Quetiapine versus typical antipsychotic medications for schizophrenia
Abstract
Background
Quetiapine is a widely used atypical antipsychotic drug for schizophrenia that has been on the market for over a decade. However, It is not clear how the effects of quetiapine differ from typical antipsychotics.
Objectives
To review the effects of quetiapine in comparison with typical antipsychotics in the treatment of schizophrenia and schizophrenia‐like psychosis.
Search methods
We searched the Cochrane Schizophrenia Group Trials Register (March 2010), and inspected references of all identified studies.
Selection criteria
We included all randomised control trials comparing oral quetiapine with typical antipsychotic drugs in people with schizophrenia or schizophrenia‐like psychosis.
Data collection and analysis
We extracted data independently. For dichotomous data, we calculated risk ratio (RR) and 95% confidence intervals (CI) using a random‐effects model. We presented chosen outcomes in a 'Summary of findings' table and comparative risks where appropriate. For continuous data, we calculated mean differences (MD) based on a random‐effects model. We assessed risk of bias for included studies.
Main results
The review includes 43 randomised controlled trials (RCTs) with 7217 participants. Most studies were from China. The percentages of participants leaving the studies early were similar (36.5% in quetiapine group and 36.9% in typical antipsychotics group) and no significant difference between groups was apparent for leaving early due to any reason (23 RCTs n = 3576 RR 0.91 CI 0.81 to 1.01, moderate quality evidence), however, fewer participants in the quetiapine group left the studies early due to adverse events (15 RCTs, n = 3010, RR 0.48 CI 0.30 to 0.77).
Overall global state was similar between groups (no clinically significant response; 16 RCTs, n = 1607, RR 0.96 CI 0.75 to 1.23, moderate quality evidence) and there was no significant difference in positive symptoms (PANSS positive subscore: 22 RCTs, n = 1934, MD 0.02 CI ‐0.39 to 0.43, moderate quality evidence). General psychopathology was equivocal (PANSS general psychopathology subscore: 18 RCTs, n = 1569, MD ‐0.20 CI ‐0.83 to 0.42) between those allocated to quetiapine and typical antipsychotics. However, quetiapine was statistically significantly more efficacious for negative symptoms (PANSS negative subscore: 22 RCTs, n = 1934, MD ‐0.82 CI ‐1.59 to ‐0.04, moderate quality evidence), however, this result was highly heterogeneous and driven by two small outlier studies with high effect sizes. Without these two studies, there was no heterogeneity and no statistically significant difference between quetiapine and typical antipsychotics.
Compared with typical antipsychotics, quetiapine might cause fewer adverse effects (9 RCTs, n = 1985, RR 0.76 CI 0.64 to 0.90 number needed to treat to induce harm (NNTH) 10, CI 8 to 17), less abnormal ECG (2 RCTs, n = 165, RR 0.38 CI 0.16 to 0.92, NNTH 8, CI 4 to 55), fewer overall extrapyramidal effects (8 RCTs, n = 1,095, RR 0.17 CI 0.09 to 0.32, NNTH 3, CI 3 to 3, moderate quality evidence) and fewer specific extrapyramidal effects including akathisia, parkinsonism, dystonia and tremor. Moreover, it might cause lower prolactin level (4 RCTs, n = 1034, MD ‐16.20 CI ‐23.34 to ‐9.07, moderate quality evidence) and less weight gain compared with some typical antipsychotics in the short term (9 RCTs, n = 866, RR 0.52 CI 0.34 to 0.80, NNTH 8, CI 6 to 15).
However, there was no significant difference between the two groups in suicide attempt, suicide, death, QTc prolongation, low blood pressure, tachycardia, sedation, gynaecomastia, galactorrhoea, menstrual irregularity and white blood cell count.
Authors' conclusions
Quetiapine may not differ from typical antipsychotics in the treatment of positive symptoms and general psychopathology. There are no clear differences in terms of the treatment of negative symptoms. However, it causes fewer adverse effects in terms of abnormal ECG, extrapyramidal effects, abnormal prolactin levels and weight gain.
PICOs
Plain language summary
Quetiapine versus typical antipsychotic drugs for schizophrenia
Antipsychotic drugs are the main treatment for schizophrenia, helping to treat both the positive symptoms (such as hearing voices, seeing things and having strange beliefs) and negative symptoms (including apathy, tiredness and loss of emotion) of this illness. Selecting the most effective antipsychotic drug that can be tolerated by people with schizophrenia is crucial to successful treatment. Older drugs (also known as typical or first generation antipsychotic drugs), such as chlorpromazine and haloperidol, have been used in treating schizophrenia for over 50 years. Although these older drugs are good at treating the positive symptoms of schizophrenia they tend to cause undesirable side effects. These side effects can mean that people do not tolerate or like taking these drugs, which may lead to relapse and admission to hospital. Since 1988, a newer generation of antipsychotic drugs has become available. These new drugs (known as atypical or second generation antipsychotic drugs) are effective in treating the symptoms of schizophrenia but thought to have less side effects than older drugs. However, although newer drugs may cause less side effects such as movement disorders, they have been linked to other side effects like heart problems or weight gain. Quetiapine is a new antipsychotic drug for schizophrenia that has been available for over a decade. However, it is not clear how the effects of quetiapine differ from older antipsychotic drugs. This review evaluated the effectiveness and tolerability of quetiapine versus older antipsychotic drugs. The review included 43 trials with a total of 7217 people. Most studies were from China. In the main, quetiapine did not differ from older drugs for the treatment of positive symptoms of mental illness. There were also no clear differences in terms of the treatment of negative symptoms. However, it is important to note that evidence from these trials suggests quetiapine causes fewer side effects (such as weight gain, dizziness, movement disorders, the inability to sit still, shaking, tremors and abnormal levels of the hormone prolactin, which can contribute to sexual and mental health problems). However, evidence from the trials is limited due to high numbers of people leaving early in almost all of the studies. More evidence through the completion of well designed studies comparing quetiapine with older antipsychotic drugs is needed.
This plain language summary has been written by a consumer, Benjamin Gray, Service User: RETHINK.
Authors' conclusions
Summary of findings
| Quetiapine compared to Typical antipsychotics 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 | |||||
| Typical antipsychotics | Quetiapine | |||||
| Global state | Study population | RR 0.96 | 1607 | ⊕⊕⊕⊝ | ||
| 145 per 1000 | 139 per 1000 | |||||
| Moderate | ||||||
| Leaving the study early due to any reason | Study population | RR 0.91 | 3576 | ⊕⊕⊕⊝ | ||
| 369 per 1000 | 336 per 1000 | |||||
| Moderate | ||||||
| Positive symptoms | The mean positive symptoms in the intervention groups was | 1934 | ⊕⊕⊕⊝ | |||
| Negative symptoms | The mean negative symptoms in the intervention groups was | 1934 | ⊕⊕⊕⊝ | |||
| Cognitive function | The mean cognitive function in the intervention groups was | 142 | ⊕⊝⊝⊝ | |||
| Extrapyramidal effects | Study population | RR 0.17 | 1095 | ⊕⊕⊕⊝ | ||
| 548 per 1000 | 93 per 1000 | |||||
| Moderate | ||||||
| Prolactin level | The mean prolactin level in the intervention groups was | 1034 | ⊕⊕⊕⊝ | |||
| *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 Limitations in design ‐ rated 'serious' : poor description of randomisation, no details about blinding, no details about concealment. PANSS: Positive and Negative Syndrome Scale | ||||||
Background
Description of the condition
Schizophrenia is often a chronic and disabling psychiatric disorder. It affects approximately one per cent of the population. The severity of symptoms often causes substantial and long‐lasting impairments. Moreover, the financial cost of treatment in schizophrenia is high for both afflicted people and health services as it often requires hospitalisation (Buchanan 2005).
Description of the intervention
Antipsychotics have been the core treatment for schizophrenia, thus selecting the most effective and tolerable antipsychotic is key to maximizing treatment outcomes. Typical antipsychotics such as chlorpromazine and haloperidol, although they have been used in treating schizophrenia for over 50 years, tend to cause undesirable adverse effects that may lead to non‐compliance. Quetiapine is a widely used atypical antipsychotic drug for schizophrenia which has been on the market for over a decade. However, It is not clear how the effects of quetiapine differ from typical antipsychotics.
How the intervention might work
Experimental laboratory studies have indicated that quetiapine is a clozapine‐like atypical antipsychotic (Goldstein 1993; Migler 1993; Saller 1993). While olanzapine, risperidone, sertindole and ziprasidone have high affinities (< 50 nM) to both D2 and 5‐HT2A receptors, quetiapine is similar to clozapine in having only moderate affinities (< 500 nM) to these sites (Goldstein 1995) but a high affinity to histamine receptors (< 50 nM) (Srisurapanont 2004). As an agent with moderate affinities to dopamine D2 and serotonin 5‐HT2A receptors, quetiapine is less likely to cause extrapyramidal side effects and hyperprolactinaemia. Norquetiapine (N‐desalkyl quetiapine) is an active metabolite of quetiapine. It has a high affinity for the norepinephrine transporter and a partial agonist activity at the serotonin 5‐HT1A receptor (Goldstein 2007). This profile might make quetiapine differ from other antipsychotics.
Why it is important to do this review
Since 1988, a newer generation of antipsychotic drugs has become available. These ‘atypical’ antipsychotics are defined as antipsychotic drugs with low propensity to induce extrapyramidal side effects (Kerwin 1994). Although atypical antipsychotics may cause less extrapyramidal adverse effects and movement disorders than typical antipsychotics, many of them are more likely to cause metabolic adverse effects. Moreover, the role of atypical antipsychotics in the treatment of schizophrenia is still under debate. Previous systematic reviews reported that there was no clear evidence that atypical antipsychotics were more effective than typical antipsychotics (Geddes 2000; Leucht 2008). Results from the two independent randomised controlled trials contradict previous trials comparing typical with atypical antipsychotics and the findings do question whether there is a meaningful difference between the old and new generation of drugs (Jones 2006; vs PERPHEN ‐ L'rman 2005).
This systematic review aims to assess the evidence of efficacy and safety of quetiapine in comparison with typical antipsychotic drugs in the treatment of schizophrenia.
Objectives
To review the effects of quetiapine in comparison with typical antipsychotics in the treatment of schizophrenia and schizophrenia‐like psychosis.
Methods
Criteria for considering studies for this review
Types of studies
We considered all relevant randomised controlled trials. We excluded quasi‐randomised studies, such as those allocating by using alternate days of the week. Where trials were described as 'double‐blind', but it was implied that the study was randomised and where the demographic details of each group's participants were similar, we included these trials and a sensitivity analysis was undertaken to the presence or absence of these data.
Randomised cross‐over studies were eligible but only data up to the point of first cross‐over because of the instability of the problem behaviours and the likely carry‐over effects of all treatments (Elbourne 2002).
Types of participants
Participants included people with schizophrenia or other types of schizophrenia‐like psychosis (for example, schizophreniform and schizoaffective disorders), irrespective of the diagnostic criteria used, age, ethnicity and sex. There is no clear evidence that the schizophrenia‐like psychoses are caused by fundamentally different disease processes or require different treatment approaches (Carpenter 1994). Where a study described the participant group as suffering from 'serious mental illnesses' and did not give a particular diagnostic grouping, we included these trials. The exception to this rule was when the majority of those randomised clearly did not have a functional non‐affective psychotic illness.
Types of interventions
1. Quetiapine: any oral form of application, any dose.
2. Typical antipsychotic drugs, that is, any other antipsychotics excluding amisulpride, sulpiride, zotepine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone and clozapine, at any dose.
Types of outcome measures
We grouped outcomes into the short term (up to 12 weeks), medium term (13‐26 weeks) and long term (over 26 weeks).
Primary outcomes
Global state
No clinically important response as defined by the individual studies ‐ for example, global impression less than much improved or less than 50% reduction on a rating scale.
Secondary outcomes
1. Leaving the studies early
Any reason, adverse events, inefficacy of treatment.
2. Relapse
Relapse (as defined by the individual studies).
3. Mental state (with particular reference to the positive and negative symptoms of schizophrenia)
3.1 No clinically important change in general mental state score
3.2 Average endpoint general mental state score
3.3 Average change in general mental state score
3.4 No clinically important change in specific symptoms (positive symptoms of schizophrenia, negative symptoms of schizophrenia)
3.5 Average endpoint specific symptom score
3.6 Average change in specific symptom score
4. General functioning
4.1 No clinically important change in general functioning
4.2 Average endpoint general functioning score
4.3 Average change in general functioning score
5. Quality of life/satisfaction with treatment
5.1 No clinically important change in general quality of life
5.2 Average endpoint general quality of life score
5.3 Average change in general quality of life score
6. Cognitive functioning
6.1 No clinically important change in overall cognitive functioning
6.2 Average endpoint of overall cognitive functioning score
6.3 Average change of overall cognitive functioning score
7. Service use
7.1 Number of participants hospitalised
8. Adverse effects
8.1 Number of participants with at least one adverse effect
8.2 Clinically important specific adverse effects (cardiac effects, death, movement disorders, prolactin increase and associated effects, sedation, seizures, weight gain, effects on white blood cell count)
8.3 Average endpoint in specific adverse effects
8.4 Average change in specific adverse effects
Search methods for identification of studies
No language restriction was applied within the limitations of the search tools.
Electronic searches
The Cochrane Schizophrenia Group Trials Register (November 2008 and March 2010) was searched with the following search strategy:
[(*quetiapine* or *seroquel* or *ICI‐204636* or (*ICI* and *204636*) or *ICI204636* in title, abstract or index terms of REFERENCE) or (*quetiapine* in interventions of STUDY)]
The Cochrane Schizophrenia Group's Trials Register is based on regular searches of BIOSIS Inside; CENTRAL; CINAHL; EMBASE; MEDLINE and PsycINFO; the handsearching of relevant journals and conference proceedings, and searches of several key grey literature sources. A full description is given in the group's module.
Searching other resources
1. Reference searching
The reference lists of all retrieved articles, previous reviews and major text books of schizophrenia were examined for additional trials.
2. Personal contact
We identified the authors of significant papers from authorship of trials and review articles found in the search. We contacted them, as well as other experts in the field, and asked for their knowledge of other studies, published or unpublished, relevant to the review.
3. Drug companies
We contacted the pharmaceutical company that manufactures quetiapine (Astra Zeneca) and requested relevant published and unpublished data. They provided a link to the studies that were carried out by the company including published and unpublished data. However, the data from the company proved to be the same as the data from the Cochrane Schizophrenia Group.
Data collection and analysis
Selection of studies
Review authors SJS and MS independently inspected citations identified from the search. We identified potentially relevant reports and ordered full papers for reassessment. Retrieved articles were assessed independently by STS and NM for inclusion according to the previously defined inclusion criteria. Any disagreement was resolved by consensus discussions with SJS. If it was impossible to resolve disagreements, we added these studies to those awaiting assessment and we contacted the authors of the papers for clarification. If there had been non‐concurrence in trial selection, we would have reported this.
Data extraction and management
1. Extraction
SJS and BM independently extracted data from included studies. Any disagreement was discussed with MS, decisions documented and, if necessary, we contacted authors of studies for clarification. Due to language barrier, the data from Chinese studies were extracted by JX only.
2. Management
We extracted data onto standard, simple forms.
3. Scale‐derived data
We included continuous data from rating scales only if: (a) the psychometric properties of the measuring instrument had been described in a peer‐reviewed journal (Marshall 2000); (b) the measuring instrument was not written or modified by one of the trialists; (c) the measuring instrument was either (i) a self‐report or (ii) completed by an independent rater or relative (not the therapist).
4. 'Summary of findings' table
We used the GRADE approach to interpret findings (Schünemann 2008) and used GRADE profiler (GRADE Profiler) to import data from RevMan 5.1 (Review Manager) to create a 'Summary of findings' table. This table provides 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.
-
Global state
-
Leaving the study early
-
Mental state: positive, negative symptoms
-
Cognitive function
-
Adverse effects: extrapyramidal effects, prolactin level
Assessment of risk of bias in included studies
SJS and MS worked independently to assess risk of bias by using criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess trial quality. This 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.
If the raters disagreed, the final rating was made by consensus discussion with BM. Where inadequate details of randomisation and other characteristics of trials were provided, we contacted the authors of the studies in order to obtain further information. Non‐concurrence in quality assessment was reported, but if disputes arose as to which category a trial was to be allocated, again, resolution was made by discussion.
The level of risk of bias is noted in both the text of the review and in the summary of findings Table for the main comparison.
Measures of treatment effect
1. Dichotomous data
Where possible, we made efforts to convert outcome measures to dichotomous data. This can be done by identifying cut‐off points on rating scales and dividing participants accordingly into 'clinically improved' or 'not clinically improved'. It is generally assumed that if there had been a 50% reduction in a scale‐derived score such as the Brief Psychiatric Rating Scale (BPRS, Overall 1962) or the Positive and Negative Syndrome Scale (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 cut‐off presented by the original authors.
We calculated the risk ratio (RR) and its 95% confidence interval (CI) based on the random‐effects model, as this takes into account any differences between studies, even if there is no statistically significant heterogeneity. It has been shown that RR is more intuitive (Boissel 1999) than odds ratios and that odds ratios tend to be interpreted as RR by clinicians (Deeks 2000). This misinterpretation then leads to an overestimate of the impression of the effect. When the overall results were significant, we calculated the number needed to treat to provide benefit (NNTB) and the number needed to treat to induce harm (NNTH) as the inverse of the risk difference.
2. Continuous data
2.1 Summary statistic
For continuous outcomes we estimated a mean difference (MD) between groups. Mean differences were based on the random‐effects model as this takes into account any differences between studies even if there is no statistically significant heterogeneity. We did not calculate standardised mean differences (SMD) measures.
2.2 Endpoint versus change data
Since there is no principal statistical reason why endpoint and change data should measure different effects (Higgins 2011), we used scale endpoint data, which is easier to interpret from a clinical point of view. If endpoint data were not available, we used changed data.
2.3 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 applied 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 zero, the standard deviation, when multiplied by two, 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 starts from a positive value (such as PANSS which can have values from 30 to 210), the calculation described above was modified 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 end point and these rules can be applied. 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 planned to enter skewed data from studies of less than 200 participants in 'other data tables' rather than into analyses. However, we found that most of the data from included studies were skewed (e.g. the data from all the studies investigated PANSS positive symptoms) and excluding all studies on the basis of estimates of the normal distribution would lead to selection bias. We therefore included all studies in the primary analysis and excluded the skewed data in the sensitivity analysis (see Differences between protocol and review).
2.4 Data synthesis
When standard errors instead of standard deviations were presented, the former were converted to standard deviations. If standard deviations were not reported and could not be calculated from available data, authors were asked to supply the data. In the absence of data from authors, the mean standard deviations from other studies were used.
2.5 Multiple doses
When a study investigated a number of fixed doses of quetiapine, we used scores from the highest dose group.
Unit of analysis issues
1. Cluster trials
Studies increasingly employ 'cluster randomisation' (such as randomisation by clinician or practice) but analysis and pooling of clustered data poses problems. Firstly, authors often fail to account for intraclass correlation in clustered studies, leading to a 'unit of analysis' error (Divine 1992) whereby P values are spuriously low, confidence intervals unduly narrow and statistical significance overestimated. This can lead to type I errors or a false positive (Bland 1997; Gulliford 1999).
Where clustering was not accounted for in primary studies, we presented the data in a table, with a (*) symbol to indicate the presence of a probable unit of analysis error. In subsequent versions of this review, we will seek to contact first authors of studies to obtain intraclass correlation coefficients (ICCs) of their clustered data and to adjust for this using accepted method (Gulliford 1999). If we had found that clustering was incorporated into the analysis of primary studies, we would have presented these data as if from a non‐cluster randomised study, but adjusted for the clustering effect.
Binary data as presented in a report were divided by a 'design effect'. This was calculated using the mean number of participants per cluster (m) and the ICC [Design effect = 1+(m‐1)*ICC] (Donner 2002). If the ICC was not reported, it was assumed to be 0.1 (Ukoumunne 1999). This assumption may be too high and, had this instance occured, we had planned to see if taking an ICC of 0.01 would make any substantive difference for the primary outcome. If it had not, we would have used 0.01 in preference across outcomes.
If we had found that cluster studies were appropriately analysed taking into account ICCs and relevant data documented in the report, we would have synthesised these with other studies using the generic inverse variance technique.
2. Cross‐over trials
A major concern of cross‐over trials is the carry‐over effect. It occurs if an effect (e.g. pharmacological, physiological or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence on entry to the second phase the participants can differ systematically from their initial state despite a wash‐out phase. For the same reason cross‐over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in schizophrenia, we would only have used data of the first phase of cross‐over studies.
3. Studies with multiple treatment groups
If we had found any study with more than two treatment groups, we would have presented the additional treatment groups in additional relevant comparisons. Data were not double counted. Where the additional treatment groups were not relevant, these data were not reproduced.
Dealing with missing data
At some degree of loss of follow‐up, data must lose credibility (Xia 2009), therefore, we planned to exclude studies with an attrition rate over 40%. However, many of the main studies including vs HLP ‐ Arvanitis 1997, vs FLUPHEN ‐ Conley 2005, vs HLP ‐ Fl'hacker 2005, vs PERPHEN ‐ L'rman 2005, vs HLP ‐ Purdon 2001 and vs HLP ‐ Velligan 2002) reported high attrition rates over 40%. Moreover, it is still unclear what degree of attrition leads to a high degree of bias (Komossa 2010). We, therefore, did not exclude these studies on the basis of the attrition rate, but we carried out sensitivity analyses of the main mental state outcomes excluding the studies with high attrition rates. We also have addressed the attrition problems as well as the use of intention‐to‐treat (ITT) in the 'Risk of bias' table, the results and discussion sections.
Intention‐to‐treat was used when available. When these data were not clearly described, data were presented on a 'once‐randomised‐always‐analyse' basis, assuming an ITT analysis. We anticipated that in some studies, in order to do an ITT analysis, the method of last‐observation‐carried‐forward (LOCF) would be employed within the study report. As with all methods of imputation to deal with missing data, LOCF introduces uncertainty about the reliability of the results. Therefore, where LOCF data have been used in the analysis, it was indicated in the review. Sensitivity analyses excluding studies with the use of ITT were undertaken to test how prone the primary outcomes were to change when 'completer' data only were included in the analyses.
Assessment of heterogeneity
1. Clinical heterogeneity
We considered all included studies hoping to use all studies together. Where clear unforeseen issues were apparent that might have added obvious clinical heterogeneity, we noted these issues, considered them in analyses and undertook sensitivity analyses for the primary outcome.
2. Statistical
2.1 Visual inspection
We visually inspected graphs to investigate the possibility of statistical heterogeneity.
2.2 Employing the I2 statistic
Heterogeneity between studies was investigated by considering the I2 method alongside the Chi2 'P' value. The I2 provides an estimate of the percentage of inconsistency thought to be due to chance (Higgins 2003). The importance of the observed value of I2 depends on i. magnitude and direction of effects and ii. strength of evidence for heterogeneity (e.g. 'P' value from Chi2 test, or a confidence interval for I2).
An I2 estimate greater than or equal to 50% accompanied by a statistically significant Chi2 statistic, was interpreted as evidence of substantial levels of heterogeneity (Section 9.5.2 ‐ Higgins 2011) and reasons for heterogeneity were explored. If the inconsistency was high and the clear reasons were found, data were presented separately.
Assessment of reporting biases
Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Egger 1997). These are described in section 10.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We are aware that funnel plots may be useful in investigating small‐study effects but are of limited power to detect such effects when there are few studies. We did not use funnel plots for outcomes where there were 10 or fewer studies, or where all studies were of similar sizes. In other cases, where funnel plots were possible, we sought statistical advice in their interpretation.
Data synthesis
Where possible, we employed a random‐effects model for analyses. We understand that there is no closed argument for preference for use of fixed‐effect or random‐effects models. The random‐effects method incorporates an assumption that the different studies are estimating different, yet related, intervention effects. This does seem true to us, however, random‐effects does put added weight onto the smaller of the studies ‐ those trials that are most vulnerable to bias.
Subgroup analysis and investigation of heterogeneity
If data were clearly heterogeneous, we checked that data were correctly extracted and entered and that we had made no unit‐of‐analysis errors. If high levels of heterogeneity remained, we did not undertake a meta‐analysis at this point as 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 planned to explore heterogeneity. We pre‐specified no characteristics of studies that may be associated with heterogeneity except for methodological quality. If no clear association could be shown by sorting studies by quality of methods, we continued to investigate for other reasons for the heterogeneity. Had we identified another characteristic of the studies by the investigation of heterogeneity, perhaps some clinical heterogeneity not hitherto predicted ‐ but plausible causes of heterogeneity ‐ we planned to discuss these post‐hoc reasons, investigate the sensitivity of the estimate of the effect size for the primary outcome to inclusion and exclusion of these causes, and analyse and present the data. However, if the heterogeneity was substantially unaffected by any investigation and no reasons for the heterogeneity were apparent, we planned to present the final data without a meta‐analysis. Subgroup analysis was not carried out in this review.
Sensitivity analysis
We planned sensitivity analyses a priori for examining the change in the robustness of the sensitivity to including studies with implied randomisation (see Criteria for considering studies for this review: Types of studies), skewed and non‐skewed data, inappropriate comparator doses of drug and different clinical groups. However, we did not find any difference in clinical groups, therefore, the sensitivity analyses on this matter was not done. We also added the sensitivity analyses of the main mental state outcomes excluding the studies with high attrition rate.
If inclusion of studies with implied randomisation made no substantive difference to the primary outcome they were left in the final analyses. For outcomes with both skewed data and non‐skewed data, we investigated the effect of combining all data together and if no substantive difference was noted then the potentially skewed data were left in the analyses. A recent review showed that some of the comparisons of antipsychotics may have been biased by using inappropriate comparator dose ranges (Heres 2006). The inappropriate dose ranges were defined as the ranges not within the range recommended in the American Psychiatric Association Practice Guideline for the treatment of patients with Schizophrenia, second edition (APA 2004).
| Drug | mg/day |
| Quetiapine | 300‐800 |
| Typical | |
| Chlorpromazine | 300‐1000 |
| Fluphenazine | 5‐20 |
| Haloperidol | 5‐20 |
| Loxapine | 30‐100 |
| Mesoridazine | 150‐400 |
| Molindone | 30‐100 |
| Perphenazine | 16‐64 |
| Thioridazine | 300‐800 |
| Thiothixene | 15‐50 |
| Trifluoperazine | 15‐50 |
If we had found the studies with implied randomisation, skewed and non‐skewed data, inappropriate comparator doses of drug and different clinical groups, we would have analysed whether the exclusion of these studies changed the results of the primary outcome and the general mental state.
Results
Description of studies
See also: Characteristics of included studies; Characteristics of excluded studies. In this review we use the style of including the comparison compound as part of the study tag. For example the study 'vs CPZ ‐ Ai 2007' involves quetiapine compared with chlorpromazine. Other abbreviations used are HLP ‐ haloperidol, FLUPHEN ‐ fluphenazine and PERPHEN ‐ perphenazine. In our opinion, this style conveys more information in each graph as simply using the name of the first author leaves unclear which comparison is being used.
Results of the search
The overall search strategy yielded 830 reports (666 in 2008 and 164 in 2010) of which 65 were closely inspected (Figure 1).
PRISMA flow diagram.
Included studies
Forty‐three studies with 7217 participants met the inclusion criteria. Twelve studies were sponsored by the pharmaceutical companies developing quetiapine.
1. Length of trials
Thirty‐five studies were short term with a duration range of four to 12 weeks. Five studies were medium term and three studies were long term.
2. Settings
Twenty‐eight studies were conducted in China. Of the 43 included studies, 11 studies were conducted in an inpatient or outpatient setting, 20 studies were conducted in inpatient settings and three studies were conducted in outpatient settings. Two studies were conducted in communities and hospitals. Seven studies did not report the setting.
3. Participants
Twenty Chinese studies included participants diagnosed by using the Chinese Classification of Mental Disorders, third version (CCMD‐3) and five Chinese studies used CCMD‐2. Eleven studies included participants diagnosed by using the Diagnostic and Statistical Manual Fourth revision (DSM‐IV) and four studies used the third edition, revised (DSM‐III‐R). Two studies diagnosed participants by using the International Classification of Diseases Version 10 (ICD‐10) and vs CPZ ‐ Zhou 2004 used both ICD‐10 and CCMD‐3. Three studies included only acutely ill participants (vs HLP ‐ Copolov 2000; vs CPZ ‐ Guo 2003; vs HLP ‐ Taneli 2003). Two studies included only participants with a first episode schizophrenia (vs HLP ‐ Fl'hacker 2005; vs CPZ ‐ Hu 2003). One study focused on participants with full or partial remission (vs HLP ‐ Velligan 2002) and one study focused on treatment‐resistant participants (vs HLP ‐ Emsley 1999).
4. Study size
vs PERPHEN ‐ L'rman 2005 was the largest study with 1493 participants and vs HLP ‐ Purdon 2001 was the smallest with only 25. Four studies had less than 50 participants but three studies randomised more than 400 people.
5. Interventions
5.1 Quetiapine
Four studies used fixed dosing (vs HLP ‐ Arvanitis 1997; vs HLP ‐ Atmaca 2002; vs HLP ‐ Emsley 1999; vs HLP ‐ Velligan 2002) while others used flexible regimens. Overall, quetiapine was given in a dose range of 50‐800 mg. However, vs CPZ ‐ Zhong 2005 and vs HLP ‐ McCue 2006 limited the upper dose range at 900 mg/day and 1200 mg/day respectively.
5.2 Typical antipsychotic drugs
The comparator typical antipsychotics were chlorpromazine, haloperidol and perphenazine. Again, four studies used fixed dosing (vs HLP ‐ Arvanitis 1997; vs HLP ‐ Atmaca 2002; vs HLP ‐ Emsley 1999; vs HLP ‐ Velligan 2002) while others used a flexible regimen. Some studies included treatment arms of participants given other atypical antipsychotics but these results were not reported in this review.
6. Outcomes
6.1 Leaving the study early
The number of participants leaving the studies early was reported for the categories 'any reason', 'adverse events' and 'lack of efficacy'.
6.2 Outcome scales
Details of scales that provided usable data are shown below.
6.2.1 Global state scales
6.2.1.1 Clinical Global Impression Scale ‐ CGI (Guy 1976)
This is used to assess both severity of illness and clinical improvement, by comparing the conditions of the person standardised against other people with the same diagnosis. A seven‐point scoring system is usually used with low scores showing decreased severity and/or overall improvement.
6.2.2 Mental state scales
6.2.2.1 Positive and Negative Syndrome Scale ‐ PANSS (Kay 1986)
This schizophrenia scale has 30 items, each of which can be defined on a seven‐point scoring system varying from one (absent) to seven (extreme). It can be divided into three subscales for measuring the severity of general psychopathology, positive symptoms (PANSS‐P) and negative symptoms (PANSS‐N). A low score indicates lesser severity.
6.2.2.2 Brief Psychiatric Rating Scale ‐ BPRS (Overall 1962)
This is used to assess the severity of abnormal mental state. The original scale has 16 items, but a revised 18‐item scale is commonly used. Each item is defined on a seven‐point scale varying from 'not present' to 'extremely severe', scoring from zero to six or one to seven. Scores can range from zero to 126 with high scores indicating more severe symptoms.
6.2.2.3 Scale for the Assessment of Negative Symptoms ‐ SANS (Andreasen 1989)
This six‐point scale gives a global rating of the following negative symptoms: alogia, affective blunting, avolition‐apathy, anhedonia‐asociality and attention impairment. Assessments are made on a six‐point scale from zero (not at all) to five (severe). Higher scores indicate more severe symptoms.
6.2.3 General functioning
6.2.3.1 Global Assessment of Functioning ‐ GAF (APA 1994)
A rating scale for a patients´ overall capacity of psychosocial functioning, scoring from one to 100. Higher scores indicate a higher level of functioning.
6.2.4 Quality of life/satisfaction with treatment
6.2.4.1 Manchester Short Assessment of Quality of Life ‐ MANSA (Priebe 1999)
A rating scale to assess quality of life focusing on satisfaction with life as a whole and with life domains. Higher scores indicate less impairment.
6.2.4.2 Quality of Life Scale ‐ QLS (Carpenter 1984)
This semi‐structured interview is administered and rated by trained clinicians. It contains 21 items rated on a seven point scale based on the interviewers´ judgment of patient functioning. A total QLS and four subscale scores are calculated, with higher scores indicate less impairment.
6.2.4.3 The Short Form (36) Health Survey ‐ SF‐36 (Ware 1992)
This self‐reporting measure consists of eight scaled scores. Each scale is directly transformed into a zero to 100 scale on the assumption that each question carries equal weight.
6.2.5 Adverse effects scales
6.2.5.1 Abnormal Involuntary Movement Scale ‐ AIMS (Guy 1976)
This has been used to assess tardive dyskinesia, a long‐term, drug‐induced movement disorder and short‐term movement disorders such as tremor.
6.2.5.2 Extrapyramidal Symptom Rating Scale ‐ ESRS (Chouinard 1980)
This is a questionnaire relating to parkinsonian symptoms (nine items), a physician’s examination for parkinsonism and dyskinetic movements (eight items), and a clinical global impression of tardive dyskinesia. High scores indicate severe levels of movement
disorder.
6.2.5.3 Simpson Angus Scale ‐ SAS (Simpson 1970)
This is a 10‐item scale, with a scoring system of zero to four for each item, measures drug‐induced parkinsonism, a short‐term drug‐induced movement disorder. A low score indicates low levels of Parkinsonism.
6.2.5.4 Treatment Emergent Symptom Scale ‐ TESS (Guy 1976)
The scale measures adverse events. A low score indicates low levels of adverse events.
6.3 Other adverse effects
Many adverse effects were reported as continuous variables for QTc prolongation (ms), cholesterol level (mg/dL), glucose levels (mg/dL), prolactin level (ng/mL) and weight (kg). Other adverse events were reported in a dichotomous manner in terms of the number of people with a given effect.
6.4 Service use
Service use was described as the number of patients re‐hospitalised during the trial.
Excluded studies
Twenty‐two studies had to be excluded for the following reasons:
Four were not randomised, 15 reported no usable data, one had high risk of bias from being an open‐label study, with incomplete outcome data, one used combined antipsychotics and one was a pooled analysis rather than a trial.
Risk of bias in included studies
For details please refer to 'Risk of bias' tables for each study and Figure 2 and Figure 3.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Allocation
All of the included studies were described as randomised. Only nine studies gave further information on the randomisation, three used random number tables (vs CPZ ‐ Chen 2001; vs CPZ ‐ Peng 2006; vs CPZ ‐ Zhou 2003), three computer‐generated randomisation (vs HLP ‐ Fl'hacker 2005; vs HLP ‐ McCue 2006; vs CPZ ‐ Zhang 2003) and two using coin tossing (vs CPZ ‐ Guo 2003;vs CPZ ‐ Zhang 2002). For all other studies, it was unclear whether the allocation strategies were appropriate.
Blinding
Four of the included studies were 'single‐blind', 12 studies were 'double‐blind'. One study used identical capsules for blinding (vs PERPHEN ‐ L'rman 2005). The other trials did not provide any information on the blinding procedure. No study examined the effectiveness of blinding. Seven studies were open‐label trials. For the other studies, blinding issues were not reported.
Incomplete outcome data
Twenty‐four studies reported the number of participants leaving the studies early for any reason. A major problem was the high attrition in which six studies had more than 40% (vs HLP ‐ Arvanitis 1997; vs FLUPHEN ‐ Conley 2005; vs HLP ‐ Fl'hacker 2005; vs PERPHEN ‐ L'rman 2005; vs HLP ‐ Purdon 2001; vs HLP ‐ Velligan 2002). In most studies the last‐observation‐carried‐forward (LOCF) method was used to compensate for attrition. The sensitivity analyses excluding studies with high attrition rates were added.
Selective reporting
Selective reporting was judged to be present in 16of the 43 included studies (37%). The main reason was the incomplete reporting of predefined outcomes.
Other potential sources of bias
Twelve studies were sponsored by pharmaceutical companies (vs HLP ‐ Arvanitis 1997; vs CPZ ‐ AstraZeneca 2005; vs FLUPHEN ‐ Conley 2005; vs HLP ‐ Copolov 2000; vs HLP ‐ Emsley 1999; vs HLP ‐ Emsley 2004; vs HLP ‐ Fl'hacker 2005; vs CPZ ‐ Link 1997; vs HLP ‐ Murasaki 1999; vs HLP ‐ Purdon 2001; vs HLP ‐ Taneli 2003; vs HLP ‐ Velligan 2002). Pharmaceutical companies sometimes highlight the benefits of the agent and mentioned less on its disadvantages (Heres 2006). One study included only female participants; therefore, gender bias could not be excluded (vs HLP ‐ Atmaca 2002).
Effects of interventions
1. Comparison 1. Quetiapine versus typical antipsychotics
Forty‐three studies met the inclusion criteria for this comparison.
1.1 Global state: 2. No clinical improvement
There was no significant difference in short‐term data (15 RCTs, n = 1479, risk ratio (RR) 1.05 confidence interval (CI) 0.81 to 1.35) but one medium‐term study found a significant difference, favouring the treatment group (1 RCT, n = 128, RR 0.16 CI 0.05 to 0.51, Analysis 1.1).
1.2 Global state: 1a. CGI: Average CGI‐S (high = poor)
There was no significant difference in short‐term endpoint data (5 RCTs, n = 347, mean difference (MD) 0.22 CI ‐0.04 to 0.49) and long‐term endpoint data (1 RCT, n = 207, MD ‐0.10 CI ‐0.93 to 0.73). However, there was a significant difference, favouring the control group in short‐term change data (2 RCTs, n = 699, MD 0.20 CI 0.04 to 0.36). The data were heterogenous (I2 = 64%). The heterogeneity was more likely due to differences in degree of change in CGI‐S than directions of effect (Analysis 1.2).
1.3 Global state: 1b. CGI: Average endpoint CGI‐I (high = poor)
There was a significant difference, favouring the control group in short‐term (4 RCTs, n = 496, MD 0.39 CI 0.30 to 0.47) but not in a medium‐term studies (1 RCT, n = 11, MD ‐0.20 CI ‐1.08 to 0.68, Analysis 1.3).
1.4 Leaving the study early: Any reason
The number of participants who left the studies early due to any reason were similar (36.5% in the treatment group and 36.9% in the control group). There was a significant difference, favouring the treatment group in medium‐term (3 RCTs, n = 203, RR 0.72 CI 0.52 to 0.99) but not in short‐term (17 RCTs, n = 2535, RR 0.88 CI 0.78 to 1.00) and long‐term studies (3 RCTs, n = 838, RR 0.99 CI 0.77 to 1.28, Analysis 1.4).
1.5 Leaving the study early: Adverse events
Fewer participants in the treatment group (6.6%) compared with the control group (11.6%) left the studies early due to adverse events. There was a significant difference, favouring the treatment group in short‐term studies (11 RCTs, n = 2044, RR 0.51 CI 0.31 to 0.84) and one medium‐term study (1 RCT, n = 128, RR 0.03 CI 0.00 to 0.53). However, there was no significant difference in long‐term study (3 RCTs, n = 838, RR 0.46 CI 0.12 to 1.78) and the long‐term data were heterogenous (Analysis 1.5).
1.6 Leaving the study early: Inefficacy
There was no significant difference in both short‐term (3 RCTs, n = 842, RR 1.20 CI 0.87 to 1.66) and long‐term studies (6 RCTs, n = 1221, RR 1.41 CI 0.94 to 2.11, Analysis 1.6).
1.7 Mental state: 1a. General ‐ average score (PANSS total, high = poor)
There was no significant difference of endpoint score in short‐term (21 RCTs, n = 2055, MD 0.84 CI ‐1.46 to 3.15), medium‐term (3 RCTs, n = 180, MD ‐7.77 CI ‐15.69 to 0.14) and long‐term studies (2 RCTs, n = 252, MD ‐0.90 CI ‐4.94 to 3.15). However, there was a significant difference, favouring the control group, in short‐term change score (2 RCTs, n = 565, MD 3.59 CI 0.09 to 7.10). Heterogeneity might be due to directions of effect and one outlier (vs CPZ ‐ Tian 2006). However, excluding this study still showed no significant difference in short‐term data (21 RCTs, n = 2052, MD ‐0.44 CI ‐0.44 to 0.68). Overall, there was no significant difference between groups on PANSS total score (27 RCTs, n = 3052, MD 0.09 CI ‐2.14 to 2.31, Analysis 1.7).
1.8 Mental state: 1b General ‐ average score ‐ short term (BPRS total, high = poor)
There was no significant difference in endpoint score (6 RCTs, n = 666, MD ‐0.24 CI ‐1.66 to 1.17) but there was a significant difference, favouring the control group, in change score (2 RCTs, n = 359, MD 3.49 CI 0.90 to 6.08). Overall, there was no significant difference between groups on BPRS total score (8 RCTs, n = 1025, MD 0.71 CI ‐0.77 to 2.20, Analysis 1.8).
1.9 Mental state: 2a. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high = poor)
There was no significant difference in short‐term (19 RCTs, n = 1801, MD 0.19 CI ‐0.25 to 0.62), medium‐term (2 RCTs, n = 88, MD ‐1.57 CI ‐3.41 to 0.26) and long‐term studies (1 RCT, n = 45, MD ‐1.30 CI ‐3.12 to 0.52, Analysis 1.9).
1.10 Mental state: 2b. Positive symptoms ‐ average score ‐ short term (BPRS positive subscore, high = poor)
There was no significant difference in endpoint score (2 RCTs, n = 128, MD 0.12 CI ‐0.42 to 0.65) but there was a significant difference, favouring the control group (1 RCT, n = 253, MD 1.34 CI 0.27 to 2.41). Overall, there was no significant difference between groups on BPRS positive subscore (3 RCTs, n = 381, MD 0.63 CI ‐0.37 to 1.62, Analysis 1.10).
1.11 Mental state: 3a. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high = poor)
There was no significant difference in short‐term (19 RCTs, n = 1801, MD ‐0.81. CI ‐1.63 to 0.01) and long‐term studies (1 RCT, n = 45, MD 1.20 CI ‐2.09 to 4.49) but there was a significant difference, favouring the treatment group, in medium‐term studies (2 RCTs, n=88, MD ‐2.45 CI ‐4.64 to ‐0.27). Overall, there was a significant difference, favouring the treatment group, on PANSS negative subscore (22 RCTs, n = 1934, MD ‐0.82 CI ‐1.59 to ‐0.04, Analysis 1.11), but this result was highly heterogeneous and driven by two small outlier studies with high effect sizes. Without these two studies, there was no heterogeneity and no statistically significant difference between the treatment and the control group.
1.12 Mental state: 3b. Negative symptoms ‐ average score ‐ short term (BPRS negative subscore, high = poor)
There was no significant difference in endpoint score (1 RCT, n = 25, MD 0.11 CI ‐2.01 to 2.23) but there was a significant difference, favouring the treatment group in change score (1 RCT, n = 253, MD ‐0.75 CI ‐1.42 to ‐0.08). Overall, there was a significant difference, favouring the treatment group, in BPRS negative subscore (2 RCTs, n = 278, MD ‐0.67 CI ‐1.31 to ‐0.04, Analysis 1.12).
1.13 Mental state: 3c. Negative symptoms ‐ average endpoint score ‐ short term (SANS total, high = poor)
There was a significant difference, favouring the control group, in endpoint score (1 RCT, n = 103, MD 1.80 CI 0.24 to 3.36) but no significant difference in change score (1 RCT, n = 228, MD ‐0.26 CI ‐1.08 to 0.56). Overall, there was no significant difference between the groups on SANS total score (2 RCTs, n = 331, MD 0.66 CI ‐1.35 to 2.66, Analysis 1.13).
1.14 Mental state: 4. General psychopathology ‐ average endpoint score (PANSS general psychopathology subscore, high = poor)
There was no significant difference in short‐term (15 RCTs, n = 1472, MD ‐0.17 CI ‐0.81 to 0.47), medium‐term (2 RCTs, n = 52, MD 0.47 CI ‐3.30 to 4.24) and long‐term studies (1 RCT, n = 45, MD ‐2.20 CI ‐6.02 to 1.62, Analysis 1.14).
1.15 General functioning: General ‐ average endpoint score ‐ long term (GAF total score, low = poor)
There was no significant difference (1 RCT, n = 207, MD ‐0.10 CI ‐9.80 to 9.60, Analysis 1.15).
1.16 Quality of life: 1a. General ‐ average endpoint score ‐ long term (SF‐36, low = poor)
There was a significant difference, favouring the treatment group (1 RCT, n = 84, MD 13.76 CI 5.95 to 21.57, Analysis 1.16).
1.17 Quality of life: 1b. General ‐ average endpoint score ‐ long term (MANSA total score, low = poor)
There was no significant difference (1 RCT, n = 207, MD 0.00 CI ‐1.38 to 1.38, Analysis 1.17).
1.18 Quality of life: 1c. General ‐ average change score ‐ long term (QLS, high = poor)
There was no significant difference (1 RCT, n = 156, MD 0.10 CI ‐0.23 to 0.43, Analysis 1.18).
1.19 Cognitive function: 1a General ‐ average change score ‐ long term (Composite score, high = poor)
There was no significant difference (2 RCTs, n = 407, MD 0.00 CI ‐0.19 to 0.20, Analysis 1.19).
1.20 Cognitive function: 1b. General ‐ average endpoint scores as defined by the original studies (low = poor)
There was a significant difference, favouring the treatment group in short‐term (WAIS) (1 RCT, n = 91, MD 8.30 CI 1.64 to 14.96) but not in long‐term studies (2 RCTs, n = 51, MD 0.82 CI ‐0.77 to 2.41, Analysis 1.20). The heterogeneity of long‐term data might be due to the differences of cognitive scales used.
1.21 Service use: number of participants re‐hospitalised ‐ long term
There was no significant difference (2 RCTs, n = 722, RR 1.23 CI 0.90 to 1.68, Analysis 1.21).
1.22 Adverse effects: 1. General ‐ at least one adverse effect
There was a significant difference, favouring the treatment group in short‐term (7 RCTs, n = 1180, RR 0.75 CI 0.62 to 0.91, NNTH 9, CI 6 to 16) but not in long‐term studies (2 RCTs, n = 805, RR 0.82 CI 0.52 to 1.29). The heterogeneity of short‐term data might be due to an outlier (vs HLP ‐ Emsley 1999), which showed a trend in favour of control. Excluding this study still showed a significant difference, favouring the treatment group, in short‐term data (6 RCTs, n = 892, RR 0.73 CI 0.61 to 0.87). Overall, there was a significant difference, favouring the treatment group, in having at least one adverse effect (9 RCTs, n = 1985, RR 0.76 CI 0.64 to 0.90, Analysis 1.22).
1.23 Adverse effects: 2. Death
There was no significant difference of suicide attempt (1 RCT, n = 598, RR 0.77 CI 0.05 to 12.32) or suicide in one long‐term study (1 RCT, n = 598, RR 0.52 CI 0.09 to 3.07) and death in one short‐term study term (1 RCT, n = 260, RR 3.00 CI 0.12 to 72.97, Analysis 1.23).
1.24 Adverse effects: 3a. Cardiac effects ‐ QTc prolongation ‐ long term
There was no significant difference (1 RCT, n = 41, RR 1.73 CI 0.17 to 17.59, Analysis 1.24).
1.25 Adverse effects: 3b. Cardiac effects ‐ abnormal ECG ‐ short term
There was a significant difference, favouring the treatment group (2 RCTs, n = 165, RR 0.38 CI 0.16 to 0.92, NNTH 8, CI 4 to 55, Analysis 1.25).
1.26 Adverse effects: 3c. Cardiac effects ‐ orthostatic hypotension
There was no significant difference in short‐term studies (4 RCTs, n = 795, RR 0.45 CI 0.13 to 1.54) and one long‐term study (1 RCT, n = 598, RR 1.01 CI 0.64 to 1.60). The heterogeneity of short‐term data might be due to an outlier (vs HLP ‐ Copolov 2000) which showed a trend in favour of control. Excluding this study revealed a significant difference in favour of quetiapine in short‐term data (3 RCTs, n = 347, RR 0.25 CI 0.12 to 0.55, Analysis 1.26).
1.27 Adverse effects: 3d. Cardiac effects ‐ low blood pressure ‐ short term
There was no significant difference (6 RCTs, n = 572, RR 0.69 CI 0.41 to 1.18, Analysis 1.27).
1.28 Adverse effects: 3e. Cardiac effects ‐ tachycardia ‐ short term
There was no significant difference (8 RCTs, n = 814, RR 0.70 CI 0.36 to 1.34, Analysis 1.28).
1.29 Adverse effects: 4. Central nervous system ‐ sedation
There was no significant difference in short‐term studies (13 RCTs, n = 1700, RR 0.69 CI 0.37 to 1.30) and one long‐term study (1 RCT, n = 598, RR 1.08 CI 0.84 to 1.39, Analysis 1.29). The heterogeneity of short term data might be due to various types of typical antipsychotics in control group.
1.30 Adverse effects: 5a. Extrapyramidal effects ‐ overall ‐ short term
There was a significant difference, favouring the treatment group (8 RCTs, n = 1095 RR 0.17 CI 0.09 to 0.32, NNTH 3, CI 3 to 3, Analysis 1.30).
1.31 Adverse effects: 5b. Extrapyramidal effects ‐ akathisia
There were significant differences, favouring the treatment group, in both short‐term (15 RCTs, n = 2059, RR 0.24 CI 0.17 to 0.35, NNTH 6, CI 5 to 8) and long‐term studies (1 RCT, n = 158, RR 0.50 CI 0.25 to 0.98, NNTH 8, CI 4 to 153, Analysis 1.31).
1.32 Adverse effects: 5c. Extrapyramidal effects ‐ parkinsonism
There were significant differences, favouring the treatment group, in both short‐term (2 RCTs, n = 185, RR 0.13 CI 0.04 to 0.48, NNTH 6, CI 4 to 11) and long‐term studies (1 RCT, n = 158, RR 0.31 CI 0.15 to 0.62, NNTH 5, CI 3 to 10, Analysis 1.32).
1.33 Adverse effects: 5d. Extrapyramidal effects ‐ dystonia
There was a significant difference, favouring the treatment group, in short‐term studies (4 RCTs, n = 834, RR 0.13 CI 0.04 to 0.51, NNTH 21, CI 15 to 38) but not in one long‐term study (1 RCT, n = 158, RR 0.86 CI 0.05 to 13.49). Overall, there was a significant difference, favouring the treatment group (5 RCTs, n = 992, RR 0.19 CI 0.06 to 0.64, Analysis 1.33).
1.34 Adverse effects: 5e. Extrapyramidal effects ‐ tremor ‐ short term
There was a significant difference, favouring the treatment group (12 RCTs, n = 1641, RR 0.33 CI 0.23 to 0.47, NNTH 8, CI 7 to 12, Analysis 1.34).
1.35 Adverse effects: 5f. Extrapyramidal effects ‐ scale measured (dichotomous data) ‐ long term
1.35.1 Extrapyramidal symptoms: Simpson‐Angus Scale (SAS >/=1)
There was no significant difference (1 RCT, n = 541, RR 0.65 CI 0.31 to 1.37).
1.35.2 Abnormal movement: Abnormal Involuntary Movement Scale (AIMS>/=2)
There was no significant difference (1 RCT, n = 473, RR 0.73 CI 0.48 to 1.14).
1.35.3 Akathisia: Barnes Akathisia Scale (BARS >/=3)
There was no significant difference (1 RCT, n = 546, RR 0.79 CI 0.40 to 1.55, Analysis 1.35).
1.36 Adverse effects: 5g. Extrapyramidal effects ‐ scale measured (continuous data, high = poor)
1.36.1 Average endpoint score ‐ Extrapyramidal symptoms (ESRS) ‐ short term
There was a significant difference, favouring the treatment group (1 RCT, n = 35, MD ‐4.55 CI ‐6.58 to ‐2.52).
1.36.2 Average endpoint score ‐ Abnormal Involuntary Movement Scale (AIMS) ‐ medium term
There was no significant difference (1 RCT, n = 11, MD 0.30 CI ‐0.83 to 1.43).
1.36.3 Average endpoint score ‐ Simpson‐Angus Scale (SAS) ‐ medium term
There was no significant difference (1 RCT, n = 11, MD 1.10 CI ‐1.94 to 4.14).
1.36.4 Average endpoint score ‐ Treatment Emergent Symptom Scale (TESS) ‐ short term
There was no significant difference (2 RCTs, n = 158, MD ‐1.09 CI ‐2.51 to 0.33).
1.36.5 Average change score ‐ Treatment Emergent Symptom Scale (TESS) ‐ short term
There was no significant difference (1 RCT, n = 117, MD ‐1.03 CI ‐2.49 to 0.43).
1.36.6 Average endpoint score ‐ Treatment Emergent Symptom Scale (TESS) ‐ medium term
There was no significant difference (1 RCT, n = 41, MD ‐2.10 CI ‐4.55 to 0.35, Analysis 1.36).
1.37 Adverse effects: 6a. Prolactin associated side effects
1.37.1 Gynaecomastia, galactorrhoea ‐ long term
There was no significant difference (1 RCT, n = 598, RR 1.16 CI 0.33 to 4.07).
1.37.2 Menstrual irregularities ‐ long term
There was no significant difference (1 RCT, n = 598, RR 0.55 CI 0.18 to 1.72, Analysis 1.37).
1.38 Adverse effects: 6b. Prolactin ‐ Hyperprolactinemia
There was a significant difference, favouring the treatment group, in two short‐term studies (2 RCTs, n = 165, RR 0.08 CI 0.01 to 0.60, NNTH 8, CI 5 to 17) but not in one long‐term study (1 RCT, n = 64, RR 0.91 CI 0.51 to 1.62, Analysis 1.38).
1.39 Adverse effects: 6c. Prolactin level ‐ average level in ng/mL
There was a significant difference, favouring the treatment group, in short‐term endpoint level (1 RCT, n = 35, MD ‐15.67 CI ‐21.00 to ‐10.34), short‐term change level (1 RCT, n = 356, MD ‐22.43 CI ‐23.20 to ‐21.66), long‐term endpoint level (1 RCT, n = 45, MD ‐16.40 CI ‐23.83 to ‐8.97) and long‐term change level (1 RCTs, n = 598, MD ‐9.70 CI ‐14.02 to ‐5.38). The heterogeneity was more likely to be due to differences in degree of prolactin decrease than directions of effect. Overall, there was a significant difference, favouring the treatment group, in prolactin level (4 RCTs, n = 1034, MD ‐16.20 CI ‐23.34 to ‐9.07, Analysis 1.39).
1.40 Adverse effects: 7a. Weight gain (as defined by the original studies)
There was a significant difference, favouring the treatment group in short‐term (9 RCTs, n = 866, RR 0.52 CI 0.34 to 0.80, NNTH 8, CI 6 to 15) but not in long‐term studies (2 RCTs, n = 646, RR 1.27 CI 0.97 to 1.66, Analysis 1.40). Heterogeneity might be due to the differences in type of typical antipsychotics.
1.41 Adverse effects: 7b. Weight gain ‐ average weight in kg
There was no significant difference in short‐term weight change (1 RCT, n = 25, MD 1.40 CI ‐5.66 to 8.46), long‐term endpoint weight (1 RCT, n = 45, MD 4.30 CI ‐0.31 to 8.91) and long‐term weight change (1 RCT, n = 98, MD 3.20 CI ‐1.79 to 8.19, Analysis 1.41).
1.42 Adverse effects: 8. Decreased white blood cell count ‐ short term
There was no significant difference (1 RCT, n = 40, RR 0.33 CI 0.01 to 7.72, Analysis 1.42).
1.43 Sensitivity analysis
Excluding studies with skewed data (Analysis 1.43; Analysis 1.44), inappropriate comparator doses (Analysis 1.45; Analysis 1.46; Analysis 1.47), high attrition rate (Analysis 1.48; Analysis 1.49; Analysis 1.50), or studies with intention‐to‐treat analysis from the evaluation of the PANSS total score, the PANSS positive subscore and the PANSS negative subscore (Analysis 1.51; Analysis 1.52; Analysis 1.53) did not reveal markedly different results.
Discussion
Summary of main results
The overall search strategy yielded 830 reports of which 65 were closely inspected. Forty‐three studies with 7217 participants met the inclusion criteria. Twelve studies were sponsored by pharmaceutical companies developing quetiapine. The comparator typical antipsychotics were chlorpromazine, haloperidol and perphenazine.
1. Global state
There was no significant difference between groups on 'no clinical improvement'. The CGI‐S and CGI‐I scores suggested the superiority of typical antipsychotics in the short term. However, no significance difference of long‐term CGI‐S scores and medium‐term CGI‐I scores were found, suggesting that the two groups might not differ in terms of global improvement.
2. Leaving the study early
The overall attrition rates from any reason were high in both groups (36%), although they were similar to those found in previous analyses (Liu‐Seifert 2005; Srisurapanont 2004). The high dropout rate may represent poor psychiatric response (Liu‐Seifert 2005). This study found no significant difference between groups on leaving the study early due to inefficacy. However, quetiapine had a significantly lower risk of leaving the study early due to adverse events. This may indicate that quetiapine is more tolerable than typical antipsychotics.
3. Mental state
3.1 Positive symptoms
Overall, the positive symptoms in both groups were not different in short‐term, medium‐term and long‐term treatment. Only one study (vs CPZ ‐ AstraZeneca 2005) that used chlorpromazine as comparator found a significant difference in favour of typical antipsychotics. However, the point difference was about one, and the clinical relevance of this is unclear.
3.2 Negative symptoms
The data on negative symptoms were relatively heterogenous. The PANSS negative subscores of two studies (n = 88) (vs CPZ ‐ Li 2003; vs HLP ‐ Purdon 2001) favoured quetiapine in medium‐term studies, but the analyses in short‐term studies (19 studies, n = 1621) and one long‐term study (one study, n = 45) found no significant difference. BPRS negative subscores favoured quetiapine in one study (n = 253) (vs CPZ ‐ AstraZeneca 2005) but not in the other (n = 25) (vs FLUPHEN ‐ Conley 2005). In contrast, the results of a single short‐term study (n = 103) using the SANS scale were in favour of haloperidol (vs HLP ‐ Arvanitis 1997), while a chlorpromazine‐controlled study using the same scale failed to reveal any significant difference (n = 228) (vs CPZ ‐ AstraZeneca 2005). The heterogeneity of these results might be due to small sample sizes and different types of typical antipsychotics. Overall, PANSS negative subscore (22 studies, n = 1934) and BPRS negative subscore (two studies, n = 278) showed significant differences in favour of quetiapine. However, the point difference was less than one, and the clinical relevance of this is unclear. Moreover, the PANSS negative subscore was highly heterogeneous and driven by two small outlier studies (vs CPZ ‐ Jin 2007; vs CPZ ‐ Zhang 2002). Without these two studies, there was no heterogeneity and no statistically significant difference between quetiapine and typical antipsychotics.
3.3 General psychopathology
PANSS general psychopathology subscore showed no significant difference between groups in general psychopathology for short‐term, medium‐term and long‐term treatment.
4. General functioning and quality of life
Only limited data are available for these outcomes. GAF score and MANSA score in a long‐term study (n = 207) (vs HLP ‐ Fl'hacker 2005) as well as QLS score in another long‐term study (n = 156) (vs PERPHEN ‐ L'rman 2005) failed to reveal any significant difference between groups. However, the quality of life assessed by SF‐36 in a single, short‐term, chlorpromazine‐controlled study (n = 84) (vs CPZ ‐ Zhong 2005) was superior in the quetiapine group.
5. Cognitive function and service use
The results of a short‐term, chlorpromazine‐controlled study (n = 91) found the superiority of quetiapine in cognitive improvement (vs CPZ ‐ Bai 2005); however, long‐term outcomes from two studies (n = 51) were not significantly different between groups.
6. Adverse effects
Quetiapine was superior to typical antipsychotics for the measures of having at least one adverse effects, abnormal ECG, overall extrapyramidal symptoms, akathisia, parkinsonism, dystonia, tremor and prolactin level. However, no significant difference between groups was found on suicide attempt, suicide, death, QTc prolongation, low blood pressure, tachycardia, sedation, gynaecomastia, galactorrhoea and menstrual irregularity. Since some outcomes, i.e. suicide attempt, suicide and death, are rare events and measured only in a small number of studies, a significant difference between groups might not been revealed. This review found that quetiapine caused less weight gain in short‐term studies (10 studies, n = 955) but not in long‐term studies (two studies, n = 646). This might have been caused by the fact that chlorpromazine was the control in most short‐term studies while haloperidol and fluphenazine were the controls for long‐term studies.
Overall completeness and applicability of evidence
1. Completeness
We could identify only one low‐powered study for some important outcomes; thus, the evidence is incomplete. The high attrition rates in many of the studies suggest the incompleteness of data. While schizophrenia is a life‐long disorder, only three long‐term studies have been carried out.
The emphasis on continuous measures leaves several questions unanswered. We remain unsure if quetiapine improves mental state, functioning, quality of life to any important extent.
2. Applicability
The applicability of this evidence is limited. Most of the studies were highly controlled explanatory trials, which may be of limit for the application of these results in the real world (Thorpe 2009).
Quality of the evidence
All studies were randomised, but their details were rarely presented. Only 10 studies were double‐blinded, and it is unclear in almost all studies whether the randomisation and blinding were appropriately carried out. Eight studies had high risk of bias in terms of incomplete data. Twelve studies were sponsored by pharmaceutical companies. All these factors may well considerably limit the quality of evidence and this is reflected in our grading within summary of findings Table for the main comparison.
Potential biases in the review process
It is perfectly feasible that we have failed to identify small relevant trials for many reasons (Easterbrook 1991), and we have not adjusted for this potential (Macaskill 2001). We feel that it is unlikely that large studies that would make a substantive difference to the results have been omitted. We could have been biased by our foreknowledge of data in Srisurapanont 2004 but, again, think that this potential for bias would have substantial effects on our extracting and writing of results.
Agreements and disagreements with other studies or reviews
A previous Cochrane review compared the efficacy between quetiapine and placebo, typical and atypical antipsychotic medications for schizophrenia (Srisurapanont 2004). The authors concluded that quetiapine was not much different from typical antipsychotics with respect to treatment withdrawal and efficacy. This review has included many recent studies. It is, therefore, more up‐to date and more comprehensive. In Srisurapanont 2004, quetiapine was superior to typical antipsychotics only in respect of antipsychotic‐induced movement disorders. In this review, we found the superiority of quetiapine on some more respects, e.g. having less overall adverse effects, abnormal ECG, prolactin level and weight gain (short term).
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 1 Global state: 1. No clinical improvement.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 2 Global state: 2a. CGI: Average CGI‐S (high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 3 Global state: 2b. CGI: Average endpoint CGI‐I (high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 4 Leaving the study early: 1. Any reason.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 5 Leaving the study early: 2. Adverse events.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 6 Leaving the study early: 3. Inefficacy.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 7 Mental state: 1a. General ‐ average score (PANSS total, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 8 Mental state: 1b. General ‐ average score ‐short term (BPRS total, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 9 Mental state: 2a. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 10 Mental state: 2b. Positive symptoms ‐ average score ‐ short term (BPRS positive subscore, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 11 Mental state: 3a. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 12 Mental state: 3b. Negative symptoms ‐ average score ‐ short term (BPRS negative subscore, high = poor)).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 13 Mental state: 3c. Negative symptoms ‐ average score ‐ short term (SANS total, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 14 Mental state: 4. General psychopathology ‐ average endpoint score (PANSS general psychopathology subscore, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 15 General functioning: General ‐ average endpoint score ‐ long term (GAF total score, low = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 16 Quality of life: 1a. General ‐ average endpoint score ‐short term (SF‐36, low = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 17 Quality of life: 1b. General ‐ average endpoint score ‐ long term (MANSA total score, low = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 18 Quality of life: 1c. General ‐ average change score ‐ long term (QLS, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 19 Cognitive function: 1a. General ‐ average change score ‐ long term (Composite score, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 20 Cognitive function: 1b. General ‐ average endpoint scores as defined by the original studies (low = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 21 Service use: number of participants re‐hospitalised ‐ long term.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 22 Adverse effects: 1. General ‐ at least one adverse effect.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 23 Adverse effects: 2. Death.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 24 Adverse effects: 3a. Cardiac effects ‐ QTc prolongation ‐ long term.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 25 Adverse effects: 3b. Cardiac effects ‐ abnormal ECG ‐ short term.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 26 Adverse effects: 3c. Cardiac effects ‐ orthostatic hypotension.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 27 Adverse effects: 3d. Cardiac effects ‐ low blood pressure ‐ short term.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 28 Adverse effects: 3e. Cardiac effects ‐ tachycardia ‐ short term.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 29 Adverse effects: 4. Central nervous system ‐ sedation.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 30 Adverse effects: 5a. Extrapyramidal effects ‐ overall ‐ short term.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 31 Adverse effects: 5b. Extrapyramidal effects ‐ akathisia.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 32 Adverse effects: 5c. Extrapyramidal effects ‐ parkinsonism.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 33 Adverse effects: 5d. Extrapyramidal effects ‐ dystonia.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 34 Adverse effects: 5e. Extrapyramidal effects ‐ tremor ‐ short term.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 35 Adverse effects: 5f. Extrapyramidal effects ‐ scale measured (dichotomous data) ‐ long term.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 36 Adverse effects: 5g. Extrapyramidal effects ‐ scale measured (continuous data, high=poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 37 Adverse effects: 6a. Prolactin associated side effects.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 38 Adverse effects: 6b. Prolactin ‐ Hyperprolactinemia.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 39 Adverse effects: 6c. Prolactin level ‐ average level in ng/mL.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 40 Adverse effects: 7a. Weight gain (as defined by the original studies).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 41 Adverse effects: 7b. Weight gain ‐ average weight in kg..
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 42 Adverse effects: 8. decreased white blood cell count ‐ short term.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 43 Sensitivity analysis (skewed data excluded), Mental state: 1. General ‐ average endpoint score (PANSS total, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 44 Sensitivity analysis (skewed data excluded), Mental state: 2. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high=poor) ‐ medium term.
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 45 Sensitivity analysis (inappropriate comparator doses excluded), Mental state: 1: General‐ average endpoint score (PANSS total, high=poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 46 Sensitivity analysis (inappropriate comparator doses excluded), Mental state: 2: Positive symptoms‐ average endpoint score (PANSS positive subscore, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 47 Sensitivity analysis (inappropriate comparator doses excluded), Mental state: 3: Negative symptoms‐ average endpoint score (PANSS negative subscore, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 48 Senstivity analysis (high attrition rate data excluded), Mental state: 1: General ‐ average score (PANSS total, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 49 Sensitivity analysis (high attrition rate data excluded), Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 50 Sensitivity analysis (high attrition rate data excluded), Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 51 Senstivity analysis (completer data only), Mental state: 1: General ‐ average score (PANSS total, high=poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 52 Sensitivity analysis (completer data only), Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high = poor).
Comparison 1 QUETIAPINE versus TYPICAL ANTIPSYCHOTICS, Outcome 53 Sensitivity analysis (completer data only), Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high = poor).
| Methods | Allocation: randomised ‐ clearly described generation of sequence and concealment of allocation. |
| Participants | Diagnosis: schizophrenia. |
| Interventions | 1. Quetiapine: dose 300‐800 mg/day. N = 300. 2. Typical antipsychotic medications. 2a. Chlorpromazine: dose 300‐1000 mg/day. N = 300.** 2b. Fluphenazine: dose 5‐20 mg/day.N = 300. 2c. Perphenazine: dose 16‐64 mg/day. N = 300. 2d. Trifluoperazine: dose 15‐50 mg/day. N = 300. 2e. Haloperidol: dose 5‐20 mg/day. N = 300. |
| Outcomes | Global impression: CGI***, relapse. Leaving study early (any reason, adverse events, inefficacy). Functioning: employment, living independently, functioning improved to an important extent. Quality of life: improved to an important extent. Economics: direct and indirect costs. |
| * Power calculation suggested 300/group would allow good chance of showing a 10% difference between groups for primary outcome. ** Of the many possible comparisons we would probably choose chlorpromazine or perphenazine. | |
| Quetiapine compared to Typical antipsychotics 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 | |||||
| Typical antipsychotics | Quetiapine | |||||
| Global state | Study population | RR 0.96 | 1607 | ⊕⊕⊕⊝ | ||
| 145 per 1000 | 139 per 1000 | |||||
| Moderate | ||||||
| Leaving the study early due to any reason | Study population | RR 0.91 | 3576 | ⊕⊕⊕⊝ | ||
| 369 per 1000 | 336 per 1000 | |||||
| Moderate | ||||||
| Positive symptoms | The mean positive symptoms in the intervention groups was | 1934 | ⊕⊕⊕⊝ | |||
| Negative symptoms | The mean negative symptoms in the intervention groups was | 1934 | ⊕⊕⊕⊝ | |||
| Cognitive function | The mean cognitive function in the intervention groups was | 142 | ⊕⊝⊝⊝ | |||
| Extrapyramidal effects | Study population | RR 0.17 | 1095 | ⊕⊕⊕⊝ | ||
| 548 per 1000 | 93 per 1000 | |||||
| Moderate | ||||||
| Prolactin level | The mean prolactin level in the intervention groups was | 1034 | ⊕⊕⊕⊝ | |||
| *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 Limitations in design ‐ rated 'serious' : poor description of randomisation, no details about blinding, no details about concealment. PANSS: Positive and Negative Syndrome Scale | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global state: 1. No clinical improvement Show forest plot | 15 | 1607 | Risk Ratio (IV, Random, 95% CI) | 0.96 [0.75, 1.23] |
| 1.1 short term | 15 | 1479 | Risk Ratio (IV, Random, 95% CI) | 1.05 [0.81, 1.35] |
| 1.2 medium term | 1 | 128 | Risk Ratio (IV, Random, 95% CI) | 0.16 [0.05, 0.51] |
| 2 Global state: 2a. CGI: Average CGI‐S (high = poor) Show forest plot | 8 | 1253 | Mean Difference (IV, Random, 95% CI) | 0.20 [0.06, 0.33] |
| 2.1 short term ‐ endpoint score | 5 | 347 | Mean Difference (IV, Random, 95% CI) | 0.22 [‐0.04, 0.49] |
| 2.2 short term ‐ change score | 2 | 699 | Mean Difference (IV, Random, 95% CI) | 0.20 [0.04, 0.36] |
| 2.3 long term ‐ endpoint score | 1 | 207 | Mean Difference (IV, Random, 95% CI) | ‐0.10 [‐0.93, 0.73] |
| 3 Global state: 2b. CGI: Average endpoint CGI‐I (high = poor) Show forest plot | 5 | 507 | Mean Difference (IV, Random, 95% CI) | 0.38 [0.28, 0.47] |
| 3.1 short term | 4 | 496 | Mean Difference (IV, Random, 95% CI) | 0.39 [0.30, 0.47] |
| 3.2 medium term | 1 | 11 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐1.08, 0.68] |
| 4 Leaving the study early: 1. Any reason Show forest plot | 23 | 3576 | Risk Ratio (IV, Random, 95% CI) | 0.91 [0.81, 1.01] |
| 4.1 short term | 17 | 2535 | Risk Ratio (IV, Random, 95% CI) | 0.88 [0.78, 1.00] |
| 4.2 medium term | 3 | 203 | Risk Ratio (IV, Random, 95% CI) | 0.72 [0.52, 0.99] |
| 4.3 long term | 3 | 838 | Risk Ratio (IV, Random, 95% CI) | 0.99 [0.77, 1.28] |
| 5 Leaving the study early: 2. Adverse events Show forest plot | 15 | 3010 | Risk Ratio (IV, Random, 95% CI) | 0.48 [0.30, 0.77] |
| 5.1 short term | 11 | 2044 | Risk Ratio (IV, Random, 95% CI) | 0.51 [0.31, 0.84] |
| 5.2 medium term | 1 | 128 | Risk Ratio (IV, Random, 95% CI) | 0.03 [0.00, 0.53] |
| 5.3 long term | 3 | 838 | Risk Ratio (IV, Random, 95% CI) | 0.46 [0.12, 1.78] |
| 6 Leaving the study early: 3. Inefficacy Show forest plot | 9 | 2063 | Risk Ratio (IV, Random, 95% CI) | 1.24 [1.00, 1.54] |
| 6.1 short term | 3 | 842 | Risk Ratio (IV, Random, 95% CI) | 1.20 [0.87, 1.66] |
| 6.2 long term | 6 | 1221 | Risk Ratio (IV, Random, 95% CI) | 1.41 [0.94, 2.11] |
| 7 Mental state: 1a. General ‐ average score (PANSS total, high = poor) Show forest plot | 27 | 3052 | Mean Difference (IV, Random, 95% CI) | 0.09 [‐2.14, 2.31] |
| 7.1 short term ‐ endpoint score | 21 | 2055 | Mean Difference (IV, Random, 95% CI) | 0.84 [‐1.46, 3.15] |
| 7.2 short term ‐ change score | 2 | 565 | Mean Difference (IV, Random, 95% CI) | 3.59 [0.09, 7.10] |
| 7.3 medium term ‐ endpoint score | 3 | 180 | Mean Difference (IV, Random, 95% CI) | ‐7.77 [‐15.69, 0.14] |
| 7.4 long term ‐ endpoint score | 2 | 252 | Mean Difference (IV, Random, 95% CI) | ‐0.90 [‐4.94, 3.15] |
| 8 Mental state: 1b. General ‐ average score ‐short term (BPRS total, high = poor) Show forest plot | 8 | 1025 | Mean Difference (IV, Random, 95% CI) | 0.71 [‐0.77, 2.20] |
| 8.1 endpoint score | 6 | 666 | Mean Difference (IV, Random, 95% CI) | ‐0.24 [‐1.66, 1.17] |
| 8.2 change score | 2 | 359 | Mean Difference (IV, Random, 95% CI) | 3.49 [0.90, 6.08] |
| 9 Mental state: 2a. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high = poor) Show forest plot | 22 | 1934 | Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.39, 0.43] |
| 9.1 short term | 19 | 1801 | Mean Difference (IV, Random, 95% CI) | 0.19 [‐0.25, 0.62] |
| 9.2 medium term | 2 | 88 | Mean Difference (IV, Random, 95% CI) | ‐1.57 [‐3.41, 0.26] |
| 9.3 long term | 1 | 45 | Mean Difference (IV, Random, 95% CI) | ‐1.30 [‐3.12, 0.52] |
| 10 Mental state: 2b. Positive symptoms ‐ average score ‐ short term (BPRS positive subscore, high = poor) Show forest plot | 3 | 381 | Mean Difference (IV, Random, 95% CI) | 0.63 [‐0.37, 1.62] |
| 10.1 endpoint score | 2 | 128 | Mean Difference (IV, Random, 95% CI) | 0.12 [‐0.42, 0.65] |
| 10.2 change score | 1 | 253 | Mean Difference (IV, Random, 95% CI) | 1.34 [0.27, 2.41] |
| 11 Mental state: 3a. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high = poor) Show forest plot | 22 | 1934 | Mean Difference (IV, Random, 95% CI) | ‐0.82 [‐1.59, ‐0.04] |
| 11.1 short term | 19 | 1801 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.63, 0.01] |
| 11.2 medium term | 2 | 88 | Mean Difference (IV, Random, 95% CI) | ‐2.45 [‐4.64, ‐0.27] |
| 11.3 long term | 1 | 45 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐2.09, 4.49] |
| 12 Mental state: 3b. Negative symptoms ‐ average score ‐ short term (BPRS negative subscore, high = poor)) Show forest plot | 2 | 278 | Mean Difference (IV, Random, 95% CI) | ‐0.67 [‐1.31, ‐0.04] |
| 12.1 endpoint score | 1 | 25 | Mean Difference (IV, Random, 95% CI) | 0.11 [‐2.01, 2.23] |
| 12.2 change score | 1 | 253 | Mean Difference (IV, Random, 95% CI) | ‐0.75 [‐1.42, ‐0.08] |
| 13 Mental state: 3c. Negative symptoms ‐ average score ‐ short term (SANS total, high = poor) Show forest plot | 2 | 331 | Mean Difference (IV, Random, 95% CI) | 0.66 [‐1.35, 2.66] |
| 13.1 endpoint score | 1 | 103 | Mean Difference (IV, Random, 95% CI) | 1.80 [0.24, 3.36] |
| 13.2 change score | 1 | 228 | Mean Difference (IV, Random, 95% CI) | ‐0.26 [‐1.08, 0.56] |
| 14 Mental state: 4. General psychopathology ‐ average endpoint score (PANSS general psychopathology subscore, high = poor) Show forest plot | 18 | 1569 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.83, 0.42] |
| 14.1 short term | 15 | 1472 | Mean Difference (IV, Random, 95% CI) | ‐0.17 [‐0.81, 0.47] |
| 14.2 medium term | 2 | 52 | Mean Difference (IV, Random, 95% CI) | 0.47 [‐3.30, 4.24] |
| 14.3 long term | 1 | 45 | Mean Difference (IV, Random, 95% CI) | ‐2.20 [‐6.02, 1.62] |
| 15 General functioning: General ‐ average endpoint score ‐ long term (GAF total score, low = poor) Show forest plot | 1 | 207 | Mean Difference (IV, Random, 95% CI) | ‐0.10 [‐9.80, 9.60] |
| 16 Quality of life: 1a. General ‐ average endpoint score ‐short term (SF‐36, low = poor) Show forest plot | 1 | 84 | Mean Difference (IV, Random, 95% CI) | 13.76 [5.95, 21.57] |
| 17 Quality of life: 1b. General ‐ average endpoint score ‐ long term (MANSA total score, low = poor) Show forest plot | 1 | 207 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐1.38, 1.38] |
| 18 Quality of life: 1c. General ‐ average change score ‐ long term (QLS, high = poor) Show forest plot | 1 | 156 | Mean Difference (IV, Random, 95% CI) | 0.1 [‐0.23, 0.43] |
| 19 Cognitive function: 1a. General ‐ average change score ‐ long term (Composite score, high = poor) Show forest plot | 2 | 407 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.19, 0.20] |
| 20 Cognitive function: 1b. General ‐ average endpoint scores as defined by the original studies (low = poor) Show forest plot | 3 | 142 | Mean Difference (IV, Random, 95% CI) | 1.55 [‐0.62, 3.72] |
| 20.1 short term | 1 | 91 | Mean Difference (IV, Random, 95% CI) | 8.30 [1.64, 14.96] |
| 20.2 long term | 2 | 51 | Mean Difference (IV, Random, 95% CI) | 0.82 [‐0.77, 2.41] |
| 21 Service use: number of participants re‐hospitalised ‐ long term Show forest plot | 2 | 722 | Risk Ratio (IV, Random, 95% CI) | 1.23 [0.90, 1.68] |
| 22 Adverse effects: 1. General ‐ at least one adverse effect Show forest plot | 9 | 1985 | Risk Ratio (IV, Random, 95% CI) | 0.76 [0.64, 0.90] |
| 22.1 short term | 7 | 1180 | Risk Ratio (IV, Random, 95% CI) | 0.75 [0.62, 0.91] |
| 22.2 long term | 2 | 805 | Risk Ratio (IV, Random, 95% CI) | 0.82 [0.52, 1.29] |
| 23 Adverse effects: 2. Death Show forest plot | 2 | 1456 | Risk Ratio (IV, Random, 95% CI) | 0.78 [0.20, 3.04] |
| 23.1 suicide attempt ‐ long term | 1 | 598 | Risk Ratio (IV, Random, 95% CI) | 0.77 [0.05, 12.32] |
| 23.2 suicide ‐ long term | 1 | 598 | Risk Ratio (IV, Random, 95% CI) | 0.52 [0.09, 3.07] |
| 23.3 death ‐ short term | 1 | 260 | Risk Ratio (IV, Random, 95% CI) | 3.0 [0.12, 72.97] |
| 24 Adverse effects: 3a. Cardiac effects ‐ QTc prolongation ‐ long term Show forest plot | 1 | 41 | Risk Ratio (IV, Random, 95% CI) | 1.73 [0.17, 17.59] |
| 25 Adverse effects: 3b. Cardiac effects ‐ abnormal ECG ‐ short term Show forest plot | 2 | 165 | Risk Ratio (IV, Random, 95% CI) | 0.38 [0.16, 0.92] |
| 26 Adverse effects: 3c. Cardiac effects ‐ orthostatic hypotension Show forest plot | 5 | 1393 | Risk Ratio (IV, Random, 95% CI) | 0.61 [0.28, 1.35] |
| 26.1 short term | 4 | 795 | Risk Ratio (IV, Random, 95% CI) | 0.45 [0.13, 1.54] |
| 26.2 long term | 1 | 598 | Risk Ratio (IV, Random, 95% CI) | 1.01 [0.64, 1.60] |
| 27 Adverse effects: 3d. Cardiac effects ‐ low blood pressure ‐ short term Show forest plot | 6 | 572 | Risk Ratio (IV, Random, 95% CI) | 0.69 [0.41, 1.18] |
| 28 Adverse effects: 3e. Cardiac effects ‐ tachycardia ‐ short term Show forest plot | 8 | 814 | Risk Ratio (IV, Random, 95% CI) | 0.70 [0.36, 1.34] |
| 29 Adverse effects: 4. Central nervous system ‐ sedation Show forest plot | 14 | 2298 | Risk Ratio (IV, Random, 95% CI) | 0.70 [0.43, 1.16] |
| 29.1 short term | 13 | 1700 | Risk Ratio (IV, Random, 95% CI) | 0.69 [0.37, 1.30] |
| 29.2 long term | 1 | 598 | Risk Ratio (IV, Random, 95% CI) | 1.08 [0.84, 1.39] |
| 30 Adverse effects: 5a. Extrapyramidal effects ‐ overall ‐ short term Show forest plot | 8 | 1095 | Risk Ratio (IV, Random, 95% CI) | 0.17 [0.09, 0.32] |
| 31 Adverse effects: 5b. Extrapyramidal effects ‐ akathisia Show forest plot | 16 | 2217 | Risk Ratio (IV, Random, 95% CI) | 0.27 [0.18, 0.39] |
| 31.1 short term | 15 | 2059 | Risk Ratio (IV, Random, 95% CI) | 0.24 [0.17, 0.35] |
| 31.2 long term | 1 | 158 | Risk Ratio (IV, Random, 95% CI) | 0.50 [0.25, 0.98] |
| 32 Adverse effects: 5c. Extrapyramidal effects ‐ parkinsonism Show forest plot | 3 | 343 | Risk Ratio (IV, Random, 95% CI) | 0.26 [0.14, 0.47] |
| 32.1 short term | 2 | 185 | Risk Ratio (IV, Random, 95% CI) | 0.13 [0.04, 0.48] |
| 32.2 long term | 1 | 158 | Risk Ratio (IV, Random, 95% CI) | 0.31 [0.15, 0.62] |
| 33 Adverse effects: 5d. Extrapyramidal effects ‐ dystonia Show forest plot | 5 | 992 | Risk Ratio (IV, Random, 95% CI) | 0.19 [0.06, 0.64] |
| 33.1 short term | 4 | 834 | Risk Ratio (IV, Random, 95% CI) | 0.13 [0.04, 0.51] |
| 33.2 long term | 1 | 158 | Risk Ratio (IV, Random, 95% CI) | 0.86 [0.05, 13.49] |
| 34 Adverse effects: 5e. Extrapyramidal effects ‐ tremor ‐ short term Show forest plot | 12 | 1641 | Risk Ratio (IV, Random, 95% CI) | 0.33 [0.23, 0.47] |
| 35 Adverse effects: 5f. Extrapyramidal effects ‐ scale measured (dichotomous data) ‐ long term Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 35.1 extrapyramidal symptoms: Simpson‐Angus Scale (SAS >/=1) | 1 | 541 | Risk Ratio (IV, Random, 95% CI) | 0.65 [0.31, 1.37] |
| 35.2 abnormal movement: Abnormal Involuntary Movement Scale (AIMS>/=2) | 1 | 473 | Risk Ratio (IV, Random, 95% CI) | 0.73 [0.48, 1.14] |
| 35.3 akathisia: Barnes Akathisia Scale (BARS >/=3) | 1 | 546 | Risk Ratio (IV, Random, 95% CI) | 0.79 [0.40, 1.55] |
| 36 Adverse effects: 5g. Extrapyramidal effects ‐ scale measured (continuous data, high=poor) Show forest plot | 5 | 373 | Mean Difference (IV, Random, 95% CI) | ‐1.24 [‐2.54, 0.05] |
| 36.1 average endpoint score ‐ Extrapyramidal symptoms (ESRS) ‐ short term | 1 | 35 | Mean Difference (IV, Random, 95% CI) | ‐4.55 [‐6.58, ‐2.52] |
| 36.2 average endpoint score ‐ Abnormal Involuntary Movement Scale ( AIMS) ‐ medium term | 1 | 11 | Mean Difference (IV, Random, 95% CI) | 0.30 [‐0.83, 1.43] |
| 36.3 average endpoint score ‐ Simpson‐Angus Scale (SAS) ‐ medium term | 1 | 11 | Mean Difference (IV, Random, 95% CI) | 1.10 [‐1.94, 4.14] |
| 36.4 average endpoint score ‐ Treatment Emergent Symptom Scale (TESS) ‐ short term | 2 | 158 | Mean Difference (IV, Random, 95% CI) | ‐1.09 [‐2.51, 0.33] |
| 36.5 average change score ‐ Treatment Emergent Symptom Scale (TESS) ‐ short term | 1 | 117 | Mean Difference (IV, Random, 95% CI) | ‐1.03 [‐2.49, 0.43] |
| 36.6 average endpoint score ‐ Treatment Emergent Symptom Scale (TESS) ‐ medium term | 1 | 41 | Mean Difference (IV, Random, 95% CI) | ‐2.1 [‐4.55, 0.35] |
| 37 Adverse effects: 6a. Prolactin associated side effects Show forest plot | 1 | 1196 | Risk Ratio (IV, Random, 95% CI) | 0.77 [0.33, 1.79] |
| 37.1 gynaecomastia, galactorrhoea ‐ long term | 1 | 598 | Risk Ratio (IV, Random, 95% CI) | 1.16 [0.33, 4.07] |
| 37.2 menstrual irregularities ‐ long term | 1 | 598 | Risk Ratio (IV, Random, 95% CI) | 0.55 [0.18, 1.72] |
| 38 Adverse effects: 6b. Prolactin ‐ Hyperprolactinemia Show forest plot | 3 | 229 | Risk Ratio (IV, Random, 95% CI) | 0.27 [0.04, 1.92] |
| 38.1 short term | 2 | 165 | Risk Ratio (IV, Random, 95% CI) | 0.08 [0.01, 0.60] |
| 38.2 long term | 1 | 64 | Risk Ratio (IV, Random, 95% CI) | 0.91 [0.51, 1.62] |
| 39 Adverse effects: 6c. Prolactin level ‐ average level in ng/mL Show forest plot | 4 | 1034 | Mean Difference (IV, Random, 95% CI) | ‐16.20 [‐23.34, ‐9.07] |
| 39.1 short term ‐ endpoint level | 1 | 35 | Mean Difference (IV, Random, 95% CI) | ‐15.67 [‐21.00, ‐10.34] |
| 39.2 short term ‐ change level | 1 | 356 | Mean Difference (IV, Random, 95% CI) | ‐22.43 [‐23.20, ‐21.66] |
| 39.3 long term ‐ endpoint level | 1 | 45 | Mean Difference (IV, Random, 95% CI) | ‐16.4 [‐23.83, ‐8.97] |
| 39.4 long term ‐ change level | 1 | 598 | Mean Difference (IV, Random, 95% CI) | ‐9.70 [‐14.02, ‐5.38] |
| 40 Adverse effects: 7a. Weight gain (as defined by the original studies) Show forest plot | 11 | 1512 | Risk Ratio (IV, Random, 95% CI) | 0.68 [0.44, 1.04] |
| 40.1 short term | 9 | 866 | Risk Ratio (IV, Random, 95% CI) | 0.52 [0.34, 0.80] |
| 40.2 long term | 2 | 646 | Risk Ratio (IV, Random, 95% CI) | 1.27 [0.97, 1.66] |
| 41 Adverse effects: 7b. Weight gain ‐ average weight in kg. Show forest plot | 3 | 168 | Mean Difference (IV, Random, 95% CI) | 3.35 [0.29, 6.40] |
| 41.1 short term ‐ change weight | 1 | 25 | Mean Difference (IV, Random, 95% CI) | 1.40 [‐5.66, 8.46] |
| 41.2 long term ‐ endpoint weight | 1 | 45 | Mean Difference (IV, Random, 95% CI) | 4.30 [‐0.31, 8.91] |
| 41.3 long term ‐ change weight | 1 | 98 | Mean Difference (IV, Random, 95% CI) | 3.2 [‐1.79, 8.19] |
| 42 Adverse effects: 8. decreased white blood cell count ‐ short term Show forest plot | 1 | 40 | Risk Ratio (IV, Random, 95% CI) | 0.33 [0.01, 7.72] |
| 43 Sensitivity analysis (skewed data excluded), Mental state: 1. General ‐ average endpoint score (PANSS total, high = poor) Show forest plot | 3 | 172 | Mean Difference (IV, Random, 95% CI) | ‐2.25 [‐5.35, 0.85] |
| 43.1 short term | 2 | 95 | Mean Difference (IV, Random, 95% CI) | ‐0.88 [‐3.63, 1.88] |
| 43.2 medium term | 1 | 77 | Mean Difference (IV, Random, 95% CI) | ‐4.90 [‐8.06, ‐1.74] |
| 44 Sensitivity analysis (skewed data excluded), Mental state: 2. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high=poor) ‐ medium term Show forest plot | 1 | 77 | Mean Difference (IV, Random, 95% CI) | ‐2.70 [‐4.96, ‐0.44] |
| 45 Sensitivity analysis (inappropriate comparator doses excluded), Mental state: 1: General‐ average endpoint score (PANSS total, high=poor) Show forest plot | 17 | 1835 | Mean Difference (IV, Random, 95% CI) | 1.55 [‐1.38, 4.49] |
| 45.1 short term ‐ endpoint | 13 | 1173 | Mean Difference (IV, Random, 95% CI) | 2.04 [‐1.67, 5.74] |
| 45.2 short term ‐ change | 2 | 565 | Mean Difference (IV, Random, 95% CI) | 3.59 [0.09, 7.10] |
| 45.3 medium term ‐ endpoint | 2 | 52 | Mean Difference (IV, Random, 95% CI) | ‐4.72 [‐7.85, ‐1.59] |
| 45.4 long term ‐ endpoint | 1 | 45 | Mean Difference (IV, Random, 95% CI) | ‐2.30 [‐10.22, 5.62] |
| 46 Sensitivity analysis (inappropriate comparator doses excluded), Mental state: 2: Positive symptoms‐ average endpoint score (PANSS positive subscore, high = poor) Show forest plot | 13 | 1011 | Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.58, 0.62] |
| 47 Sensitivity analysis (inappropriate comparator doses excluded), Mental state: 3: Negative symptoms‐ average endpoint score (PANSS negative subscore, high = poor) Show forest plot | 13 | 1011 | Mean Difference (IV, Random, 95% CI) | ‐0.98 [‐2.09, 0.14] |
| 47.1 short term | 10 | 878 | Mean Difference (IV, Random, 95% CI) | ‐0.99 [‐2.26, 0.28] |
| 47.2 medium term | 2 | 88 | Mean Difference (IV, Random, 95% CI) | ‐2.45 [‐4.64, ‐0.27] |
| 47.3 long term | 1 | 45 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐2.09, 4.49] |
| 48 Senstivity analysis (high attrition rate data excluded), Mental state: 1: General ‐ average score (PANSS total, high = poor) Show forest plot | 25 | 2834 | Mean Difference (IV, Random, 95% CI) | 0.08 [‐2.26, 2.42] |
| 48.1 short term ‐ endpoint score | 21 | 2055 | Mean Difference (IV, Random, 95% CI) | 0.84 [‐1.46, 3.15] |
| 48.2 short term ‐ change score | 2 | 565 | Mean Difference (IV, Random, 95% CI) | 3.59 [0.09, 7.10] |
| 48.3 medium term ‐ endpoint score | 2 | 169 | Mean Difference (IV, Random, 95% CI) | ‐9.11 [‐17.54, ‐0.68] |
| 48.4 long term ‐ endpoint score | 1 | 45 | Mean Difference (IV, Random, 95% CI) | ‐2.30 [‐10.22, 5.62] |
| 49 Sensitivity analysis (high attrition rate data excluded), Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high = poor) Show forest plot | 21 | 1923 | Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.39, 0.43] |
| 49.1 short term | 19 | 1801 | Mean Difference (IV, Random, 95% CI) | 0.19 [‐0.25, 0.62] |
| 49.2 medium term | 1 | 77 | Mean Difference (IV, Random, 95% CI) | ‐1.80 [‐3.70, 0.10] |
| 49.3 long term | 1 | 45 | Mean Difference (IV, Random, 95% CI) | ‐1.30 [‐3.12, 0.52] |
| 50 Sensitivity analysis (high attrition rate data excluded), Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high = poor) Show forest plot | 21 | 1923 | Mean Difference (IV, Random, 95% CI) | ‐0.83 [‐1.62, ‐0.04] |
| 50.1 short term | 19 | 1801 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.63, 0.01] |
| 50.2 medium term | 1 | 77 | Mean Difference (IV, Random, 95% CI) | ‐2.70 [‐4.96, ‐0.44] |
| 50.3 long term | 1 | 45 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐2.09, 4.49] |
| 51 Senstivity analysis (completer data only), Mental state: 1: General ‐ average score (PANSS total, high=poor) Show forest plot | 18 | 1628 | Mean Difference (IV, Random, 95% CI) | ‐0.41 [‐3.32, 2.51] |
| 51.1 short term ‐ endpoint score | 16 | 1342 | Mean Difference (IV, Random, 95% CI) | 0.55 [‐2.27, 3.38] |
| 51.2 short term ‐ change score | 1 | 117 | Mean Difference (IV, Random, 95% CI) | 3.88 [‐1.68, 9.44] |
| 51.3 medium term ‐ endpoint score | 2 | 169 | Mean Difference (IV, Random, 95% CI) | ‐9.11 [‐17.54, ‐0.68] |
| 52 Sensitivity analysis (completer data only), Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high = poor) Show forest plot | 16 | 1385 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.46, 0.46] |
| 52.1 short term | 15 | 1308 | Mean Difference (IV, Random, 95% CI) | 0.11 [‐0.36, 0.59] |
| 52.2 medium term | 1 | 77 | Mean Difference (IV, Random, 95% CI) | ‐1.80 [‐3.70, 0.10] |
| 53 Sensitivity analysis (completer data only), Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high = poor) Show forest plot | 16 | 1385 | Mean Difference (IV, Random, 95% CI) | ‐1.16 [‐2.08, ‐0.25] |
| 53.1 short term | 15 | 1308 | Mean Difference (IV, Random, 95% CI) | ‐1.06 [‐2.01, ‐0.12] |
| 53.2 medium term | 1 | 77 | Mean Difference (IV, Random, 95% CI) | ‐2.70 [‐4.96, ‐0.44] |
