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Quetiapine immediate release v. placebo for schizophrenia: systematic review, meta-analysis and reappraisal

  • Paul Hutton (a1), Peter J. Taylor (a2), Lee Mulligan (a3), Sarah Tully (a4) and Joanna Moncrieff (a5)...



Immediate-release (IR) quetiapine has been used to treat schizophrenia since 1997, although all the principal placebo-controlled trials have >50% missing outcome data. New studies with relatively lower rates of participant withdrawal have since been published.


To assess the efficacy and adverse effects of quetiapine IR for schizophrenia, with consideration of outcome quality and clinical meaningfulness of results, and to examine the potential impact of missing data on the main efficacy findings.


We conducted a systematic review and meta-analysis of randomised controlled trials comparing quetiapine IR and placebo (or subtherapeutic dose in relapse prevention trials) for the treatment of schizophrenia (PROSPERO registration CRD4201100165). Primary outcomes were change in overall symptoms and response rates. We also examined whether high rates of participant withdrawal (⩾50%) attenuated effect sizes, and assessed the impact of making different assumptions about these people's outcomes.


We identified 15 relevant trials (including 2 unpublished), providing the first 12-week data for this drug and the first data on self-reported quality of life. We found quetiapine IR to have a weighted mean difference (WMD) of 6.5 points (95% CI −8.9 to −4) on Positive and Negative Syndrome Scale (PANSS) total scores, which corresponds to a standardised mean difference (SMD) of −0.33 (95% CI −0.46 to −0.21). Longer trials reported larger mean differences favouring quetiapine IR, but the overall estimate was smaller if more conservative assumptions about the outcomes of people who left the trial early were made. Approximately 21 people needed to take quetiapine IR for 1 person to experience at least a 50% improvement in PANSS score. No difference in quality of life was observed (two RCTs), although small to moderate improvements in social functioning were found (three RCTs). Quetiapine IR caused sedation and increased rates of clinically significant weight gain, but no extrapyramidal effects were observed.


Quetiapine IR has a small beneficial effect on overall psychotic symptoms over 2–12 weeks, but also leads to weight gain and sedation.

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Corresponding author

Dr Paul Hutton, Department of Clinical Psychology, Doorway 6, Medical Building, Teviot Place, Edinburgh EH8 9AG, UK. Email:


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Quetiapine immediate release v. placebo for schizophrenia: systematic review, meta-analysis and reappraisal

  • Paul Hutton (a1), Peter J. Taylor (a2), Lee Mulligan (a3), Sarah Tully (a4) and Joanna Moncrieff (a5)...
Submit a response


Why Quetiapine?

Foluke T Odeyale, ST4 General Adult Psychiatry, St Mary's Hospital campus, Solent NHS Trust, Portsmouth
Itoro I Udo, Consultant Psychiatrist, Broadoak unit, Merseycare NHS Trust, Liverpool
13 June 2015

Dear Editor,

We have read the paper by Hutton et al with keen interest. [1] We wish to commend the authors for their exhaustive efforts in obtaining relevant studies and unpublished data that were imputed into their paper. The authors argued that data supporting the use of Quetiapine at sub therapeutic or therapeutic doses to reduce relapse and readmission were very low to low in quality. We note their conclusions that Quetiapine IR has a small beneficial effect on overall psychotic symptoms over a 2-12 week period that was studied.[1]

This paper has generated interesting conversations. Having discussed this paper in detail, we note that there is no clearly demarcated declaration of interest by the investigators. We inevitably wonder why Quetiapine, in particular, was chosen as the medication for subject of this study. It is possible that some other second generation antipsychotic would have met the same criteria expressed in the introduction and could have been chosen as appropriate medication to be studied.

This paper caught our attention when it was published because we had noticed about the same time that we were having readmissions due to psychotic relapses of community patients with long term psychotic illnesses into our acute inpatient unit. Some of these patients stated that they had been adherent to their medications prior to their relapse. At the same time, we acknowledge that we have also had patients who have improved remarkably from their acute illness when they commenced Quetiapine in the same setting. We have psychiatric colleagues who find Quetiapine a useful antipsychotic in their practice. Hence one cannot totally discountenance the clinical efficacy of Quetiapine as an antipsychotic.

It may suffice to say that in practice, psychiatry is still in search for the ideal antipsychotic that would cure or prevent relapse in 100% of cases despite 100% compliance.Noting that, ‘although there has been clear progress over the past 50 years in developing antipsychotics, clinical needs remain. What we desire from an antipsychotic is a medication that can treat psychosis, reduce symptoms (produce response), lead to symptom resolution (symptoms below the threshold to make a diagnosis), and maintain the patient with no more than mild positive and negative symptoms for at least 6 months (remission), with the ultimate goal being recovery. The “ideal medication” would also overcome treatment resistance and effectively protect against relapse’. [2] The search for this "ideal" antipsychotic has been on since Kraepelin.

One has to bring to mind that unlike most other antipsychotics, Quetiapine does have the unique property of acting on various other receptors apart from dopaminergic ones: serotonergic, histaminergic, muscarinic and adrenergic ones. [3] It may then appear that just like Cognitive Behavioural Therapy (CBT) has been shown to be beneficial to patients with psychosis, majorly through its ability to reduce anxiety,[4,5] Quetiapine's usefulness as an antipsychotic may be in large parts from its effects on reducing anxiety and agitation.

One also wonders whether there may be genomic and/or metabolic explanations for some of the variations in clinical effects that have been noticed and is supported by this paper; where a subpopulation of those taking Quetiapine are able to effectively utilise it as an antipsychotic while a bigger group are unable to do so.

Until our knowledge in these areas expands appreciably, we would still be in search of the ideal antipsychotic.


1. Hutton P, Taylor PJ, Mulligan L, Tully S, Moncrieff J. Quetiapine Immediate Release v. Placebo for Schizophrenia: Systematic Review, Meta-analysis and Reappraisal. British Journal of Psychiatry 2015;206: 360-370.

2. Correll CU. What Are We Looking for in New Antipsychotics? The Journal of Clinical Psychiatry 2011;72(suppl 1): 9-13. doi 10.4088/JCP.10075su1.02

3. Stahl SM. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th Edition. Cambridge: Cambridge University Press: 2013.

4. Naeem F, Kingdon D, Turkington D. Cognitive Behaviour Therapy for Schizophrenia: Relationship between Anxiety Symptoms and Therapy. Psychology and Psychotherapy: Theory, Research and Practice 2006:79; 153–164. doi: 10.1348/147608305X91538.

5. Hartley S, Barrowclough C, Haddock G. Anxiety and Depression in Psychosis: A Systematic Review of Associations with Positive Psychotic Symptoms. ActaPsychiatricaScandinavica 2013:128(5); 327–346.

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