Quetiapine versus other atypical antipsychotics for schizophrenia
Abstract
Background
In many countries, second‐generation ('atypical') antipsychotic drugs have become the first‐line drug treatment for people with schizophrenia. It is not clear how the effects of the various second‐generation antipsychotic drugs differ.
Objectives
To evaluate the effects of quetiapine compared with other second‐generation (atypical) antipsychotic drugs in the treatment of people with schizophrenia and schizophrenia‐like psychoses.
Search methods
We searched the Cochrane Schizophrenia Group Trials Register (May 2010), inspected references of all identified studies, and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information.
Selection criteria
We included all randomised controlled trials (RCTs) comparing oral quetiapine with other oral forms of atypical antipsychotic medication in people with schizophrenia or schizophrenia‐like psychoses.
Data collection and analysis
We extracted data independently. For dichotomous data, we calculated risk ratios (RRs) and their 95% confidence intervals (CIs) on an intention‐to‐treat basis based on a random‐effects model. We calculated number needed to treat for an additional beneficial outcome (NNTB) where appropriate. For continuous data, we calculated mean differences (MDs), again based on a random‐effects model.
Main results
Efficacy data tended to favour the control drugs over quetiapine (Positive and Negative Syndrome Scale (PANSS) total score vs olanzapine: 11 RCTs, n = 1486, mean quetiapine endpoint score 3.67 higher, CI 1.95 to 5.39, low quality; vs risperidone: 13 RCTs, n = 2155, mean quetiapine endpoint score 1.74 higher, CI 0.19 to 3.29, moderate quality; vs paliperidone: 1 RCT, n = 319, mean quetiapine endpoint score 6.30 higher, CI 2.77 to 9.83, moderate quality), but the clinical meaning of these data is unclear. No clear mental state differences were noted when quetiapine was compared with clozapine, aripiprazole or ziprasidone. Compared with olanzapine, quetiapine produced slightly fewer movement disorders (7 RCTs, n = 1127, RR use of antiparkinson medication 0.51, CI 0.32 to 0.81, moderate quality) and less weight gain (8 RCTs, n = 1667, RR 0.68, CI 0.51 to 0.92, moderate quality) and glucose elevation, but increased QTc prolongation (3 RCTs, n = 643, MD 4.81, CI 0.34 to 9.28). Compared with risperidone, quetiapine induced slightly fewer movement disorders (8 RCTs, n = 2163, RR use of antiparkinson medication 0.5, CI 0.36 to 0.69, moderate quality), less prolactin increase (7 RCTs, n = 1733, MD ‐35.25, CI ‐43.59 to ‐26.91) and some related adverse effects but greater cholesterol increase (6 RCTs, n = 1473, MD 8.57, CI 4.85 to 12.29). On the basis of limited data, compared with paliperidone, quetiapine induced fewer parkinsonian side effects (1 RCT, n = 319, RR use of antiparkinson medication 0.64, CI 0.45 to 0.91, moderate quality) and less prolactin increase (1 RCT, n = 319, MD ‐49.30, CI ‐57.80 to ‐40.80) and weight gain (1 RCT, n = 319, RR weight gain of 7% or more of total body weight 2.52, CI 0.5 to 12.78, moderate quality). Compared with ziprasidone, quetiapine induced slightly fewer extrapyramidal adverse effects (1 RCT, n = 522, RR use of antiparkinson medication 0.43, CI 0.2 to 0.93, moderate quality) and less prolactin increase. On the other hand, quetiapine was more sedating and led to greater weight gain (2 RCTs, n = 754, RR 2.22, CI 1.35 to 3.63, moderate quality) and cholesterol increase when compared with ziprasidone.
Authors' conclusions
Available evidence from trials suggests that most people who start quetiapine stop taking it within a few weeks (around 60%). Comparisons with amisulpride, sertindole and zotepine do not exist. Although efficacy data favour olanzapine and risperidone compared with quetiapine, the clinical meaning of these data remains unclear. Quetiapine may produce fewer parkinsonian effects than paliperidone, aripiprazole, ziprasidone, risperidone and olanzapine. Quetiapine appears to have a similar weight gain profile to risperidone, as well as clozapine and aripiprazole (although data are very limited for the latter two comparators). Quetiapine may produce greater weight gain than ziprasidone and less weight gain than olanzapine and paliperidone. Most data that have been reported within existing comparisons are of very limited value because of assumptions and biases within them. Much scope is available for further research into the effects of this widely used drug.
PICOs
Plain language summary
Quetiapine versus other atypical antipsychotic drugs for schizophrenia
Quetiapine is a second‐generation antipsychotic. Second‐generation or atypical antipsychotic drugs have become the mainstay of treatment in many countries for people with schizophrenia. They are called second‐generation drugs because they are newer than the older drugs, known as typical antipsychotics. Second‐generation drugs are thought to be better than the older drugs in reducing the symptoms of schizophrenia, such as hearing voices and seeing things, and are suggested to produce fewer side effects, such as sleepiness, weight gain, tremors and shaking. However, it is not clear how the various second‐ generation antipsychotic drugs differ from one other. The aim of this review therefore was to evaluate the effects of quetiapine compared with other second‐generation antipsychotic drugs for people with schizophrenia. The review included a total of 35 studies with 5971 people, which provided information on six comparisons (quetiapine vs the following: clozapine, olanzapine, risperidone, ziprasidone, paliperidone and aripiprazole). Comparisons with amisulpride, sertindole and zotepine do not exist, so more research is needed. A major limitation of all findings was the large number of people leaving studies and stopping quetiapine treatment (50.2% of people). The most important finding to note is that if a group is started on quetiapine, most will be off this drug within a few weeks (although the reasons for stopping quetiapine treatment are not covered by the review and so remain uncertain). Quetiapine may be slightly less effective than risperidone and olanzapine in reducing symptoms, and it may cause less weight gain and fewer side effects and associated problems (such as heart problems and diabetes) than olanzapine and paliperidone, but more than are seen with risperidone and ziprasidone. The limited information tends to suggest that people taking quetiapine may need to be hospitalised more frequently than those taking risperidone or olanzapine. This may lead to higher costs in some settings, but the information is not robust enough to guide managers.
This summary has been written by a consumer, Ben Gray (Benjamin Gray, Service User and Service User Expert, Rethink Mental Illness).
Authors' conclusions
Summary of findings
| QUETIAPINE versus ARIPIPRAZOLE for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus ARIPIPRAZOLE | |||||
| Mental state: 1. General ‐ average endpoint score | Mean mental state: 1. General ‐ average endpoint score in the intervention groups was | 297 | ⊕⊕⊝⊝ | |||
| Mental state: 2. Positive symptoms average endpoint score | Mean mental state: 2. Positive symptoms ‐ average endpoint score in the intervention groups was | 297 | ⊕⊕⊝⊝ | |||
| Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high = poor) | Mean mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high = poor) in the intervention groups was | 297 | ⊕⊕⊝⊝ | |||
| Quality of life: substantial improvement | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome in any form |
| Adverse effects: 1. Sedation | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome in any form |
| Adverse effects: 2. Extrapyramidal effects ‐ use of antiparkinson medication | Low4 | RR 0.67 | 40 | ⊕⊕⊝⊝ | ||
| 50 per 1000 | 34 per 1000 | |||||
| Moderate4 | ||||||
| 150 per 1000 | 101 per 1000 | |||||
| High4 | ||||||
| 250 per 1000 | 168 per 1000 | |||||
| Adverse effects: 3. Metabolic ‐ weight gain ≥7% of total body weight | Low4 | RR 0.52 | 155 | ⊕⊕⊝⊝ | ||
| 10 per 1000 | 5 per 1000 | |||||
| Moderate4 | ||||||
| 50 per 1000 | 26 per 1000 | |||||
| High4 | ||||||
| 100 per 1000 | 52 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1 Risk of bias: rated serious ‐ only one study adequately described appropriate allocation concealment methods (but not sequence generation). All other studies did not adequately describe sequence generation and allocation concealment. | ||||||
| QUETIAPINE versus CLOZAPINE all data short term for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus CLOZAPINE all data short term | |||||
| Mental state: 1. General ‐ average endpoint score short term (PANSS total, high = poor) | Mental state: 1. General ‐ average endpoint score short term (PANSS total, high = poor) in the intervention groups was | 232 | ⊕⊕⊝⊝ | |||
| Mental state: 2. Positive symptoms ‐ average endpoint score | Mean mental state: 2. Positive symptoms ‐ average endpoint score in the intervention groups was | 142 | ⊕⊕⊝⊝ | |||
| Mental state: 3. Negative symptoms ‐ average endpoint score short term | Mental state: 3. Negative symptoms ‐ average endpoint score short term in the intervention groups was | 142 | ⊕⊕⊝⊝ | |||
| Quality of life: substantial improvement | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome in any form |
| Adverse effects: 1. Sedation | Low5 | RR 0.22 | 135 | ⊕⊕⊕⊝ | ||
| 200 per 1000 | 44 per 1000 | |||||
| Moderate5 | ||||||
| 500 per 1000 | 110 per 1000 | |||||
| High5 | ||||||
| 800 per 1000 | 176 per 1000 | |||||
| Adverse effects: 2. Extrapyramidal effects ‐ use of antiparkinson medication | Moderate | See comment | 28 | ⊕⊕⊝⊝ | Risks were calculated from pooled risk differences. No events in either group (RD 0.0 CI ‐0.13 to 0.13) | |
| 0 per 1000 | 0 per 1000 | |||||
| Adverse effects: 3. Metabolic ‐ weight gain | Low5 | RR 0.53 | 135 | ⊕⊕⊝⊝ | ||
| 100 per 1000 | 53 per 1000 | |||||
| Moderate5 | ||||||
| 250 per 1000 | 132 per 1000 | |||||
| High5 | ||||||
| 400 per 1000 | 212 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1Risk of bias: rated serious none of the studies adequately described sequence generation and allocation concealment. | ||||||
| QUETIAPINE versus OLANZAPINE for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus OLANZAPINE | |||||
| Mental state: 1. General ‐ average endpoint score (PANSS total, high = poor) | Mental state: 1. General ‐ average endpoint score (PANSS total, high = poor) in the intervention groups was | 1486 | ⊕⊕⊝⊝ | |||
| Mental state: 2. Positive symptoms ‐ average endpoint score | Mental state: 2. Positive symptoms ‐ average endpoint score in the intervention groups was | 801 | ⊕⊕⊕⊝ | |||
| Mental state: 3. Negative symptoms ‐ endpoint score | Mental state: 3. Negative symptoms ‐ average endpoint score in the intervention groups was | 801 | ⊕⊕⊕⊝ | |||
| Quality of life: general ‐ average change in endpoint score medium term | Mean quality of life: general ‐ average change in endpoint score medium term in the intervention groups was | 286 | ⊕⊕⊕⊝ | |||
| Adverse effects: 1. Sedation | Low7 | RR 0.98 | 1615 | ⊕⊕⊕⊝ | ||
| 100 per 1000 | 98 per 1000 | |||||
| Moderate7 | ||||||
| 300 per 1000 | 294 per 1000 | |||||
| High7 | ||||||
| 500 per 1000 | 490 per 1000 | |||||
| Adverse effects: 2. Extrapyramidal effects ‐ use of antiparkinson medication | Low7 | See comment | 1127 | ⊕⊕⊕⊝ | Risks were calculated from pooled risk differences | |
| 50 per 1000 | 28 per 1000 | |||||
| Moderate7 | ||||||
| 100 per 1000 | 55 per 1000 | |||||
| High7 | ||||||
| 150 per 1000 | 82 per 1000 | |||||
| Adverse effects: 3. Metabolic ‐ weight significant gain | Low7 | RR 0.69 | 1321 | ⊕⊕⊕⊝ | ||
| 200 per 1000 | 138 per 1000 | |||||
| Moderate7 | ||||||
| 400 per 1000 | 276 per 1000 | |||||
| High7 | ||||||
| 600 per 1000 | 414 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1Risk of bias: rated serious no studies adequately described sequence generation and allocation concealment. | ||||||
| QUETIAPINE versus PALIPERIDONE for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus PALIPERIDONE | |||||
| Mental state: 1. General ‐ average endpoint score | Mental state: 1. General ‐ average endpoint score in the intervention groups was | 319 | ⊕⊕⊕⊝ | |||
| Mental state: 2. Positive symptoms ‐ average endpoint score | Mental state: 2. Positive symptoms average endpoint score in the intervention groups was | 319 | ⊕⊕⊕⊝ | |||
| Mental state: 3. Negative symptoms ‐ average endpoint score | Mental state: 3. Negative symptoms ‐ average endpoint score in the intervention groups was | 319 | ⊕⊕⊕⊝ | |||
| Quality of life: substantial improvement | See comment | See comment | Not estimable | 0 | See comment | No trial reported this outcome in any form |
| Adverse effects: 1. Sedation | See comment | See comment | Not estimable | 0 | See comment | No trial reported this outcome in any form |
| Adverse effects: 2. Extrapyramidal effects use of antiparkinson medication | Low3 | RR 0.64 | 319 | ⊕⊕⊕⊝ | ||
| 200 per 1000 | 128 per 1000 | |||||
| Moderate3 | ||||||
| 400 per 1000 | 256 per 1000 | |||||
| High3 | ||||||
| 600 per 1000 | 384 per 1000 | |||||
| Adverse effects: 3. Metabolic weight gain ≥7% of total body weight | Moderate3 | RR 2.52 | 319 | ⊕⊕⊕⊝ | ||
| 10 per 1000 | 25 per 1000 | |||||
| High3 | ||||||
| 100 per 1000 | 252 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1Calculated using generic inverse variance. | ||||||
| QUETIAPINE versus RISPERIDONE for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus RISPERIDONE | |||||
| Mental state: 1. General ‐ average endpoint score | Mental state: 1. General ‐ average endpoint score in the intervention groups was | 2155 | ⊕⊕⊕⊝ | |||
| Mental state: 2. Positive symptoms ‐ average endpoint score | Mental state: 2. Positive symptoms ‐ average endpoint score in the intervention groups was | 1492 | ⊕⊕⊕⊝ | |||
| Mental state: 3. Negative symptoms ‐ average endpoint score | Mean mental state: 3. Negative symptoms ‐ average endpoint score in the intervention groups was | 1367 | ⊕⊕⊝⊝ | |||
| Quality of life: general average endpoint score | Mean quality of life: general average endpoint score in the intervention groups was | 152 | ⊕⊕⊝⊝ | |||
| Adverse effects: 1. Sedation | Study population | RR 1.21 | 2226 | |||
| 246 per 1000 | 298 per 1000 | |||||
| Moderate | ||||||
| 239 per 1000 | 289 per 1000 | |||||
| Adverse effects: 2. Extrapyramidal effects ‐ use of antiparkinson medication | Low6 | RR 0.5 | 2163 | ⊕⊕⊕⊝ | ||
| 50 per 1000 | 25 per 1000 | |||||
| Moderate6 | ||||||
| 150 per 1000 | 75 per 1000 | |||||
| High6 | ||||||
| 250 per 1000 | 125 per 1000 | |||||
| Adverse effects: 3. Metabolic weight gain ≥7% of total body weight | Low6 | RR 0.96 | 2070 | ⊕⊕⊕⊝ | ||
| 100 per 1000 | 96 per 1000 | |||||
| Moderate6 | ||||||
| 200 per 1000 | 192 per 1000 | |||||
| High6 | ||||||
| 300 per 1000 | 288 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1Risk of bias: rated serious overall inadequate description of sequence generation and allocation concealment. Only two studies adequately described sequence generation. | ||||||
| QUETIAPINE versus ZIPRASIDONE for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus ZIPRASIDONE | |||||
| Mental state: 1. General ‐ average endpoint score | Mental state: 1. General ‐ average endpoint score in the intervention groups was | 198 | ⊕⊕⊝⊝ | |||
| Mental state: 2. Positive symptoms ‐ average endpoint score medium term | Mental state: 2. Positive symptoms ‐ average endpoint score medium term in the intervention groups was | 198 | ⊕⊕⊝⊝ | |||
| Mental state: 3. Negative symptoms ‐ average endpoint score medium term | Mental state: 3. Negative symptoms ‐ average endpoint score medium term in the intervention groups was | 198 | ⊕⊕⊝⊝ | |||
| Quality of life: substantial improvement | See comment | See comment | Not estimable | 0 | See comment | No trial reported this outcome in any form |
| Adverse effects: 1. Sedation | Low3 | RR 1.36 | 754 | ⊕⊕⊝⊝ | ||
| 100 per 1000 | 136 per 1000 | |||||
| Moderate3 | ||||||
| 200 per 1000 | 272 per 1000 | |||||
| High3 | ||||||
| 300 per 1000 | 408 per 1000 | |||||
| Adverse effects: 2. Extrapyramidal effects ‐ use of antiparkinson medication | Low3 | RR 0.43 | 522 | ⊕⊕⊝⊝ | ||
| 50 per 1000 | 22 per 1000 | |||||
| Moderate3 | ||||||
| 100 per 1000 | 43 per 1000 | |||||
| High3 | ||||||
| 150 per 1000 | 65 per 1000 | |||||
| Adverse effects: 3. Metabolic weight gain ≥7% of total body weight | Low3 | RR 2.22 | 754 | ⊕⊕⊕⊝ | ||
| 10 per 1000 | 22 per 1000 | |||||
| Moderate3 | ||||||
| 50 per 1000 | 111 per 1000 | |||||
| High3 | ||||||
| 100 per 1000 | 222 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1Risk of bias: rated serious ‐ inadequately described sequence generation and allocation concealment. | ||||||
Background
Description of the condition
Schizophrenia is a serious psychiatric disorder that affects almost 1% of the population at some point in their lives (Andreasen 1991). Its typical manifestations are positive symptoms such as fixed, false beliefs (delusions) and perceptions without cause (hallucinations), negative symptoms such as apathy and lack of drive and disorganisation of behaviour and thought and catatonic symptoms such as mannerisms and bizarre posturing, as well as cognitive impairment (Carpenter 1994; Mueser and McGurk 2004). The degree of suffering and disability is considerable, with 80% to 90% not working (Marvaha 2004) and a two‐fold increase in mortality (Allebeck 1986). Conventional antipsychotic drugs, such as chlorpromazine and haloperidol, have traditionally been used as first‐line antipsychotic drugs for people with schizophrenia (Kane 1993). The re‐introduction of clozapine in the United States and findings indicating that clozapine seemed more effective than other drugs, as well as its association with fewer movement disorders than chlorpromazine (Kane 1988), have boosted the development of new/second‐generation/atypical antipsychotic drugs (SGAs).
Description of the intervention
No good definition has been put forth for what an 'atypical' antipsychotic is, but these agents were initially said to differ from typical antipsychotic drugs in that they do not cause movement disorders (catalepsy) in rats at clinically effective doses (Arnt 1998). The terms 'new' and 'second‐generation' antipsychotic drugs are not much better because clozapine is now a very old drug. According to treatment guidelines (APA 2004; Gaebel 2006), second‐generation antipsychotic drugs include agents such as amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine and paliperidone. It remains unclear whether some older compounds such as sulpiride or perazine have atypical properties (Moller 2000); therefore, they have been excluded from this review. The second‐generation antipsychotic drugs have raised hopes for superior effects in several areas, such as compliance, cognitive functioning, negative symptoms, movement disorders, quality of life and the treatment of people whose illness had formerly been resistant to treatment.
How the intervention might work
Experimental laboratory studies have suggested that quetiapine is a clozapine‐like atypical antipsychotic (Figure 1; Goldstein 1993; Migler 1993; Saller 1993). In contrast to olanzapine, risperidone, sertindole and ziprasidone, which have high affinities (<50 nM) for both dopamine‐2 (D2) and serotonin‐2A (5‐HT2A) receptors, quetiapine is similar to clozapine in having only moderate affinities (<500 nM) for these sites (Goldstein 1995). Quetiapine has a high affinity for histamine receptors (<50 nM) (Arnt 1998).
Quetiapine.
Why it is important to do this review
The debate continues as to how much the second‐generation antipsychotic drugs improve these outcomes compared with conventional antipsychotic drugs (Duggan 2005; El‐Sayeh 2006), and the results of recent studies are sobering (Jones 2006; Liebermann 2005). Nevertheless, in some parts of the world, especially in the highly industrialised countries, second‐generation antipsychotic drugs have become the mainstay of treatment. They also differ in terms of their costs: although amisulpride and risperidone are already available in generic formulations in many countries, quetiapine for example still is not. Therefore, the question as to whether these agents differ from each other in terms of their clinical effects becomes increasingly important. In this review, we aim to summarise evidence from randomised controlled trials (RCTs) that compared quetiapine with other second‐generation antipsychotic drugs.
Objectives
To evaluate the effects of quetiapine compared with other second‐generation (atypical) antipsychotic drugs in the treatment of people with schizophrenia and schizophrenia‐like psychoses.
Methods
Criteria for considering studies for this review
Types of studies
We included relevant RCTs that were at least single‐blind (blind raters). When a trial was described as double‐blind but it was only implied that the study was randomised, we included it in a sensitivity analysis. If no substantive difference within primary outcomes was noted (see Types of outcome measures) when these implied randomisation studies were added, we included them in the final analysis. If a substantive difference within primary outcomes was described, we used only clearly randomised trials and described the results of the sensitivity analysis in the text. We excluded quasi‐randomised studies, such as those that allocated by using alternate days of the week. We included randomised cross‐over studies 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.
Please note: This update adopted the same criteria for considering the types of studies for inclusion as were applied in the previous version of this review, wherein only RCTs that were at least single‐blind (blind raters) were included. We therefore did not include open‐label studies in this update. However, open‐label trials provide valuable information, particularly for objective outcomes, and will be included in the next update.
Types of participants
We included people with schizophrenia and other types of schizophrenia‐like psychosis (e.g. schizophreniform and schizoaffective disorders), irrespective of the diagnostic criteria used. No clear evidence suggests that the schizophrenia‐like psychoses are caused by fundamentally different disease processes or require different treatment approaches (Carpenter 1994).
Types of interventions
1. Quetiapine
Any oral form of application, any dose.
2. Other 'atypical' antipsychotic drugs
Amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole, ziprasidone, zotepine: any oral form of application, any dose.
Types of outcome measures
We grouped outcomes into short term (up to 12 weeks), medium term (13 to 26 weeks) and long term (over 26 weeks).
Primary outcomes
1. Global state
No clinically important response as defined by the individual studies (e.g. clinical global impression (CGI) less than much improved or less than 50% reduction on a rating scale)
Secondary outcomes
1. Leaving the study early (any reason, adverse events, inefficacy of treatment)
2. Global state
2.1 No clinically important change in global state (as defined by individual studies)
2.2 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 overall cognitive functioning score
6.3 Average change in overall cognitive functioning score
7. Service use
7.1 Admitted
8. Adverse effects
8.1 Number of people 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 specific adverse effects
8.4 Average change in specific adverse effects
9. Summary of findings table
We used the GRADE approach to interpret findings (Schünemann 2008) and used the GRADEPRO profiler to import data from Review Manager 5 (RevMan) to create 'Summary of findings' tables. These tables provide outcome‐specific information concerning the overall quality of evidence from each included study in the comparison, the magnitude of effect of the interventions examined and the sum of available data on all outcomes that we rated as important to patient care and decision making. We selected the following main outcomes for inclusion in the 'Summary of findings' table.
1. Mental state: general average endpoint score (Positive and Negative Syndrome Scale (PANSS) total, high = poor).
2. Mental state: positive symptoms average endpoint score (PANSS positive subscore, high = poor).
3. Mental state: negative symptoms average endpoint score (PANSS negative subscore, high = poor)
4. Quality of life: general average endpoint score (quality of life total score (QLS), low = poor).
5. Adverse effects: central nervous system sedation.
6. Adverse effects: extrapyramidal effects use of antiparkinson medication.
7. Adverse effects: metabolic weight gain of 7% or more of total body weight.
Search methods for identification of studies
No language restriction was applied within the limitations of the search tools.
Electronic searches
1. Cochrane Schizophrenia Group Trials Register (update May 2010)
We searched the Specialised Register of the Cochrane Schizophrenia Group (May 2010) using the phrase:
[(quetiapine* or seroquel* or ICI‐204636* or (ICI and 204636) or ICI204636* in title or *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)
This register is compiled by systematic searches of major databases, handsearches and searches of conference proceedings (see Group Module). The Cochrane Schizophrenia Group Trials Register is maintained on Meerkat 1.5. This version of Meerkat stores references as studies. When an individual reference is selected through a search, all references that have been identified as the same study are also selected.
2. Previous searches from earlier versions of this review
Please see Appendix 1.
Searching other resources
1. Reference searching
We inspected the references of all identified studies for more trials.
2. Personal contact
We contacted the first author of each included study to request missing information.
3. Drug companies
We contacted the manufacturers of all included atypical antipsychotic drugs to ask for additional data.
Data collection and analysis
For previous data collection methods, see Appendix 2.
Selection of studies
Two review authors (LA and SJF for the 2010 update, KK and CRK for the 2007 review, JW in discussion with LA for Chinese language studies) independently inspected all reports. We resolved any disagreement by discussion, and when there was still doubt, we acquired the full article for further inspection. Once the full articles were obtained, we independently decided whether the studies met the review criteria. If disagreement could not be resolved by discussion, we sought further information and added these trials to the list of those awaiting assessment.
Data extraction and management
1. Extraction
Review authors LA, SJF and JW extracted data from included studies for the 2010 update; review authors KK and CRK extracted data for the 2007 review. We extracted only data presented in graphs and figures whenever possible. When further information was necessary, we contacted authors of studies to obtain missing data or to ask for clarification. If studies were multi‐centre, where possible, we separately extracted data relevant to each component centre.
2. Management
2.1 Forms
We extracted data onto standard, simple forms.
2.2 Scale‐derived data
We included continuous data from rating scales only if:
a. the psychometric properties of the measuring instrument have been described in a peer‐reviewed journal (Marshall 2000); and
b. the measuring instrument has not been written or modified by one of the trialists for that particular trial.
Ideally the measuring instrument should be a self‐report or should be completed by an independent rater or relative (not the therapist). We realise that this is not often reported clearly; we have noted whether or not this is the case in Description of studies.
2.3 Endpoint versus change data
Both endpoint and change data provide advantages. Change data can remove a component of between‐person variability from the analysis. On the other hand, calculation of change needs two assessments (baseline and endpoint), which can be challenging to perform in unstable and difficult to measure conditions such as schizophrenia. We decided to primarily use endpoint data and to use change data only if the former were not available. We combined endpoint and change data in the analysis by using mean differences (MDs) rather than standardised mean differences throughout (Higgins 2011, Chapter 9.4.5.2).
2.4 Skewed data
Continuous data on clinical and social outcomes often are not normally distributed. To avoid the pitfalls of applying parametric tests to non‐parametric data, we aimed to apply the following standards to all data before inclusion: (1) standard deviations (SDs) and means are reported in the paper or are obtainable from the authors; (2) when a scale starts from the finite number zero, the SD, 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)); and (3) if a scale started from a positive value (such as PANSS, which can have values ranging from 30 to 210), we modified the calculation described above to take the scale starting point into account. In these cases, skew is present if 2 SDs > (S S min), where S is the mean score and S min is the minimum score. Endpoint scores on scales often have finite starting and ending points, and these rules can be applied. We entered skewed endpoint data from studies of fewer than 200 participants into other tables within the data analyses section rather than into a statistical analysis. Skewed data pose less of a problem when the mean is examined if the sample size is large; we entered such endpoint data into syntheses. When continuous data are presented on a scale that includes a possibility of negative values (such as change data), it is difficult to tell whether or not data are skewed. If we found skewed change data according to the above rules, we entered these into statistical analyses.
2.5 Common measure
To facilitate comparison between trials, we intended to convert variables that can be reported in different metrics, such as days in hospital (mean days per year, per week or per month), to a common metric (e.g. mean days per month).
2.6 Conversion of continuous to binary
Where possible, we made efforts to convert outcome measures to dichotomous data. This can be done by identifying cut‐off points on rating scales and dividing participants accordingly into 'clinically improved' and 'not clinically improved' subgroups. It is generally assumed that if a 50% reduction is noted in a scale‐derived score such as the Brief Psychiatric Rating Scale (BPRS; Overall 1962) or the PANSS (Kay 1986), this could be considered a clinically significant response (Leucht 2005; Leucht 2005a). If data based on these thresholds were not available, we used the primary cut‐off presented by the original authors.
2.7 Direction of graphs
Where possible, we entered data in such a way that the area to the left of the line of no effect indicated a favourable outcome for quetiapine.
Assessment of risk of bias in included studies
Review authors worked independently by using criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess trial quality. This new set of criteria is based on evidence of associations between overestimate of effect and high risk of bias of the article, such as sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting.
Where inadequate details of randomisation and other characteristics of trials were provided, we contacted authors of the studies to request additional information.
We have noted the level of risk of bias both in the text of the review and in the 'Summary of findings' tables.
Measures of treatment effect
1. Binary data
For binary outcomes, we calculated a standard estimation of the risk ratio (RR) and its 95% confidence interval (CI). It has been shown that the RR is more intuitive (Boissel 1999) than the odds ratio and that odds ratios tend to be interpreted by clinicians as RRs (Deeks 2000). The number needed to treat for an additional beneficial outcome (NNTB)/number needed to treat for an additional harmful outcome (NNTH) statistic with its CIs is intuitively attractive to clinicians but is problematic in its inaccuracy of calculations in meta‐analyses and in interpretation (Hutton 2009). For binary data presented in the 'Summary of findings' table/s, where possible, we calculated illustrative comparative risks.
2. Continuous data
For continuous outcomes, we used estimated mean differences (MDs) between groups. We prefer not to calculate effect size measures (standardised mean differences (SMDs)). However, if scales of considerable similarity were used, we presumed that a small difference in measurement would be noted, and we calculated effect size and transformed the effect back to the units of one or more of the specific instruments.
Unit of analysis issues
1. Cluster trials
Studies increasingly employ 'cluster randomisation' (such as randomisation by clinician or practice), but analysis and pooling of clustered data pose problems. Authors often fail to account for intraclass correlation in clustered studies, leading toward a 'unit of analysis' error (Divine 1992), whereby P values are spuriously low, confidence intervals unduly narrow and statistical significance overestimated. This causes type I errors (Bland 1997; Gulliford 1999).
If we had found studies in which clustering was not accounted for in primary studies, we would have presented data in a table, with an (*) 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 for their clustered data and to adjust for this by using accepted methods (Gulliford 1999). If we had found studies for which clustering had been incorporated into the analysis of primary studies, we would have presented these data as if from a non cluster randomised study but would have adjusted for the clustering effect.
We have sought statistical advice and have been advised that the binary data presented in a report should be divided by a 'design effect'. This is calculated using the mean number of participants per cluster (m) and the intraclass correlation coefficient (ICC) [Design effect = 1 + (m 1) * ICC] (Donner 2002). If the ICC was not reported, it was assumed to be 0.1 (Ukoumunne 1999).
If cluster studies had been appropriately analysed by taking ICCs into account, and if relevant data had been documented in the report, synthesis with other studies using the generic inverse variance technique would have been possible.
2. Cross‐over trials
A major concern associated with cross‐over trials is the carry‐over effect. This occurs if an effect (e.g. pharmacological, physiological, psychological) of treatment in the first phase is carried over to the second phase. As a consequence, on entry to the second phase, 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). Both effects are very likely in severe mental illness; therefore we used data only from the first phase of cross‐over studies.
3. Studies with multiple treatment groups
When a study involves more than two treatment arms, we presented the additional treatment arms in comparisons if they were relevant. If data were binary, we simply added these and combined them within the two‐by‐two table. If data were continuous, we combined them in accordance with the formula in Section 7.7.3.8 (Combining groups) of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). When the additional treatment arms were not relevant, we did not reproduce these data.
Dealing with missing data
At some degree of loss of follow‐up, data must lose credibility (Xia 2007). Although high rates of premature discontinuation are a major problem in this field, we believe that it is unclear which degree of attrition leads to a high degree of bias. Therefore, we did not exclude trials on the basis of the percentage of participants completing them. However, we addressed the attrition problem in all parts of the review, including the abstract. For this purpose, we calculated, presented and commented on frequency statistics (overall rates of leaving the studies early among all studies and comparators pooled).
Assessment of heterogeneity
1. Clinical heterogeneity
We considered all included studies initially to judge clinical heterogeneity without seeing comparison data. We simply inspected all studies for clearly outlying people or situations that we had not predicted would arise. When such situations or participant groups arose, we fully discussed these.
2. Methodological heterogeneity
We considered all included studies initially to judge methodological heterogeneity without seeing comparison data. We simply inspected all studies for clearly outlying methods that we had not predicted would arise. When such methodological outliers arose, we fully discussed these.
3. Statistical heterogeneity
3.1 Visual inspection
We visually inspected graphs to investigate the possibility of statistical heterogeneity.
3.2 Employing the I2 statistic
We investigated heterogeneity between studies by considering the I2 method alongside the Chi2 P value. The I2 statistic 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 magnitude and direction of effects and 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 around 50% accompanied by a statistically significant Chi2 statistic was interpreted as evidence of substantial levels of heterogeneity (Higgins 2011). When substantial levels of heterogeneity were found in the primary outcome, we explored reasons for heterogeneity (Subgroup analysis and investigation of heterogeneity).
Assessment of reporting biases
Reporting biases arise when dissemination of research findings is influenced by the nature and direction of results (Egger 1997). These are described in Section 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We are aware that funnel plots may be useful in investigating reporting biases, but they have limited power to detect small‐study effects. We did not use funnel plots for outcomes when 10 or fewer studies were included, or when all studies were of similar size. In other cases, for which funnel plots were possible, we sought statistical advice in their interpretation.
Data synthesis
We understand that there is no closed argument regarding 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 often seems to be true to us, and the random‐effects model takes into account differences between studies even if no statistically significant heterogeneity is noted. However, use of the random‐effects model creates a disadvantage: It puts added weight onto small studies, which often are the most biased ones. Depending on the direction of effect, these studies can inflate or deflate the effect size. We chose the random‐effects model for all analyses. However, the reader is able to choose to inspect the data using the fixed‐effect model, if preferred.
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 inconsistency was high and clear reasons explaining the heterogeneity were found, we presented the data separately. If not, we commented on the heterogeneity of the data.
Sensitivity analysis
We planned sensitivity analyses to examine the change in robustness of sensitivity to include studies with potentially skewed data. A recent report showed that some of the comparisons of atypical antipsychotic drugs may have been biased by the use of inappropriate comparator doses (Heres 2006). Therefore, we also analysed whether exclusion of studies with inappropriate comparator doses changed the results of the primary outcome and the general mental state.
Results
Description of studies
For substantive descriptions of studies, please see Characteristics of included studies and Characteristics of excluded studies tables.
Results of the search
Results of the search are presented in Figure 2 (study flow diagram). We found 537 references, of which 134 were closely inspected during the May 2010 search. The original April 2007 search strategy yielded 3620 references, of which 104 were closely inspected.
Study flow diagram.
Included studies
We were able to include 35 studies in total; this includes 14 added in the 2010‐2011 update. Seven studies were sponsored by pharmaceutical companies producing quetiapine, six were sponsored by the manufacturer of the comparator antipsychotic and ten had a neutral sponsor. For the remaining twelve studies, the sponsor was unclear.
1. Length of trials
Twenty‐six studies were short term with a duration of 2 to 12 weeks. Six studies were medium term, and two trials fell into the long‐term category.
2. Setting
Seven trials were conducted in an inpatient or outpatient setting, sixteen studies were conducted exclusively in an inpatient setting and two studies were conducted exclusively in an outpatient setting. Ten studies did not report the setting.
3. Participants
Twenty‐three studies included participants with diagnoses derived from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV). Riedel 2005 and Hatta 2009 additionally used the International Classification of Diseases, Tenth Revision (ICD‐10). Ten studies diagnosed participants according to the Chinese Classification of Mental Disorders Version 3 (CCMD‐3).Li 2003b used CCMD‐2. Five studies included only acutely ill people (Canuso 2008; Riedel 2007; Svestka 2003b; Wang 2006; Wei 2006b), and four included only people with a first episode of schizophrenia (Hu 2008; Luo Xin 2008; McEvoy 2007; Wei 2006a). Two studies included people with chronic schizophrenia or people with more than one schizophrenic episode (Lieberman 2005, Stroup 2006). Only one study focused on treatment‐resistant participants (Conley 2005).
4. Study size
Lieberman 2005 was the largest study, with 1453 participants; Ozguven 2004 was the smallest, randomly assigning only 22 people. Six studies had fewer than 50 participants, and three randomly assigned more than 400 people.
5. Interventions
5.1 Quetiapine: All included studies used flexible dosing
Overall, quetiapine was given in a dose range from 50 mg/d to 800 mg/d. Conley 2005 limited the upper dose range to 500 mg/d, Wei 2006b used a dose range of 100 mg/d to 400 mg/d and Ozguven 2004 had a mean dose that was higher than the upper dose range of 800 mg/d (827 mg/d).
5.2 Comparators
The comparator drugs were aripiprazole, clozapine, olanzapine, paliperidone, risperidone and ziprasidone, again given in flexible doses. Some studies also included treatment arms with fluphenazine, perphenazine and perospirone, but because these are not second‐generation antipsychotic drugs, we did not report these results.
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 No clinically significant response
We pre‐specified at least 50% PANSS/BPRS reduction from baseline as a clinical relevant cut‐off to define, but only Svestka 2003b reported this outcome. Instead, Liu 2004 indicated at least 50% SANS reduction from baseline, Potkin 2006 and Zhong 2006a at least 30 % PANSS total score reduction from baseline, Ozguven 2004 at least 20% SANS total score reduction from baseline, Conley 2005 a CGI (Guy 1976) of mild or better combined with at least 20% BPRS total reduction from baseline and McEvoy 2007 all PANSS items mild or better plus a CGI of mild or better.
6.3 Outcome scales
Details of scales that provided usable data are shown below. Reasons for exclusion of data from other instruments are given under 'Outcomes' in the 'Included studies' section.
6.3.1 Global state scales
6.3.1.1 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 standardised person against other people with the same diagnosis. A seven‐point scoring system is usually used, and low scores show decreased severity and/or overall improvement.
6.3.2 Mental state scales
6.3.2.1 Positive and Negative Syndrome Scale ‐ PANSS (Kay 1986)
This schizophrenia scale consists of 30 items, each of which can be defined on a seven‐point scoring system ranging from 1 (absent) to 7 (extreme). It can be divided into three subscales that can be used to measure the severity of general psychopathology, positive symptoms (PANSS‐P) and negative symptoms (PANSS‐N). A low score indicates lesser severity.
6.3.2.2 Brief Psychiatric Rating Scale ‐ BPRS (Overall 1962)
This scale is used to assess the severity of the abnormal mental state. The original scale consists of 16 items, but a revised 18‐item scale is commonly used. Each item is defined on a seven‐point scale ranging from 'not present' to 'extremely severe', and scoring ranges from 0 to 6 or from 1 to 7. Scores can range from 0 to 126, and high scores indicate more severe symptoms.
6.3.2.3 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‐associality and attention impairment. Higher scores indicate more severe symptoms.
6.3.2.4 Scale for the Assessment of Positive Symptoms ‐ SAPS (Andreasen 1984)
This four‐point scale gives a global rating for the following positive symptoms: hallucination, delusion, bizarre attitudes and positive formal thought disorder.
6.3.3 Global Assessment of Functioning ‐ GAF (DSM IV, 1994)
A rating scale for patients´ overall capacity of psychosocial functioning, with scores ranging from 1 to 100. Higher scores indicate a higher level of functioning.
6.3.4. Quality of Life Scales
6.3.4.1 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 on the basis of interviewers' judgement of patient functioning. A total QLS and four subscale scores are calculated, with higher scores indicating less impairment.
6.3.5 Adverse effects scales
6.3.5.1 Abnormal Involuntary Movement Scale ‐ AIMS (Guy 1976)
This scale has been used to assess tardive dyskinesia, a long‐term, drug‐induced movement disorder, and short‐term movement disorders such as tremor.
6.3.5.2 Barnes Akathisia Scale ‐ BAS (Barnes 1989)
This scale comprises items rating the observable, restless movements that characterise akathisia, a subjective awareness of restlessness and any distress associated with the condition. These items are rated from 0 (normal) to 3 (severe). In addition, an item for rating global severity is included (ranging from 0 (absent) to 5 (severe)). A low score indicates low levels of akathisia.
6.3.5.3 Extrapyramidal Symptom Rating Scale ‐ ESRS (Chouinard 1980)
This is a questionnaire that pertains to parkinsonian symptoms (nine items), a physician's examination for parkinsonism and dyskinetic movements (eight items) and a CGI of tardive dyskinesia. High scores indicate severe levels of movement disorder.
6.3.5.4 Simpson Angus Scale ‐ SAS (Simpson 1970)
This ten‐item scale, which includes a scoring system of 0 to 4 for each item, measures drug‐induced parkinsonism, a short‐term drug‐induced movement disorder. A low score indicates low levels of parkinsonism.
6.4 Other adverse effects
Other adverse effects were reported as continuous variables for QTc prolongation (ms), cholesterol level (mg/dL), glucose level (mg/dL), prolactin level (ng/mL) and weight (kg). Still other adverse events were reported in a dichotomous manner in terms of the number of people with a given effect.
6.5 Service use
Service use was described as the number of participants re‐hospitalised during the trial.
Excluded studies
We excluded 196 studies for the following reasons: 51 (26%) were not randomised, 113 (58%) were open label, 22 (11%) employed inappropriate interventions, 9 (5%) reported no usable data, 1 included participants with mood disorders and 1 was a pooled analysis rather than a trial.
Awaiting assessment
One trial (Gafoor 2005) is awaiting assessment until further information can be obtained.
Ongoing studies
Four randomised trials comparing quetiapine with other antipsychotic drugs seem to be ongoing (Eli Lilly 2004b; Li 2009b; Ratna 2003; Reynolds 2001). For further details, see 'Characteristics of ongoing studies'.
Risk of bias in included studies
For details, please refer to the risk of bias tables (Figure 3, Figure 4).
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Allocation
All of the included studies were described as randomised; however, only five studies from the total of 37 described the method of randomisation (Canuso 2008; Eerdekens 2007; Kinon 2006b; Lu 2006; Wang 2006). Only four were explicit about the method of allocation concealment used (Canuso 2008; Eerdekens 2007; Hatta 2009; Potkin 2006). For all other studies, it was unclear whether the allocation strategies were appropriate.
Blinding
Thirteen of the included studies were 'single‐blind' (blind raters); all other included studies were 'double‐blind'. Nine studies used identical capsules for blinding (Canuso 2008; Eerdekens 2007; Kinon 2006b; Li 2002; Lieberman 2005; McEvoy 2006; Potkin 2006; Riedel 2005; Stroup 2006). The other trials did not provide any information on the blinding procedure. No study examined whether blinding was effective. We found that the adverse effect profiles of some of the compounds are quite different, and we believe that this may have made blinding difficult. We therefore conclude that the risk of bias for objective outcomes (e.g. death, laboratory values) was less than that for subjective outcomes, and for the latter, risk was considerable as a result of poor blinding.
Incomplete outcome data
Nineteen studies displayed attrition bias. Other than poorly described reasons for premature study discontinuation, a major problem was the very high attrition, which in thirteen studies was higher than 30% (50.2% overall, Astrazeneca 1998; Canuso 2008; Conley 2005; Deberdt 2008; Hatta 2009; Kinon 2006b; Lieberman 2005; McEvoy 2006; McEvoy 2007; Riedel 2005; Riedel 2007; Stroup 2006; Zhong 2006). In most studies, the last‐observation‐carried‐forward method was used to account for attrition. This is an imperfect method, which assumes that a participant's outcome would not have changed if he/she had remained in the study; this is often wrong. However, it is questionable whether other methods (e.g. imputation strategies, mixed‐effects models) could have coped better with such dramatically high rates of attrition. The high loss to follow‐up is a clear threat to the validity of findings.
Selective reporting
Only five studies were judged to be free of selective reporting (Atmaca 2003; Byerly 2008; Li 2002; Lieberman 2005; Hatta 2009). For most of the other trials, risk of bias was high, mainly because of incomplete reporting of pre‐defined outcomes (Conley 2005; Kinon 2006b; Li 2003; Li 2005b; Liu 2004; McEvoy 2006; Mori 2004; Ozguven 2004; Riedel 2005; Riedel 2007; Sacchetti 2004, Sirota 2006; Stroup 2006; Svestka 2003b; Voruganti 2007). In other studies, only adverse events that occurred in at least 5% or 10% of participants, or that were moderately severe, have been reported (McEvoy 2007; Potkin 2006; Zhong 2006). The former method is problematic because rare but important adverse effects may have been missed. In Lieberman 2005, all data from one site were excluded before analysis because of concerns about their integrity.
Other potential sources of bias
No study was clearly free of other potential sources of bias. In six studies, the risk of ‘other bias’ was, however, unclear. Nine studies were industry sponsored (Kinon 2006b; McEvoy 2007; Potkin 2006; Riedel 2005; Riedel 2007; Sacchetti 2004; Sirota 2006; Voruganti 2007; Zhong 2006). Evidence suggests that pharmaceutical companies sometimes highlight the benefits of their compounds and tend to suppress their disadvantages (Heres 2006). Other reasons for potential bias included heterogeneity of pre‐study treatment (Atmaca 2003; Stroup 2006), lack of or only short wash‐out phases (Li 2005b; Lieberman 2005; McEvoy 2006; Mori 2004; Voruganti 2007), baseline imbalance in terms of numbers of previous hospitalisations (Conley 2005), no information on the allowed dose range (Atmaca 2003; Li 2003; Voruganti 2007) and too‐fast titration of clozapine, which may be associated with a greater number of adverse events (Liu 2004).
Effects of interventions
See: Summary of findings for the main comparison QUETIAPINE versus ARIPIPRAZOLE for schizophrenia; Summary of findings 2 QUETIAPINE versus CLOZAPINE ‐ all data short term for schizophrenia; Summary of findings 3 QUETIAPINE versus OLANZAPINE for schizophrenia; Summary of findings 4 QUETIAPINE versus PALIPERIDONE for schizophrenia; Summary of findings 5 QUETIAPINE versus RISPERIDONE for schizophrenia; Summary of findings 6 QUETIAPINE versus ZIPRASIDONE for schizophrenia
1. Comparison 1. QUETIAPINE versus ARIPIPRAZOLE
Four studies met the inclusion criteria for the comparison of quetiapine with aripiprazole.
1.1 Leaving the study early
On the basis of two studies, no significant difference was noted in the numbers of participants leaving the studies early for any reason (2 RCTs, n = 149, RR 1.00, CI 0.59 to 1.70; Analysis 1.1).
1.2 Mental state: 1. General ‐ average endpoint score (PANSS total)
No significant difference was noted in the average endpoint total PANSS score between quetiapine and aripiprazole (4 RCTs, n = 297, MD 1.62, CI ‐0.89 to 4.14; Analysis 1.2). Exclusion of potentially skewed data (Luo Xin 2008; Peng 2007) did not significantly change the results (2 RCTs, n = 142, MD 1.24, CI ‐1.91 to 4.39; Analysis 7.1).
1.3 Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore)
No significant difference was noted in the average endpoint PANSS positive subscore (4 RCTs, n = 297, MD 0.62, CI ‐1.13 to 2.38; Analysis 1.3). However, data from all studies for this outcome were potentially skewed, and a sensitivity analysis could not be performed.
1.4 Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore)
No significant difference was noted in the average endpoint PANSS negative subscore (4 RCTs, n = 297, MD 1.00, CI ‐0.25 to 2.25; Analysis 1.4). Again, data from all studies for this outcome were potentially skewed, and a sensitivity analysis could not be performed.
1.5 General functioning
No significant difference was noted in the general average endpoint score (GAF total score, 1 RCT, n = 41, MD ‐1.20, CI ‐14.43 to 12.03; Analysis 1.5).
1.6 Adverse effects: 1. Numbers of participants with at least one adverse effect
No significant difference was noted (3 RCTs, n = 215, RR 0.91, CI 0.71 to 1.17; Analysis 1.6).
1.7 Adverse effects: 2a. Cardiac effects ‐ QTc prolongation
No significant difference in QTc prolongation was noted (1 RCT, n = 85, RR 3.21, CI 0.13 to 76.74; Analysis 1.7).
1.8 Adverse effects: 2b. Cardiac effects ‐ tachycardia
A trend towards quetiapine producing fewer tachycardia events was noted on the basis of one trial (1 RCT, n = 85, RR 7.50, CI 0.40 to 140.91; Analysis 1.8).
1.9 Adverse effects: 3. Extrapyramidal effects
No significant difference was noted in akathisia (3 RCTs, n = 196, RR 0.57, CI 0.08 to 4.02), tremor (2 RCTs, n = 155, RR 1.68, CI 0.08 to 35.92), dystonia (2 RCTs, n = 126, RR 1.42, CI 0.10 to 20.77), dyskinesia (1 RCT, n = 41, RR 3.14, CI 0.14 to 72.92), parkinsonism (1 RCT, n = 41, RR 0.75, CI 0.28 to 1.98) or use of antiparkinson medication (1 RCT, n = 40, RR 0.67, CI 0.12 to 3.57; Analysis 1.9).
1.10 Adverse effects: 4. Prolactin ‐ associated side effects
Quetiapine was associated with increased risk of galactorrhea on the basis of one trial (n = 85, RR 3.21, CI 0.13 to 76.74; Analysis 1.10).
1.11 Adverse effects: 5a. Metabolic ‐ weight gain of 7% or more of total body weight
On the basis of limited data, no significant difference was noted in the number of participants with significant weight gain (2 RCTs, n = 155, RR 0.52, CI 0.10 to 2.74; Analysis 1.11).
1.12 Adverse effects: 5b. Metabolic ‐ weight gain (change from baseline in kilograms
No difference or significant change in weight was noted from baseline (1 RCT, n = 41, MD 1.70, CI ‐0.14 to 3.54; Analysis 1.12).
1.13 Adverse effects: 5c. Metabolic ‐ cholesterol (change from baseline in mg/dL)
No significant difference was noted on the basis of one study (1 RCT, n = 41, MD 8.20, CI ‐12.24 to 28.64; Analysis 1.13).
1.14 Adverse effects: 5d. Metabolic ‐ glucose (change from baseline in mg/dL)
One small study showed an advantage of quetiapine (1 RCT, n = 41, MD ‐9.40, CI ‐17.90 to ‐0.90; Analysis 1.14).
1.15 Adverse effects: 6. Death
One study recorded no deaths from suicide or natural causes in the quetiapine and aripiprazole groups (1 RCT, n = 37, RR not estimable; Analysis 1.15).
1.16 Publication bias
We did not perform a funnel plot analysis because so few studies were identified.
2. Comparison 2. QUETIAPINE versus CLOZAPINE
Five studies met the inclusion criteria for the comparison of quetiapine with clozapine. All data were short term
2.1 Leaving the study early
No significant difference was noted in the number of participants leaving the studies early for any reason (2 RCTs, n = 95, RR 0.67, CI 0.18 to 2.43), because of adverse events (1 RCT, n = 72, RR 0.14, CI 0.01 to 2.6) or as the result of inefficacy of treatment (1 RCT, n = 72, RR not estimable; Analysis 2.1).
2.2 Global state: 1a. No clinically significant response (as defined by original studies)
No significant difference was noted in clinical response as defined by the original studies (1 RCT, n = 72, RR 0.94, CI 0.78 to 1.13; Analysis 2.2).
2.3 Global state: 1b. No clinically important change ‐ short term (CGI)
No significant difference was noted in clinical change using the CGI (1 RCT, n = 72, RR 0.94, CI 0.74 to 1.18; Analysis 2.3).
2.4 Mental state: 1a. General ‐ no clinically important change (< 50% PANSS total score reduction from baseline)
No clear difference was found (1 RCT, n = 63, RR 1.07, CI 0.53 to 2.14; Analysis 2.4).
2.5 Mental state: 1b. General ‐ average endpoint score (PANSS total)
Four short‐term studies did not indicate a significant difference (4 RCTs, n = 232, MD ‐0.5, CI ‐2.85 to 1.86; Analysis 2.5).
2.6 Mental state: 1c. General ‐ average endpoint score (BPRS total)
No significant difference was found at short term (1 RCT, n = 67, MD ‐0.89, CI ‐3.20 to 1.42; Analysis 2.6).
2.7 Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore)
No significant difference was found (2 RCTs, n = 142, MD ‐0.7, CI ‐2.07 to 0.68; Analysis 2.7).
2.8 Mental state: 3a. Negative symptom ‐ average endpoint score (PANSS negative subscore)
Two small Chinese studies showed significant superiority of quetiapine (2 RCTs, n = 142, MD ‐2.23, CI ‐3.48 to ‐0.99; Analysis 2.8).
2.9 Mental state: 3b. Negative symptoms ‐ no clinically important change (< 50% SANS total score reduction from baseline)
No significant difference was found (1 RCT, n = 72, RR 0.94, CI 0.78 to 1.13; Analysis 2.9).
2.10 Mental state: 3c. Negative symptoms ‐ average endpoint score (SANS total)
No significant difference was found (1 RCT, n = 67, MD ‐1.64, CI ‐8.17 to 4.89; Analysis 2.10).
2.11 Adverse effects: 1. General ‐ numbers of participants with at least one adverse effect
A significant difference noted on the basis of data from Li 2002, favoured the treatment group (1 RCT, n = 63, RR 0.42, CI 0.26 to 0.66, NNTH 2, CI 1 to 3; Analysis 2.11).
2.12 Adverse effects: 2. Cardiac effects ‐ ECG abnormalities
A significant difference favoured quetiapine (1 RCT, n = 72, RR 0.13, CI 0.02 to 0.95; Analysis 2.12).
2.13 Adverse effects: 3. Central nervous system ‐sedation
Fewer participants in the quetiapine group reported this outcome (2 RCTs, n = 135, RR 0.22, CI 0.11 to 0.47; Analysis 2.13).
2.14 Adverse effects: 4. Extrapyramidal effects
No significant difference was noted in akathisia (2 RCTs, n = 135, RR 0.4, CI 0.08 to 1.99), rigour (1 RCT, n = 63, RR 1.94, CI 0.18 to 20.3), tremor (2 RCTs, n = 135, RR 0.99, CI 0.29 to 3.34) or use of antiparkinson medication (1 RCT, n = 28, RR not estimable; Analysis 2.14).
2.15 Adverse effects: 5 Haematological ‐ important decline in white blood cells
No significant difference was noted (1 RCT, n = 33, RR 0.19, CI 0.01 to 3.88; Analysis 2.15).
2.16 Adverse effects: 6a Metabolic ‐ weight gain (number of participants with significant weight gain)
No significant difference was noted (2 RCTs, n = 135, RR 0.53, CI 0.25 to 1.11; Analysis 2.16).
2.17 Adverse effects: 6b. Metabolic ‐ weight gain (change from baseline in kilograms)
One small study reported a trend in favour of quetiapine (1 RCT, n = 27, MD ‐2.11, CI ‐4.3 to 0.08; Analysis 2.17).
2.18 Publication bias
We did not perform a funnel plot analysis because so few studies were identified.
2.19 Investigation for heterogeneity and sensitivity analysis
The exclusion of Li 2002; Li 2003b and Li 2005b from analysis of the PANSS total score because of possibly skewed data did not change the results to a marked extent (Analysis 8.1).
3. Comparison 3. QUETIAPINE versus OLANZAPINE
Fourteen studies met the inclusion criteria for this comparison.
3.1 Leaving the study early
Fewer participants in the olanzapine group (54%) compared with the quetiapine group (69%) left the studies early for ‘any reason’ (12 RCTs, n = 1821, RR 1.26, CI 1.12 to 1.42) or because of ‘inefficacy’ (14% vs 25%, 9 RCTs, n = 1600, RR 1.83, CI 1.42 to 2.36) but not as the result of adverse events (12% vs 11%, 9 RCTs, n = 1610, RR 0.90, CI 0.69 to 1.18; Analysis 3.1).
3.2 Global state: 1a. No clinically significant response ‐ as defined by the original studies
No significant difference was noted (3 RCTs, n = 339, RR 1.11, CI 0.86 to 1.43; Analysis 3.2).
3.3 Global state: 1b. No clinically important change ‐ as defined by the original studies
No significant difference was noted (2 RCTs, n = 309, RR 1.18, CI 0.89 to 1.57; Analysis 3.3).
3.4 Mental state: 1a. General mental state ‐ no clinically important change ‐ short term (< 50% PANSS total score reduction)
No significant difference was noted (1 RCT, n = 42, RR 0.91, CI 0.54 to 1.53; Analysis 3.4).
3.5 Mental state: 1b. General mental state ‐ average endpoint score (PANSS total)
A significant difference favoured olanzapine overall (11 RCTs, n = 1486, MD 3.67, CI 1.95 to 5.39), medium term (3 RCTs, n = 482, MD 5.57, CI 1.97 to 9.17) and long term (3 RCTs, n = 825, MD 3.40, CI 0.91 to 5.88). A difference was not seen in the short term (5 RCTs, n = 179, MD 2.29, CI ‐1.30 to 5.87; Analysis 3.5). Exclusion of Voruganti 2007, which potentially contributed skewed data to the long‐term studies, favoured olanzapine further (2 RCTs, n = 740, MD 4.31, CI 1.60 to 7.01; Analysis 9.1).
3.6 Mental state: 2a. Positive symptoms ‐ no clinically important change ‐ short term (< 20% SAPS total score reduction)
No difference was identified with confidence (1 RCT, n = 30, RR 15.0, CI 0.93 to 241.2; Analysis 3.6).
3.7 Mental state: 2b. Positive symptoms ‐ average endpoint (PANSS positive subscore)
Overall data on PANSS positive average endpoint score did not show a statistically significant difference between groups (9 RCTs, n = 801, MD 1.02, CI ‐0.81 to 2.85), short term (4 RCTs, n = 152, MD 1.24, CI ‐0.48 to 2.96), medium term (3 RCTs, n = 483, MD 2.21, CI 0.90 to 3.52) or long term (2 RCT, n = 166, MD 3.70, CI ‐0.48 to 7.88; Analysis 3.7). However, exclusion of potentially skewed data (Mori 2004; Voruganti 2007) revealed an overall significant difference in favour of olanzapine (7 RCTs, n = 676, MD 1.84, CI 1.02 to 2.67; Analysis 9.2).
3.8 Mental state: 2c. Positive symptoms ‐ average change in score ‐ short term (SAPS total score ‐ percentage change from baseline)
A significant difference favoured olanzapine (1 RCT, n = 30, MD 40.84, CI 23.97 to 57.71; Analysis 3.8).
3.9 Mental state: 3a. Negative symptoms ‐ no clinically important change ‐ short term (< 20% SANS total score reduction from baseline)
No significant difference was noted (1 RCT, n = 30, RR 1.5, CI 0.53 to 4.26; Analysis 3.9).
3.10 Mental state: 3b. Negative symptoms ‐ average endpoint score (PANSS negative subscore)
No significant difference was noted between groups (9 RCTs, n = 801, MD 0.86, CI ‐0.32 to 2.03), short term (4 RCTs, n = 152, MD ‐0.07, CI ‐1.70 to 1.56), medium term (3 RCTs, n = 483, MD 0.40, CI ‐0.67 to 1.47) or long term (2 RCTs, n = 166, MD 2.64, CI ‐1.29 to 6.56; Analysis 3.10). Exclusion of potentially skewed data (Voruganti 2007) yielded no significant difference in the results of long‐term data studies (1 RCT, n = 81, MD 0.7, CI 0.73 to 2.13; Analysis 9.3).
3.11 Mental state: 3c. Negative symptoms ‐ average endpoint score (SANS total)
No significant difference was noted (1 RCT, n = 335, MD 3.7, CI ‐0.48 to 7.88; Analysis 3.11).
3.12 Mental state: 3d. Negative symptoms ‐ average change in endpoint score (SANS total ‐ percent change from baseline)
No significant difference was noted (1 RCT, n = 30, MD 2.46, CI ‐31.9 to 36.82; Analysis 3.12).
3.13 General functioning ‐ average endpoint score ‐ medium term (GAF total)
A significant difference favoured olanzapine (3 RCT, n = 400, MD 2.55, CI 0.33 to 4.76; Analysis 3.13).
3.14 Quality of life ‐ average endpoint score ‐ medium term (QLS total)
No significant difference was noted (1 RCT, n = 286, MD 1.8, CI ‐2.42 to 6.02; Analysis 3.14).
3.15 Service use ‐ number of participants re‐hospitalised
A significant difference favoured olanzapine (3 RCTs, n = 1009, RR 1.83, CI 1.33 to 2.52; Analysis 3.15).
3.16 Adverse effects: 1. General ‐ at least one adverse effect
No significant difference was noted in the number of participants experiencing at least one adverse effect (7 RCTs, n = 1306, RR 0.96, CI 0.88 to 1.05; Analysis 3.16).
3.17 Adverse effects: 2. Death
No significant difference was noted (4 RCTs, n = 1450, RR 0.74, CI 0.13 to 4.23; Analysis 3.17).
3.18 Adverse effects: 3a. Cardiac effects ‐ number of participants with QTc prolongation
No significant difference was noted (1 RCT, n = 673, RR 12.96, CI 0.73 to 229.17; Analysis 3.18).
3.19 Adverse effects: 3b. Cardiac effects ‐ mean change of QTc interval from baseline in ms
A significant difference favoured olanzapine (3 RCTs, n = 643, MD 4.81, CI 0.34 to 9.28; Analysis 3.19).
3.20 Adverse effects: 4a. Central nervous system ‐ sedation
No significant difference was noted (7 RCTs, n = 1615, RR 0.97, CI 0.78 to 1.2; Analysis 3.20).
3.21 Adverse effects: 4b. Central nervous system ‐ seizures
No significant difference was noted (1 RCT, n = 40, RR 3.3, CI 0.14 to 76.46; Analysis 3.21).
3.22 Adverse effects: 5a. Extrapyramidal effects
Fewer participants in the quetiapine group used antiparkinson medication at least once (7 RCTs, n = 1127, RR 0.51, CI 0.32 to 0.81). Apart from this, no significant differences in extrapyramidal symptoms (EPS) were found for akathisia (7 RCTs, n = 1314, RR 0.97, CI 0.68 to 1.38), akinesia (1 RCT, n = 267, RR 1.02, CI 0.67 to 1.56), dystonia (3 RCTs, n = 752 RR 1.13, CI 0.21 to 6.23), any EPS (2 RCTs, n = 245, RR 1.62, CI 0.72 to 3.67), parkinsonism (2 RCTs, n = 77, RR 0.77, CI 0.34 to 1.74) or tremor (1 RCT, n = 42, RR 0.39, CI 0.12 to 1.31; Analysis 3.22).
3.23 Adverse effects: 5b. Scale measured
Extrapyramidal adverse effects were evaluated with the Barnes Akathisia Scale, the Extrapyramidal Side Effects Rating Scale and the Simpson‐Angus Scale. None of these indicated a significant difference between groups (Analysis 3.23).
3.24 Adverse effects: 6a. Prolactin‐associated side effects
Fewer participants in the quetiapine group suffered from sexual dysfunction (4 RCTs, n = 1177, RR 0.8, CI 0.64 to 0.99). No significant difference was noted in abnormally high prolactin (1 RCT, n = 42, RR 0.10, CI 0.01 to 1.77), amenorrhoea (3 RCTs, n = 252, RR 0.66, CI 0.36 to 1.21), galactorrhoea (4 RCTs, n = 1025, RR 0.66, CI 0.25 to 1.73) and gynaecomastia (1 RCT, n = 267, RR 0.33, CI 0.09 to 1.20; Analysis 3.24).
3.25 Adverse effects: 6b. Prolactin ‐ change from baseline in ng/mL
Quetiapine was associated with less prolactin increase than olanzapine (5 RCTs, n = 1021, RR ‐5.89, CI ‐11.62 to ‐0.16), but the data were heterogeneous (Analysis 3.25). Nevertheless, the single studies reported a consistent effect in favour of quetiapine (Svestka 2003b: n = 35, MD ‐40.07, CI ‐64.10 to ‐16.04; Lieberman 2005: n = 673, MD ‐3.20, CI ‐ 6.81 to 0.41; McEvoy 2006: n = 29, MD ‐9.10, CI ‐19.88 to 1.68; Stroup 2006: n = 203, MD ‐3.20, CI ‐11.17 to 4.77 and McEvoy 2007: n = 81, MD ‐2.80, CI ‐10.03 to 4.43). Heterogeneity seems more likely to be due to differences in degree of prolactin increase rather than to direction of effect.
3.26 Adverse effects: 7a. Metabolic ‐ cholesterol ‐ significant cholesterol increase
No significant difference was noted in the number of participants with an abnormally high cholesterol increase (1 RCT, n = 267, RR 0.99, CI 0.59 to 1.68; Analysis 3.26).
3.27 Adverse effects: 7b. Metabolic ‐ cholesterol ‐ mean change from baseline in mg/dL
Overall data on cholesterol change from baseline did not show a statistically significant difference between groups (6 RCTs, n = 1156, MD ‐2.73, CI ‐8.05 to 2.59; Analysis 3.27).
3.28 Adverse effects: 7c. Metabolic ‐ glucose ‐ number of participants with abnormally high fasting glucose
No significant difference was noted (3 RCTs, n = 1025, RR 0.47, CI 0.21 to 1.02; Analysis 3.28).
3.29 Adverse effects: 7d. Metabolic ‐ glucose ‐ change from baseline in mg/dL
The mean increase in glucose from baseline was lower in the quetiapine group than in the olanzapine group (6 RCTs, n = 1156, MD ‐4.67, CI ‐9.41.to 0.07; Analysis 3.29). Although significant heterogeneity was noted between the studies, all favoured quetiapine.
3.30 Adverse effects: 7e. Metabolic ‐ weight gain
Fewer participants in the quetiapine group had a significant weight gain (8 RCTs, n = 1667, RR 0.68, CI 0.51 to 0.92; Analysis 3.30).
3.31 Adverse effects: 7f. Metabolic ‐ weight change from baseline in kilograms
Overall, participants in the quetiapine group gained less weight than those in the olanzapine group (10 RCTs, n = 1428, MD ‐2.54, CI ‐3.82 to ‐1.26; Analysis 3.31). Again, significant heterogeneity was noted, but the results of the single studies consistently favoured quetiapine (Atmaca 2003: n = 27, MD ‐4.51, CI ‐6.57 to ‐2.45; Deberdt 2008: n = 133, MD ‐1.81, CI ‐3.70 to 0.08; Lieberman 2005: n = 612, MD ‐3.8, CI ‐4.91 to ‐2.69; Kinon 2006b: n = 346, MD ‐0.64, CI ‐1.76 to 0.48); McEvoy 2006: n = 34, MD ‐2.3, CI ‐10.18 to 5.58; Sirota 2006: n = 40, MD ‐3.2, CI ‐5.51 to ‐0.89; McEvoy 2007: n = 81, MD ‐5.18, CI ‐10.00 to ‐0.36; Riedel 2007: n = 33, MD ‐0.48, CI ‐2.52 to 1.56; Hatta 2009: n = 37, MD 0.1, CI ‐2.19 to 2.39 and Voruganti 2007: n = 85, MD ‐4.40, CI ‐5.30 to ‐3.50).
3.32 Publication bias
Funnel plots did not suggest a possible publication bias.
3.33 Investigation for heterogeneity and sensitivity analysis
When Mori 2004 was excluded from the evaluation of the PANSS positive score because of possibly skewed data, olanzapine remained more effective.
4. Comparison 4. QUETIAPINE versus PALIPERIDONE
Only two short‐term studies with limited outcome measures met the inclusion criteria for the comparison of quetiapine with paliperidone.
4.1 Leaving the study early
No significant difference was noted in the number of participants who left the study early in the paliperidone group compared with the quetiapine group for ‘any reason’ (2 RCTs, n = 406, RR 1.03, CI 0.61 to 1.73), because of ‘inefficacy’ (1 RCT, n = 319, RR 4.97, CI 0.59 to 42.05) or as the result of adverse events (2 RCTs, n = 406, RR 0.90, CI 0.37 to 2.17; Analysis 4.1).
4.2 Mental state: 1. General ‐ average endpoint score (PANSS total)
A significant difference favoured paliperidone on the basis of one RCT (n = 319, MD 6.30, CI 2.77 to 9.83; Analysis 4.2).
4.3 Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore)
A significant difference favoured paliperidone (1 RCT, n = 319, MD 1.60, CI 0.42 to 2.78; Analysis 4.3).
4.4 Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore)
A significant difference favoured paliperidone (1 RCT, n = 319, MD 1.30, CI 0.52 to 2.08; Analysis 4.4).
4.5 Adverse effects: 1. Numbers of participants with at least one adverse effect
A significant difference favoured paliperidone (1 RCT, n = 87, RR 1.27, CI 1.06 to 1.53; Analysis 4.5).
4.6 Adverse effects: 2a. Cardiac effects ‐ QTc prolongation
Only one study examined for this side effect, and the risk ratio was not estimable because of a low event rate (Analysis 4.6).
4.7 Adverse effects: 2b. Cardiac effects ‐ QTc abnormalities (change from baseline in ms)
No significant difference was noted (1 RCT, n = 87, RR 2.30, CI ‐2.50 to 7.10; Analysis 4.7).
4.8 Adverse effects: 3a. Extrapyramidal effects
More participants in the paliperidone group used antiparkinson medication at least once (1 RCT, n = 319, RR 0.64, CI 0.45 to 0.91). The paliperidone group was significantly more likely to experience rigidity (2 RCTs, n = 406, RR 0.34, CI 0.12 to 0.92) and tremor (1 RCT, n = 319, RR 0.37, CI 0.17 to 0.80). No difference was noted in dystonia (1 RCT, n = 87 RR 1.02, CI 0.15 to 6.94) or akathisia (2 RCTs, n = 406, RR 1.35, CI 0.55 to 3.34; Analysis 4.8).
4.9 Adverse effects: 3b. Extrapyramidal effects ‐ scale measured
Extrapyramidal adverse effects were evaluated in one RCT with the Barnes Akathisia Scale, the Extrapyramidal Side Effects Rating Scale and the Simpson‐Angus Scale. None of these scales reported a significant difference between groups (Analysis 4.9).
4.10 Adverse effects: 4a. Prolactin ‐ associated effects ‐ sexual dysfunction
No difference was noted in the number of participants who suffered from sexual dysfunction (1 RCT, n = 317, RR 0.02, CI 0.01 to 4.16; Analysis 4.10).
4.11 Adverse effects: 4b. Prolactin ‐ change from baseline (ng/mL)
On the basis of one study, quetiapine was associated with significantly less prolactin increase than paliperidone (1 RCT, n = 317, MD ‐49.30, CI ‐57.80 to ‐40.80; Analysis 4.11).
4.12 Adverse effects: 5a. Metabolic ‐ weight gain ‐ number of participants with weight gain of 7% or more of total body weight
Participants in the paliperidone group were not more likely to experience significant weight gain as defined by the study investigators (1 RCT, n = 319, RR 2.52, CI 0.50 to 12.78; Analysis 4.12).
4.13 Adverse effects: 5b. Metabolicweight gain ‐ mean change from baseline in kilograms
Paliperidone did cause a significantly greater weight gain in terms of change from baseline in kilograms (1 RCT, n = 319, MD 0.40, CI 0.20 to 0.60; Analysis 4.13).
4.13 Publication bias
Funnel plots were not performed because of the paucity of studies.
5. Comparison 5. QUETIAPINE versus RISPERIDONE
Nineteen studies met the inclusion criteria for the comparison of quetiapine with risperidone.
5.1 Leaving the study early
Leaving the studies early for any reason showed an almost significant superiority of risperidone (quetiapine 54%, risperidone 49%; 13 RCTs, n = 2784, RR 1.09, CI 1.00 to 1.19). Leaving early because of inefficacy showed a small significant advantage of risperidone over quetiapine (25% vs 19%; 8 RCTs, n = 1891, RR 1.32, CI 1.02 to 1.71). No significant difference was noted in the number of participants leaving early as the result of adverse events (10% vs 9%; 9 RCTs, n = 2299, RR 1.12, CI 0.80 to 1.57; Analysis 5.1).
5.2 Global state: 1a. No clinically significant response ‐ as defined by the original studies
Overall, no significant difference was evident when all studies were considered (4 RCTs, n = 1264, RR 1.07, CI 0.95 to 1.22; Analysis 5.2). The first three studies reported short‐term data, and only McEvoy 2007 reported long‐term data. Heterogeneity was moderate (I2 = 57%); however, on exclusion of potentially skewed data from Potkin 2006, there remained no significant difference between groups (3 RCTs, n = 965, RR 1.01, CI 0.93 to 1.09; Analysis 10.1).
5.3 Global state: 1b. No clinically important change ‐ as defined by the original studies
A small superiority of risperidone was noted, but it did not reach statistical significance (5 RCTs, n = 1342, RR 1.10, CI 0.98 to 1.25; Analysis 5.3).
5.4 Mental state: 1a. General ‐ no clinically important change ‐ short term (< 30% PANSS total score reduction from baseline)
No significant difference was noted (2 RCTs, n = 982, RR 1.11, CI 0.87 to 1.42), but the results were heterogeneous (Analysis 5.4). We therefore present the single studies separately: Potkin 2006 (n = 177, RR 1.27, CI 1.05 to 1.55) and Zhong 2006a (n = 495, RR 1.0, CI 0.91 to 1.09).
5.5 Mental state: 1b. General: no clinically important change ‐ short term (< 20% BPRS total score reduction)
No significant difference was noted (1 RCT, n = 25, RR 0.98, CI 0.63 to 1.52; Analysis 5.5).
5.6 Mental state: 1c. General: average endpoint score (PANSS total)
A significant difference favoured risperidone: overall (14 RCTs, n = 2302, MD 1.67, CI 0.39 to 2.96), short term (8 RCTs, n = 1232, MD 1.37, CI ‐0.28 to 3.01) and long term (2 RCTs, n = 743, MD 3.11, CI 0.40 to 5.82; Analysis 5.6). Medium‐term studies displayed considerable heterogeneity; the results are therefore presented separately. Stroup 2006 reported a significant difference in favour of risperidone (n = 132, MD 10, CI 2.38 to 17.62); McEvoy 2006 (n = 14, MD ‐1.0, CI ‐15.41 to 13.41), Wei 2006a (n = 51, MD 1.60, CI ‐5.69 to 2.49) and Lu 2006 (n = 64, MD 3.82, CI ‐2.51 to 10.15) found no significant difference between groups.
5.7 Mental state: 1d. General mental state: average endpoint score ‐ short term (BPRS total)
No significant difference was noted (1 RCT, n = 25, MD 1.68, CI ‐8.33 to 11.69; Analysis 5.7).
5.8 Mental state: 2a. Positive symptoms ‐ no clinically important change in PANSS positive subscore
No significant difference was noted in the number of people with no clinically important change in PANSS score in the short term, as measured by < 40% PANSS positive score reduction from baseline (1 RCT, n = 673, RR 1.00, CI 0.9 to 1.12; Analysis 5.8).
5.9 Mental state: 2b. Positive symptoms ‐ average endpoint score (PANSS positive subscore)
A significant difference favoured risperidone overall (11 RCTs, n = 1639, MD 1.22, CI 0.51 to 1.94), medium term (5 RCTs, n = 327, MD 1.21, CI ‐0.21 to 2.63) and long term (1 RCT, n = 81, MD 1.30, CI ‐0.13 to 2.73; Analysis 5.9). Despite considerable heterogeneity, short‐term studies tended to favour risperidone: Mori 2004 (n = 39, MD 2.5, CI 0.37 to 4.63), Potkin 2006 (n = 308, MD 2.80, CI 1.42 to 4.18), Riedel 2005 (n = 44, MD 3.80, CI ‐0.51 to 8.11), Song 2008 (n = 66, MD 0.16, CI ‐1.12 to 1.44) and Wang 2006 (n = 60, MD 0.1, CI ‐1.87 to 2.07). Hu 2008 favoured quetiapine but had a wide CI (n = 68, MD‐0.50, CI ‐3.81 to 2.81). Excluding data from potentially skewed short‐term (Hu 2008; Mori 2004; Song 2008; Wang 2006) and medium‐term (Lu 2006; Song 2008; Wei 2006a) studies in a sensitivity analysis maintained a significant difference in favour of risperidone (6 RCTs, n = 1225, MD 1.76, CI 1.04 to 2.48).
5.10 Mental state: 2c. Positive symptoms ‐ average change endpoint score ‐ short term (BPRS positive subscore)
A significant difference favoured risperidone (1 RCT, n = 25, MD 1.1, CI 0.18 to 2.02; Analysis 5.10).
5.11 Mental state: 3a. Negative symptoms ‐ no clinically important change ‐ PANSS negative subscore short term (< 40% PANSS negative score reduction from baseline)
No significant difference was noted in the number of people with no clinically important change in the PANSS negative subscore in the short term, as measured by < 40% PANSS negative score reduction from baseline (1 RCT, n = 673, RR 0.98, CI 0.93 to 1.04; Analysis 5.11).
5.12 Mental state: 3b. Negative symptoms ‐ average endpoint score (PANSS negative subscore)
No significant difference was noted in short‐term studies (6 RCTs, n = 1106, MD 0.55, CI ‐0.25 to 1.34), medium‐term studies (5 RCTs, n = 327, MD 1.05, CI ‐0.24 to 2.34) and long‐term studies (1 RCT, n = 81, MD 0.8, CI ‐0.64 to 2.24; Analysis 5.12). Exclusion of potentially skewed data in a sensitivity analysis for short‐term and medium‐term studies yielded no significant difference in results (Analysis 10.4).
5.13 Mental state: 3c. Negative symptoms ‐ average change endpoint score ‐ short term (BPRS negative subscore)
A significant difference favoured risperidone (1 RCT, n = 25, MD 0.57, CI 0.17 to 0.97; Analysis 5.13).
5.14 Quality of life ‐ average endpoint score (QLS total score)
A significant difference favoured quetiapine (3 RCTs, n = 152, MD ‐3.44, CI ‐4.46 to ‐2.43; Analysis 5.14).
5.15 Service use: 1. Number of participants re‐hospitalised
The difference almost reached statistical significance, with a slight benefit for the risperidone group (2 RCTs, n = 877, RR 1.34, CI 1.0 to 1.79; Analysis 5.15).
5.16 Adverse effects: 1. General ‐ at least one adverse effect
No significant difference was noted (13 RCTs, n = 2868, RR 1.01, CI 0.91 to 1.13; Analysis 5.16).
5.17 Adverse effects: 2. Death
No significant difference was noted (6 RCTs, n = 3146, RR 0.73, CI 0.17 to 3.09; Analysis 5.17).
5.18 Adverse effects: 3a. Cardiac effects ‐ number of participants with QTc prolongation
No significant difference was noted (3 RCTs, n = 1419, RR 1.34, CI 0.36 to 5.04; Analysis 5.18).
5.19 Adverse effects: 3b. Mean change in QTc interval from baseline in ms
Overall, no significant difference was noted (3 RCTs, n = 940, MD 2.21, CI ‐5.05 to 9.48). The data were heterogeneous. In the individual studies, Lieberman 2005 found a significant difference in favour of risperidone (n = 432, MD 5.7, CI 0.57 to 10.83), but Stroup 2006 (n = 166, MD 6.3, CI ‐3.41 to 16.01) and Zhong 2006a (n = 342, MD ‐3.6, CI ‐7.55 to 0.35) found no significant difference between groups (Analysis 5.19).
5.20 Adverse effect: 4. Central nervous system ‐ sedation
A significant difference favoured risperidone (8 RCTs, n = 2226, RR 1.21, CI 1.06 to 1.38; Analysis 5.20).
5.21 Adverse effects: 5a. Extrapyramidal effects
Quetiapine produced fewer movement disorders than risperidone in terms of 'extrapyramidal symptoms' (2 RCTs, n = 872, RR 0.59, CI 0.43 to 0.81), dystonia (4 RCTs, n = 1451, RR 0.13, CI 0.04 to 0.43), use of antiparkinson medication at least once (8 RCTs, n = 2163, RR 0.50, CI 0.36 to 0.69), akathisia (8 RCTs, n = 2270, RR 0.55, CI 0.32 to 0.95), akinesia (1 RCT, n = 267, RR 0.91, CI 0.61 to 1.37) and lesser parkinsonism (4 RCTs, n = 825, RR 0.39, CI 0.19 to 0.78; Analysis 5.21).
5.22 Adverse effects: 5c. Extrapyramidal effects as measured by scales
Quetiapine produced fewer extrapyramidal side effects than risperidone according to the Simpson‐Angus Scale (5 RCTs, n = 1077, MD ‐0.59, CI ‐1.16 to ‐0.02). No significant difference was noted in dyskinesia (AIMS, 2 RCTs, n = 958, MD ‐0.34, CI ‐0.76 to 0.08) and akathisia (BAS, 2 RCTs, n = 700, MD ‐0.73, CI ‐2.0 to 0.54; Analysis 5.22).
5.23 Adverse effects: 6. Haematological ‐ important decline in white blood cells
No significant difference was noted (1 RCT, n = 673, RR 2.97, CI 0.12 to 72.73; Analysis 5.23).
5.24 Adverse effects: 7a. Prolactin associated adverse effects
Quetiapine produced significantly fewer cases of amenorrhoea (5 RCTs, n = 427, RR 0.55, CI 0.32 to 0.96), galactorrhoea (5 RCTs, n = 1188, RR 0.37, CI 0.16 to 0.85) and gynaecomastia (1 RCT, n = 78, RR 0.23, CI 0.07 to 0.75) but not dysmenorrhoea (1 RCT, n = 163, RR 0.45, CI 0.08 to 2.38). Data on sexual dysfunction showed an almost significant superiority of quetiapine (6 RCTs, n = 2157, RR 0.70, CI 0.48 to 1.01; Analysis 5.24).
5.25 Adverse effects: 7b. Prolactin ‐ change from baseline in ng/mL
A significant and consistent difference favoured quetiapine, although the extent of the difference varied, leading to statistical heterogeneity (7 RCTs, n = 1773, MD ‐35.25, CI ‐43.59 to ‐26.91; the results of the single studies were as follows: Byerly 2008: n = 44, MD ‐35.10, CI ‐50.68 to ‐19.52; Lieberman 2005: n = 678, MD ‐24.70, CI ‐28.72 to ‐20.68; McEvoy 2006: n = 24, MD ‐28.6, CI ‐43.02 to ‐14.18; Potkin 2006: n = 309, MD ‐50.4, CI ‐60.24 to ‐40.56; Stroup 2006: n = 199, MD ‐30.3, CI ‐37.1 to ‐23.5; Zhong 2006a: n = 440, MD ‐47.0, CI ‐52.97 to ‐41.03and McEvoy 2007: n = 81, MD ‐30.8, CI ‐38.1 to ‐23.5; Analysis 5.25).
5.26 Adverse effects: 8a. Metabolic ‐ cholesterol ‐ number of participants with a significant cholesterol increase
No significant difference was noted (2 RCTs, n = 940, RR 1.27, CI 0.72 to 2.24; Analysis 5.26).
5.27 Adverse effects: 8b. Metabolic ‐ cholesterol ‐ mean change from baseline in mg/dL
A significant difference favoured risperidone (6 RCTs, n = 1473, MD 8.57, CI 4.85 to 12.29; Analysis 5.27).
5.28 Adverse effects: 8c. Metabolic ‐ glucose ‐ number of participants with abnormally high fasting glucose
No significant difference was noted (3 RCTs, n = 1618, RR 0.89, CI 0.47 to 1.69; Analysis 5.28).
5.29 Adverse effects: 8d. Metabolic ‐ glucose ‐ mean change from baseline in mg/dL
No significant difference was noted (6 RCTs, n = 1476, MD 0.30, CI ‐2.45 to 3.05; Analysis 5.29).
5.30 Adverse effects: 8e. Metabolic ‐ weight gain ‐ number of participants with weight gain of 7% or more of total body weight
No significant difference was noted (9 RCTs, n = 2070, RR 0.96, CI 0.82 to 1.14; Analysis 5.30).
5.31 Adverse effects: 8f. Metabolic ‐ weight gain ‐ mean change from baseline in kilograms
Overall, no significant difference was noted, but the data were highly heterogeneous, presumably because of one small outlier study (Atmaca 2003) that showed a dramatic advantage of risperidone (8 RCTs, n = 1486, MD 0.94, CI ‐0.59 to 2.46; Analysis 5.31). Nevertheless, excluding this study did not change the overall result.
5.32 Publication bias
A reasonable funnel plot analysis was possible only for the PANSS total score (> 10 included studies). It did not suggest a possible publication bias.
5.33 Investigation for heterogeneity and sensitivity analysis
Exclusion of Mori 2004 from the evaluation of the PANSS positive subscore as the result of possibly skewed data did not reveal markedly different results. The data on akathisia (Barnes Akathisia Scale) indicated considerable heterogeneity, but clear reasons to explain this could not be found.
6. Comparison 6. QUETIAPINE versus ZIPRASIDONE
Two studies met the inclusion criteria for the comparison of quetiapine versus ziprasidone.
6.1 Leaving the study early
No significant difference was noted in the number of participants leaving the studies early for any reason (2 RCTs, n = 722, RR 1.05, CI 0.97 to 1.13), because of adverse events (2 RCTs, n = 722, RR 1.04, CI 0.72 to 1.49) or as the result of inefficacy of treatment (2 RCTs, n = 722, RR 1.14, CI 0.89 to 1.47).
6.2 Mental state: 1. General mental state ‐ average endpoint score (PANSS total)
No significant difference was noted, but the data from two studies were heterogeneous and therefore are presented separately. Neither Stroup 2006 (medium‐term data, n = 198, MD 3.7, CI ‐2.97 to 10.37) nor Lieberman 2005 (long‐term data, n = 512, MD ‐2.78, CI ‐6.81 to 1.25) found a significant difference between groups (Analysis 6.2).
6.3 Mental state: 2. Positive symptoms ‐ average endpoint score ‐ medium term (PANSS positive subscore)
No significant difference was noted (1 RCT, n = 198, MD 0.0, CI ‐2.18 to 2.18; Analysis 6.3).
6.4 Mental state: 3. Negative symptoms: average endpoint score ‐ medium term (PANSS negative subscore)
No significant difference was noted (1 RCT, n = 198, MD 1.6, CI ‐0.34 to 3.54; Analysis 6.4).
6.5 Service use: 1. Number of participants re‐hospitalised
No significant differencewas noted in the overall analysis (2 RCTs, n = 754, RR 1.17, CI 0.85 to 1.59) or in the analysis of medium‐term data (1 RCT, n = 232, RR 1.25, CI 0.71 to 2.17) or long‐term data (1 RCT, n = 522, RR 1.13, CI 0.78 to 1.65; Analysis 6.5).
6.6 Adverse effects: 1. General ‐ at least one adverse effect
No significant difference was noted (2 RCTs, n = 754, RR 1.03, CI 0.91 to 1.17; Analysis 6.6).
6.7 Adverse effects: 2. Death
No significant difference was noted (2 RCTs, n = 754, RR 0.41, CI 0.05 to 3.15; Analysis 6.7).
6.8 Adverse effects: 3a. Cardiac effects ‐ QTc prolongation
No significant difference was noted in the number of participants with QTc prolongation (1 RCT, n = 522, RR 1.65, CI 0.34 to 8.08; Analysis 6.8).
6.9 Adverse effects: 3b. Cardiac effects ‐ mean change in QTc interval in ms
No significant difference was noted (2 RCTs, n = 549, MD 3.41, CI ‐1.37 to 8.18; Analysis 6.9).
6.10 Adverse effects: 4. Central nervous system ‐ sedation
Significantly fewer participants in the ziprasidone group than in the quetiapine group felt sedated (2 RCTs, n = 754, RR 1.36, CI 1.04 to 1.77, NNH 14, CI 7 to 100; Analysis 6.10).
6.11 Adverse effects: 5. Extrapyramidal effects
Significantly fewer people in the quetiapine group used antiparkinson medication at least once (1 RCT, n = 522, RR 0.43, CI 0.2 to 0.93), but no clear differences were noted in akathisia (2 RCTs, n = 754, RR 0.78, CI 0.42 to 1.45) or in 'any extrapyramidal symptoms' (1 RCT, n = 232, RR 2.02, CI 0.66 to 6.17; Analysis 6.11).
6.12 Adverse effects: 6a. Prolactin ‐ associated effects
No significant difference was noted in amenorrhoea (1 RCT, n = 138, RR 0.43, CI 0.15 to 1.24), galactorrhoea (2 RCTs, n = 202, RR 0.68, CI 0.23 to 2.01) or sexual dysfunction (2 RCTs, n = 754, RR 0.96, CI 0.64 to 1.42; Analysis 6.12).
6.13 Adverse effects: 6b. Prolactin ‐ change from baseline in ng/mL
A significant difference favoured quetiapine (2 RCTs, n = 754, MD ‐4.77, CI ‐8.16 to ‐1.37; Analysis 6.13).
6.14 Adverse effects: 7a. Metabolic ‐ cholesterol ‐ mean change from baseline in mg/dL
Ziprasidone was associated with significantly less cholesterol increase than quetiapine (2 RCTs, n = 754, MD 16.01, CI 8.57 to 23.46; Analysis 6.14).
6.15 Adverse effects: 7b. Metabolic ‐ glucose ‐ mean change from baseline in mg/dL
No significant difference was noted (2 RCTs, n = 754, MD 3.1, CI ‐3.99 to 10.19; Analysis 6.15).
6.16 Adverse effects: 7c. Metabolic ‐ glucose ‐ abnormally high fasting glucose value
No significant difference was noted (1 RCT, n = 522, RR 0.64, CI 0.3 to 1.36; Analysis 6.16).
6.17 Adverse effects: 7d. Metabolic ‐ weight gain ‐ number of participants with weight gain of 7% or more of total body weight
Significantly more participants in the quetiapine group than in the ziprasidone group gained weight (2 RCTs, n = 754, RR 2.22, CI 1.35 to 3.63; Analysis 6.17).
6.18 Adverse effects: 7e. Metabolic ‐ weight gain ‐ change from baseline in kilograms
A superiority of ziprasidone almost reached statistical significance (1 RCT, n = 466, MD 1.2, CI ‐0.05 to 2.45; Analysis 6.18).
6.19 Publication bias
Because of the small number of included studies, we did not perform a funnel plot analysis.
6.20 Investigation for heterogeneity and sensitivity analysis
The reasons for the preplanned sensitivity analysis did not apply; therefore it was not performed.
Discussion
Summary of main results
General
This analysis of the effects of quetiapine compared with other second‐generation antipsychotic drugs in the treatment of schizophrenia currently includes 37 studies reporting data on only six of nine possible comparisons. High discontinuation rates (overall 50.2%) limit the value of findings. In addition, 26 of the 37 included studies randomly assigned fewer than 100 people. The duration of the trials was usually short, and we identified only two long‐term studies. Short‐term trials are not ideal for judging the efficacy and tolerability of treatments for a chronic disease. Eighteen of the 37 studies were sponsored by a pharmaceutical industry with a clear pecuniary interest in the result. This is likely to be a further problem.
1. Comparison 1. QUETIAPINE versus ARIPIPRIZOLE
Four small short‐term studies with a total of 293 participants fell into this comparison. Data were available for only one study for a number of outcomes. Please see summary of findings Table for the main comparison.
1.1 Leaving the studies early
The overall rate of participants leaving studies early was 19.5%, with no clear difference between groups. However, this finding was based on only two small, short‐term trials, limiting interpretation (Analysis 1.1).
1.2 Efficacy outcomes (overall and specific mental state)
Four studies of low‐quality evidence found no significant difference in general mental state, positive symptoms or negative symptoms. Data from all studies measuring efficacy were potentially skewed and should be interpreted with caution (Analysis 1.2; Analysis 1.3; Analysis 1.4).
1.3 Adverse effects
We found limited data on ‘at least one adverse effect’ (Analysis 1.6), cardiac effects (Analysis 1.7), extrapyramidal symptoms (Analysis 1.9) and weight gain (Analysis 1.11;Analysis 1.12), showing no significant difference between quetiapine and aripiprazole.
1.4 Quality of life
Quality of life was not measured and was not reported in these studies.
2. Comparison 2. QUETIAPINE versus CLOZAPINE
Five studies with a total of 334 participants fell into this comparison. Please see summary of findings Table 2.
2.1 Leaving the studies early
The overall rate of participants leaving studies early was remarkably low (8.4%) and showed no clear difference between groups. Nevertheless, this finding was based on only two small (n = 135), short‐term trials, limiting any interpretation (Analysis 2.1).
2.2 Efficacy outcomes (global state, overall and specific mental state)
No significant difference was noted in global state, general mental state or positive symptoms on the basis of studies of low‐quality evidence (Analysis 2.4; Analysis 2.5; Analysis 2.6; Analysis 2.7; Analysis 2.9; Analysis 2.8; Analysis 2.10). A small reduction in negative symptoms was noted in those taking quetiapine, but this result must be interpreted with caution, as it was based on two small trials with low‐quality evidence (Li 2003b; Li 2005b).
2.3 Adverse effects
We found limited data on ‘at least one adverse effect’ (Analysis 2.11), cardiac effects (Analysis 2.12), sedation (Analysis 2.13), extrapyramidal symptoms (Analysis 2.14), white blood cell count (Analysis 2.15) and weight gain (Analysis 2.16; Analysis 2.17). Results on ‘at least one adverse effect’, cardiac effects and sedation indicated an advantage for quetiapine. These findings were based on only one or two studies; therefore, they cannot be considered to be robust.
2.4 Quality of life
Quality of life was not measured and was not reported in these studies.
3. Comparison 3. QUETIAPINE versus OLANZAPINE
Most of the studies included in the review contributed data to this comparison (14 studies, n = 1953) (summary of findings Table 3).
3.1 Leaving the studies early
Fewer people in the olanzapine group compared with the quetiapine group left studies early for ‘any reason’ or because of ‘inefficacy of treatment’. This finding suggests that olanzapine is a more acceptable treatment than quetiapine, at least in the confines of clinical trials. Nevertheless, the overall rate of premature study discontinuations was high (61.7%), limiting the validity of all other results (Analysis 3.1).
3.2 Efficacy outcomes (global state, overall and specific mental state)
Quetiapine is probably slightly less effective than olanzapine in reducing general mental state symptoms according to studies of moderate‐quality evidence (Analysis 3.4; Analysis 3.5). No significant difference was noted in the reduction of negative symptoms or positive symptoms (Analysis 3.6; Analysis 3.7; Analysis 3.8; Analysis 3.9; Analysis 3.10; Analysis 3.11; Analysis 3.12). The latter findings should be interpreted with caution; studies measuring negative and positive symptoms were of low and very low quality, respectively.
3.3 Service use: number of participants re‐hospitalised
The number of participants re‐hospitalised was significantly higher in the quetiapine group (Analysis 3.15). This may reflect a certain efficacy advantage of olanzapine.
3.4 Adverse effects
Adverse effects were reported as at least one adverse effect, cardiac effects, QTc abnormalities and an increase in serum cholesterol, serum glucose and serum prolactin, as well as associated side effects, death, extrapyramidal symptoms, the occurrence of sedation, seizures and weight gain. Among these adverse effects, a benefit for quetiapine was found for the use of antiparkinson medication (a proxy measure for extrapyramidal adverse effects; Analysis 3.22), weight gain (Analysis 3.30; Analysis 3.31), glucose elevation (Analysis 3.28; Analysis 3.29), prolactin increase (Analysis 3.25) and some prolactin‐associated adverse effects. On the other hand, a certain superiority of olanzapine was noted in terms of QTc prolongation (Analysis 3.18). Overall, it seems that quetiapine may be more tolerable than olanzapine, but this is weighed against slightly less efficacy.
3.5 General functioning and quality of life
Very limited data on these important outcomes are available. Olanzapine may improve general functioning (GAF total score) to a greater extent than quetiapine (Analysis 3.13). One study of moderate quality reported no difference in quality of life measures between olanzapine and quetiapine (Analysis 3.14).
4. Comparison 4. QUETIAPINE versus PALIPERIDONE
Only two studies (Canuso 2008; Eerdekens 2007) with 406 participants provided data on this comparison. Eerdekens contributed only to adverse effects outcomes. Both studies were short term and were sponsored by the manufacturers of paliperidone. Please see summary of findings Table 4.
4.1 Leaving the studies early
The overall number of participants leaving the studies early was relatively low compared with other comparisons (14.0%). No significant difference was reported between groups or for reasons why participants left the studies (Analysis 4.1).
4.2 Efficacy outcomes (global state, overall and specific mental state)
Paliperidone showed better efficacy than quetiapine in improving the overall mental state score and in reducing positive and negative symptoms (Analysis 4.2; Analysis 4.3; Analysis 4.4). However, this finding was based on only one small, short‐term trial, thus limiting interpretation.
4.3 Adverse effects
In one small study, more participants reported at least one side effect while taking quetiapine compared with paliperidone (Analysis 4.5). However, the Canuso 2008 study showed an advantage of quetiapine in terms of parkinsonian side effects, prolactin levels, sexual side effects and weight gain. Further studies are required to clarify the differences in adverse effect profiles between these two medications.
5. Comparison 5. QUETIAPINE versus RISPERIDONE
Nineteen studies including 3123 participants met the inclusion criteria for this comparison. Please see summary of findings Table 5.
5.1 Leaving the studies early
No clear difference was evident in the number of participants leaving the studies early, suggesting a similar overall acceptability of quetiapine and risperidone (Analysis 5.1). Nevertheless, the overall discontinuation rate was high (51.8%), thus limiting the interpretation of all other results.
5.2 Efficacy outcomes (global state, overall and specific mental state)
Differences in efficacy were found for the general mental state, positive symptoms and, on exclusion of an outlier, negative symptoms (Analysis 5.4; Analysis 5.5; Analysis 5.6; Analysis 5.7; Analysis 5.8; Analysis 5.9; Analysis 5.10; Analysis 5.11; Analysis 5.12; Analysis 5.13). Quetiapine was less effective than risperidone in these aspects of psychopathology. Nevertheless, the differences were small (e.g. only three points on the PANSS total score).
5.3 Adverse effects
Adverse effects were reported as at least one adverse effect, cardiac effects, cholesterol increase, changes in serum glucose, increase in prolactin level and associated side effects, death, extrapyramidal adverse effects, sedation, weight gain and white blood cell count. Among these, quetiapine was better than risperidone in various measures of extrapyramidal adverse effects (Analysis 5.21; Analysis 5.22) and prolactin‐associated effects (Analysis 5.24; Analysis 5.25). On the other hand, quetiapine was associated with increased sedation (Analysis 5.20) and cholesterol (Analysis 5.26; Analysis 5.27) compared with risperidone. These differences in the adverse effect profile and the slightly lower efficacy of quetiapine may be weighed in drug selection.
5.4 Quality of life
Three studies of moderate quality assessed quality of life (Analysis 5.14). Participants treated with quetiapine reported significantly higher quality of life scores than those treated with risperidone.
6. Comparison 6. QUETIAPINE versus ZIPRASIDONE
Only two studies with 722 participants provided data on this comparison. Please see summary of findings Table 6.
6.1 Leaving the studies early
The overall number of participants leaving the studies early was very high (80.7%), clearly limiting the interpretation of any findings beyond the outcome of ‘leaving the study early’. No significant difference was noted between groups, but the acceptability of both compounds seems to be poor (Analysis 6.1).
6.2 Efficacy outcomes (global state, overall and specific mental state)
No significant difference in global state, general mental state or positive symptoms was noted in studies with evidence of very low (general state) or low (positive and negative symptoms) quality (Analysis 6.2; Analysis 6.3; Analysis 6.4).
6.3 Adverse effects
Adverse effects were reported as at least one adverse effect; cardiac effects; death; extrapyramidal side effects; changes in cholesterol, glucose and prolactin; the occurrence of sedation and weight gain. Quetiapine was advantageous in the use of antiparkinson medication (one study, low‐quality evidence; Analysis 6.11) and for prolactin levels (two studies, moderate‐quality evidence; Analysis 6.12; Analysis 6.13), and two studies with moderate‐quality evidence favoured ziprasidone for weight gain (Analysis 6.17; Analysis 6.18) and sedation (Analysis 6.10).
6.4 Quality of life
Quality of life was not measured in these studies.
Overall completeness and applicability of evidence
We did not identify a single study for almost half of the possible comparisons of quetiapine with other second‐generation antipsychotic drugs. Evidence, therefore, is incomplete. Only two studies were long term, limiting applicability of the evidence, as, after all, schizophrenia is a chronic, often lifelong, disorder. Furthermore, most of the included studies were efficacy studies; therefore external validity is limited, and further effectiveness (pragmatic/real‐world) studies are needed.
Quality of the evidence
All studies were randomised and at least single‐blind, but details were rarely presented. Therefore it is unclear in almost all studies whether randomisation and blinding were really done appropriately. Furthermore, the high numbers of participants leaving the studies early (overall 50.2%) and the small number of long‐term studies (Lieberman 2005; McEvoy 2007; Voruganti 2007) call the validity of the findings into question. Selective reporting was evident in all but five studies, and thirteen studies were sponsored by an industry with considerable pecuniary interest in the results. All these factors limit the quality of the evidence.
Potential biases in the review process
We are aware of flaws in our review process. We are unclear whether or not these have add biases to the review.
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First: The search took place some time ago. This review has been a considerable undertaking, and its expansion and upgrading have taken time. We are aware that more trials are likely to be available, and we do hope to update swiftly.
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Second: We have excluded studies that are not fully blinded. This excludes many trials. On one hand, by doing this we have attempted to find trials that have taken some precautions against performance bias and detection bias. On the other hand, however, we have not made judgements to suggest that this has really been successful (and from the profile of adverse effects, this seems unlikely). In addition, quetiapine or the control drugs are not given blindly in the real world. The intervention in everyday care is not solely prescription of the drug, it is open giving of the drug with potential biases surrounding that open giving. This review, therefore, attempts to summarise the more explanatory studies (Thorpe 2009) by providing their advantages, drawbacks and potential biases.
Agreements and disagreements with other studies or reviews
This update substantially expands the earlier version (Komossa 2009). However, generally its findings are consistent with findings from previous versions.
A previous Cochrane review compared the effects of quetiapine with those of placebo, first‐generation antipsychotic drugs and second‐generation antipsychotic drugs for schizophrenia (Srisurasapont 2004). A single study fell into the last category and compared quetiapine with risperidone. This update with reformatting of the review has identified many new studies, and the data included are far more comprehensive than those provided previously.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 1 Leaving the study early.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 2 Mental state: 1. General ‐ average endpoint score (PANSS total, high=poor).
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 3 Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high=poor).
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 4 Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high=poor).
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 5 General functioning: General ‐ average endpoint score ‐ medium term (GAF total score, high=poor.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 6 Adverse effects: 1. General ‐ at least one adverse effect.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 7 Adverse effects: 2a. Cardiac effects ‐ QTc prolongation.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 8 Adverse effects: 2b. Cardiac effects ‐ Tachycardia.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 9 Adverse effects: 3a. Extrapyramidal effects.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 10 Adverse effects: 4a. Prolactin associated side effects.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 11 Adverse effects: 5a. Metabolic ‐ weight gain of 7% or more of total body weight.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 12 Adverse effects. 5b. Metabolic ‐ weight gain ‐ change from baseline in kg.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 13 Adverse effects: 5c. Metabolic ‐ cholesterol ‐ change from baseline in mg/dl.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 14 Adverse effects: 5d. Metabolic ‐ glucose ‐ change from baseline in mg/dl.
Comparison 1 QUETIAPINE versus ARIPIPRAZOLE, Outcome 15 Adverse effects: 6. Death .
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 1 Leaving the study early.
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 2 Global state: 1a. No clinically significant response (as defined by original studies).
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 3 Global state: 1b. No clinically important change ‐ short term (as measured by CGI).
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 4 Mental state: 1a. General ‐ no clinically important change ‐ short term (less than 50% PANSS total score reduction).
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 5 Mental state: 1b. General ‐ average endpoint score ‐ short term (PANSS total, high=poor).
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 6 Mental state: 1c. General ‐ average endpoint score ‐ short term (BPRS total, high=poor).
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 7 Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high=poor).
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 8 Mental state: 3a. Negative symptoms ‐ average endpoint score ‐ short term (PANSS negative subscore, high=poor).
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 9 Mental state: 3b. Negative symptoms ‐ no clinically important change ‐ short term (less than 50% SANS total score reduction).
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 10 Mental state: 3c. Negative symptoms ‐ average endpoint score ‐ short term (SANS total, high=poor).
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 11 Adverse effects: 1. General ‐ at least one adverse effect.
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 12 Adverse effects: 2. Cardiac effects: ECG abnormalities.
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 13 Adverse effects: 3. Central nervous system ‐ sedation.
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 14 Adverse effects: 4. Extrapyramidal effects.
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 15 Adverse effects: 5. Haematological: Important decline in white blood cells.
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 16 Adverse effects: 6a. Metabolic ‐ weight ‐ gain.
Comparison 2 QUETIAPINE versus CLOZAPINE ‐ all data short term, Outcome 17 Adverse effects: 6b. Metabolic ‐ weight ‐ change from baseline (kg).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 1 Leaving the study early.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 2 Global state: 1a. No clinically significant response (as defined by the original studies).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 3 Global state: 1b. No clinically important change (as measured by CGI).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 4 Mental state: 1a. General ‐ no clinically important change ‐ short term (less than 50% PANSS total score reduction).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 5 Mental state: 1b. General ‐ average endpoint score (PANSS total, high=poor).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 6 Mental state: 2a. Positive symptoms ‐ no clinically important change ‐ short term (less than 20% SAPS total score reduction).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 7 Mental state: 2b. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high=poor).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 8 Mental state: 2c. Positive symptoms ‐ SAPS total score ‐ percent change ‐ short term (high=poor).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 9 Mental state: 3a. Negative symptoms ‐ no clinically important change ‐ short term (less than 20% SANS total score reduction).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 10 Mental state: 3b. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high=poor).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 11 Mental state: 3c. Negative symptoms ‐ average endpoint score ‐ medium term (SANS, high=poor).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 12 Mental state: 3d. Negative symptoms ‐ average change in endpoint score ‐ short term (SANS, high=poor).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 13 General functioning: General ‐ average endpoint score ‐ medium term (GAF total score, low=poor).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 14 Quality of life: General ‐ average change in endpoint score ‐ medium term (QLS total score, low=poor).
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 15 Service use: 1. Number of participants re‐hospitalised.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 16 Adverse effects: 1. General ‐ at least one adverse effect.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 17 Adverse effects: 2. Death.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 18 Adverse effects: 3a. Cardiac effects ‐ QTc prolongation.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 19 Adverse effects: 3b. Cardiac effects ‐ QTc abnormalities ‐ change from baseline in ms.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 20 Adverse effects: 4a. Central nervous system ‐ sedation.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 21 Adverse effects: 4b. Central nervous system ‐ seizures.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 22 Adverse effects: 5a. Extrapyramidal effects.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 23 Adverse effects: 5b. Extrapyramidal effects ‐ scale measured.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 24 Adverse effects: 6a. Prolactin associated side effects.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 25 Adverse effects: 6b. Prolactin ‐ change from baseline in ng/ml.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 26 Adverse effects: 7a. Metabolic ‐ cholesterol ‐ significant cholesterol increase.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 27 Adverse effects: 7b. Metabolic ‐ cholesterol ‐ change from baseline in mg/dl.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 28 Adverse effects: 7c. Metabolic ‐ glucose ‐ abnormally high fasting glucose value.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 29 Adverse effects: 7d. Metabolic ‐ glucose ‐ change from baseline in mg/dl.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 30 Adverse effects: 7e. Metabolic ‐ weight ‐ gain.
Comparison 3 QUETIAPINE versus OLANZAPINE, Outcome 31 Adverse effects: 7f. Metabolic ‐ weight ‐ change from baseline in kg.
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 1 Leaving the study early.
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 2 Mental state: 1. General ‐ average endpoint score (PANSS total, high=poor).
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 3 Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high=poor).
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 4 Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high=poor).
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 5 Adverse effects: 1. General ‐ at least one adverse effect.
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 6 Adverse effects: 2a. Cardiac effects ‐ QTc prolongation.
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 7 Adverse effects: 2b. Cardiac effects ‐ QTc abnormalities ‐ change from baseline in ms.
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 8 Adverse effects: 3a. Extrapyramidal effects.
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 9 Adverse effects: 3b. Extrapyramidal effects ‐ scale measured.
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 10 Adverse effects: 4a. Prolactin associated effects.
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 11 Adverse effects: 4b. Prolactin ‐ change from baseline in ng/ml.
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 12 Adverse effects: 5a. Metabolic ‐ weight gain ‐ change from baseline in kg.
Comparison 4 QUETIAPINE versus PALIPERIDONE, Outcome 13 Adverse effects: 5b. Metabolic ‐ weight gain of 7% or more of total body weight.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 1 Leaving the study early.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 2 Global state: 1a. No clinically significant response (as defined by the original studies).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 3 Global state: 1b. No clinically important change (as measured by CGI).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 4 Mental state: 1a General ‐ no clinically important change ‐ short term (less than 30% PANSS total score reduction).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 5 Mental state: 1b. General ‐ no clinically important change ‐ short term (less than 20% BPRS total score reduction).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 6 Mental state: 1c. General ‐average endpoint score (PANSS total score, high=poor).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 7 Mental state: 1d. General ‐ average endpoint score ‐ short term (BPRS total score, high=poor).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 8 Mental state: 2a. Positive symptoms ‐ no clinically important change ‐ short term (less than 40% PANSS positive reduction).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 9 Mental state: 2b. Positive symptoms ‐ average endpoint score ‐ (PANSS positive subscore, high=poor).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 10 Mental state: 2c. Positive symptoms ‐ average change in endpoint score ‐ short term (BPRS positive subscore, high=poor).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 11 Mental state: 3a. Negative symptoms ‐ no clinically important change ‐ short term (less than 40% PANSS negative reduction).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 12 Mental state: 3b. Negative symptoms ‐average endpoint score ‐ (PANSS negative subscore, high=poor).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 13 Mental state: 3c. Negative symptoms ‐ average change in endpoint score ‐ (BPRS negative subscore, high=poor).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 14 Quality of life: General ‐ average endpoint score ‐ (QLS total score, low=poor).
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 15 Service use: number of participants re‐hospitalised.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 16 Adverse effects: 1. General ‐ at least one adverse effect.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 17 Adverse effects: 2. Death.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 18 Adverse effects: 3a. Cardiac effects ‐ QTc prolongation.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 19 Adverse effects: 3b. Cardiac effects ‐ QTc abnormalities ‐ change from baseline in ms.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 20 Adverse effects: 4. Central nervous system ‐ sedation.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 21 Adverse effects: 5a. Extrapyramidal effects.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 22 Adverse effects: 5b. Extrapyramidal effects ‐ scale measured ‐ endpoint/ change to endpoint score.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 23 Adverse effects: 6. Haematological: important decline in white blood cells.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 24 Adverse effects: 7a. Prolactin associated side effects.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 25 Adverse effects: 7b. Prolactin ‐ change from baseline in mg/dl.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 26 Adverse effects: 8a. Metabolic ‐ cholesterol ‐ significant cholesterol increase.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 27 Adverse effects: 8b. Metabolic ‐ cholesterol ‐ change from baseline in mg/dl.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 28 Adverse effects: 8c. Metabolic ‐ glucose ‐ abnormally high fasting glucose value.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 29 Adverse effects: 8d. Metabolic ‐ glucose ‐ change from baseline in mg/dl.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 30 Adverse effects: 8e. Metabolic ‐ weight gain of 7% or more of total body weight.
Comparison 5 QUETIAPINE versus RISPERIDONE, Outcome 31 Adverse effects: 8f. Metabolic ‐ weight gain ‐ change from baseline in kg.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 1 Leaving the study early.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 2 Mental state: 1. General ‐ average endpoint score (PANSS total score, high=poor).
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 3 Mental state: 2. Positive symptoms ‐ average endpoint score ‐ medium term (PANSS positive subscore, high=poor).
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 4 Mental state: 3. Negative symptoms ‐ average endpoint score ‐ medium term (PANSS negative subscore, high=poor).
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 5 Service use: number of participants re‐hospitalised.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 6 Adverse effects: 1. General ‐ at least one adverse effect.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 7 Adverse effects: 2. Death.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 8 Adverse effects: 3a. Cardiac effects ‐ QTc prolongation.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 9 Adverse effects: 3b. Cardiac effects ‐ QTc abnormalities ‐ change from baseline in ms.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 10 Adverse effects: 4. Central nervous system ‐ sedation.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 11 Adverse effects: 5. Extrapyramidal effects.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 12 Adverse effects: 6a. Prolactin associated effects.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 13 Adverse effects: 6b. Prolactin ‐ change from baseline in ng/ml.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 14 Adverse effects: 7a. Metabolic ‐ cholesterol ‐ change from baseline in mg/dl.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 15 Adverse effects: 7b. Metabolic ‐ glucose‐ change from baseline in mg/dl.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 16 Adverse effects: 7c. Metabolic ‐ glucose ‐ abnormally high fasting glucose value.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 17 Adverse effects: 7d. Metabolic ‐ weight gain of 7% or more of total body weight.
Comparison 6 QUETIAPINE versus ZIPRASIDONE, Outcome 18 Adverse effects: 7e. Metabolic ‐ weight gain ‐ change from baseline in kg.
Comparison 7 QUETIAPINE versus ARIPIPRAZOLE ‐ sensitivity analyses (skewed data excluded), Outcome 1 Mental state: 1. General ‐ average endpoint score ‐ short term (PANSS total, high=poor).
Comparison 8 QUETIAPINE versus CLOZAPINE‐ sensitivity analysis (skewed data excluded), Outcome 1 Mental state: 1. General ‐ average endpoint score ‐ short term (PANSS total, high=poor).
Comparison 9 QUETIAPINE versus OLANZAPINE‐ sensitivity analysis (skewed data excluded), Outcome 1 Mental state: 1. General ‐ average endpoint score (PANSS total subscore, high=poor).
Comparison 9 QUETIAPINE versus OLANZAPINE‐ sensitivity analysis (skewed data excluded), Outcome 2 Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high=poor).
Comparison 9 QUETIAPINE versus OLANZAPINE‐ sensitivity analysis (skewed data excluded), Outcome 3 Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high=poor).
Comparison 10 QUETIAPINE versus RISPERIDONE‐ sensitivity analysis (skewed data excluded), Outcome 1 Global state: 1a. No clinically significant response (as defined by the original studies).
Comparison 10 QUETIAPINE versus RISPERIDONE‐ sensitivity analysis (skewed data excluded), Outcome 2 Mental state: 1. General ‐ average endpoint score ‐ (PANSS total score, high=poor).
Comparison 10 QUETIAPINE versus RISPERIDONE‐ sensitivity analysis (skewed data excluded), Outcome 3 Mental state: 6. Positive symptoms ‐ average endpoint score ‐ (PANSS positive subscore, high=poor).
Comparison 10 QUETIAPINE versus RISPERIDONE‐ sensitivity analysis (skewed data excluded), Outcome 4 Mental state: 6. Negative symptoms ‐ average endpoint score ‐ (PANSS negative subscore, high=poor).
Comparison 10 QUETIAPINE versus RISPERIDONE‐ sensitivity analysis (skewed data excluded), Outcome 5 Adverse effects: 1. Extrapyramidal effects ‐ Simpson‐Angus Scale (high=poor).
| Excluded study | Comparison |
| quetiapine versus quetiapine + clozapine | |
| Cao 2006d; Guo 2008; Nai 2007; Zhang 2006; Sun 2006e; Xu 2006; Zhang 2007a | quetiapine versus chlorpramazine |
| quetiapine versus haloperidol | |
| quetiapine versus perphenazine | |
| quetiapine versus sulpiride | |
| quetiapine from non‐domestic source vs domestic quetiapine |
| Methods | Allocation: randomised ‐ clearly described generation of sequence and concealment of allocation. |
| Participants | Diagnosis: schizophrenia (operational criteria). |
| Interventions | 1. Quetiapine: dose ˜300‐800 mg/day. N=300. 2. Amisulpride: dose ˜ 400‐800 mg/day. N=300. 3. Aripiprazole: dose ˜ 10‐30 mg/day. N=300. 4. Clozapine: dose ˜ 300‐800 mg/day. N=300. 5. Olanzapine: dose ˜ 10‐20 mg/day. N=300. 6. Ziprasidone: dose ˜ 120‐160 mg/day. N=300. 7. Risperidone: dose ˜ 4‐8 mg/day. N=300. 8. Sertindole: dose ˜ 12‐24 mg/day. N=300. 9. Zotepine: dose ˜ 100‐300 mg/day. N=300. 10. Paliperidone: dose˜ 6‐12 mg/day. N=300. |
| Outcomes | Global state: CGI**, relapse. Leaving study early (any reason, adverse events, inefficacy). |
| *Power calculation suggested 300/group would allow good chance of showing a 10% difference between groups for primary outcome. | |
| QUETIAPINE versus ARIPIPRAZOLE for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus ARIPIPRAZOLE | |||||
| Mental state: 1. General ‐ average endpoint score | Mean mental state: 1. General ‐ average endpoint score in the intervention groups was | 297 | ⊕⊕⊝⊝ | |||
| Mental state: 2. Positive symptoms average endpoint score | Mean mental state: 2. Positive symptoms ‐ average endpoint score in the intervention groups was | 297 | ⊕⊕⊝⊝ | |||
| Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high = poor) | Mean mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high = poor) in the intervention groups was | 297 | ⊕⊕⊝⊝ | |||
| Quality of life: substantial improvement | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome in any form |
| Adverse effects: 1. Sedation | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome in any form |
| Adverse effects: 2. Extrapyramidal effects ‐ use of antiparkinson medication | Low4 | RR 0.67 | 40 | ⊕⊕⊝⊝ | ||
| 50 per 1000 | 34 per 1000 | |||||
| Moderate4 | ||||||
| 150 per 1000 | 101 per 1000 | |||||
| High4 | ||||||
| 250 per 1000 | 168 per 1000 | |||||
| Adverse effects: 3. Metabolic ‐ weight gain ≥7% of total body weight | Low4 | RR 0.52 | 155 | ⊕⊕⊝⊝ | ||
| 10 per 1000 | 5 per 1000 | |||||
| Moderate4 | ||||||
| 50 per 1000 | 26 per 1000 | |||||
| High4 | ||||||
| 100 per 1000 | 52 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1 Risk of bias: rated serious ‐ only one study adequately described appropriate allocation concealment methods (but not sequence generation). All other studies did not adequately describe sequence generation and allocation concealment. | ||||||
| QUETIAPINE versus CLOZAPINE all data short term for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus CLOZAPINE all data short term | |||||
| Mental state: 1. General ‐ average endpoint score short term (PANSS total, high = poor) | Mental state: 1. General ‐ average endpoint score short term (PANSS total, high = poor) in the intervention groups was | 232 | ⊕⊕⊝⊝ | |||
| Mental state: 2. Positive symptoms ‐ average endpoint score | Mean mental state: 2. Positive symptoms ‐ average endpoint score in the intervention groups was | 142 | ⊕⊕⊝⊝ | |||
| Mental state: 3. Negative symptoms ‐ average endpoint score short term | Mental state: 3. Negative symptoms ‐ average endpoint score short term in the intervention groups was | 142 | ⊕⊕⊝⊝ | |||
| Quality of life: substantial improvement | See comment | See comment | Not estimable | 0 | See comment | No study reported this outcome in any form |
| Adverse effects: 1. Sedation | Low5 | RR 0.22 | 135 | ⊕⊕⊕⊝ | ||
| 200 per 1000 | 44 per 1000 | |||||
| Moderate5 | ||||||
| 500 per 1000 | 110 per 1000 | |||||
| High5 | ||||||
| 800 per 1000 | 176 per 1000 | |||||
| Adverse effects: 2. Extrapyramidal effects ‐ use of antiparkinson medication | Moderate | See comment | 28 | ⊕⊕⊝⊝ | Risks were calculated from pooled risk differences. No events in either group (RD 0.0 CI ‐0.13 to 0.13) | |
| 0 per 1000 | 0 per 1000 | |||||
| Adverse effects: 3. Metabolic ‐ weight gain | Low5 | RR 0.53 | 135 | ⊕⊕⊝⊝ | ||
| 100 per 1000 | 53 per 1000 | |||||
| Moderate5 | ||||||
| 250 per 1000 | 132 per 1000 | |||||
| High5 | ||||||
| 400 per 1000 | 212 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1Risk of bias: rated serious none of the studies adequately described sequence generation and allocation concealment. | ||||||
| QUETIAPINE versus OLANZAPINE for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus OLANZAPINE | |||||
| Mental state: 1. General ‐ average endpoint score (PANSS total, high = poor) | Mental state: 1. General ‐ average endpoint score (PANSS total, high = poor) in the intervention groups was | 1486 | ⊕⊕⊝⊝ | |||
| Mental state: 2. Positive symptoms ‐ average endpoint score | Mental state: 2. Positive symptoms ‐ average endpoint score in the intervention groups was | 801 | ⊕⊕⊕⊝ | |||
| Mental state: 3. Negative symptoms ‐ endpoint score | Mental state: 3. Negative symptoms ‐ average endpoint score in the intervention groups was | 801 | ⊕⊕⊕⊝ | |||
| Quality of life: general ‐ average change in endpoint score medium term | Mean quality of life: general ‐ average change in endpoint score medium term in the intervention groups was | 286 | ⊕⊕⊕⊝ | |||
| Adverse effects: 1. Sedation | Low7 | RR 0.98 | 1615 | ⊕⊕⊕⊝ | ||
| 100 per 1000 | 98 per 1000 | |||||
| Moderate7 | ||||||
| 300 per 1000 | 294 per 1000 | |||||
| High7 | ||||||
| 500 per 1000 | 490 per 1000 | |||||
| Adverse effects: 2. Extrapyramidal effects ‐ use of antiparkinson medication | Low7 | See comment | 1127 | ⊕⊕⊕⊝ | Risks were calculated from pooled risk differences | |
| 50 per 1000 | 28 per 1000 | |||||
| Moderate7 | ||||||
| 100 per 1000 | 55 per 1000 | |||||
| High7 | ||||||
| 150 per 1000 | 82 per 1000 | |||||
| Adverse effects: 3. Metabolic ‐ weight significant gain | Low7 | RR 0.69 | 1321 | ⊕⊕⊕⊝ | ||
| 200 per 1000 | 138 per 1000 | |||||
| Moderate7 | ||||||
| 400 per 1000 | 276 per 1000 | |||||
| High7 | ||||||
| 600 per 1000 | 414 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1Risk of bias: rated serious no studies adequately described sequence generation and allocation concealment. | ||||||
| QUETIAPINE versus PALIPERIDONE for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus PALIPERIDONE | |||||
| Mental state: 1. General ‐ average endpoint score | Mental state: 1. General ‐ average endpoint score in the intervention groups was | 319 | ⊕⊕⊕⊝ | |||
| Mental state: 2. Positive symptoms ‐ average endpoint score | Mental state: 2. Positive symptoms average endpoint score in the intervention groups was | 319 | ⊕⊕⊕⊝ | |||
| Mental state: 3. Negative symptoms ‐ average endpoint score | Mental state: 3. Negative symptoms ‐ average endpoint score in the intervention groups was | 319 | ⊕⊕⊕⊝ | |||
| Quality of life: substantial improvement | See comment | See comment | Not estimable | 0 | See comment | No trial reported this outcome in any form |
| Adverse effects: 1. Sedation | See comment | See comment | Not estimable | 0 | See comment | No trial reported this outcome in any form |
| Adverse effects: 2. Extrapyramidal effects use of antiparkinson medication | Low3 | RR 0.64 | 319 | ⊕⊕⊕⊝ | ||
| 200 per 1000 | 128 per 1000 | |||||
| Moderate3 | ||||||
| 400 per 1000 | 256 per 1000 | |||||
| High3 | ||||||
| 600 per 1000 | 384 per 1000 | |||||
| Adverse effects: 3. Metabolic weight gain ≥7% of total body weight | Moderate3 | RR 2.52 | 319 | ⊕⊕⊕⊝ | ||
| 10 per 1000 | 25 per 1000 | |||||
| High3 | ||||||
| 100 per 1000 | 252 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1Calculated using generic inverse variance. | ||||||
| QUETIAPINE versus RISPERIDONE for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus RISPERIDONE | |||||
| Mental state: 1. General ‐ average endpoint score | Mental state: 1. General ‐ average endpoint score in the intervention groups was | 2155 | ⊕⊕⊕⊝ | |||
| Mental state: 2. Positive symptoms ‐ average endpoint score | Mental state: 2. Positive symptoms ‐ average endpoint score in the intervention groups was | 1492 | ⊕⊕⊕⊝ | |||
| Mental state: 3. Negative symptoms ‐ average endpoint score | Mean mental state: 3. Negative symptoms ‐ average endpoint score in the intervention groups was | 1367 | ⊕⊕⊝⊝ | |||
| Quality of life: general average endpoint score | Mean quality of life: general average endpoint score in the intervention groups was | 152 | ⊕⊕⊝⊝ | |||
| Adverse effects: 1. Sedation | Study population | RR 1.21 | 2226 | |||
| 246 per 1000 | 298 per 1000 | |||||
| Moderate | ||||||
| 239 per 1000 | 289 per 1000 | |||||
| Adverse effects: 2. Extrapyramidal effects ‐ use of antiparkinson medication | Low6 | RR 0.5 | 2163 | ⊕⊕⊕⊝ | ||
| 50 per 1000 | 25 per 1000 | |||||
| Moderate6 | ||||||
| 150 per 1000 | 75 per 1000 | |||||
| High6 | ||||||
| 250 per 1000 | 125 per 1000 | |||||
| Adverse effects: 3. Metabolic weight gain ≥7% of total body weight | Low6 | RR 0.96 | 2070 | ⊕⊕⊕⊝ | ||
| 100 per 1000 | 96 per 1000 | |||||
| Moderate6 | ||||||
| 200 per 1000 | 192 per 1000 | |||||
| High6 | ||||||
| 300 per 1000 | 288 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1Risk of bias: rated serious overall inadequate description of sequence generation and allocation concealment. Only two studies adequately described sequence generation. | ||||||
| QUETIAPINE versus ZIPRASIDONE for schizophrenia | ||||||
| Patient or population: participants with schizophrenia | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | QUETIAPINE versus ZIPRASIDONE | |||||
| Mental state: 1. General ‐ average endpoint score | Mental state: 1. General ‐ average endpoint score in the intervention groups was | 198 | ⊕⊕⊝⊝ | |||
| Mental state: 2. Positive symptoms ‐ average endpoint score medium term | Mental state: 2. Positive symptoms ‐ average endpoint score medium term in the intervention groups was | 198 | ⊕⊕⊝⊝ | |||
| Mental state: 3. Negative symptoms ‐ average endpoint score medium term | Mental state: 3. Negative symptoms ‐ average endpoint score medium term in the intervention groups was | 198 | ⊕⊕⊝⊝ | |||
| Quality of life: substantial improvement | See comment | See comment | Not estimable | 0 | See comment | No trial reported this outcome in any form |
| Adverse effects: 1. Sedation | Low3 | RR 1.36 | 754 | ⊕⊕⊝⊝ | ||
| 100 per 1000 | 136 per 1000 | |||||
| Moderate3 | ||||||
| 200 per 1000 | 272 per 1000 | |||||
| High3 | ||||||
| 300 per 1000 | 408 per 1000 | |||||
| Adverse effects: 2. Extrapyramidal effects ‐ use of antiparkinson medication | Low3 | RR 0.43 | 522 | ⊕⊕⊝⊝ | ||
| 50 per 1000 | 22 per 1000 | |||||
| Moderate3 | ||||||
| 100 per 1000 | 43 per 1000 | |||||
| High3 | ||||||
| 150 per 1000 | 65 per 1000 | |||||
| Adverse effects: 3. Metabolic weight gain ≥7% of total body weight | Low3 | RR 2.22 | 754 | ⊕⊕⊕⊝ | ||
| 10 per 1000 | 22 per 1000 | |||||
| Moderate3 | ||||||
| 50 per 1000 | 111 per 1000 | |||||
| High3 | ||||||
| 100 per 1000 | 222 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence: | ||||||
| 1Risk of bias: rated serious ‐ inadequately described sequence generation and allocation concealment. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Leaving the study early Show forest plot | 2 | 149 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.59, 1.70] |
| 1.1 any reason | 2 | 149 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.59, 1.70] |
| 2 Mental state: 1. General ‐ average endpoint score (PANSS total, high=poor) Show forest plot | 4 | 297 | Mean Difference (IV, Random, 95% CI) | 1.62 [‐0.89, 4.14] |
| 2.1 short term | 4 | 297 | Mean Difference (IV, Random, 95% CI) | 1.62 [‐0.89, 4.14] |
| 3 Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high=poor) Show forest plot | 4 | 297 | Mean Difference (IV, Random, 95% CI) | 0.62 [‐1.13, 2.38] |
| 3.1 short term | 4 | 297 | Mean Difference (IV, Random, 95% CI) | 0.62 [‐1.13, 2.38] |
| 4 Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high=poor) Show forest plot | 4 | 297 | Mean Difference (IV, Random, 95% CI) | 1.00 [‐0.25, 2.25] |
| 4.1 short term | 4 | 297 | Mean Difference (IV, Random, 95% CI) | 1.00 [‐0.25, 2.25] |
| 5 General functioning: General ‐ average endpoint score ‐ medium term (GAF total score, high=poor Show forest plot | 1 | 41 | Mean Difference (IV, Random, 95% CI) | ‐1.20 [‐14.43, 12.03] |
| 6 Adverse effects: 1. General ‐ at least one adverse effect Show forest plot | 3 | 215 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.71, 1.17] |
| 7 Adverse effects: 2a. Cardiac effects ‐ QTc prolongation Show forest plot | 1 | 85 | Risk Ratio (M‐H, Random, 95% CI) | 3.21 [0.13, 76.74] |
| 8 Adverse effects: 2b. Cardiac effects ‐ Tachycardia Show forest plot | 1 | 85 | Risk Ratio (M‐H, Random, 95% CI) | 7.50 [0.40, 140.91] |
| 9 Adverse effects: 3a. Extrapyramidal effects Show forest plot | 3 | 599 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.45, 1.82] |
| 9.1 akathisia | 3 | 196 | Risk Ratio (M‐H, Random, 95% CI) | 0.57 [0.08, 4.02] |
| 9.2 dyskinesia | 1 | 41 | Risk Ratio (M‐H, Random, 95% CI) | 3.14 [0.14, 72.92] |
| 9.3 dystonia | 2 | 126 | Risk Ratio (M‐H, Random, 95% CI) | 1.42 [0.10, 20.77] |
| 9.4 parkinsonism | 1 | 41 | Risk Ratio (M‐H, Random, 95% CI) | 0.75 [0.28, 1.98] |
| 9.5 tremor | 2 | 155 | Risk Ratio (M‐H, Random, 95% CI) | 1.68 [0.08, 35.92] |
| 9.6 use of antiparkinson medication | 1 | 40 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.12, 3.57] |
| 10 Adverse effects: 4a. Prolactin associated side effects Show forest plot | 1 | 85 | Risk Ratio (M‐H, Random, 95% CI) | 3.21 [0.13, 76.74] |
| 10.1 galactorrhea | 1 | 85 | Risk Ratio (M‐H, Random, 95% CI) | 3.21 [0.13, 76.74] |
| 11 Adverse effects: 5a. Metabolic ‐ weight gain of 7% or more of total body weight Show forest plot | 2 | 155 | Risk Ratio (M‐H, Random, 95% CI) | 0.52 [0.10, 2.74] |
| 12 Adverse effects. 5b. Metabolic ‐ weight gain ‐ change from baseline in kg Show forest plot | 1 | 41 | Mean Difference (IV, Random, 95% CI) | 1.7 [‐0.14, 3.54] |
| 13 Adverse effects: 5c. Metabolic ‐ cholesterol ‐ change from baseline in mg/dl Show forest plot | 1 | 41 | Mean Difference (IV, Random, 95% CI) | 8.2 [‐12.24, 28.64] |
| 14 Adverse effects: 5d. Metabolic ‐ glucose ‐ change from baseline in mg/dl Show forest plot | 1 | 41 | Mean Difference (IV, Random, 95% CI) | ‐9.4 [‐17.90, ‐0.90] |
| 15 Adverse effects: 6. Death Show forest plot | 1 | 74 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15.1 natural causes | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15.2 suicide | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Leaving the study early Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 any reason | 2 | 95 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.18, 2.43] |
| 1.2 due to adverse events | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 0.14 [0.01, 2.67] |
| 1.3 due to inefficacy | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 2 Global state: 1a. No clinically significant response (as defined by original studies) Show forest plot | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.78, 1.13] |
| 3 Global state: 1b. No clinically important change ‐ short term (as measured by CGI) Show forest plot | 1 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.74, 1.18] |
| 4 Mental state: 1a. General ‐ no clinically important change ‐ short term (less than 50% PANSS total score reduction) Show forest plot | 1 | 63 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.53, 2.14] |
| 5 Mental state: 1b. General ‐ average endpoint score ‐ short term (PANSS total, high=poor) Show forest plot | 4 | 232 | Mean Difference (IV, Random, 95% CI) | ‐0.50 [‐2.85, 1.86] |
| 6 Mental state: 1c. General ‐ average endpoint score ‐ short term (BPRS total, high=poor) Show forest plot | 1 | 67 | Mean Difference (IV, Random, 95% CI) | ‐0.89 [‐3.20, 1.42] |
| 7 Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high=poor) Show forest plot | 2 | 142 | Mean Difference (IV, Random, 95% CI) | ‐0.70 [‐2.07, 0.68] |
| 8 Mental state: 3a. Negative symptoms ‐ average endpoint score ‐ short term (PANSS negative subscore, high=poor) Show forest plot | 2 | 142 | Mean Difference (IV, Random, 95% CI) | ‐2.23 [‐3.48, ‐0.99] |
| 9 Mental state: 3b. Negative symptoms ‐ no clinically important change ‐ short term (less than 50% SANS total score reduction) Show forest plot | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.78, 1.13] |
| 10 Mental state: 3c. Negative symptoms ‐ average endpoint score ‐ short term (SANS total, high=poor) Show forest plot | 1 | 67 | Mean Difference (IV, Random, 95% CI) | ‐1.64 [‐8.17, 4.89] |
| 11 Adverse effects: 1. General ‐ at least one adverse effect Show forest plot | 1 | 63 | Risk Ratio (M‐H, Random, 95% CI) | 0.42 [0.26, 0.66] |
| 12 Adverse effects: 2. Cardiac effects: ECG abnormalities Show forest plot | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 0.13 [0.02, 0.95] |
| 13 Adverse effects: 3. Central nervous system ‐ sedation Show forest plot | 2 | 135 | Risk Ratio (M‐H, Random, 95% CI) | 0.22 [0.11, 0.47] |
| 14 Adverse effects: 4. Extrapyramidal effects Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 14.1 akathisia | 2 | 135 | Risk Ratio (M‐H, Random, 95% CI) | 0.40 [0.08, 1.99] |
| 14.2 rigor | 1 | 63 | Risk Ratio (M‐H, Random, 95% CI) | 1.94 [0.18, 20.30] |
| 14.3 tremor | 2 | 135 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.29, 3.34] |
| 14.4 use of antiparkinson medication | 1 | 28 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 15 Adverse effects: 5. Haematological: Important decline in white blood cells Show forest plot | 1 | 63 | Risk Ratio (M‐H, Random, 95% CI) | 0.19 [0.01, 3.88] |
| 16 Adverse effects: 6a. Metabolic ‐ weight ‐ gain Show forest plot | 2 | 135 | Risk Ratio (M‐H, Random, 95% CI) | 0.53 [0.25, 1.11] |
| 17 Adverse effects: 6b. Metabolic ‐ weight ‐ change from baseline (kg) Show forest plot | 1 | 27 | Mean Difference (IV, Random, 95% CI) | ‐2.11 [‐4.30, 0.08] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Leaving the study early Show forest plot | 13 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 any reason | 12 | 1821 | Risk Ratio (M‐H, Random, 95% CI) | 1.26 [1.12, 1.42] |
| 1.2 due to adverse events | 9 | 1610 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.69, 1.18] |
| 1.3 due to inefficacy | 9 | 1600 | Risk Ratio (M‐H, Random, 95% CI) | 1.83 [1.42, 2.36] |
| 2 Global state: 1a. No clinically significant response (as defined by the original studies) Show forest plot | 3 | 339 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.86, 1.43] |
| 3 Global state: 1b. No clinically important change (as measured by CGI) Show forest plot | 2 | 309 | Risk Ratio (M‐H, Random, 95% CI) | 1.18 [0.89, 1.57] |
| 3.1 short term | 1 | 42 | Risk Ratio (M‐H, Random, 95% CI) | 1.36 [0.59, 3.15] |
| 3.2 long term | 1 | 267 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.86, 1.57] |
| 4 Mental state: 1a. General ‐ no clinically important change ‐ short term (less than 50% PANSS total score reduction) Show forest plot | 1 | 42 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.54, 1.53] |
| 5 Mental state: 1b. General ‐ average endpoint score (PANSS total, high=poor) Show forest plot | 11 | 1486 | Mean Difference (IV, Random, 95% CI) | 3.67 [1.95, 5.39] |
| 5.1 short term | 5 | 179 | Mean Difference (IV, Random, 95% CI) | 2.29 [‐1.30, 5.87] |
| 5.2 medium term | 3 | 482 | Mean Difference (IV, Random, 95% CI) | 5.57 [1.97, 9.17] |
| 5.3 long term | 3 | 825 | Mean Difference (IV, Random, 95% CI) | 3.40 [0.91, 5.88] |
| 6 Mental state: 2a. Positive symptoms ‐ no clinically important change ‐ short term (less than 20% SAPS total score reduction) Show forest plot | 1 | 30 | Risk Ratio (M‐H, Random, 95% CI) | 15.0 [0.93, 241.20] |
| 7 Mental state: 2b. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high=poor) Show forest plot | 9 | 801 | Mean Difference (IV, Random, 95% CI) | 1.02 [‐0.81, 2.85] |
| 7.1 short term | 4 | 152 | Mean Difference (IV, Random, 95% CI) | 1.24 [‐0.48, 2.96] |
| 7.2 medium term | 3 | 483 | Mean Difference (IV, Random, 95% CI) | 2.21 [0.90, 3.52] |
| 7.3 long term | 2 | 166 | Mean Difference (IV, Random, 95% CI) | ‐1.25 [‐7.28, 4.79] |
| 8 Mental state: 2c. Positive symptoms ‐ SAPS total score ‐ percent change ‐ short term (high=poor) Show forest plot | 1 | 30 | Mean Difference (IV, Random, 95% CI) | 40.84 [23.97, 57.71] |
| 9 Mental state: 3a. Negative symptoms ‐ no clinically important change ‐ short term (less than 20% SANS total score reduction) Show forest plot | 1 | 30 | Risk Ratio (M‐H, Random, 95% CI) | 1.5 [0.53, 4.26] |
| 10 Mental state: 3b. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high=poor) Show forest plot | 9 | 801 | Mean Difference (IV, Random, 95% CI) | 0.86 [‐0.32, 2.03] |
| 10.1 short term | 4 | 152 | Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐1.70, 1.56] |
| 10.2 medium term | 3 | 483 | Mean Difference (IV, Random, 95% CI) | 0.40 [‐0.67, 1.47] |
| 10.3 long term | 2 | 166 | Mean Difference (IV, Random, 95% CI) | 2.64 [‐1.29, 6.56] |
| 11 Mental state: 3c. Negative symptoms ‐ average endpoint score ‐ medium term (SANS, high=poor) Show forest plot | 1 | 335 | Mean Difference (IV, Random, 95% CI) | 3.70 [‐0.48, 7.88] |
| 12 Mental state: 3d. Negative symptoms ‐ average change in endpoint score ‐ short term (SANS, high=poor) Show forest plot | 1 | 30 | Mean Difference (IV, Random, 95% CI) | 2.46 [‐31.90, 36.82] |
| 13 General functioning: General ‐ average endpoint score ‐ medium term (GAF total score, low=poor) Show forest plot | 3 | 400 | Mean Difference (IV, Random, 95% CI) | 2.55 [0.33, 4.76] |
| 14 Quality of life: General ‐ average change in endpoint score ‐ medium term (QLS total score, low=poor) Show forest plot | 1 | 286 | Mean Difference (IV, Random, 95% CI) | 1.80 [‐2.42, 6.02] |
| 15 Service use: 1. Number of participants re‐hospitalised Show forest plot | 3 | 1009 | Risk Ratio (M‐H, Random, 95% CI) | 1.83 [1.33, 2.52] |
| 15.1 medium term | 2 | 336 | Risk Ratio (M‐H, Random, 95% CI) | 1.98 [1.05, 3.75] |
| 15.2 long term | 1 | 673 | Risk Ratio (M‐H, Random, 95% CI) | 1.78 [1.24, 2.58] |
| 16 Adverse effects: 1. General ‐ at least one adverse effect Show forest plot | 7 | 1306 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.88, 1.05] |
| 17 Adverse effects: 2. Death Show forest plot | 4 | 1450 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.13, 4.23] |
| 17.1 suicide attempt | 2 | 940 | Risk Ratio (M‐H, Random, 95% CI) | 0.35 [0.05, 2.29] |
| 17.2 suicide | 3 | 510 | Risk Ratio (M‐H, Random, 95% CI) | 4.96 [0.24, 102.41] |
| 18 Adverse effects: 3a. Cardiac effects ‐ QTc prolongation Show forest plot | 1 | 673 | Risk Ratio (M‐H, Random, 95% CI) | 12.96 [0.73, 229.17] |
| 19 Adverse effects: 3b. Cardiac effects ‐ QTc abnormalities ‐ change from baseline in ms Show forest plot | 3 | 643 | Mean Difference (IV, Random, 95% CI) | 4.81 [0.34, 9.28] |
| 20 Adverse effects: 4a. Central nervous system ‐ sedation Show forest plot | 7 | 1615 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.78, 1.20] |
| 21 Adverse effects: 4b. Central nervous system ‐ seizures Show forest plot | 1 | 40 | Risk Ratio (M‐H, Random, 95% CI) | 3.3 [0.14, 76.46] |
| 22 Adverse effects: 5a. Extrapyramidal effects Show forest plot | 9 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 22.1 akathisia | 7 | 1314 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.68, 1.38] |
| 22.2 akinesia | 1 | 267 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.67, 1.56] |
| 22.3 dyskinesia | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 2.57 [0.11, 59.30] |
| 22.4 dystonia | 3 | 752 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.21, 6.23] |
| 22.5 extrapyramidal symptoms | 2 | 245 | Risk Ratio (M‐H, Random, 95% CI) | 1.62 [0.72, 3.67] |
| 22.6 parkinsonism | 2 | 77 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.34, 1.74] |
| 22.7 tremor | 1 | 42 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.12, 1.31] |
| 22.8 use of antiparkinson medication | 7 | 1127 | Risk Ratio (M‐H, Random, 95% CI) | 0.51 [0.32, 0.81] |
| 23 Adverse effects: 5b. Extrapyramidal effects ‐ scale measured Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 23.1 akathisia: Barnes Akathisia Scale (high=poor) | 2 | 135 | Mean Difference (IV, Random, 95% CI) | 0.06 [‐0.10, 0.22] |
| 23.2 extrapyramidal symptoms: ESRS total score (high=poor) | 1 | 33 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐2.68, 2.68] |
| 23.3 extrapyramidal symptoms: Simpson‐Angus Scale (high=poor) | 2 | 135 | Mean Difference (IV, Random, 95% CI) | ‐0.06 [‐0.57, 0.44] |
| 23.4 extrapyramidal symptoms: Abnormal Involuntary Movement Scale (AIMS, high=poor) | 1 | 85 | Mean Difference (IV, Random, 95% CI) | 0.17 [‐0.38, 0.72] |
| 24 Adverse effects: 6a. Prolactin associated side effects Show forest plot | 5 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 24.1 abnormally high prolactin value | 1 | 42 | Risk Ratio (M‐H, Random, 95% CI) | 0.10 [0.01, 1.77] |
| 24.2 amenorrhea | 3 | 252 | Risk Ratio (M‐H, Random, 95% CI) | 0.66 [0.36, 1.21] |
| 24.3 galactorrhea | 4 | 1025 | Risk Ratio (M‐H, Random, 95% CI) | 0.66 [0.25, 1.73] |
| 24.4 gynecomastia | 1 | 267 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.09, 1.20] |
| 24.5 sexual dysfunction | 4 | 1177 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.64, 0.99] |
| 25 Adverse effects: 6b. Prolactin ‐ change from baseline in ng/ml Show forest plot | 5 | 1021 | Mean Difference (IV, Random, 95% CI) | ‐5.89 [‐11.62, ‐0.16] |
| 26 Adverse effects: 7a. Metabolic ‐ cholesterol ‐ significant cholesterol increase Show forest plot | 1 | 267 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.59, 1.68] |
| 27 Adverse effects: 7b. Metabolic ‐ cholesterol ‐ change from baseline in mg/dl Show forest plot | 6 | 1156 | Mean Difference (IV, Random, 95% CI) | ‐2.73 [‐8.05, 2.59] |
| 28 Adverse effects: 7c. Metabolic ‐ glucose ‐ abnormally high fasting glucose value Show forest plot | 3 | 1025 | Risk Ratio (M‐H, Random, 95% CI) | 0.47 [0.21, 1.02] |
| 29 Adverse effects: 7d. Metabolic ‐ glucose ‐ change from baseline in mg/dl Show forest plot | 6 | 1156 | Mean Difference (IV, Random, 95% CI) | ‐4.67 [‐9.41, 0.07] |
| 30 Adverse effects: 7e. Metabolic ‐ weight ‐ gain Show forest plot | 8 | 1667 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.51, 0.92] |
| 30.1 significant weight gain (as defined by the original studies) | 7 | 1321 | Risk Ratio (M‐H, Random, 95% CI) | 0.69 [0.51, 0.95] |
| 30.2 as "weight gain" reported adverse events | 1 | 346 | Risk Ratio (M‐H, Random, 95% CI) | 0.49 [0.04, 5.34] |
| 31 Adverse effects: 7f. Metabolic ‐ weight ‐ change from baseline in kg Show forest plot | 10 | 1428 | Mean Difference (IV, Random, 95% CI) | ‐2.54 [‐3.82, ‐1.26] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Leaving the study early Show forest plot | 2 | 1131 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.70, 1.62] |
| 1.1 any reason | 2 | 406 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.61, 1.73] |
| 1.2 due to adverse events | 2 | 406 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.37, 2.17] |
| 1.3 due to inefficacy | 1 | 319 | Risk Ratio (M‐H, Random, 95% CI) | 4.97 [0.59, 42.05] |
| 2 Mental state: 1. General ‐ average endpoint score (PANSS total, high=poor) Show forest plot | 1 | Mean Difference (Random, 95% CI) | 6.3 [2.77, 9.83] | |
| 2.1 short term | 1 | Mean Difference (Random, 95% CI) | 6.3 [2.77, 9.83] | |
| 3 Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high=poor) Show forest plot | 1 | Mean Difference (Random, 95% CI) | 1.6 [0.42, 2.78] | |
| 3.1 short term | 1 | Mean Difference (Random, 95% CI) | 1.6 [0.42, 2.78] | |
| 4 Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high=poor) Show forest plot | 1 | Mean Difference (Random, 95% CI) | 1.30 [0.52, 2.08] | |
| 4.1 short term | 1 | Mean Difference (Random, 95% CI) | 1.30 [0.52, 2.08] | |
| 5 Adverse effects: 1. General ‐ at least one adverse effect Show forest plot | 1 | 87 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [1.06, 1.53] |
| 6 Adverse effects: 2a. Cardiac effects ‐ QTc prolongation Show forest plot | 1 | 319 | Risk Difference (M‐H, Random, 95% CI) | 0.0 [‐0.01, 0.01] |
| 7 Adverse effects: 2b. Cardiac effects ‐ QTc abnormalities ‐ change from baseline in ms Show forest plot | 1 | 87 | Mean Difference (IV, Random, 95% CI) | 2.3 [‐2.50, 7.10] |
| 8 Adverse effects: 3a. Extrapyramidal effects Show forest plot | 2 | 1537 | Risk Ratio (M‐H, Random, 95% CI) | 0.61 [0.42, 0.89] |
| 8.1 akathisia | 2 | 406 | Risk Ratio (M‐H, Random, 95% CI) | 1.35 [0.55, 3.34] |
| 8.2 dystonia | 1 | 87 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.15, 6.94] |
| 8.3 rigidity | 2 | 406 | Risk Ratio (M‐H, Random, 95% CI) | 0.34 [0.12, 0.92] |
| 8.4 tremor | 1 | 319 | Risk Ratio (M‐H, Random, 95% CI) | 0.37 [0.17, 0.80] |
| 8.5 use of antiparkinson medication | 1 | 319 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.45, 0.91] |
| 9 Adverse effects: 3b. Extrapyramidal effects ‐ scale measured Show forest plot | 1 | Mean Difference (Random, 95% CI) | 0.45 [‐0.43, 1.33] | |
| 9.1 abnormal involuntary movement: AIMS (high=poor) | 1 | Mean Difference (Random, 95% CI) | 0.0 [‐0.39, 0.39] | |
| 9.2 extrapyramidal symptoms: Simpson‐Angus Scale (high=poor) | 1 | Mean Difference (Random, 95% CI) | 0.9 [0.51, 1.29] | |
| 10 Adverse effects: 4a. Prolactin associated effects Show forest plot | 1 | 317 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.01, 4.16] |
| 10.1 sexual dysfunction | 1 | 317 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.01, 4.16] |
| 11 Adverse effects: 4b. Prolactin ‐ change from baseline in ng/ml Show forest plot | 1 | 317 | Mean Difference (IV, Random, 95% CI) | ‐49.3 [‐57.80, ‐40.80] |
| 12 Adverse effects: 5a. Metabolic ‐ weight gain ‐ change from baseline in kg Show forest plot | 1 | Mean Difference (Random, 95% CI) | 0.40 [0.20, 0.60] | |
| 13 Adverse effects: 5b. Metabolic ‐ weight gain of 7% or more of total body weight Show forest plot | 1 | 319 | Risk Ratio (M‐H, Random, 95% CI) | 2.52 [0.50, 12.78] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Leaving the study early Show forest plot | 13 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 any reason | 13 | 2784 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [1.00, 1.19] |
| 1.2 due to adverse events | 9 | 2299 | Risk Ratio (M‐H, Random, 95% CI) | 1.12 [0.80, 1.57] |
| 1.3 due to inefficacy | 8 | 1891 | Risk Ratio (M‐H, Random, 95% CI) | 1.32 [1.02, 1.71] |
| 2 Global state: 1a. No clinically significant response (as defined by the original studies) Show forest plot | 4 | 1274 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.95, 1.22] |
| 3 Global state: 1b. No clinically important change (as measured by CGI) Show forest plot | 5 | 1342 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.98, 1.25] |
| 3.1 short term | 4 | 1075 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.95, 1.26] |
| 3.2 long term | 1 | 267 | Risk Ratio (M‐H, Random, 95% CI) | 1.18 [0.87, 1.60] |
| 4 Mental state: 1a General ‐ no clinically important change ‐ short term (less than 30% PANSS total score reduction) Show forest plot | 2 | 982 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.87, 1.42] |
| 5 Mental state: 1b. General ‐ no clinically important change ‐ short term (less than 20% BPRS total score reduction) Show forest plot | 1 | 25 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.63, 1.52] |
| 6 Mental state: 1c. General ‐average endpoint score (PANSS total score, high=poor) Show forest plot | 14 | 2302 | Mean Difference (IV, Random, 95% CI) | 1.67 [0.39, 2.96] |
| 6.1 short term | 8 | 1232 | Mean Difference (IV, Random, 95% CI) | 1.37 [‐0.28, 3.01] |
| 6.2 medium term | 5 | 327 | Mean Difference (IV, Random, 95% CI) | 1.93 [‐1.56, 5.42] |
| 6.3 long term | 2 | 743 | Mean Difference (IV, Random, 95% CI) | 3.11 [0.40, 5.82] |
| 7 Mental state: 1d. General ‐ average endpoint score ‐ short term (BPRS total score, high=poor) Show forest plot | 1 | 25 | Mean Difference (IV, Random, 95% CI) | 1.68 [‐8.33, 11.69] |
| 8 Mental state: 2a. Positive symptoms ‐ no clinically important change ‐ short term (less than 40% PANSS positive reduction) Show forest plot | 1 | 673 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.90, 1.12] |
| 9 Mental state: 2b. Positive symptoms ‐ average endpoint score ‐ (PANSS positive subscore, high=poor) Show forest plot | 12 | 1639 | Mean Difference (IV, Random, 95% CI) | 1.22 [0.51, 1.94] |
| 9.1 short term | 7 | 1231 | Mean Difference (IV, Random, 95% CI) | 1.29 [0.28, 2.29] |
| 9.2 medium term | 5 | 327 | Mean Difference (IV, Random, 95% CI) | 1.21 [‐0.21, 2.63] |
| 9.3 long term | 1 | 81 | Mean Difference (IV, Random, 95% CI) | 1.30 [‐0.13, 2.73] |
| 10 Mental state: 2c. Positive symptoms ‐ average change in endpoint score ‐ short term (BPRS positive subscore, high=poor) Show forest plot | 1 | 25 | Mean Difference (IV, Random, 95% CI) | 1.1 [0.18, 2.02] |
| 11 Mental state: 3a. Negative symptoms ‐ no clinically important change ‐ short term (less than 40% PANSS negative reduction) Show forest plot | 1 | 673 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.93, 1.04] |
| 12 Mental state: 3b. Negative symptoms ‐average endpoint score ‐ (PANSS negative subscore, high=poor) Show forest plot | 11 | 1514 | Mean Difference (IV, Random, 95% CI) | 0.70 [0.13, 1.26] |
| 12.1 short term | 6 | 1106 | Mean Difference (IV, Random, 95% CI) | 0.55 [‐0.25, 1.34] |
| 12.2 medium term | 5 | 327 | Mean Difference (IV, Random, 95% CI) | 1.05 [‐0.24, 2.34] |
| 12.3 long term | 1 | 81 | Mean Difference (IV, Random, 95% CI) | 0.80 [‐0.64, 2.24] |
| 13 Mental state: 3c. Negative symptoms ‐ average change in endpoint score ‐ (BPRS negative subscore, high=poor) Show forest plot | 1 | 25 | Mean Difference (IV, Random, 95% CI) | 0.57 [0.17, 0.97] |
| 14 Quality of life: General ‐ average endpoint score ‐ (QLS total score, low=poor) Show forest plot | 3 | 152 | Mean Difference (IV, Random, 95% CI) | ‐3.44 [‐4.46, ‐2.43] |
| 14.1 short term | 1 | 22 | Mean Difference (IV, Random, 95% CI) | ‐0.5 [‐13.87, 12.87] |
| 14.2 medium term | 2 | 130 | Mean Difference (IV, Random, 95% CI) | ‐3.46 [‐4.48, ‐2.45] |
| 15 Service use: number of participants re‐hospitalised Show forest plot | 2 | 877 | Risk Ratio (M‐H, Random, 95% CI) | 1.34 [1.00, 1.79] |
| 15.1 medium term | 1 | 199 | Risk Ratio (M‐H, Random, 95% CI) | 1.3 [0.71, 2.38] |
| 15.2 long term | 1 | 678 | Risk Ratio (M‐H, Random, 95% CI) | 1.35 [0.97, 1.88] |
| 16 Adverse effects: 1. General ‐ at least one adverse effect Show forest plot | 13 | 2868 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.91, 1.13] |
| 17 Adverse effects: 2. Death Show forest plot | 6 | 3146 | Risk Ratio (M‐H, Random, 95% CI) | 0.73 [0.17, 3.09] |
| 17.1 natural causes | 3 | 1022 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 17.2 suicide attempt | 2 | 945 | Risk Ratio (M‐H, Random, 95% CI) | 0.43 [0.06, 2.95] |
| 17.3 suicide | 4 | 1179 | Risk Ratio (M‐H, Random, 95% CI) | 1.41 [0.11, 18.32] |
| 18 Adverse effects: 3a. Cardiac effects ‐ QTc prolongation Show forest plot | 3 | 1419 | Risk Ratio (M‐H, Random, 95% CI) | 1.34 [0.36, 5.04] |
| 19 Adverse effects: 3b. Cardiac effects ‐ QTc abnormalities ‐ change from baseline in ms Show forest plot | 3 | 940 | Mean Difference (IV, Random, 95% CI) | 2.21 [‐5.05, 9.48] |
| 20 Adverse effects: 4. Central nervous system ‐ sedation Show forest plot | 8 | 2226 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.21 [1.06, 1.38] |
| 21 Adverse effects: 5a. Extrapyramidal effects Show forest plot | 13 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 21.1 akathisia | 8 | 2270 | Risk Ratio (M‐H, Random, 95% CI) | 0.55 [0.32, 0.95] |
| 21.2 akinesia | 1 | 267 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.61, 1.37] |
| 21.3 dyskinesia | 1 | 40 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.07, 14.90] |
| 21.4 dystonia | 4 | 1451 | Risk Ratio (M‐H, Random, 95% CI) | 0.13 [0.04, 0.43] |
| 21.5 extrapyramidal symptoms | 2 | 872 | Risk Ratio (M‐H, Random, 95% CI) | 0.59 [0.43, 0.81] |
| 21.6 parkinsonism | 4 | 825 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.19, 0.78] |
| 21.7 rigor | 1 | 309 | Risk Ratio (M‐H, Random, 95% CI) | 0.45 [0.16, 1.25] |
| 21.8 tremor | 2 | 126 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.04, 27.67] |
| 21.9 use of antiparkinson medication | 8 | 2163 | Risk Ratio (M‐H, Random, 95% CI) | 0.50 [0.36, 0.69] |
| 22 Adverse effects: 5b. Extrapyramidal effects ‐ scale measured ‐ endpoint/ change to endpoint score Show forest plot | 5 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 22.1 abnormal involuntary movement: AIMS (high=poor) | 2 | 958 | Mean Difference (IV, Random, 95% CI) | ‐0.34 [‐0.76, 0.08] |
| 22.2 akathisia: Barnes Akathisia Scale (high=poor) | 2 | 700 | Mean Difference (IV, Random, 95% CI) | ‐0.73 [‐2.00, 0.54] |
| 22.3 extrapyramidal symptoms: Simpson‐Angus Scale (high=poor) | 5 | 1077 | Mean Difference (IV, Random, 95% CI) | ‐0.59 [‐1.16, ‐0.02] |
| 23 Adverse effects: 6. Haematological: important decline in white blood cells Show forest plot | 1 | 673 | Risk Ratio (M‐H, Random, 95% CI) | 2.97 [0.12, 72.73] |
| 24 Adverse effects: 7a. Prolactin associated side effects Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 24.1 amenorrhea | 5 | 427 | Risk Ratio (M‐H, Random, 95% CI) | 0.55 [0.32, 0.96] |
| 24.2 dysmenorrhea | 1 | 163 | Risk Ratio (M‐H, Random, 95% CI) | 0.45 [0.08, 2.38] |
| 24.3 galactorrhea | 5 | 1188 | Risk Ratio (M‐H, Random, 95% CI) | 0.37 [0.16, 0.85] |
| 24.4 gynecomastia | 1 | 267 | Risk Ratio (M‐H, Random, 95% CI) | 0.23 [0.07, 0.79] |
| 24.5 sexual dysfunction | 6 | 2157 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.48, 1.01] |
| 25 Adverse effects: 7b. Prolactin ‐ change from baseline in mg/dl Show forest plot | 7 | 1773 | Mean Difference (IV, Random, 95% CI) | ‐35.25 [‐43.59, ‐26.91] |
| 26 Adverse effects: 8a. Metabolic ‐ cholesterol ‐ significant cholesterol increase Show forest plot | 2 | 940 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [0.72, 2.24] |
| 27 Adverse effects: 8b. Metabolic ‐ cholesterol ‐ change from baseline in mg/dl Show forest plot | 6 | 1473 | Mean Difference (IV, Random, 95% CI) | 8.57 [4.85, 12.29] |
| 28 Adverse effects: 8c. Metabolic ‐ glucose ‐ abnormally high fasting glucose value Show forest plot | 3 | 1618 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.47, 1.69] |
| 29 Adverse effects: 8d. Metabolic ‐ glucose ‐ change from baseline in mg/dl Show forest plot | 6 | 1476 | Mean Difference (IV, Random, 95% CI) | 0.30 [‐2.45, 3.05] |
| 30 Adverse effects: 8e. Metabolic ‐ weight gain of 7% or more of total body weight Show forest plot | 9 | 2070 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.82, 1.14] |
| 31 Adverse effects: 8f. Metabolic ‐ weight gain ‐ change from baseline in kg Show forest plot | 8 | 1486 | Mean Difference (IV, Random, 95% CI) | 0.94 [‐0.59, 2.46] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Leaving the study early Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 any reason | 2 | 722 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.97, 1.13] |
| 1.2 adverse events | 2 | 722 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.72, 1.49] |
| 1.3 inefficacy | 2 | 722 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [0.89, 1.47] |
| 2 Mental state: 1. General ‐ average endpoint score (PANSS total score, high=poor) Show forest plot | 2 | 710 | Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐6.36, 6.14] |
| 2.1 medium term | 1 | 198 | Mean Difference (IV, Random, 95% CI) | 3.70 [‐2.97, 10.37] |
| 2.2 long term | 1 | 512 | Mean Difference (IV, Random, 95% CI) | ‐2.78 [‐6.81, 1.25] |
| 3 Mental state: 2. Positive symptoms ‐ average endpoint score ‐ medium term (PANSS positive subscore, high=poor) Show forest plot | 1 | 198 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐2.18, 2.18] |
| 4 Mental state: 3. Negative symptoms ‐ average endpoint score ‐ medium term (PANSS negative subscore, high=poor) Show forest plot | 1 | 198 | Mean Difference (IV, Random, 95% CI) | 1.60 [‐0.34, 3.54] |
| 5 Service use: number of participants re‐hospitalised Show forest plot | 2 | 754 | Risk Ratio (M‐H, Random, 95% CI) | 1.17 [0.85, 1.59] |
| 5.1 medium term | 1 | 232 | Risk Ratio (M‐H, Random, 95% CI) | 1.25 [0.71, 2.17] |
| 5.2 long term | 1 | 522 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.78, 1.65] |
| 6 Adverse effects: 1. General ‐ at least one adverse effect Show forest plot | 2 | 754 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.91, 1.17] |
| 7 Adverse effects: 2. Death Show forest plot | 2 | 754 | Risk Ratio (M‐H, Random, 95% CI) | 0.41 [0.05, 3.15] |
| 7.1 suicide attempt | 1 | 522 | Risk Ratio (M‐H, Random, 95% CI) | 0.55 [0.03, 8.73] |
| 7.2 suicide | 1 | 232 | Risk Ratio (M‐H, Random, 95% CI) | 0.29 [0.01, 5.92] |
| 8 Adverse effects: 3a. Cardiac effects ‐ QTc prolongation Show forest plot | 1 | 522 | Risk Ratio (M‐H, Random, 95% CI) | 1.65 [0.34, 8.08] |
| 9 Adverse effects: 3b. Cardiac effects ‐ QTc abnormalities ‐ change from baseline in ms Show forest plot | 2 | 549 | Mean Difference (IV, Random, 95% CI) | 3.41 [‐1.37, 8.18] |
| 10 Adverse effects: 4. Central nervous system ‐ sedation Show forest plot | 2 | 754 | Risk Ratio (M‐H, Random, 95% CI) | 1.36 [1.03, 1.81] |
| 11 Adverse effects: 5. Extrapyramidal effects Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 11.1 akathisia | 2 | 754 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.42, 1.45] |
| 11.2 dystonia | 1 | 522 | Risk Ratio (M‐H, Random, 95% CI) | 0.18 [0.02, 1.75] |
| 11.3 extrapyramidal symptoms | 1 | 232 | Risk Ratio (M‐H, Random, 95% CI) | 2.02 [0.66, 6.17] |
| 11.4 use of antiparkinson medication | 1 | 522 | Risk Ratio (M‐H, Random, 95% CI) | 0.43 [0.20, 0.93] |
| 12 Adverse effects: 6a. Prolactin associated effects Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 12.1 amenorrhea | 1 | 138 | Risk Ratio (M‐H, Random, 95% CI) | 0.43 [0.15, 1.24] |
| 12.2 galactorrhea | 2 | 572 | Risk Ratio (M‐H, Random, 95% CI) | 0.55 [0.18, 1.68] |
| 12.3 sexual dysfunction | 2 | 754 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.64, 1.42] |
| 13 Adverse effects: 6b. Prolactin ‐ change from baseline in ng/ml Show forest plot | 2 | 754 | Mean Difference (IV, Random, 95% CI) | ‐4.77 [‐8.16, ‐1.37] |
| 14 Adverse effects: 7a. Metabolic ‐ cholesterol ‐ change from baseline in mg/dl Show forest plot | 2 | 754 | Mean Difference (IV, Random, 95% CI) | 16.01 [8.57, 23.46] |
| 15 Adverse effects: 7b. Metabolic ‐ glucose‐ change from baseline in mg/dl Show forest plot | 2 | 754 | Mean Difference (IV, Random, 95% CI) | 3.10 [‐3.99, 10.19] |
| 16 Adverse effects: 7c. Metabolic ‐ glucose ‐ abnormally high fasting glucose value Show forest plot | 1 | 522 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.30, 1.36] |
| 17 Adverse effects: 7d. Metabolic ‐ weight gain of 7% or more of total body weight Show forest plot | 2 | 754 | Risk Ratio (M‐H, Random, 95% CI) | 2.22 [1.35, 3.63] |
| 18 Adverse effects: 7e. Metabolic ‐ weight gain ‐ change from baseline in kg Show forest plot | 1 | 466 | Mean Difference (IV, Random, 95% CI) | 1.2 [‐0.05, 2.45] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mental state: 1. General ‐ average endpoint score ‐ short term (PANSS total, high=poor) Show forest plot | 2 | 142 | Mean Difference (IV, Random, 95% CI) | 1.24 [‐1.91, 4.39] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mental state: 1. General ‐ average endpoint score ‐ short term (PANSS total, high=poor) Show forest plot | 1 | 27 | Mean Difference (IV, Random, 95% CI) | 0.18 [‐4.11, 4.47] |
| 1.1 short term | 1 | 27 | Mean Difference (IV, Random, 95% CI) | 0.18 [‐4.11, 4.47] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mental state: 1. General ‐ average endpoint score (PANSS total subscore, high=poor) Show forest plot | 10 | 1401 | Mean Difference (IV, Random, 95% CI) | 4.10 [2.25, 5.95] |
| 1.1 short term | 5 | 179 | Mean Difference (IV, Random, 95% CI) | 2.29 [‐1.30, 5.87] |
| 1.2 medium term | 3 | 482 | Mean Difference (IV, Random, 95% CI) | 5.57 [1.97, 9.17] |
| 1.3 long term | 2 | 740 | Mean Difference (IV, Random, 95% CI) | 4.31 [1.60, 7.01] |
| 2 Mental state: 2. Positive symptoms ‐ average endpoint score (PANSS positive subscore, high=poor) Show forest plot | 7 | 676 | Mean Difference (IV, Random, 95% CI) | 1.84 [1.02, 2.67] |
| 2.1 short term | 3 | 112 | Mean Difference (IV, Random, 95% CI) | 0.69 [‐1.87, 3.24] |
| 2.2 medium term | 3 | 483 | Mean Difference (IV, Random, 95% CI) | 2.21 [0.90, 3.52] |
| 2.3 long term | 1 | 81 | Mean Difference (IV, Random, 95% CI) | 1.80 [0.39, 3.21] |
| 3 Mental state: 3. Negative symptoms ‐ average endpoint score (PANSS negative subscore, high=poor) Show forest plot | 8 | 716 | Mean Difference (IV, Random, 95% CI) | 0.38 [‐0.37, 1.14] |
| 3.1 short term | 4 | 152 | Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐1.70, 1.56] |
| 3.2 medium term | 3 | 483 | Mean Difference (IV, Random, 95% CI) | 0.40 [‐0.67, 1.47] |
| 3.3 long term | 1 | 81 | Mean Difference (IV, Random, 95% CI) | 0.70 [‐0.73, 2.13] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Global state: 1a. No clinically significant response (as defined by the original studies) Show forest plot | 3 | 965 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.93, 1.09] |
| 2 Mental state: 1. General ‐ average endpoint score ‐ (PANSS total score, high=poor) Show forest plot | 9 | 1986 | Mean Difference (IV, Random, 95% CI) | 3.10 [1.49, 4.71] |
| 2.1 short term | 5 | 1097 | Mean Difference (IV, Random, 95% CI) | 2.77 [0.50, 5.03] |
| 2.2 medium term | 2 | 146 | Mean Difference (IV, Random, 95% CI) | 6.27 [‐3.94, 16.48] |
| 2.3 long term | 2 | 743 | Mean Difference (IV, Random, 95% CI) | 3.11 [0.40, 5.82] |
| 3 Mental state: 6. Positive symptoms ‐ average endpoint score ‐ (PANSS positive subscore, high=poor) Show forest plot | 6 | 1225 | Mean Difference (IV, Random, 95% CI) | 1.76 [1.04, 2.48] |
| 3.1 short term | 3 | 998 | Mean Difference (IV, Random, 95% CI) | 2.08 [0.60, 3.56] |
| 3.2 medium term | 2 | 146 | Mean Difference (IV, Random, 95% CI) | 2.15 [‐0.01, 4.31] |
| 3.3 long term | 1 | 81 | Mean Difference (IV, Random, 95% CI) | 1.30 [‐0.13, 2.73] |
| 4 Mental state: 6. Negative symptoms ‐ average endpoint score ‐ (PANSS negative subscore, high=poor) Show forest plot | 6 | 1139 | Mean Difference (IV, Random, 95% CI) | 0.79 [0.04, 1.54] |
| 4.1 short term | 3 | 912 | Mean Difference (IV, Random, 95% CI) | 0.53 [‐0.82, 1.88] |
| 4.2 medium term | 2 | 146 | Mean Difference (IV, Random, 95% CI) | 1.30 [‐0.75, 3.35] |
| 4.3 long term | 1 | 81 | Mean Difference (IV, Random, 95% CI) | 0.80 [‐0.64, 2.24] |
| 5 Adverse effects: 1. Extrapyramidal effects ‐ Simpson‐Angus Scale (high=poor) Show forest plot | 4 | 1033 | Mean Difference (IV, Random, 95% CI) | ‐0.82 [‐1.95, 0.31] |
