 to 3.96) (Analysis 2.20).
2.21 Adverse effects: 7b. metabolic ‐ average endpoint value on lipid profile ‐ short term (up to 12 weeks)
For this outcome we found a single study and categorised data into four subsets.
2.21.1 cholesterol ‐ total (mg/dl)
We found 1 trial to be relevant to this subset, with a total of 56 participants. For this subset, we did not find evidence of a clear difference between the two treatments (MD ‐6.60, 95% CI ‐29.05 to 15.85) (Analysis 2.21).
2.21.2 high‐density lipoprotein cholesterol (mg/dl)
We found 1 trial to be relevant to this subset, with a total of 52 participants. For this subset, we did not find evidence of a clear difference between the two treatments (MD 0.00, 95% CI ‐8.44 to 8.44) (Analysis 2.21).
2.21.3 low‐density lipoprotein cholesterol (mg/dl)
There was a single trial in this subset, with a total of 53 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD ‐6.90, 95% CI ‐26.02 to 12.22) (Analysis 2.21).
2.21.4 triglycerides (mg/dl)
There was a single trial in this subset, with a total of 56 participants. For this subset, we did not find evidence of a clear difference between the two treatments (MD 6.20, 95% CI ‐57.57 to 69.97) (Analysis 2.21).
2.22 Adverse effects: 7c. metabolic ‐ average endpoint value ‐ short term (up to 12 weeks)
We identified two studies relevant to this outcome, the data from which we divided into four subsets.
2.22.1 body mass index
We found 1 trial to be relevant to this subset, with a total of 63 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD 1.70, 95% CI ‐0.99 to 4.39) (Analysis 2.22).
2.22.2 fasting glucose (mg/dl)
We found 1 trial to be relevant to this subset, with a total of 51 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD 16.20 95% CI ‐3.12 to 35.52) (Analysis 2.22).
2.22.3 waist circumference (cm)
There was a single trial in this subset, with a total of 61 participants. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' within this subset (MD 5.10, 95% CI ‐4.14 to 14.34) (Analysis 2.22).
2.22.4 weight gain
We found 2 trials to be relevant to this subset, with a total of 94 participants. For this subset, we did not find evidence of a clear difference between the two treatments (MD 0.34, 95% CI ‐0.84 to 1.53) (Analysis 2.22).
2.23 Adverse effects: 8. sleep ‐ skewed data ‐ average change score (UKU) ‐ short term (up to 12 weeks)
These continuous data, from a single trial, had such large SDs as to suggest that analysis within RevMan would be inadvisable. Therefore, we have presented them in a separate data table (Analysis 2.23).
2.24 Quality of life: average endpoint score (QLS, high = good) ‐ short term (up to 12 weeks)
We identified 1 study relevant to this outcome involving 30 participants. There were no subsets in this outcome. There was not a clear difference between 'risperidone plus clozapine' and 'placebo plus clozapine' (MD 0.80, 95% CI ‐5.44 to 7.04) (Analysis 2.24).
3. COMPARISON 3: SENSITIVITY ANALYSIS: RISPERIDONE versus PLACEBO (based on attrition)
This particular comparison had only one outcome.
3.1 Mental state: 1. no clinically significant response (defined by PANSS/BPRS) ‐ short term (up to 12 weeks)
We identified six studies relevant to this outcome and categorised data into two subsets (in keeping with our protocol).
3.1.1 defined by PANSS/BPRS < 20% decline
We found 6 trials to be relevant to this subset, with a total of 864 participants. We found evidence of a clear difference between 'sensitivity analysis: risperidone' and 'placebo (based on attrition)' within this subset (RR 0.64, 95% CI 0.52 to 0.78). For this outcome heterogeneity was high (Chi2 = 12.27; df = 5.0; P = 0.03; I2 = 59%) (Analysis 3.1).
3.1.2 defined by PANSS/BPRS < 20% decline (without studies with > 50% leaving the study early)
There were 3 relevant trials in this subset, with a total of 589 participants. We found evidence of a clear difference between 'sensitivity analysis: risperidone' and 'placebo (based on attrition)' within this subgroup (RR 0.77, CI 0.67 to 0.88) (Analysis 3.1).
Discussion
Summary of main results
1. COMPARISON 1: RISPERIDONE versus PLACEBO
All of the included studies contributed data towards the comparison of risperidone versus placebo. Despite there being data from 15 studies in total, more often than not only a few studies contributed useable data towards each outcome. Most of the findings were based on few data, which in the majority of cases was of poor quality. The ratings within the Summary of findings table 1 reflect this, as we have judged the overall quality of evidence to be low or very low for each of the four main clinically relevant outcomes.
There is a clear difference in the treatment effect favouring risperidone group. Compared to placebo, people who received risperidone has a 36% risk reduction (very low quality of evidence) in not achieving clinically significant improvement in psychotic symptoms. The effect withstood, even when three studies with >50% attrition rate were removed from the analysis (3 RCTs, N = 589, RR 0.77, CI 0.67 to 0.88). Risperidone group also achieved greater reduction on BPRS score (a reduction of 12.69 compared to placebo group) and PANSS score (a reduction of 17.81 compared to placebo group). However the quality of evidence is compromised due to risk of bias of included studies, the slight heterogeneity and the involvement of industry sponsorship. Similarly, risperidone group are more likely to achieve significant clinical improvement than placebo group (a risk reduction of 31% in risperidone group, very low quality of evidence).
A variety of reasons have caused people to leave the study early, but most showed no clear difference between groups. However, placebo group had significantly more people left the study early due to lack of efficacy (a risk reduction of 61% if one receives risperidone, low quality evidence). Overall, risperidone group is 31% less likely to drop out early compared to placebo group (low quality evidence). The participants have also experienced a range of adverse events, but most had similar incidence rate between groups, but some clearly favoured placebo group including, EPS (1.56 times less likely compared to risperidone group), akathisia (2.58 times times less likely compared to risperidone group), hypertonia (2.98 times times less likely compared to risperidone group) and parkinsonism (7.64 times times less likely compared to risperidone group), somnolence (1.61 times times less likely compared to risperidone group), constipation (1.88 times less likely), weight gain (3.77 times less likely), upper respiratory infection (2.83 times less likely), rhinitis (10.81 times less likely).
2. COMPARISON 2: RISPERIDONE plus CLOZAPINE versus PLACEBO plus CLOZAPINE
When combined with clozapine, there was no obvious difference between groups in achieving clinically significant response in psychotic symptoms (low quality evidence). However, placebo plus clozapine group achieved greater reduction in PANSS score (MD = 5.56, 95% CI 1.59 to 9.53), while risperidone plus clozapine group appeared to produce more improvement in general functioning as assessed by GAF (MD = ‐4.5, 95% CI ‐8.38 to ‐0.62). Participants left the study early for a variety of reasons, but none of which discriminated against any interventions (very low quality of evidence). Similarly, we did not find any clear difference in the adverse events experienced between groups.
Overall completeness and applicability of evidence
The review included 15 studies (n = 2428) of relatively short duration, between 8 and 16 weeks, hence limiting the applicability of the results of this review to long term use of risperidone. All participants in included trials were adults diagnosed with schizophrenia or schizoaffective disorder. The studies took place in both primary and secondary care settings, however, most were conducted in high income countries, hence the evidence should be applied with care in developing countries. There was a lack of data in included studies on the following outcome, including service utilisation and quality of life.
Issue of placebo‐controlled trials
Placebo‐controlled trials have been used as a licensing requirement by the US Food and Drug Administration (FDA) and other regulatory authorities for some time. Since 1964, the Helsinki Ethical Principles for Medical Research Involving Human Subjects WMA 2008 have been considered a benchmark for trialists around the world (WMA 2008). However, recently it has been argued that it is unethical to conduct trials involving placebo arms for conditions that have an established standard treatment. Also recently, the FDA has adopted the less rigorous Good Clinical Practice as an alternative to the Helsinki declaration, although this has invited numerous criticisms (Lurie 1997; Lurie 2005). Nevertheless, placebo trials do still have an important place, and some ethical bodies around the world do approve of trial methodologies with placebo arms. We suggest that the findings of this review support the continued need for placebo‐controlled studies. risperidone is a widely used drug. That many of the effects of this compound are not that different from a placebo is important and would not have been highlighted but for the use of this type of study.
Quality of the evidence
The quality of reporting in most studies could have been much better (Figure 4). Well over half of the included studies have concerns in sequence generation and allocation concealment. There has also been some controversy over the trials conducted by Borison, with the author being accused of scientific fraud (see Included studies). Although, the trialists have not been found to have fabricated research data, this cast a shadow to the findings of his trials (AHRP 2006; CBS News 2000CBS News 2000AHRP 2006).
Now, years after the first Consolidated Standards of Reporting Trials (CONSORT) statement (Begg 1996), it is expected that all relevant details of methodology that are likely to influence outcome, such as means of allocation and concealment of allocation, are documented and reported. Only 5 out of 13 studies provided information about sequence generation, and 3 out of 13 provided any details about allocation concealment. Good randomisation methodology is essential, and more so for smaller trials, as it ensures that confounding variables are as equally distributed as possible between the intervention and control groups. Poor quality or inadequate randomisation procedures would instead produce imbalance between groups in terms of participant selection and could potentially bias the result.
Potential biases in the review process
The authors of this review made every effort to minimise bias in the review process by strictly following the Cochrane Handbook and conduct expectations. The majority of data in this review were collected from published reports. Even though we identified substantial number of conference proceedings and unpublished reports, however, we were not able to extract much data from these reports due to either poor reporting or lack of collection at trial stage, therefore, could not be used in this review. For example, in some studies trialists reported mean without standard deviation. Our attempts to contact authors of trials for additional data were unsuccessful. This directly results in
2. Omission of relevant data or studies
As defined in our protocol, we had to omit efficacy measures from studies that had attrition rates of higher than 50% at study endpoint in a sensitivity analysis for our main outcomes. We are not sure if this is correct, but have identified no ready solution to the problem of missing data and when assumptions become too much and undermine credibility (Xia 2009). Certainly, high attrition rates, poor reporting, and poor methodology, combined with the rules we had set ourselves within our protocol, limited the information available for us to use. We feel that people can leave the trials for several reasons, most of which are not specified in the reports. Many studies carried the last observation of such people to the end of the trial period and used those data as if things stayed stable beyond leaving the study. This may or may not be correct but has gone untested. We have taken a conservative approach in presentation of the available data.
Agreements and disagreements with other studies or reviews
This review substantially updates the previous work in the area of risperidone. It also completes the series of direct comparison of risperidone with other drugs (Gilbody 2000; Hosalli 2003; Hunter 2003; Jayaram 2006; Kennedy 2000; Komossa 2007; Li 2009). The findings of this review were similar to the findings of other reviews involving risperidone.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 1 Mental state: no clinically significant response in psychotic symptoms (defined by various scale total score change) ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 2 Leaving the study early ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 3 Global state: 1. average endpoint scores of CGI severity scale (high=poor) ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 4 Global state: 2. no significant clinical improvement CGI ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 5 Global state: 3. needing additional medication ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 6 Mental state: 1. average endpoint scores on various scales on psychotic symptoms (high=poor) ‐ short term (up to 12 weeks).
| Study | Intervention | Mean | SD | N |
| average endpoint score BPRS total (high=poor) | ||||
| Pai 2002 | Resperidone | 14.7 | 7.4 | 22 |
| Pai 2002 | Placebo | 19.0 | 12.2 | 20 |
| average change score of CGI‐C (larger decline=good) | ||||
| Potkin 2006 | Resperidone | 2.4 | 1.23 | 152 |
| Potkin 2006 | Placebo | 2.9 | 0.84 | 71 |
| average change score of CGI‐SI (larger decline=good) | ||||
| Potkin 2006 | Resperidone | ‐1.84 | 1.23 | 152 |
| Potkin 2006 | Placebo | ‐1.1 | 0.84 | 71 |
| average change score of HAM‐D‐17 (larger decline=good) | ||||
| Potkin 2006 | Resperidone | ‐5.6 | 4.93 | 152 |
| Potkin 2006 | Placebo | ‐4.4 | 4.21 | 71 |
| average change score of PANSS total (larger decline=good) | ||||
| Potkin 2006 | Resperidone | ‐27.7 | 18.49 | 152 |
| Potkin 2006 | Placebo | ‐20.2 | 16.85 | 71 |
| average change score of PANSS negative symptom (larger decline=good) | ||||
| Potkin 2006 | Resperidone | ‐4.0 | 4.93 | 152 |
| Potkin 2006 | Placebo | ‐3.5 | 5.06 | 71 |
| average change score of PANSS positive symptom (larger decline=good) | ||||
| Potkin 2006 | Resperidone | ‐8.7 | 6.16 | 152 |
| Potkin 2006 | Placebo | ‐5.3 | 5.9 | 71 |
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 7 Mental state: 2. skewed data ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 8 Adverse effects: 1a. extrapyramidal ‐ various effects ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 9 Adverse effects: 1b. extrapyramidal ‐ AIMS average endpoint score ‐ short term (up to 12 weeks).
| Study | Intervention | Mean | SD | N |
| average change score of AIMS | ||||
| Potkin 2006 | Risperidone | 0.3 | 2.47 | 153 |
| Potkin 2006 | Placebo | ‐0.1 | 2.56 | 73 |
| average change score of CGI severity dyskinesia | ||||
| Chouinard 1992 | Risperidone | 0.3 | 3.3 | 22 |
| Chouinard 1992 | Placebo | 3.5 | 5.3 | 22 |
| average change score of CGI severity parkinsonism | ||||
| Chouinard 1992 | Risperidone | 0.9 | 1.5 | 22 |
| Chouinard 1992 | Placebo | 0.4 | 1.3 | 22 |
| average change score of ESRS | ||||
| Marder 1994a | Risperidone | 2.9 | 5.7 | 63 |
| Marder 1994a | Placebo | 2.4 | 5.8 | 65 |
| average change score of ESRS ‐ akathisia | ||||
| Marder 1994a | Risperidone | 0.6 | 1.1 | 63 |
| Marder 1994a | Placebo | 0.6 | 1.6 | 65 |
| average change score of ESRS ‐ dystonia | ||||
| Chouinard 1992 | Risperidone | 0.3 | 0.8 | 22 |
| Chouinard 1992 | Placebo | 1.0 | 2.3 | 22 |
| Marder 1994a | Risperidone | 1.3 | 1.3 | 63 |
| Marder 1994a | Placebo | 1.6 | 1.5 | 64 |
| Pai 2002 | Risperidone | 2.1 | 1.7 | 22 |
| Pai 2002 | Placebo | 2.8 | 1.8 | 20 |
| average change score of ESRS ‐ dyskinesia | ||||
| Chouinard 1992 | Risperidone | 2.6 | 4.5 | 22 |
| Chouinard 1992 | Placebo | 5.7 | 7.2 | SD |
| Marder 1994a | Risperidone | 0.6 | 1.1 | 63 |
| Marder 1994a | Placebo | 0.5 | 1.1 | 65 |
| average change score of ESRS ‐ parkinsonism | ||||
| Chouinard 1992 | Risperidone | 2.1 | 7.5 | 22 |
| Chouinard 1992 | Placebo | 2.3 | 8.7 | 22 |
| Marder 1994a | Risperidone | 0.6 | 1.1 | 63 |
| Marder 1994a | Placebo | 0.5 | 1.1 | 65 |
| Pai 2002 | Risperidone | 2.1 | 1.3 | 22 |
| Pai 2002 | Placebo | 2.5 | 1.5 | 20 |
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 10 Adverse effects: 1c. extrapyramidal ‐ skewed data (various scales) ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 11 Adverse effects: 2. any adverse event ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 12 Adverse effects: 3. cardiovascular ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 13 Adverse effects: 4. central nervous system ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 14 Adverse effects: 5. endocrine ‐ serum prolactin increase above reference range (23 ng/ml) ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 15 Adverse effects: 6. gastrointestinal system ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 16 Adverse effects: 7a. metabolic ‐ weight gain ‐ short term (up to 12 weeks).
| Study | Intervention | Mean | SD | N |
| cholesterol ‐ total | ||||
| Durgam 2014 | Risperidone | 4.6 | 34.6 | 140 |
| Durgam 2014 | Placebo | ‐1.3 | 30.4 | 151 |
| Heisterberg 2007 | Risperidone | ‐2.2 | 31.4 | 154 |
| Heisterberg 2007 | Placebo | ‐14.2 | 32.0 | 149 |
| HDL | ||||
| Durgam 2014 | Risperidone | ‐0.6 | 10.1 | 140 |
| Durgam 2014 | Placebo | ‐1.1 | 9.4 | 151 |
| Heisterberg 2007 | Risperidone | 2.1 | 10.3 | 154 |
| Heisterberg 2007 | Placebo | ‐0.7 | 6.8 | 149 |
| LDL | ||||
| Durgam 2014 | Risperidone | 3.8 | 30.6 | 140 |
| Durgam 2014 | Placebo | ‐0.1 | 25.3 | 151 |
| Heisterberg 2007 | Risperidone | ‐2.8 | 28.8 | 154 |
| Heisterberg 2007 | Placebo | ‐7.5 | 29.8 | 149 |
| triglycerides | ||||
| Durgam 2014 | Risperidone | 6.3 | 84.2 | 140 |
| Durgam 2014 | Placebo | ‐3.1 | 59.9 | 151 |
| Heisterberg 2007 | Risperidone | ‐6.7 | 136.2 | 154 |
| Heisterberg 2007 | Placebo | ‐27.9 | 104.4 | 149 |
| VLDL | ||||
| Heisterberg 2007 | Risperidone | ‐1.4 | 17.7 | 154 |
| Heisterberg 2007 | Placebo | ‐3.7 | 16.9 | 149 |
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 17 Adverse effects: 7b. metabolic ‐ skewed data ‐ average change value on lipid profile ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 18 Adverse effects: 8. musculoskeletal system ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 19 Adverse effects: 9. physiology ‐ short term (up to 12 weeks).
Comparison 1 RISPERIDONE vs PLACEBO, Outcome 20 Adverse effects: 10. respiratory system ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 1 Mental state: no clinically significant response in psychotic symptoms (defined by PANSS/BPRS<20% decline) ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 2 Leaving the study early ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 3 Global state: 1. average endpoint scores of CGI severity scale (high=poor) ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 4 Global state: 2. no significant clinical improvement CGI ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 5 Global state: 3. general functioning ‐ average endpoint GAF score (high=good) ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 6 Mental state: 1. average endpoint scores on various scales on psychotic symptoms (high=poor) ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 7 Mental state: 2. average endpoint scores on various scales on psychotic symptoms (high=poor) ‐ medium term (up to 26 weeks).
| Study | Intervention | Mean | SD | N |
| average endpoint score of CDS total (high=poor) | ||||
| Yagcioglu 2005 | Resperidone | 1.6 | 2 | 16 |
| Yagcioglu 2005 | Placebo | 1.4 | 1.9 | 14 |
| average endpoint score on verbal working memory (SD, high=good) | ||||
| Honer 2006 | Resperidone | 0.08 | 0.99 | 152 |
| Honer 2006 | Placebo | 0.14 | 0.83 | 71 |
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 8 Mental state: 3. skewed data ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 9 Adverse effects: 1a. extrapyramidal ‐ average endpoint SAS score ‐ short term (up to 12 weeks).
| Study | Intervention | Mean | SD | N |
| average endpoint score of AIMS | ||||
| Yagcioglu 2005 | Risperidone | 1.3 | 0.88 | 16 |
| Yagcioglu 2005 | Placebo | 1.0 | 0.86 | 14 |
| average change score of Barnes akathisia rating scale | ||||
| Honer 2006 | Risperidone | 0.5 | 0.7 | 32 |
| Honer 2006 | Placebo | 0.4 | 0.8 | 33 |
| Yagcioglu 2005 | Risperidone | 0.18 | 0.6 | 16 |
| Yagcioglu 2005 | Placebo | 0.72 | 0.6 | 14 |
| average change score of ESRS | ||||
| Honer 2006 | Risperidone | 9.3 | 6.9 | 32 |
| Honer 2006 | Placebo | 7.8 | 7.0 | 32 |
| average change score of ESRS ‐ dystonia | ||||
| Honer 2006 | Risperidone | 0.2 | 0.7 | 32 |
| Honer 2006 | Placebo | 0.1 | 0.5 | 33 |
| average change score of ESRS ‐ dyskinesia | ||||
| Honer 2006 | Risperidone | 2.4 | 4.1 | 32 |
| Honer 2006 | Placebo | 2.1 | 4.2 | 33 |
| average change score of ESRS ‐ parkinsonism | ||||
| Honer 2006 | Risperidone | 6.7 | 4.3 | 32 |
| Honer 2006 | Placebo | 5.5 | 4 | 32 |
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 10 Adverse effects: 1b. extrapyramidal ‐ skewed data (various scales) ‐ short term (up to 12 weeks).
| Study | Intervention | Mean | SD | N |
| average endpoint score of AIMS | ||||
| Bachmann 2003 | Risperidone | 3.5 | 5.5 | 25 |
| Bachmann 2003 | Placebo | 2.2 | 2.8 | 28 |
| average endpoint score of SAS | ||||
| Bachmann 2003 | Risperidone | 1.8 | 3.4 | 25 |
| Bachmann 2003 | Placebo | 1.8 | 2.5 | 28 |
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 11 Adverse effects: 1c. extrapyramidal ‐ skewed data (various scales) ‐ medium term (up to 26 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 12 Adverse effects: 2. any adverse event ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 13 Adverse effects: 3a. cardiovascular ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 14 Adverse effects: 3b. cardiovascular ‐ QTc interval ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 15 Adverse effects: 4. central nervous system ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 16 Adverse effects: 5. gastrointestinal system ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 17 Adverse effects: 6a. haematological ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 18 Adverse effects: 6b. haematological ‐ medium term (up to 26 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 19 Adverse effects: 7a. metabolic ‐ weight gain ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 20 Adverse effects: 7a. metabolic ‐ weight gain ‐ medium term (up to 26 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 21 Adverse effects: 7b. metabolic ‐ average endpoint value on lipid profile ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 22 Adverse effects: 7c. metabolic ‐ average endpoint value ‐ short term (up to 12 weeks).
| Study | Intervention | Mean | SD | N |
| Yagcioglu 2005 | Risperidone | 0.7 | 0.36 | 16 |
| Yagcioglu 2005 | Placebo | 0.2 | 0.37 | 14 |
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 23 Adverse effects: 8. sleep ‐ skewed data ‐ average change score (UKU) ‐ short term (up to 12 weeks).
Comparison 2 RISPERIDONE + CLOZAPINE vs PLACEBO + CLOZAPINE, Outcome 24 Quality of life: average endpoint score (QLS, high=good) ‐ short term (up to 12 weeks).
Comparison 3 SENSITIVITY ANALYSIS: RISPERIDONE vs PLACEBO (based on attrition), Outcome 1 Mental state: 1. no clinically significant response (defined by PANSS/BPRS) ‐ short term (up to 12 weeks).
| Broad category of comparison | Intervention | Control | Excluded study/studies | Existing Cochrane reviews | |
| Augmentation [of] | risperidone | by | antioxidants | ‐ | |
| buflomedil | |||||
| celecoxib | |||||
| D‐alanine | |||||
| sarcosine | |||||
| valproate | |||||
| clozapine | risperidone | ||||
| Long‐acting preparation | depot risperidone | versus | olanzapine | ||
| placebo | Cada 2004, Ciliberto 2005, Lauriello 2005, Nasrallah 2004a, Urioste 2004, NCT00249119 | ||||
| Experimental compound | risperidone | versus | BL‐1020 | NCT01363349a | ‐ |
| LY2140023 | NCT01086748a | ||||
| PF‐02545920 | DeMartinis 2012a, NCT01175135a | ||||
| Versus another antipsychotic | risperidone | versus | amisulpride | ||
| aripiprazole | Dubitsky 2002, Chan 2007, Hwang 2005, NCT00202007, Kane 2005 | ||||
| asenapine | |||||
| cariprazine | Bose 2010b | Protocol underway | |||
| clozapine | Bondolfi 1998, Cavazzoni 2002a | ||||
| clocapramine | ‐ | ||||
| haloperidol | Claus 1992, Friedman 2000, Lindstrom 1994, Lopez 1996, Lopez‐Ibor 1992, NCT00253136, Peuskens 1995, Rabinowitz 2001, Wirshing 1995, Borison 1992a, Csernansky 1999 | ||||
| molindone | |||||
| olanzapine | Tollefson 1996, Edgell 2000, Tran 1997, Conley 1998, Harvey 2001, Brecher 1998, McClellan 2009, Cavazzoni 2002a, Cooper 1997, NCT00034892 | ||||
| quetiapine | |||||
| sertindole | |||||
| zuclopenthixol dihydrochloride | |||||
| Not risperidone | amisulpride | versus | placebo | ||
| aripiprazole | haloperidol | ||||
| olanzapine | |||||
| perphenazine | |||||
| placebo | |||||
| haloperidol | placebo | ||||
| olanzapine | fluphenazine | ||||
| haloperidol | Beasley 1996, Crawford 1997, Gregor 2000, Kinon 1998, Lieberman 2005, Revicki 1996 | ||||
| paliperidone | |||||
| placebo | Protocol underway | ||||
| paliperidone | placebo | ||||
| Single vs polypharmacy | risperidone | versus | amisulpride + haloperidol | ‐ | |
| Miscellaneous | antipsychotic drugs | versus | miscellaneous (risperidone, olanzapine, quetiapine) | ||
| risperidone | valproate + miscellaneous antipsychotic drugs | ||||
| riluzole (a drug used to treat amyotrophic lateral sclerosis) | Rujescu 2009a | ||||
| talnetant (a neurokinin 3 receptor antagonist) | GlaxoSmithKline 2006a |
| Methods | Allocation: randomised, clearly described and concealed. |
| Participants | Diagnosis: schizophrenia, schizotypal, schizoaffective, delusional disorder, acute psychosis, comorbid alcohol problems, and substance misuse. |
| Interventions | 1. Risperidone: dose 4 mg/day or above. |
| Outcomes | Healthy days. |
| Notes | Free of all industry influence. |
| RISPERIDONE compared to PLACEBO for schizophrenia | ||||||
| Patient or population: patients with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| PLACEBO | RISPERIDONE | |||||
| Mental state: no clinically significant response in psychotic symptoms (defined by various scale total score change) ‐ short term (up to 12 weeks) ‐ defined by PANSS/BPRS <20% decline | Study population | RR 0.64 | 864 | ⊕⊝⊝⊝ | ||
| 692 per 1000 | 443 per 1000 | |||||
| Moderate | ||||||
| 733 per 1000 | 469 per 1000 | |||||
| Leaving the study early ‐ short term (up to 12 weeks) ‐ any reason | Study population | RR 0.69 | 2261 | ⊕⊕⊝⊝ | ||
| 495 per 1000 | 342 per 1000 | |||||
| Moderate | ||||||
| 486 per 1000 | 335 per 1000 | |||||
| Global state: 2. no significant clinical improvement ‐ CGI, short term (up to 12 weeks) | Study population | RR 0.69 | 594 | ⊕⊝⊝⊝ | ||
| 744 per 1000 | 513 per 1000 | |||||
| Moderate | ||||||
| 732 per 1000 | 505 per 1000 | |||||
| Adverse effects: 1a. extrapyramidal ‐ various effects ‐ short term (up to 12 weeks) ‐ general ‐ any significant EPS | Study population | RR 1.56 | 1511 | ⊕⊕⊝⊝ | ||
| 73 per 1000 | 113 per 1000 | |||||
| Moderate | ||||||
| 106 per 1000 | 165 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to risk of bias: studies contributing data to this body of evidence have unclear or high risk of bias in one or more domains, some were also sponsored by pharmaceutical companies. | ||||||
| RISPERIDONE + CLOZAPINE compared to PLACEBO + CLOZAPINE for schizophrenia | ||||||
| Patient or population: people with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| PLACEBO + CLOZAPINE | RISPERIDONE + CLOZAPINE | |||||
| Mental state: no clinically significant response in psychotic symptoms ‐ short term | Moderate1 | RR 1.15 | 98 | ⊕⊕⊝⊝ | ||
| 725 per 1000 | 834 per 1000 | |||||
| Leaving the study early due to any reason ‐ short term Follow‐up: 12 weeks | 119 per 1000 | 135 per 1000 (63 to 288) | RR1.13 (0.53 to 2.42) | 167 | ⊕⊝⊝⊝ | |
| Global state: no significant clinical improvement ‐ CGI short term | 735 per 10003 | 824 per 1000 | RR 1.12 | 68 | ⊕⊕⊝⊝ | |
| Adverse effects: extrapyramidal ‐ short term Follow‐up: 12 weeks | See comment | See comment | Not estimable | ‐ | See comment | No study reported this outcome |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to risk of bias: studies contributing data to this body of evidence have unclear risk of bias in one or more domains. | ||||||
| Comparison | Reference | |
| Oral risperidone | vs other atypical drugs | |
| vs olanzapine | ||
| vs typical drugs | ||
| Depot risperidone | ||
| Risperidone dose | ||
| Risperidone for acute aggression | ||
| Score | Judgement |
| 91‐100 | Superior functioning in a wide range of activities, life's problems never seem to get out of hand, is sought out by others because of his or her many qualities. No symptoms. |
| 81‐90 | Absent or minimal symptoms, good functioning in all areas, interested and involved in a wide range of activities, socially effective, generally satisfied with life, no more than everyday problems or concerns. |
| 71‐80 | If symptoms are present they are transient and expectable reactions to psychosocial stresses; no more than slight impairment in social, occupational, or school functioning. |
| 61‐70 | Some mild symptoms OR some difficulty in social, occupational, or school functioning, but generally functioning pretty well, has some meaningful interpersonal relationships. |
| 51‐60 | Moderate symptoms OR any moderate difficulty in social, occupational, or school functioning. |
| 41‐50 | Serious symptoms OR any serious impairment in social, occupational, or school functioning. |
| 31‐40 | Some impairment in reality testing or communication OR major impairment in several areas, such as work or school, family relations, judgement, thinking, or mood. |
| 21‐30 | Behavior is considerably influenced by delusions or hallucinations OR serious impairment in communications or judgment OR inability to function in all areas. |
| 11‐20 | Some danger of hurting self or others OR occasionally fails to maintain minimal personal hygiene OR gross impairment in communication. |
| 1‐10 | Persistent danger of severely hurting self or others OR persistent inability to maintain minimum personal hygiene OR serious suicidal act with clear expectation of death. |
| 0 | Not enough information available to provide GAF. |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mental state: no clinically significant response in psychotic symptoms (defined by various scale total score change) ‐ short term (up to 12 weeks) Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 defined by PANSS<30% decline | 3 | 707 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.67, 0.83] |
| 1.2 defined by PANSS/BPRS <20% decline | 6 | 864 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.52, 0.78] |
| 2 Leaving the study early ‐ short term (up to 12 weeks) Show forest plot | 12 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 any reason | 12 | 2261 | Risk Ratio (M‐H, Random, 95% CI) | 0.69 [0.62, 0.78] |
| 2.2 due to adverse events | 10 | 2081 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.59, 1.03] |
| 2.3 due to lack of efficacy | 11 | 2211 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.29, 0.51] |
| 2.4 due to noncompliance | 4 | 534 | Risk Ratio (M‐H, Random, 95% CI) | 1.15 [0.33, 4.05] |
| 2.5 lost to follow‐up | 6 | 1545 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.25, 2.56] |
| 2.6 protocol violation | 4 | 1257 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.39, 1.62] |
| 2.7 reported death | 10 | 1532 | Risk Ratio (M‐H, Random, 95% CI) | 3.07 [0.13, 74.28] |
| 2.8 withdrawal of consent | 7 | 1589 | Risk Ratio (M‐H, Random, 95% CI) | 1.12 [0.80, 1.56] |
| 2.9 other | 3 | 615 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.68, 1.57] |
| 3 Global state: 1. average endpoint scores of CGI severity scale (high=poor) ‐ short term (up to 12 weeks) Show forest plot | 3 | 457 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐0.89, ‐0.73] |
| 4 Global state: 2. no significant clinical improvement CGI ‐ short term (up to 12 weeks) Show forest plot | 4 | 594 | Risk Ratio (M‐H, Random, 95% CI) | 0.69 [0.57, 0.83] |
| 5 Global state: 3. needing additional medication ‐ short term (up to 12 weeks) Show forest plot | 6 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 5.1 benzodiazepine | 1 | 42 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.77, 1.20] |
| 5.2 benzodiazepine derivatives ‐ Lorazepam | 2 | 228 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.68, 1.27] |
| 5.3 benzodiazepine derivatives ‐ Nitrazepam | 1 | 184 | Risk Ratio (M‐H, Random, 95% CI) | 0.51 [0.10, 2.72] |
| 5.4 benzodiazepine related drugs ‐ Zolpidem | 1 | 184 | Risk Ratio (M‐H, Random, 95% CI) | 0.81 [0.53, 1.23] |
| 5.5 sedative/hypnotic | 2 | 230 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.69, 1.06] |
| 5.6 antiparkinsonian | 2 | 172 | Risk Ratio (M‐H, Random, 95% CI) | 1.21 [0.79, 1.86] |
| 5.7 psychotropics | 1 | 186 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.45, 0.85] |
| 6 Mental state: 1. average endpoint scores on various scales on psychotic symptoms (high=poor) ‐ short term (up to 12 weeks) Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 6.1 BPRS total | 2 | 171 | Mean Difference (IV, Random, 95% CI) | ‐12.69 [‐17.06, ‐8.32] |
| 6.2 PANSS total | 3 | 457 | Mean Difference (IV, Random, 95% CI) | ‐17.81 [‐18.17, ‐17.45] |
| 6.3 PANSS general pathology | 1 | 44 | Mean Difference (IV, Random, 95% CI) | ‐13.20 [‐20.15, ‐6.25] |
| 6.4 PANSS negative symptom | 3 | 457 | Mean Difference (IV, Random, 95% CI) | ‐3.10 [‐3.19, ‐3.01] |
| 6.5 PANSS positive symptom | 3 | 457 | Mean Difference (IV, Random, 95% CI) | ‐5.49 [‐6.18, ‐4.80] |
| 7 Mental state: 2. skewed data ‐ short term (up to 12 weeks) Show forest plot | Other data | No numeric data | ||
| 7.1 average endpoint score BPRS total (high=poor) | Other data | No numeric data | ||
| 7.2 average change score of CGI‐C (larger decline=good) | Other data | No numeric data | ||
| 7.3 average change score of CGI‐SI (larger decline=good) | Other data | No numeric data | ||
| 7.4 average change score of HAM‐D‐17 (larger decline=good) | Other data | No numeric data | ||
| 7.5 average change score of PANSS total (larger decline=good) | Other data | No numeric data | ||
| 7.6 average change score of PANSS negative symptom (larger decline=good) | Other data | No numeric data | ||
| 7.7 average change score of PANSS positive symptom (larger decline=good) | Other data | No numeric data | ||
| 8 Adverse effects: 1a. extrapyramidal ‐ various effects ‐ short term (up to 12 weeks) Show forest plot | 11 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 8.1 general ‐ any significant EPS | 7 | 1511 | Risk Ratio (M‐H, Random, 95% CI) | 1.56 [1.13, 2.15] |
| 8.2 general ‐ no improvement on AIMS score | 1 | 42 | Risk Ratio (M‐H, Random, 95% CI) | 0.30 [0.15, 0.61] |
| 8.3 general ‐ no improvement on BAS score | 1 | 226 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [1.01, 1.28] |
| 8.4 general ‐ needing medication for EPS | 2 | 94 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [0.78, 1.67] |
| 8.5 specific ‐ akathisia | 5 | 1204 | Risk Ratio (M‐H, Random, 95% CI) | 2.58 [1.41, 4.72] |
| 8.6 specific ‐ bradykinesia | 2 | 485 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.60, 1.24] |
| 8.7 specific ‐ dyskinesia | 1 | 303 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.01, 7.86] |
| 8.8 specific ‐ dystonia | 3 | 687 | Risk Ratio (M‐H, Random, 95% CI) | 3.40 [0.26, 44.46] |
| 8.9 specific ‐ hypertonia | 3 | 505 | Risk Ratio (M‐H, Random, 95% CI) | 2.98 [1.35, 6.59] |
| 8.10 specific ‐ parkinsonism | 2 | 485 | Risk Ratio (M‐H, Random, 95% CI) | 7.64 [1.40, 41.59] |
| 8.11 specific ‐ tardive dyskinesia | 1 | 303 | Risk Ratio (M‐H, Random, 95% CI) | 6.77 [0.35, 130.03] |
| 8.12 specific ‐ tremor | 5 | 1204 | Risk Ratio (M‐H, Random, 95% CI) | 1.60 [0.89, 2.88] |
| 9 Adverse effects: 1b. extrapyramidal ‐ AIMS average endpoint score ‐ short term (up to 12 weeks) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 10 Adverse effects: 1c. extrapyramidal ‐ skewed data (various scales) ‐ short term (up to 12 weeks) Show forest plot | Other data | No numeric data | ||
| 10.1 average change score of AIMS | Other data | No numeric data | ||
| 10.2 average change score of CGI severity dyskinesia | Other data | No numeric data | ||
| 10.3 average change score of CGI severity parkinsonism | Other data | No numeric data | ||
| 10.4 average change score of ESRS | Other data | No numeric data | ||
| 10.5 average change score of ESRS ‐ akathisia | Other data | No numeric data | ||
| 10.6 average change score of ESRS ‐ dystonia | Other data | No numeric data | ||
| 10.7 average change score of ESRS ‐ dyskinesia | Other data | No numeric data | ||
| 10.8 average change score of ESRS ‐ parkinsonism | Other data | No numeric data | ||
| 11 Adverse effects: 2. any adverse event ‐ short term (up to 12 weeks) Show forest plot | 9 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 11.1 any adverse event | 7 | 1610 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.96, 1.15] |
| 11.2 asthenia | 2 | 639 | Risk Ratio (M‐H, Random, 95% CI) | 1.93 [0.62, 6.02] |
| 11.3 back pain | 1 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.38, 2.86] |
| 11.4 blurred vision | 1 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 4.16 [0.47, 36.59] |
| 11.5 cogwheel rigidity | 1 | 226 | Risk Ratio (M‐H, Random, 95% CI) | 5.25 [0.69, 39.88] |
| 11.6 death | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 3.13 [0.13, 75.92] |
| 11.7 dental disorder | 1 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 3.64 [0.78, 17.11] |
| 11.8 dysmenorrhoea | 2 | 495 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.04, 30.00] |
| 11.9 fatigue | 2 | 558 | Risk Ratio (M‐H, Random, 95% CI) | 2.23 [0.69, 7.22] |
| 11.10 fever | 1 | 130 | Risk Ratio (M‐H, Random, 95% CI) | 9.28 [0.51, 168.90] |
| 11.11 infection | 1 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 0.52 [0.10, 2.78] |
| 11.12 salivation ‐ increased | 1 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 7.28 [0.38, 139.15] |
| 11.13 pyrexia | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.45, 3.16] |
| 11.14 pain | 1 | 121 | Risk Ratio (M‐H, Random, 95% CI) | 1.58 [0.47, 5.31] |
| 11.15 rash (skin) | 1 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.45, 3.16] |
| 11.16 vaginitis | 1 | 58 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.07, 16.32] |
| 11.17 hyperhidrosis | 1 | 437 | Risk Ratio (M‐H, Random, 95% CI) | 10.35 [0.50, 214.17] |
| 12 Adverse effects: 3. cardiovascular ‐ short term (up to 12 weeks) Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 12.1 dizziness ‐ orthostatic | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.13, 69.87] |
| 12.2 ECG abnormal | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 9.40 [0.51, 172.11] |
| 12.3 heart rate decreased | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 0.52 [0.05, 5.66] |
| 12.4 heart rate increased | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 0.85 [0.37, 1.96] |
| 12.5 hypotension ‐ postural | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.13, 69.87] |
| 12.6 QTc > 450 milliseconds or > 10% increase from baseline | 2 | 380 | Risk Ratio (M‐H, Random, 95% CI) | 8.46 [1.07, 67.07] |
| 12.7 tachycardia | 2 | 332 | Risk Ratio (M‐H, Random, 95% CI) | 12.22 [2.33, 64.10] |
| 13 Adverse effects: 4. central nervous system ‐ short term (up to 12 weeks) Show forest plot | 10 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 13.1 agitation | 8 | 1388 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.75, 1.17] |
| 13.2 anxiety | 6 | 1225 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.73, 1.48] |
| 13.3 dizziness | 5 | 970 | Risk Ratio (M‐H, Random, 95% CI) | 1.41 [0.65, 3.05] |
| 13.4 headache | 10 | 1905 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.81, 1.21] |
| 13.5 insomnia | 10 | 1905 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.97, 1.39] |
| 13.6 sedation | 2 | 517 | Risk Ratio (M‐H, Random, 95% CI) | 1.84 [0.52, 6.50] |
| 13.7 somnolence | 6 | 951 | Risk Ratio (M‐H, Random, 95% CI) | 1.61 [1.06, 2.45] |
| 13.8 restlessness | 2 | 619 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.49, 2.74] |
| 14 Adverse effects: 5. endocrine ‐ serum prolactin increase above reference range (23 ng/ml) ‐ short term (up to 12 weeks) Show forest plot | 2 | 323 | Risk Ratio (M‐H, Random, 95% CI) | 12.14 [4.38, 33.68] |
| 15 Adverse effects: 6. gastrointestinal system ‐ short term (up to 12 weeks) Show forest plot | 10 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 15.1 constipation | 8 | 1695 | Risk Ratio (M‐H, Random, 95% CI) | 1.88 [1.19, 2.96] |
| 15.2 diarrhoea | 1 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.37, 2.30] |
| 15.3 dry mouth | 1 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 2.43 [0.65, 9.12] |
| 15.4 dyspepsia | 5 | 1058 | Risk Ratio (M‐H, Random, 95% CI) | 1.24 [0.64, 2.40] |
| 15.5 nausea | 6 | 1225 | Risk Ratio (M‐H, Random, 95% CI) | 1.18 [0.75, 1.86] |
| 15.6 vomiting | 5 | 1181 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.65, 2.07] |
| 16 Adverse effects: 7a. metabolic ‐ weight gain ‐ short term (up to 12 weeks) Show forest plot | 6 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 16.1 any gain | 3 | 910 | Risk Ratio (M‐H, Random, 95% CI) | 3.77 [1.34, 10.63] |
| 16.2 >7% increase from baseline | 3 | 606 | Risk Ratio (M‐H, Random, 95% CI) | 3.47 [1.64, 7.33] |
| 17 Adverse effects: 7b. metabolic ‐ skewed data ‐ average change value on lipid profile ‐ short term (up to 12 weeks) Show forest plot | Other data | No numeric data | ||
| 17.1 cholesterol ‐ total | Other data | No numeric data | ||
| 17.2 HDL | Other data | No numeric data | ||
| 17.3 LDL | Other data | No numeric data | ||
| 17.4 triglycerides | Other data | No numeric data | ||
| 17.5 VLDL | Other data | No numeric data | ||
| 18 Adverse effects: 8. musculoskeletal system ‐ short term (up to 12 weeks) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 18.1 myalgia | 1 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 0.69 [0.12, 4.06] |
| 18.2 Joint disorder | 1 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 2.60 [0.52, 13.10] |
| 19 Adverse effects: 9. physiology ‐ short term (up to 12 weeks) Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 19.1 ALT increased | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.07, 16.45] |
| 19.2 AST increased | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 19.3 blood CPK increased | 2 | 619 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.23, 1.95] |
| 19.4 blood pressure increased | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.15, 7.26] |
| 20 Adverse effects: 10. respiratory system ‐ short term (up to 12 weeks) Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 20.1 upper respiratory infection | 2 | 323 | Risk Ratio (M‐H, Random, 95% CI) | 2.83 [1.03, 7.74] |
| 20.2 pharyngitis | 1 | 202 | Risk Ratio (M‐H, Random, 95% CI) | 0.42 [0.08, 2.10] |
| 20.3 rhinitis | 2 | 306 | Risk Ratio (M‐H, Random, 95% CI) | 10.81 [2.58, 45.29] |
| 20.4 sinusitis | 1 | 437 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.09, 11.36] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mental state: no clinically significant response in psychotic symptoms (defined by PANSS/BPRS<20% decline) ‐ short term (up to 12 weeks) Show forest plot | 2 | 98 | Risk Ratio (M‐H, Random, 95% CI) | 1.15 [0.93, 1.42] |
| 2 Leaving the study early ‐ short term (up to 12 weeks) Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 any reason | 3 | 167 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.53, 2.42] |
| 2.2 due to adverse events | 2 | 137 | Risk Ratio (M‐H, Random, 95% CI) | 4.11 [0.47, 36.24] |
| 2.3 due to lack of efficacy | 1 | 69 | Risk Ratio (M‐H, Random, 95% CI) | 0.55 [0.11, 2.78] |
| 2.4 due to noncompliance | 1 | 69 | Risk Ratio (M‐H, Random, 95% CI) | 0.36 [0.02, 8.61] |
| 2.5 lost to follow‐up | 1 | 69 | Risk Ratio (M‐H, Random, 95% CI) | 0.36 [0.02, 8.61] |
| 2.6 reported death | 1 | 68 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2.7 withdrawal of consent | 3 | 167 | Risk Ratio (M‐H, Random, 95% CI) | 1.41 [0.28, 7.09] |
| 2.8 administrative reasons | 1 | 69 | Risk Ratio (M‐H, Random, 95% CI) | 5.44 [0.27, 109.34] |
| 2.9 abnormal lab results | 1 | 69 | Risk Ratio (M‐H, Random, 95% CI) | 0.36 [0.02, 8.61] |
| 3 Global state: 1. average endpoint scores of CGI severity scale (high=poor) ‐ short term (up to 12 weeks) Show forest plot | 1 | 65 | Mean Difference (IV, Random, 95% CI) | 0.51 [0.02, 1.00] |
| 4 Global state: 2. no significant clinical improvement CGI ‐ short term (up to 12 weeks) Show forest plot | 1 | 68 | Risk Ratio (M‐H, Random, 95% CI) | 1.12 [0.87, 1.44] |
| 5 Global state: 3. general functioning ‐ average endpoint GAF score (high=good) ‐ short term (up to 12 weeks) Show forest plot | 1 | 30 | Mean Difference (IV, Random, 95% CI) | ‐4.5 [‐8.38, ‐0.62] |
| 6 Mental state: 1. average endpoint scores on various scales on psychotic symptoms (high=poor) ‐ short term (up to 12 weeks) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 6.1 PANSS total | 2 | 95 | Mean Difference (IV, Random, 95% CI) | 5.56 [1.59, 9.53] |
| 6.2 PANSS general pathology | 1 | 30 | Mean Difference (IV, Random, 95% CI) | 2.5 [0.03, 4.97] |
| 6.3 PANSS delusion | 1 | 30 | Mean Difference (IV, Random, 95% CI) | 0.70 [0.09, 1.31] |
| 6.4 PANSS negative symptom | 2 | 95 | Mean Difference (IV, Random, 95% CI) | 0.69 [‐0.68, 2.05] |
| 6.5 PANSS positive symptom | 2 | 95 | Mean Difference (IV, Random, 95% CI) | 2.30 [0.98, 3.62] |
| 7 Mental state: 2. average endpoint scores on various scales on psychotic symptoms (high=poor) ‐ medium term (up to 26 weeks) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 7.1 BPRS total | 1 | 53 | Mean Difference (IV, Random, 95% CI) | ‐4.60 [‐9.88, 0.68] |
| 7.2 BPRS positive symptom | 1 | 53 | Mean Difference (IV, Random, 95% CI) | ‐0.90 [‐2.81, 1.01] |
| 7.3 BPRS anxiety/depression factor | 1 | 53 | Mean Difference (IV, Random, 95% CI) | ‐1.0 [‐2.80, 0.80] |
| 7.4 SANS total | 1 | 53 | Mean Difference (IV, Random, 95% CI) | ‐3.10 [‐10.30, 4.10] |
| 8 Mental state: 3. skewed data ‐ short term (up to 12 weeks) Show forest plot | Other data | No numeric data | ||
| 8.1 average endpoint score of CDS total (high=poor) | Other data | No numeric data | ||
| 8.2 average endpoint score on verbal working memory (SD, high=good) | Other data | No numeric data | ||
| 9 Adverse effects: 1a. extrapyramidal ‐ average endpoint SAS score ‐ short term (up to 12 weeks) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 10 Adverse effects: 1b. extrapyramidal ‐ skewed data (various scales) ‐ short term (up to 12 weeks) Show forest plot | Other data | No numeric data | ||
| 10.1 average endpoint score of AIMS | Other data | No numeric data | ||
| 10.2 average change score of Barnes akathisia rating scale | Other data | No numeric data | ||
| 10.3 average change score of ESRS | Other data | No numeric data | ||
| 10.4 average change score of ESRS ‐ dystonia | Other data | No numeric data | ||
| 10.5 average change score of ESRS ‐ dyskinesia | Other data | No numeric data | ||
| 10.6 average change score of ESRS ‐ parkinsonism | Other data | No numeric data | ||
| 11 Adverse effects: 1c. extrapyramidal ‐ skewed data (various scales) ‐ medium term (up to 26 weeks) Show forest plot | Other data | No numeric data | ||
| 11.1 average endpoint score of AIMS | Other data | No numeric data | ||
| 11.2 average endpoint score of SAS | Other data | No numeric data | ||
| 12 Adverse effects: 2. any adverse event ‐ short term (up to 12 weeks) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 12.1 any adverse event | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [0.83, 1.58] |
| 12.2 amenorrhoea | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.13, 71.00] |
| 12.3 asthenia | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.08 [0.61, 1.91] |
| 12.4 depression | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.2 [0.61, 2.37] |
| 12.5 emotional indifference | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.52, 2.37] |
| 12.6 fatigue | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.08 [0.61, 1.91] |
| 12.7 failing memory | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.32, 1.41] |
| 12.8 increased duration of sleep | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.51, 1.97] |
| 12.9 salivation ‐ increased | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.25 [0.81, 1.94] |
| 13 Adverse effects: 3a. cardiovascular ‐ short term (up to 12 weeks) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 13.1 dizziness ‐ orthostatic | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.43, 2.34] |
| 13.2 palpitation | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.27, 3.66] |
| 13.3 tachycardia | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.27, 3.66] |
| 14 Adverse effects: 3b. cardiovascular ‐ QTc interval ‐ short term (up to 12 weeks) Show forest plot | 1 | 30 | Mean Difference (IV, Random, 95% CI) | ‐19.70 [‐42.08, 2.68] |
| 15 Adverse effects: 4. central nervous system ‐ short term (up to 12 weeks) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 15.1 sedation | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.46 [0.88, 2.43] |
| 15.2 somnolence | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.51, 1.97] |
| 15.3 tension | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.23 [0.71, 2.12] |
| 16 Adverse effects: 5. gastrointestinal system ‐ short term (up to 12 weeks) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 16.1 constipation | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 0.71 [0.25, 2.02] |
| 17 Adverse effects: 6a. haematological ‐ short term (up to 12 weeks) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 17.1 neutrophil count | 1 | 57 | Mean Difference (IV, Random, 95% CI) | 0.37 [‐0.42, 1.16] |
| 17.2 prolactin level, ng/mL | 1 | 30 | Mean Difference (IV, Random, 95% CI) | 60.10 [46.52, 73.68] |
| 17.3 white cell count | 1 | 61 | Mean Difference (IV, Random, 95% CI) | 0.66 [‐0.20, 1.52] |
| 18 Adverse effects: 6b. haematological ‐ medium term (up to 26 weeks) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 18.1 prolactin level ng/mL | 1 | 44 | Mean Difference (IV, Random, 95% CI) | 34.1 [17.63, 50.57] |
| 18.2 fasting glucose | 1 | 40 | Mean Difference (IV, Random, 95% CI) | ‐4.60 [‐17.09, 7.89] |
| 19 Adverse effects: 7a. metabolic ‐ weight gain ‐ short term (up to 12 weeks) Show forest plot | 1 | 64 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.40, 2.52] |
| 20 Adverse effects: 7a. metabolic ‐ weight gain ‐ medium term (up to 26 weeks) Show forest plot | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.2 [0.01, 3.96] |
| 21 Adverse effects: 7b. metabolic ‐ average endpoint value on lipid profile ‐ short term (up to 12 weeks) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 21.1 cholesterol ‐ total (mg/dl) | 1 | 56 | Mean Difference (IV, Random, 95% CI) | ‐6.60 [‐29.05, 15.85] |
| 21.2 HDL cholesterol (mg/dl) | 1 | 52 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐8.44, 8.44] |
| 21.3 LDL cholesterol (mg/dl) | 1 | 53 | Mean Difference (IV, Random, 95% CI) | ‐6.90 [‐26.02, 12.22] |
| 21.4 triglycerides (mg/dl) | 1 | 56 | Mean Difference (IV, Random, 95% CI) | 6.20 [‐57.57, 69.97] |
| 22 Adverse effects: 7c. metabolic ‐ average endpoint value ‐ short term (up to 12 weeks) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 22.1 body mass index | 1 | 63 | Mean Difference (IV, Random, 95% CI) | 1.70 [‐0.99, 4.39] |
| 22.2 fasting glucose (mg/dl) | 1 | 51 | Mean Difference (IV, Random, 95% CI) | 16.20 [‐3.12, 35.52] |
| 22.3 waist circumference (cm) | 1 | 61 | Mean Difference (IV, Random, 95% CI) | 5.10 [‐4.14, 14.34] |
| 22.4 weight gain | 2 | 94 | Mean Difference (IV, Random, 95% CI) | 0.34 [‐0.84, 1.53] |
| 23 Adverse effects: 8. sleep ‐ skewed data ‐ average change score (UKU) ‐ short term (up to 12 weeks) Show forest plot | Other data | No numeric data | ||
| 24 Quality of life: average endpoint score (QLS, high=good) ‐ short term (up to 12 weeks) Show forest plot | 1 | 30 | Mean Difference (IV, Random, 95% CI) | 0.80 [‐5.44, 7.04] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mental state: 1. no clinically significant response (defined by PANSS/BPRS) ‐ short term (up to 12 weeks) Show forest plot | 6 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 defined by PANSS/BPRS <20% decline | 6 | 864 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.52, 0.78] |
| 1.2 defined by PANSS/BPRS <20% decline (without studies with >50% left the study early) | 3 | 589 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.67, 0.88] |
