Intervention Review

You have free access to this content

Quetiapine versus typical antipsychotic medications for schizophrenia

  1. Sirijit Suttajit1,*,
  2. Manit Srisurapanont1,
  3. Jun Xia2,
  4. Siritree Suttajit3,
  5. Benchalak Maneeton1,
  6. Narong Maneeton1

Editorial Group: Cochrane Schizophrenia Group

Published Online: 31 MAY 2013

Assessed as up-to-date: 28 MAR 2010

DOI: 10.1002/14651858.CD007815.pub2


How to Cite

Suttajit S, Srisurapanont M, Xia J, Suttajit S, Maneeton B, Maneeton N. Quetiapine versus typical antipsychotic medications for schizophrenia. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD007815. DOI: 10.1002/14651858.CD007815.pub2.

Author Information

  1. 1

    Chiang Mai University, Department of Psychiatry, Faculty of Medicine, Chiang Mai, Thailand

  2. 2

    The University of Nottingham, Cochrane Schizophrenia Group, Nottingham, UK

  3. 3

    Chiang Mai University, Faculty of Pharmacy, Chiang Mai, Thailand

*Sirijit Suttajit, Department of Psychiatry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand. sirijits@gmail.com. ssuttaji@mail.med.cmu.ac.th.

Publication History

  1. Publication Status: New
  2. Published Online: 31 MAY 2013

SEARCH

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 
Summary of findings for the main comparison. Quetiapine compared to Typical antipsychotics for schizophrenia

Quetiapine compared to Typical antipsychotics for schizophrenia

Patient or population: patients with schizophrenia
Settings:
Intervention: Quetiapine
Comparison: Typical antipsychotics

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Typical antipsychoticsQuetiapine

Global state
No clinical significant response as defined by the individual studies
Study populationRR 0.96
(0.75 to 1.23)
1607
(16 studies)
⊕⊕⊕⊝
moderate1

145 per 1000139 per 1000
(109 to 178)

Moderate


Leaving the study early due to any reasonStudy populationRR 0.91
(0.81 to 1.01)
3576
(23 studies)
⊕⊕⊕⊝
moderate1

369 per 1000336 per 1000
(299 to 373)

Moderate


Positive symptoms
PANSS positive subscore
The mean positive symptoms in the intervention groups was
0.02 higher
(0.39 lower to 0.43 higher)
1934
(22 studies)
⊕⊕⊕⊝
moderate1

Negative symptoms
PANSS negative subscore
The mean negative symptoms in the intervention groups was
0.82 lower
(1.59 to 0.04 lower)
1934
(22 studies)
⊕⊕⊕⊝
moderate1

Cognitive function
Average endpoint scores as defined by the original studies
The mean cognitive function in the intervention groups was
1.55 higher
(0.62 lower to 3.72 higher)
142
(3 studies)
⊕⊝⊝⊝
very low1,2,3

Extrapyramidal effectsStudy populationRR 0.17
(0.09 to 0.32)
1095
(8 studies)
⊕⊕⊕⊝
moderate1

548 per 100093 per 1000
(49 to 175)

Moderate


Prolactin level
Average level in ng/mL
The mean prolactin level in the intervention groups was
16.20 lower
(23.34 to 9.07 lower)
1034
(4 studies)
⊕⊕⊕⊝
moderate1

*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).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Limitations in design - rated 'serious' : poor description of randomisation, no details about blinding, no details about concealment.
2 Inconsistency -rated 'serious' : the measurement of cognitive function were various.
3 Imprecision - rated 'serious' : number of participants was very small.
PANSS: Positive and Negative Syndrome Scale

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

To review the effects of quetiapine in comparison with typical antipsychotics in the treatment of schizophrenia and schizophrenia-like psychosis.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

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 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).


Drugmg/day

Quetiapine300-800

Typical

Chlorpromazine300-1000

Fluphenazine5-20

Haloperidol5-20

Loxapine30-100

Mesoridazine150-400

Molindone30-100

Perphenazine16-64

Thioridazine300-800

Thiothixene15-50

Trifluoperazine15-50



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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

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).

 FigureFigure 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.

 FigureFigure 2. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
 FigureFigure 3. 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

See:  Summary of findings for the main comparison Quetiapine compared to Typical antipsychotics for schizophrenia

 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

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 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).

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 

Implications for practice
1. For people with schizophrenia

For people with schizophrenia it is important to know that quetiapine may be less likely to cause adverse effects, such as abnormal ECG, extrapyramidal effects, abnormal prolactin levels and weight gain (short term). However, its efficacy in treating positive symptoms and general psychopathology seems to be similar to that of typical antipsychotics. There is no clear differences in terms of the treatment of negative symptoms.

2. For clinicians

Clinicians should be aware that the evidence is limited due to high attrition rates in almost all studies. Well-designed studies comparing quetiapine with typical antipsychotics are needed. See  Table 1 for a suggested study design.

3. For managers/policy makers

Limited data suggest no difference between quetiapine and typical antipsychotics in term of re-hospitalisation. This finding is important because in many countries hospitalisation is a main cost of schizophrenia treatment.

 
Implications for research
1. General

Outcome reporting remains insufficient in antipsychotic drug trials. Strict adherence to the CONSORT statement (Moher 2001) would improve the conduct, and reporting of clinical trials. This statement has been available since 1996 and there seems little justification for authors or journal editors ignoring its proven value.

2. Specific

Pragmatic, real world, randomised controlled trials should be carried out to determine the effectiveness of quetiapine in standard clinical practice (Thorpe 2009). Studies of medium- and long-term risks, including mortality and cost-effectiveness, are a priority.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

We thank Prof. Clive Adams, Prof. Stefan Leucht, Bethany York and Claire Irving for their support during the development of the protocol and full review. We thank Samantha Roberts for her assistance in developing the search strategy for this review, and for her help in conducting the electronic searches. We would also like to thank all members of the Cochrane Schizophrenia Group editorial base for their editorial assistance.

The Schizophrenia Group produce a standard template for the methodology of their reviews. We have used this template and adapted it.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
Comparison 1. QUETIAPINE versus TYPICAL ANTIPSYCHOTICS

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global state: 1. No clinical improvement151607Risk Ratio (IV, Random, 95% CI)0.96 [0.75, 1.23]

    1.1 short term
151479Risk Ratio (IV, Random, 95% CI)1.05 [0.81, 1.35]

    1.2 medium term
1128Risk Ratio (IV, Random, 95% CI)0.16 [0.05, 0.51]

 2 Global state: 2a. CGI: Average CGI-S (high = poor)81253Mean Difference (IV, Random, 95% CI)0.20 [0.06, 0.33]

    2.1 short term - endpoint score
5347Mean Difference (IV, Random, 95% CI)0.22 [-0.04, 0.49]

    2.2 short term - change score
2699Mean Difference (IV, Random, 95% CI)0.20 [0.04, 0.36]

    2.3 long term - endpoint score
1207Mean Difference (IV, Random, 95% CI)-0.10 [-0.93, 0.73]

 3 Global state: 2b. CGI: Average endpoint CGI-I (high = poor)5507Mean Difference (IV, Random, 95% CI)0.38 [0.28, 0.47]

    3.1 short term
4496Mean Difference (IV, Random, 95% CI)0.39 [0.30, 0.47]

    3.2 medium term
111Mean Difference (IV, Random, 95% CI)-0.20 [-1.08, 0.68]

 4 Leaving the study early: 1. Any reason233576Risk Ratio (IV, Random, 95% CI)0.91 [0.81, 1.01]

    4.1 short term
172535Risk Ratio (IV, Random, 95% CI)0.88 [0.78, 1.00]

    4.2 medium term
3203Risk Ratio (IV, Random, 95% CI)0.72 [0.52, 0.99]

    4.3 long term
3838Risk Ratio (IV, Random, 95% CI)0.99 [0.77, 1.28]

 5 Leaving the study early: 2. Adverse events153010Risk Ratio (IV, Random, 95% CI)0.48 [0.30, 0.77]

    5.1 short term
112044Risk Ratio (IV, Random, 95% CI)0.51 [0.31, 0.84]

    5.2 medium term
1128Risk Ratio (IV, Random, 95% CI)0.03 [0.00, 0.53]

    5.3 long term
3838Risk Ratio (IV, Random, 95% CI)0.46 [0.12, 1.78]

 6 Leaving the study early: 3. Inefficacy92063Risk Ratio (IV, Random, 95% CI)1.24 [1.00, 1.54]

    6.1 short term
3842Risk Ratio (IV, Random, 95% CI)1.20 [0.87, 1.66]

    6.2 long term
61221Risk Ratio (IV, Random, 95% CI)1.41 [0.94, 2.11]

 7 Mental state: 1a. General - average score (PANSS total, high = poor)273052Mean Difference (IV, Random, 95% CI)0.09 [-2.14, 2.31]

    7.1 short term - endpoint score
212055Mean Difference (IV, Random, 95% CI)0.84 [-1.46, 3.15]

    7.2 short term - change score
2565Mean Difference (IV, Random, 95% CI)3.59 [0.09, 7.10]

    7.3 medium term - endpoint score
3180Mean Difference (IV, Random, 95% CI)-7.77 [-15.69, 0.14]

    7.4 long term - endpoint score
2252Mean Difference (IV, Random, 95% CI)-0.90 [-4.94, 3.15]

 8 Mental state: 1b. General - average score -short term (BPRS total, high = poor)81025Mean Difference (IV, Random, 95% CI)0.71 [-0.77, 2.20]

    8.1 endpoint score
6666Mean Difference (IV, Random, 95% CI)-0.24 [-1.66, 1.17]

    8.2 change score
2359Mean 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)221934Mean Difference (IV, Random, 95% CI)0.02 [-0.39, 0.43]

    9.1 short term
191801Mean Difference (IV, Random, 95% CI)0.19 [-0.25, 0.62]

    9.2 medium term
288Mean Difference (IV, Random, 95% CI)-1.57 [-3.41, 0.26]

    9.3 long term
145Mean 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)3381Mean Difference (IV, Random, 95% CI)0.63 [-0.37, 1.62]

    10.1 endpoint score
2128Mean Difference (IV, Random, 95% CI)0.12 [-0.42, 0.65]

    10.2 change score
1253Mean 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)221934Mean Difference (IV, Random, 95% CI)-0.82 [-1.59, -0.04]

    11.1 short term
191801Mean Difference (IV, Random, 95% CI)-0.81 [-1.63, 0.01]

    11.2 medium term
288Mean Difference (IV, Random, 95% CI)-2.45 [-4.64, -0.27]

    11.3 long term
145Mean 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))2278Mean Difference (IV, Random, 95% CI)-0.67 [-1.31, -0.04]

    12.1 endpoint score
125Mean Difference (IV, Random, 95% CI)0.11 [-2.01, 2.23]

    12.2 change score
1253Mean 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)2331Mean Difference (IV, Random, 95% CI)0.66 [-1.35, 2.66]

    13.1 endpoint score
1103Mean Difference (IV, Random, 95% CI)1.80 [0.24, 3.36]

    13.2 change score
1228Mean 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)181569Mean Difference (IV, Random, 95% CI)-0.20 [-0.83, 0.42]

    14.1 short term
151472Mean Difference (IV, Random, 95% CI)-0.17 [-0.81, 0.47]

    14.2 medium term
252Mean Difference (IV, Random, 95% CI)0.47 [-3.30, 4.24]

    14.3 long term
145Mean 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)1207Mean 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)184Mean 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)1207Mean 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)1156Mean 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)2407Mean 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)3142Mean Difference (IV, Random, 95% CI)1.55 [-0.62, 3.72]

    20.1 short term
191Mean Difference (IV, Random, 95% CI)8.30 [1.64, 14.96]

    20.2 long term
251Mean Difference (IV, Random, 95% CI)0.82 [-0.77, 2.41]

 21 Service use: number of participants re-hospitalised - long term2722Risk Ratio (IV, Random, 95% CI)1.23 [0.90, 1.68]

 22 Adverse effects: 1. General - at least one adverse effect91985Risk Ratio (IV, Random, 95% CI)0.76 [0.64, 0.90]

    22.1 short term
71180Risk Ratio (IV, Random, 95% CI)0.75 [0.62, 0.91]

    22.2 long term
2805Risk Ratio (IV, Random, 95% CI)0.82 [0.52, 1.29]

 23 Adverse effects: 2. Death21456Risk Ratio (IV, Random, 95% CI)0.78 [0.20, 3.04]

    23.1 suicide attempt - long term
1598Risk Ratio (IV, Random, 95% CI)0.77 [0.05, 12.32]

    23.2 suicide - long term
1598Risk Ratio (IV, Random, 95% CI)0.52 [0.09, 3.07]

    23.3 death - short term
1260Risk Ratio (IV, Random, 95% CI)3.0 [0.12, 72.97]

 24 Adverse effects: 3a. Cardiac effects - QTc prolongation - long term141Risk Ratio (IV, Random, 95% CI)1.73 [0.17, 17.59]

 25 Adverse effects: 3b. Cardiac effects - abnormal ECG - short term2165Risk Ratio (IV, Random, 95% CI)0.38 [0.16, 0.92]

 26 Adverse effects: 3c. Cardiac effects - orthostatic hypotension51393Risk Ratio (IV, Random, 95% CI)0.61 [0.28, 1.35]

    26.1 short term
4795Risk Ratio (IV, Random, 95% CI)0.45 [0.13, 1.54]

    26.2 long term
1598Risk Ratio (IV, Random, 95% CI)1.01 [0.64, 1.60]

 27 Adverse effects: 3d. Cardiac effects - low blood pressure - short term6572Risk Ratio (IV, Random, 95% CI)0.69 [0.41, 1.18]

 28 Adverse effects: 3e. Cardiac effects - tachycardia - short term8814Risk Ratio (IV, Random, 95% CI)0.70 [0.36, 1.34]

 29 Adverse effects: 4. Central nervous system - sedation142298Risk Ratio (IV, Random, 95% CI)0.70 [0.43, 1.16]

    29.1 short term
131700Risk Ratio (IV, Random, 95% CI)0.69 [0.37, 1.30]

    29.2 long term
1598Risk Ratio (IV, Random, 95% CI)1.08 [0.84, 1.39]

 30 Adverse effects: 5a. Extrapyramidal effects - overall - short term81095Risk Ratio (IV, Random, 95% CI)0.17 [0.09, 0.32]

 31 Adverse effects: 5b. Extrapyramidal effects - akathisia162217Risk Ratio (IV, Random, 95% CI)0.27 [0.18, 0.39]

    31.1 short term
152059Risk Ratio (IV, Random, 95% CI)0.24 [0.17, 0.35]

    31.2 long term
1158Risk Ratio (IV, Random, 95% CI)0.50 [0.25, 0.98]

 32 Adverse effects: 5c. Extrapyramidal effects - parkinsonism3343Risk Ratio (IV, Random, 95% CI)0.26 [0.14, 0.47]

    32.1 short term
2185Risk Ratio (IV, Random, 95% CI)0.13 [0.04, 0.48]

    32.2 long term
1158Risk Ratio (IV, Random, 95% CI)0.31 [0.15, 0.62]

 33 Adverse effects: 5d. Extrapyramidal effects - dystonia5992Risk Ratio (IV, Random, 95% CI)0.19 [0.06, 0.64]

    33.1 short term
4834Risk Ratio (IV, Random, 95% CI)0.13 [0.04, 0.51]

    33.2 long term
1158Risk Ratio (IV, Random, 95% CI)0.86 [0.05, 13.49]

 34 Adverse effects: 5e. Extrapyramidal effects - tremor - short term121641Risk Ratio (IV, Random, 95% CI)0.33 [0.23, 0.47]

 35 Adverse effects: 5f. Extrapyramidal effects - scale measured (dichotomous data) - long term1Risk Ratio (IV, Random, 95% CI)Subtotals only

    35.1 extrapyramidal symptoms: Simpson-Angus Scale (SAS >/=1)
1541Risk Ratio (IV, Random, 95% CI)0.65 [0.31, 1.37]

    35.2 abnormal movement: Abnormal Involuntary Movement Scale (AIMS>/=2)
1473Risk Ratio (IV, Random, 95% CI)0.73 [0.48, 1.14]

    35.3 akathisia: Barnes Akathisia Scale (BARS >/=3)
1546Risk Ratio (IV, Random, 95% CI)0.79 [0.40, 1.55]

 36 Adverse effects: 5g. Extrapyramidal effects - scale measured (continuous data, high=poor)5373Mean Difference (IV, Random, 95% CI)-1.24 [-2.54, 0.05]

    36.1 average endpoint score - Extrapyramidal symptoms (ESRS) - short term
135Mean Difference (IV, Random, 95% CI)-4.55 [-6.58, -2.52]

    36.2 average endpoint score - Abnormal Involuntary Movement Scale ( AIMS) - medium term
111Mean Difference (IV, Random, 95% CI)0.30 [-0.83, 1.43]

    36.3 average endpoint score - Simpson-Angus Scale (SAS) - medium term
111Mean Difference (IV, Random, 95% CI)1.10 [-1.94, 4.14]

    36.4 average endpoint score - Treatment Emergent Symptom Scale (TESS) - short term
2158Mean Difference (IV, Random, 95% CI)-1.09 [-2.51, 0.33]

    36.5 average change score - Treatment Emergent Symptom Scale (TESS) - short term
1117Mean Difference (IV, Random, 95% CI)-1.03 [-2.49, 0.43]

    36.6 average endpoint score - Treatment Emergent Symptom Scale (TESS) - medium term
141Mean Difference (IV, Random, 95% CI)-2.1 [-4.55, 0.35]

 37 Adverse effects: 6a. Prolactin associated side effects11196Risk Ratio (IV, Random, 95% CI)0.77 [0.33, 1.79]

    37.1 gynaecomastia, galactorrhoea - long term
1598Risk Ratio (IV, Random, 95% CI)1.16 [0.33, 4.07]

    37.2 menstrual irregularities - long term
1598Risk Ratio (IV, Random, 95% CI)0.55 [0.18, 1.72]

 38 Adverse effects: 6b. Prolactin - Hyperprolactinemia3229Risk Ratio (IV, Random, 95% CI)0.27 [0.04, 1.92]

    38.1 short term
2165Risk Ratio (IV, Random, 95% CI)0.08 [0.01, 0.60]

    38.2 long term
164Risk Ratio (IV, Random, 95% CI)0.91 [0.51, 1.62]

 39 Adverse effects: 6c. Prolactin level - average level in ng/mL41034Mean Difference (IV, Random, 95% CI)-16.20 [-23.34, -9.07]

    39.1 short term - endpoint level
135Mean Difference (IV, Random, 95% CI)-15.67 [-21.00, -10.34]

    39.2 short term - change level
1356Mean Difference (IV, Random, 95% CI)-22.43 [-23.20, -21.66]

    39.3 long term - endpoint level
145Mean Difference (IV, Random, 95% CI)-16.4 [-23.83, -8.97]

    39.4 long term - change level
1598Mean Difference (IV, Random, 95% CI)-9.70 [-14.02, -5.38]

 40 Adverse effects: 7a. Weight gain (as defined by the original studies)111512Risk Ratio (IV, Random, 95% CI)0.68 [0.44, 1.04]

    40.1 short term
9866Risk Ratio (IV, Random, 95% CI)0.52 [0.34, 0.80]

    40.2 long term
2646Risk Ratio (IV, Random, 95% CI)1.27 [0.97, 1.66]

 41 Adverse effects: 7b. Weight gain - average weight in kg.3168Mean Difference (IV, Random, 95% CI)3.35 [0.29, 6.40]

    41.1 short term - change weight
125Mean Difference (IV, Random, 95% CI)1.40 [-5.66, 8.46]

    41.2 long term - endpoint weight
145Mean Difference (IV, Random, 95% CI)4.30 [-0.31, 8.91]

    41.3 long term - change weight
198Mean Difference (IV, Random, 95% CI)3.2 [-1.79, 8.19]

 42 Adverse effects: 8. decreased white blood cell count - short term140Risk 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)3172Mean Difference (IV, Random, 95% CI)-2.25 [-5.35, 0.85]

    43.1 short term
295Mean Difference (IV, Random, 95% CI)-0.88 [-3.63, 1.88]

    43.2 medium term
177Mean 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 term177Mean 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)171835Mean Difference (IV, Random, 95% CI)1.55 [-1.38, 4.49]

    45.1 short term - endpoint
131173Mean Difference (IV, Random, 95% CI)2.04 [-1.67, 5.74]

    45.2 short term - change
2565Mean Difference (IV, Random, 95% CI)3.59 [0.09, 7.10]

    45.3 medium term - endpoint
252Mean Difference (IV, Random, 95% CI)-4.72 [-7.85, -1.59]

    45.4 long term - endpoint
145Mean 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)131011Mean 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)131011Mean Difference (IV, Random, 95% CI)-0.98 [-2.09, 0.14]

    47.1 short term
10878Mean Difference (IV, Random, 95% CI)-0.99 [-2.26, 0.28]

    47.2 medium term
288Mean Difference (IV, Random, 95% CI)-2.45 [-4.64, -0.27]

    47.3 long term
145Mean 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)252834Mean Difference (IV, Random, 95% CI)0.08 [-2.26, 2.42]

    48.1 short term - endpoint score
212055Mean Difference (IV, Random, 95% CI)0.84 [-1.46, 3.15]

    48.2 short term - change score
2565Mean Difference (IV, Random, 95% CI)3.59 [0.09, 7.10]

    48.3 medium term - endpoint score
2169Mean Difference (IV, Random, 95% CI)-9.11 [-17.54, -0.68]

    48.4 long term - endpoint score
145Mean 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)211923Mean Difference (IV, Random, 95% CI)0.02 [-0.39, 0.43]

    49.1 short term
191801Mean Difference (IV, Random, 95% CI)0.19 [-0.25, 0.62]

    49.2 medium term
177Mean Difference (IV, Random, 95% CI)-1.80 [-3.70, 0.10]

    49.3 long term
145Mean 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)211923Mean Difference (IV, Random, 95% CI)-0.83 [-1.62, -0.04]

    50.1 short term
191801Mean Difference (IV, Random, 95% CI)-0.81 [-1.63, 0.01]

    50.2 medium term
177Mean Difference (IV, Random, 95% CI)-2.70 [-4.96, -0.44]

    50.3 long term
145Mean 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)181628Mean Difference (IV, Random, 95% CI)-0.41 [-3.32, 2.51]

    51.1 short term - endpoint score
161342Mean Difference (IV, Random, 95% CI)0.55 [-2.27, 3.38]

    51.2 short term - change score
1117Mean Difference (IV, Random, 95% CI)3.88 [-1.68, 9.44]

    51.3 medium term - endpoint score
2169Mean 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)161385Mean Difference (IV, Random, 95% CI)0.00 [-0.46, 0.46]

    52.1 short term
151308Mean Difference (IV, Random, 95% CI)0.11 [-0.36, 0.59]

    52.2 medium term
177Mean 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)161385Mean Difference (IV, Random, 95% CI)-1.16 [-2.08, -0.25]

    53.1 short term
151308Mean Difference (IV, Random, 95% CI)-1.06 [-2.01, -0.12]

    53.2 medium term
177Mean Difference (IV, Random, 95% CI)-2.70 [-4.96, -0.44]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Appendix 1. Data collection and analysis published in protocol

 

Data collection and analysis  

 

Selection of studies  

Two review authors will independently inspect citations identified from the search. We will identify potentially relevant reports and order full papers for reassessment. Retrieved articles will be independently assessed by the two review authors for inclusion according to our defined inclusion criteria. Any disagreement will be resolved by consensus discussions with the third member of the review team. If it is impossible to resolve disagreements, these studies will be added to those awaiting assessment and we will contact the authors of the papers for clarification. Non-concurrence in trial selection will be reported.

 

Data extraction and management  

1. Extraction
Two review authors will independently extract data from included studies. Again, any disagreement will be discussed with the third member of the review team, decisions documented and, if necessary, we will contact authors of studies for clarification.

2. Management
Data will be extracted onto standard, simple forms.

3. Scale-derived data
We will include continuous data from rating scales only if: (a) the psychometric properties of the measuring instrument has 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).

 

Assessment of risk of bias in included studies  

Two review authors will independently assess risk of bias in accordance with The Cochrane Collaboration’s tool for assessing quality and risk of bias (Higgins 2008). This tool encourages consideration of how the sequence was generated, how allocation was concealed, the integrity of blinding, the completeness of outcome data, selective reporting and other biases.

The risk of bias in each domain and overall will be assessed and categorised into:

A. low risk of bias: plausible bias unlikely to seriously alter the results (categorised as 'Yes' in 'Risk of bias' table);
B. high risk of bias: plausible bias that seriously weakens confidence in the results (categorised as 'No' in 'Risk of bias' table);
C. unclear risk of bias: plausible bias that raises some doubt about the results (categorised as 'Unclear' in 'Risk of bias' table).

Trials with a high risk of bias (defined as at least three out of five domains categorised as 'No') will not be included in the meta-analysis. If the raters disagree, the final rating will be made by consensus with the involvement of another member of the review group. Where inadequate details of randomisation and other characteristics of trials are provided, we will contact authors of the studies in order to obtain further information. Non-concurrence in quality assessment will be reported.

 

Measures of treatment effect  

1. Dichotomous data.
Where possible, efforts will be made to convert outcome measures to dichotomous data. This may be done by identifying cut-off points on rating scales and dividing participants accordingly into 'clinically improved' or 'not clinically improved'. It will be 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 are not available, we will use the primary cut-off presented by the original authors.

We will calculate 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. If the overall results are significant, we will calculate 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 will estimate a mean difference (MD) between groups. Mean differences will be based on the random-effects model as this takes into account any differences between studies even if there is no statistically significant heterogeneity. We will not calculate standardised mean differences measures.

2.2 Endpoint versus change data
Since there is no principal statistical reason why endpoint and change data should measure different effects (Higgins 2008), we will use scale endpoint data which is easier to interpret from a clinical point of view. If endpoint data are not available, we will use 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 will apply the following standards to all data before inclusion:
(a) standard deviations and means are reported in the paper or obtainable from the authors;
(b) when a scale starts from the finite number 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 will be 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. Skewed data from studies of less than 200 participants will be entered in additional tables rather than into an analysis. Skewed data pose less of a problem when looking at means if the sample size is large and will be entered into syntheses.

2.4 Data synthesis
If standard errors instead of standard deviations are presented, the former will be converted to standard deviations. If standard deviations are not reported and can not be calculated from available data, we will ask the study authors to supply the data. In the absence of data from authors, the mean standard deviations from other studies will be used.

2.5 Multiple doses
If a study has investigated a number of fixed doses of quetiapine, the scores from the highest dose group will be used.

 

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 error or a false positive (Bland 1997; Gulliford 1999).

If clustering is not accounted for in primary studies, we will present 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 will adjust for this using accepted method (Gulliford 1999). Where clustering has been incorporated into the analysis of primary studies, we will also present these data as if from a non-cluster randomised study, but will adjust for the clustering effect.

Binary data as presented in a report will be divided by a 'design effect'. This will be calculated using the mean number of participants per cluster (m) and the ICC [Design effect = 1+(m-1)*ICC] (Donner 2002). If the ICC is not reported, it will be assumed to be 0.1 (Ukoumunne 1999). This assumption may be too high and, should this instance occur, we will see if taking an ICC of 0.01 would make any substantive difference for the primary outcome. If it does, we will use 0.01 in preference across outcomes.

If cluster studies have been appropriately analysed taking into account ICCs and relevant data documented in the report, we will synthesise 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 will only use data of the first phase of cross-over studies.

3. Studies with multiple treatment groups
Where a study involves more than two treatment groups, if relevant, the additional treatment groups will be presented in additional relevant comparisons. Data will not be double counted. Where the additional treatment groups are not relevant, these data will not be reproduced.

 

Dealing with missing data  

1. Overall loss of credibility
At some degree of loss of follow-up, data must lose credibility (Xia 2007 - direct link). We are forced to make a judgment where this is for the short-term trials likely to be included in this review. Should more than 40% of data be unaccounted for, we willnot reproduce these data or use them within analyses.

2. Binary
In the case where attrition for a binary outcome is between 0% and 40% and outcomes of these people are described, we will include these data as reported. Where these data are not clearly described, we will present data on a 'once-randomised-always-analyse' basis, assuming an intention-to-treat (ITT) analysis. Those lost to follow-up will be assumed to have a negative outcome, with the exception of the outcome of death. For example, for the outcome of relapse, those lost to follow-up will all be considered as relapsed. A final sensitivity analysis will be undertaken to test how prone the primary outcomes are to change when 'completed' data only are compared with the ITT analysis using the negative assumption.

3. Continuous
In the case where attrition for a continuous outcome is between 0% and 40% and completer-only data are reported, we will reproduce these.

4. Intention-to-treat (ITT)
Intention-to-treat analysis will be used when available. We anticipate that in some studies, in order to do an ITT analysis, the method of last-observation-carried-forward (LOCF) will have been 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, if LOCF data are used in the analysis, we will indicate this in the review.

 

Assessment of heterogeneity  

1. Clinical heterogeneity
We will consider all included studies with the intention of using all studies together. Should clear unforeseen issues be apparent that may add obvious clinical heterogeneity, we will note these issues, consider them in analyses and undertake sensitivity analyses for the primary outcome.

2. Statistical
2.1 Visual inspection
We will visually inspect graphs to investigate the possibility of statistical heterogeneity.

2.2 Employing the I-squared (I2) statistic
Heterogeneity between studies will be 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, will be interpreted as evidence of substantial levels of heterogeneity (Section 9.5.2 - Higgins 2008) and reasons for heterogeneity will be explored. If the inconsistency is high and the clear reasons are found, we will present data 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 2008). 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 will not use funnel plots for outcomes where there are 10 or fewer studies, or where all studies were of similar sizes. In other cases, where funnel plots are possible, we will seek statistical advice in their interpretation.

 

Data synthesis  

Where possible, we will employ 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 are clearly heterogeneous, we will check that data are correctly extracted and entered and that we have made no unit-of-analysis errors. If high levels of heterogeneity remain, we will not undertake a meta-analysis at this point for 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. However, we would want to explore heterogeneity. We have not pre-specified any characteristics of studies that may be associated with heterogeneity except quality of trial method. If no clear association can be shown by sorting studies by quality of methods, we will continue to investigate for other reasons for the heterogeneity. Should another characteristic of the studies be highlighted by the investigation of heterogeneity, perhaps some clinical heterogeneity not hitherto predicted - but plausible causes of heterogeneity - these post-hoc reasons will be discussed, the sensitivity of the estimate of effect size for the primary outcome to inclusion and exclusion of these causes investigated and data analysed and presented. However, should the heterogeneity be substantially unaffected by any investigation and no reasons for the heterogeneity being clear, the final data will be presented without a meta-analysis.

 

Sensitivity analysis  

We have planned sensitivity analyses a priori for examining the change in the robustness of the sensitivity to include 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 - the latter being defined post hoc.

If inclusion of studies with implied randomisation makes no substantive difference to the primary outcome, they will be left in the final analyses. For outcomes with both skewed data and non-skewed data, we will investigate the effect of combining all data together and if no substantive difference is noted then the potentially skewed data will be 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): 300-800 mg/day of quetiapine, 300-1000 mg/day of chlorpromazine, 5-20 mg/day of Fluphenazine, 150-400 mg/day of mesoridazine, 16-64 mg/day of perphenazine, 300-800 mg/day of thioridazine, 15-50 mg/day of trifluoperazine, 5-20 mg/day of haloperidol, 30-100 mg/day of loxapine, 30-100 mg/day of molindone and 15-50 mg/day of thiothixene. If we find studies with implied randomisation, skewed and non-skewed data, inappropriate comparator doses of drug and different clinical groups, we will analyse whether the exclusion of these studies changes the results of the primary outcome and the general mental state.

 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Sirijit Suttajit - protocol development, study selection, data extraction, analysis and writing of the final report.

Manit Srisurapanont - protocol development, study selection and writing of the final report.

Jun Xia - study selection, data extraction, analysis and writing of the final report.

Siritree Suttajit - protocol development, study selection and writing of the final report.

Benchalak Maneeton - protocol development, data extraction and writing of the final report.

Narong Maneeton - protocol development and writing of the final report.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Sirijit Suttajit and Manit Srisurapanont received support for attending national and international scientific meetings from AstraZeneca (Thailand), Eli Lilly Asia, Inc. (Thailand), GlaxoSmithKline (Thailand), Janssen-Cilag (Thailand) and Servier (Thailand).

Benchalak Maneeton and Narong Maneeton received similar supports for attending national scientific meetings from GlaxoSmithKline (Thailand) and Janssen-Cilag (Thailand).

Jun Xia and Siritree Suttajit: none known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Internal sources

  • Chiang Mai University, Chiang Mai, Thailand.

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

We have updated the methods section to reflect changes in the standard schizophrenia group template since publication of our protocol, for example inclusion of a 'Summary of findings' table. The methods published in the protocol are in Appendix 1.

We planned that two review authors would independently extract the data, however; due to language barrier, the Chinese data were extracted by one review author, JX.

One of the secondary outcomes (no clinical important change in global state) replicated the global state, which was the primary outcome, therefore, we deleted the duplicated outcome in the secondary outcomes and changed the title of the remaining outcome to be relapse.

We planned to enter skewed data from studies of less than 200 participants in additional tables rather than into the 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 analyses.

We planned to exclude studies with an attrition rate over 40%. However, many 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 undertook sensitivity analyses of the main mental state outcomes, excluding studies with high attrition rates. We also addressed the attrition problems as well as the use of intention-to-treat in the 'Risk of bias' table, the results and the discussion.

We planned to carry out sensitivity analyses in different clinical groups. However, we did not find any difference in clinical groups, therefore, these sensitivity analyses were not done.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
vs CPZ - Ai 2007 {published data only}
  • Ai L. A comparative study of efficacy and safety of seroquel versus chlorpromazine in the treatment of schizophrenia. Heilongjiang Medical Journal 2007;31(4):285.
vs CPZ - AstraZeneca 2005 {unpublished data only}
  • AstraZeneca. A Multicenter, double-blind, randomized, comparison of quetiapine (SEROQUEL®) and chlorpromazine in the treatment of subjects with treatment-resistant schizophrenia. http://www.clinicalstudyresults.org/ 2005.
vs CPZ - Bai 2005 {published data only}
  • Bai Y, Jiang K, Wang L. A random chlorpromazine-controlled study of the effects of quetiapine on cognition in schizophrenia. Shanghai Archives of Psychiatry 2005;17(3):151-4.
vs CPZ - Cao 2005 {published data only}
  • Cao D, Xie SP, Chen QB, Yuan YG, Fang Q. Characteristics of the sexual disturbance caused by chlorpromazine, risperidone, quetiapine and olanzapine and their associations with the changes of blood glucose and blood lipids in male patients with schizophrenia. Chinese Journal of Clinical Rehabilitation [Zhongguo Lin Chuang Kang Fu] 2005;9(36):63-8.
vs CPZ - Chen 2001 {published data only}
  • Chen J, Zhao J, Li L. Multi-center, double blind control study of domestic manufactured quetiapine on schizophrenia. Chinese Journal of Psychiatry 2001;34(4):193-6.
  • Zhao JP, Chen JD, Chen YG, Shu L, Ma C. A double-blind and double-dummy comparative study of quetiapine and chlorpromazine in the treatment of schizophrenia. Chinese New Drugs Journal 2002;11(2):149-51.
vs CPZ - Chen 2007b {published data only}
  • Chen F, Chen Y, Zhou B, Cheng F, Liu Y, Zho XW, et al. Quetiapine treatment in schizophrenia curative effect and quality of life. Linchuang Jingshen Yixue Zazhi 2007;17(5):319-20.
vs CPZ - Guo 2003 {published data only}
  • Guo BY, Wang YB. Control studies on efficacy of quetiapine vs chlorpromazine in first - episode schizophrenics. Journal of Clinical Psychosomatic Diseases 2003;9(2):75-7.
vs CPZ - Guo 2007 {published data only}
  • Guo J, Cao C, Wu D. Effect of quetiapine and chlorpromazine on cognitive function in first-episode schizophrenic. Chinese Journal of Health Psychology 2007;15(7):583-4.
vs CPZ - He 2003 {published data only}
  • He YD, Zhao CM, Shao AL, Chen YN. A comparative study of quetiapine and chlorpromazine in the treatment of patients with schizophrenia. Herald of Medicine 2003;22(10):680-2.
vs CPZ - Hu 2003 {published data only}
  • Hu JM, Li Yi, Li Tao, Wang HM, Liu XH, Huo KJ. The effects of antipsychotics on serum prolactin in the first-episode schizophrenia patients. West China Journal of Pharmaceutical Sciences 2003;18(6):467-9.
vs CPZ - Ji 2004 {published data only}
  • Ji J, Ou W. Comparative study between the quality of life and its curative effect in schizophrenic patients treated with quetiapine or chlorpromazine. Sichuan Mental Health 2004;17(2):73-5.
vs CPZ - Jiang 2006 {published data only}
  • Jiang KD, Bai YL, Peng DH, Tang MQ, Fan JX, Ma JS. A random and controlled study of quetiapine and chlorpromazine in patients with schizophrenia. Linchuang Jingshen Yixue Zazhi 2006;16(6):352-3.
vs CPZ - Jin 2007 {published data only}
  • Jin S, Liu S, Sang W, Zhao M. Seroquel and chlorpromazine in treatment of schizophrenia: a random, controlled trial. China Pharmaceuticals 2007;16(19):56-7.
vs CPZ - Li 2003 {published data only}
  • Li M, Hu F, Wang S. A study of quetiapine and chlorpromazine on the effects and quality of life in the treatment of schizophrenia. Shandong Archives of Psychiatry 2003;7488(3):135-7.
vs CPZ - Link 1997 {published data only}
vs CPZ - Mei 2007 {published data only}
  • Mei AC. Comparison of efficacy and safety of quetiapine and chlorpromazine in the treatment of schizophrenia. Medical Journal of Chinese People's Health 2007;19(17):723-4.
vs CPZ - Peng 2006 {published data only}
  • Peng ZG, Zhou JX, Kuang WH, Li J, Huang MS. A randomized double - blind controlled study on the efficacy of quetiapine and chlorpromazine in treatment of schizophrenia. West China Journal of Pharmaceutical Sciences 2006;21(6):606-8.
vs CPZ - Tian 2006 {published data only}
  • Tian H, He Q, Du L, Wu R, Hui S, Zheng Q, et al. Comparative study on the effect of seroquel and chlorpromazine on schizophrenia. China Pharmacy 2006;17(9):682-3.
vs CPZ - Wang 2004 {published data only}
  • Wang XL, Jiang F, Li T. Comparison of efficacy and safety of quetiapine and larctigal in the treatment of schizophrenia. Chinese Journal of Behavioral Medical Science 2004;13(3):288-90.
vs CPZ - Wang 2005 {published data only}
  • Wang H, Peng D, Bai Y. Efficacy of quetiapine in the treatment of female patients with schizophrenia. Shanghai Archives of Psychiatry 2005;17(2):83-6.
vs CPZ - Zhang 2002 {published data only}
  • Zhang S, Li Y, Xu J. A double-blind study of domestic quetiapine and chlorpromazine in the treatment of schizophrenia. Shandong Archives of Psychiatry 2002;15(3):149-51. [EMBASE: 2006303274; MEDLINE: 16797162]
vs CPZ - Zhang 2003 {published data only}
  • Zhang HY, Wang X, Liu C, Shu L, Li H, Gu N, et al. A comparison study on efficacy and safety of quetiapine and chlorpromazine in the treatment of schizophrenia. Chinese Journal of Clinical Pharmacology 2003;19(3):163-6.
vs CPZ - Zhong 2005 {published data only}
  • Zhong CL, Cui YH. Comparative study of influence of quetiapine on life quality in schizophrenic patients. Journal of Clinical Psychological Medicine 2005;15(2):103-5.
vs CPZ - Zhou 2003 {published data only}
  • Zhou J, Li J, Kuang W. Comparison between quetiapine and chlorpromazine in cognitive function of schizophrenic patients. Chinese Mental Health Journal 2003;17(10):699, 700-1.
vs CPZ - Zhou 2004 {published data only}
  • Zhou SB, Sun XD, Li YM. A comparative study on quetiapine and chlorpromazine in the treatment of schizophrenia. Medical Journal of Chinese Peoples Health 2004;16(11):657-9.
vs CPZ - Zou 2006 {published data only}
  • Zou X, Zhou Y, Zhang W. Study on quetiapine and chlorpromazine in treatment of schizophrenia. China Pharmaceuticals 2006;15(12):51-2.
vs FLUPHEN - Conley 2005 {published data only}
  • Conely RR, Kelly DL, Nelson MW, Richardson CM, Feldman S, Benham R, et al. Risperidone, quetiapine, and fluphenazine in the treatment of patients with therapy-refractory schizophrenia. Clinical Neuropharmacology 2005;28(4):163-8.
vs HLP - Arvanitis 1997 {published data only}
  • Arvanitis LA, Miller BG, and the Seroquel Trial 13 Study Group. Multiple fixed doses of "seroquel" (quetiapine) in patients with acute exacerbation of schizophrenia: A comparison with haloperidol and placebo. Biological Psychiatry 1997;42:233-46.
vs HLP - Atmaca 2002 {published data only}
  • Atmaca M, Kuloglu M, Tezcan E, Canatan H, Gecici O. Quetiapine is not associated with increase in prolactin secretion in contrast to haloperidol. Archives of Medical Research 2002;33:562-5.
vs HLP - Copolov 2000 {published data only}
  • Copolov DL, Link CGG, Kowalcyk B. A multicentre, double-blind, randomized comparison of quetiapine (ICI 204,636, 'Seroquel') and haloperidol in schizophrenia. Psychological Medicine 2000;30:95-105.
vs HLP - Emsley 1999 {published data only}
  • Emsley RA, Raniwalla J, Bailey PJ, Jones AM, on behalf of the PRIZE Study Group. A comparison of the effects of quetiapine ('Seroquel') and haloperidol in schizophrenic patients with a history of and a demonstrated partial response to conventional antipsychotic treatment. International Clinical Psychophramacology 2000;15:121-31.
vs HLP - Emsley 2004 {published data only}
  • Emsley R, Turner HJ, Schronen J, Botha K, Smit R, Oosthuizen PP. A single-blind, randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia. Journal of Clinical Psychiatry 2004;65:696-701.
vs HLP - Fl'hacker 2005 {published data only}
  • Davidson M, Galderisi S, Weiser M, Werbeloff N, Fleischhacker WW, Keefe RS, et al. Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: A randomized, open-label clinical trial (EUFEST). American Journal of Psychiatry 2009;166:675-82.
  • Fleischhacker WW, Keet IPM, Kahn RS and EUFEST Steering Committee. The European First Episode Schizophrenia Trial (EUFEST): Rationale and design of the trial. Schizophrenia Research 2005;78(2-3):147-56.
  • Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IPM, et al for the EUFEST study group. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008;371:1085-97.
vs HLP - Huang 2007 {published data only}
  • Huang J, Xue S, Ye R. Comparison of compliance and effectiveness of quetiapine and haloperidol in the treatment of schizophrenia. International Medicine and Health Guidance News 2007;13(16):96-9.
vs HLP - McCue 2006 {published data only}
  • McCue RE, Waheed R, Urcuyo L, Orendain G, Joseph MD, Charles R, et al. Comparative effectiveness of second-generation antipsychotics and haloperidol in acute schizophrenia. British Journal of Psychiatry 2006;189:433-40.
vs HLP - Murasaki 1999 {published data only}
  • Murasaki M, Koyama T, Yamauchi T, Yagi MG, Ushijima S, Kamijima K. Clinical evaluation of quetiapine in schizophrenia - efficacy and tolerability of quetiapine compared with haloperidol in patients with schizophrenia. Proceedings of the 11th World Congress of Psychiatry; 1999 Aug 6-11; Hamburg, Germany. Hamburg, Germany, 1999.
vs HLP - Purdon 2001 {published data only}
  • Purdon SE, Malla A, Labelle A, Lit W. Neuropsychological change in patients with schizophrenia after treatment with schizophrenia after treatment with quetiapine or haloperidol. Journal of Psychiatry & Neuroscience 2001;26:137-49.
vs HLP - Taneli 2003 {published data only}
  • Taneli B, Alptekin K, Bilici M, Birsoz S, Eker E, Cosar B, et al. Comparison of efficacy and tolerability of quetiapine and haloperidol in acute exacerbation of chronic or subchronic schizophrenia. Proceedings of the 16th European College of Neuropsychopharmacology Congress; 2003 Sep 20-24; Prague, Czech Republic. Prague, Czech Republic, 2003.
vs HLP - Velligan 2002 {published data only}
  • Velligan DI, Newcomer J, Pultz J, Csernansky J, Hoff AL, Mahurin R, et al. Does cognitive function improve with quetiapine in comparison to haloperidol?. Schizophrenia Research 2002;53:239-48.
vs HLP - Zou 2007 {published data only}
  • Zou JH, Zhou Y, Li XL. A clinical analysis between quetiapine and haloperidol in the treatment of schizophrenia. Medical Journal of Chinese People's Health 2007;19(11):434-5, 7.
vs PERPHEN - Chen 2007a {published data only}
  • Chen H, Liu JH. Controlled observation on senile schizophrenics treated with quetiapine and perphenazine. Linchuang Jingshen Yixue Zazhi 2007;17(5):321-2.
vs PERPHEN - L'rman 2005 {published data only}
  • Keefe RSE, Cilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, et al for the CATIE investigators and the neurocognitive working group. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Archives of General Psychiatry 2007;64:633-47.
  • Lieberman JA, Stroup S, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 2005;353:1209–23.
  • Swartz MS, Perkins DO, Stroup TS, Davis SM, Capuano G, Rosenheck RA, et al for the CATIE investigators. Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: Findings from the NIMH CATIE study. American Journal of Psychiatry 2007;164:428-36.
vs PERPHEN - Yi 2006 {published data only}
  • Yi QM, Fan WL, Chen ZQ. The contrast investigation between quetiapine and perphenazlne in the treatment of first episode of schizophrenia in children. Journal of the North Sichuan Medical College 2006;2(6):522-4.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
Buckley 2001 {published data only}
  • Buckley PF. Comparison of the effects of quetiapine and haloperidol in a cohort of patients with treatment resistant schizophrenia. Schizophrenia Research 2001;49(1,2):221.
Cheng 2003 {published data only}
  • Cheng XF. Control observation of quetiapine vs chlorpromazine in schizophrenia. Journal of Clinical Psychosomatic Diseases 2003;9(2):78-80.
Du 2004 {published data only}
  • Du QX, Yu CF, Zhong W. A clinical comparative analysis of quetiapine and chlorpromazine in treatment of schizophrenia. Medical Journal of Chinese Peoples Health 2004;16(7):398-9.
Glick 2005 {published data only}
  • Glick ID, Marder SR. Long-term maintenance therapy with quetiapine versus haloperidol decanoate in patients with schizophrenia or schizoaffective disorder. Journal of Clinical Psychiatry 2005;66(5):638-41.
Goldstein 1999 {published data only}
  • Goldstein J, Emsley R, Raniwalla J, Bailey P, Jones M. Efficacy and tolerability of quetiapine compared with haloperidol in schizophrenic patients partially responsive to conventional antipsychotic treatment. Proceedings of the 39th Annual Meeting of the New Clinical Drug Evaluation Unit; 1999 Jun 1-4; Boca Raton, Florida, USA. Boca Raton, Florida, USA., 1999.
Grecu 2006 {published data only}
  • Grecu G, Grecu GM, Pop M. Clinical effectiveness of atypical vs typical antipsychotics in treatment of schizophrenia patients. Proceedings of the 19th European College of Neuropsychopharmacology Congress; 2006 Sep 16-20; Paris, France. Paris, France, 2006.
Guo 2006 {published data only}
  • Guo XF, Zhao JP, Chen JD, Zhang ZC. The effect of chlorpromazine and quetiapine on serum lipid and glucose. Journal of Clinical Psychological Medicine 2006;16(5):257-9.
Hammond 2001 {published data only}
  • Hammond R, Bustillo J, Lauriello J, Keith SJ, Nadiga D. Efficacy of quetiapine in antipsychotic naïve patients. Schizophrenia Research 2001;49(1,2):231.
Jones 2006 {published data only}
  • Jones PB, Barnes TRE, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia. Cost Utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS 1). Archives of General Psychiatry 2006;63:1079-87.
Keleman 2006 {published data only}
  • Kelemen O, Nagy O, Máttyássy A, Kiss I, Janka Z, Kéri S. Do second-generation antipsychotics disrupt decision-making abilities in schizophrenia?. European Neuropsychopharmacology 2006;16(Suppl 4):S430.
Kelly 2005 {published data only}
  • Kelly DL, Conley RR. Thyroid function in treatment-resistant schizophrenia patients treated with quetiapine, risperidone, or fluphenazine. Journal of Clinical Psychiatry 2005;66(1):80-4.
Kelly 2006 {published data only}
  • Kelly DL, Conley RR. A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia. Psychoneuroendocrinology 2006;31(3):340-6.
Kong 2003 {published data only}
  • Kong DL, Zhang SQ, Shu MQ. Effects of quetiapine and chlorpromazine on serum prolactin of schizophrenics. Journal of Clinical Psychosomatic Diseases 2003; Vol. 9, issue 4:200-1.
Lee 2001 {published data only}
  • Lee M, Meltzer HY. Quetiapine is significantly superior to haloperidol and placebo in improving mood in patients with schizophrenia. Proceedings of the 7th World Congress of Biological Psychiatry; 2001 Jul 1-6; Berlin, Germany. Berlin, Germany, 2001.
Loza 2001 {published data only}
  • Loza B, Kucharska-Pietura K, Debowska G. Atypical versus typical antipsychotic treatment prognosis in first-episode paranoid schizophrenia based on WCST and dichotic listening scores. European Neuropsychopharmacology 2001;11(3):285.
Ma 2004 {published data only}
  • Ma ZW, Li MX, Shi YZ, Wang LH. Quetipine (35 patients) vs chlorpromazine (34 patients) in treatment of schizophrenia. Chinese Journal of New Drugs and Clinical Remedies 2004; Vol. 23, issue 5:273-5.
Nai 2007 {published data only}
  • Nai X, Hu X, Qiu S. Effect of quetiapine on cognition function of patients with first episode schizophrenia. Journal of Medical Forum 2007;28(2):38-9.
Qiu 2003 {published data only}
  • Qiu Y, Ma L. A comparative study between quetiapine and haloperidol on the life quality of the patients with schizophrenia. Shandong Archives of Psychiatry 2003;7489(3):138-40.
Reveley 2001 {unpublished data only}
  • Reveley M. Seroquel Outcome Study (SOS): a multicentre double-blind randomised trial to compare the effects of seroquel and chlorpromazine on treatment outcome of schizophrenic patients. National Research Register 2001.
Richardson 2005 {published data only}
  • Richardson CM, Kelly DL, Gold JM, McMahon R, Yu Y, Conley RR. Risperidone vs quetiapine vs fluphenazine in treatment - resistant schizophrenia: neuropsychological outcome. Schizophrenia Bulletin. 2005; Vol. 31:501-2.
Sharma 2002 {published data only}
  • Sharma T. A multi-centre, double-blind, randomised trial to compare the effects of "seroquel" and haloperidol in schizophrenic patients with a history of partial response to antipsychotic treatment. National Research Register 2001.
Zhang 2007 {published data only}
  • Zhang L. A comparative study of quetiapine and chlorpromazine in the treatment of schizophrenia. Modern Medicine Journal of China 2007;9(2):97-8.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
Altman 1996
  • Altman DG, Bland JM. Detecting skewness from summary information. BMJ 1996;313:1200.
Andreasen 1989
  • Andreasen NC. Scale for the assessment of negative symptoms (SANS). British Journal of Psychiatry 1989;7:53-8.
APA 1994
  • American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th Edition. Washington DC: APA, 1994.
APA 2004
  • American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. 2nd Edition. Arlington (VA): American Psychiatric Association, 2004.
Bland 1997
  • Bland JM, Kerry SM. Statistics notes. Trials randomised in clusters. BMJ 1997;315:600.
Boissel 1999
  • Boissel JP, Cucherat M, Li W, Chatellier G, Gueyffier F, Buyse M, et al. The problem of therapeutic efficacy indices. 3. Comparison of the indices and their use. Therapie 1999;54(4):405-11.
Buchanan 2005
  • Buchanan RW, Carpenter WT. Concept of schizophrenia. Kaplan & Sadock's Comprehensive Textbook of Psychiatry. Lippincott Wiliams & Wilkins, 2005.
Carpenter 1984
  • Heinrichs DW, Hanlon ET, Carpenter WT Jr. The quality of life scale: an instrument for rating the schizophrenic deficit syndrome. Schizophrenia Bulletin 1984;10:388-96.
Carpenter 1994
Chouinard 1980
  • Chouinard G, Ross-Chouinard A, Annable L, Jones BD. The extrapyramidal symptom rating scale. Canadian Journal of Neurological Sciences 1980;7:233.
Deeks 2000
  • Deeks JJ. Issues in the selection of a summary statistic for meta-analyses of binary data. Abstracts of 8th International Cochrane Colloquium; 2000 Oct 25-28th; Cape Town, South Africa. The Cochrane Collaboration, 2000.
Divine 1992
Donner 2002
Easterbrook 1991
Egger 1997
  • Egger M, Davey-Smith G, Schneider M, Minder CSO. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;13:629-34.
Elbourne 2002
  • Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140-9. [PUBMED: 11914310]
Geddes 2000
Goldstein 1993
Goldstein 1995
  • Goldstein JM. Preclinical tests that predict clozapine-like atypical antipsychotic actions. Critical Issues in the Treatment of Schizophrenia 1995;10:95-101.
Goldstein 2007
  • Goldstein JM, Cristoph G, Grimm S, Liu JW, Widzowski D, Brecher M. Unique mechanism of action for the antidepressant properties of the atypical antipsychotic quetiapine. Proceedings of the 160th Annual Meeting of the American Psychiatric Association; 2007 May 19-24; San Diego, CA. 2007.
Gulliford 1999
  • Gulliford MC, Ukoumunne OC, Chinn S. Components of variance and intraclass correlations for the design of community-based surveys and intervention studies: Data from the health survey for England 1994. American Journal of Epidemiology 1999;149:876-83.
Guy 1976
  • Guy U. ECDEU Assessment Manual for Psychopharmacology. National Institute of Mental Health, 1976.
Heres 2006
  • Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. American Journal of Psychiatry 2006;163:185-94.
Higgins 2003
Higgins 2008
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org 2008.
Higgins 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Kay 1986
  • Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale (PANSS) Manual. New York: Multi-Health Systems Inc, 1986.
Kerwin 1994
Komossa 2010
Leucht 2005a
Leucht 2005b
Leucht 2008
  • Leucht S, Arbter D, Engel RR, Kissling W, Davis JM. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. http://www.nature.com/mp/journal/vaop/ncurrent/full/4002136a.html (accessed 08 January 2008):1-19. [DOI: 10.1038/sj.mp.4002136]
Liu-Seifert 2005
  • Liu-Seifert H. Discontinuation of treatment of schizophrenic patients is driven by poor symptom response: a pooled post-hoc analysis of four atypical antipsychotic drugs. BMC Medicine 2005;3(21):1-10.
Macaskill 2001
Marshall 2000
  • Marshall M, Lockwood A, Bradley C, Adams C, Joy C, Fenton M. Unpublished rating scales: a major source of bias in randomised controlled trials of treatments for schizophrenia. British Journal of Psychiatry 2000;176:249-52.
Migler 1993
Moher 2001
  • Moher D, Schulz KF, Altman D for the CONSORT group. The CONSORT statement:revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 2001;285(15):1987-91.
Overall 1962
  • Overall JE, Gorham DR. The brief psychiatric rating scale. Psychological Reports 1962;10:799-12.
Priebe 1999
Saller 1993
Schünemann 2008
  • Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2008:359-83.
Simpson 1970
  • Simpson EN, Angus JWF. A rating scale for extrapyramidal side-effects. Acta Psychiatrica Scandinavica Supplementum 1970;212:11-9.
    Direct Link:
Srisurapanont 2004
Thorpe 2009
  • Thorpe KE, Zwarenstein M, Oxman AD, Treweek S, Furberg CD, Altman DG, et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. CMAJ : Canadian Medical Association journal (Journal de l'Association Medicale Canadienne) 2009;180(10):E47-57. [PUBMED: 19372436]
Ukoumunne 1999
  • Ukoumunne OC, Gulliford MC, Chinn S, Sterne JAC, Burney PGJ. Methods for evaluating area-wide and organisation-based interventions in health and health care: a systematic review. Health Technology Assessment 1999;3(5):3-92.
Ware 1992
Xia 2007
  • Xia J, Adams CE, Bhagat N, Bhagat V, Bhoopathi P, El-Sayeh H, et al. The Leeds Outcomes Stakeholders Survey (LOSS) Study. Proceedings of the 15th Cochrane Colloquium; 2007 23-27 October; Sao Paulo. 2007.
Xia 2009
  • Xia J, Adams CE, Bhagat N, Bhagat V, Bhoopathi P, El-Sayeh H, et al. Loss to outcomes stakeholder survey: the LOSS study. Psychiatric Bulletin 2009;33(7):254-7.