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Meta-Analysis
. 2015 Nov 24;2015(11):CD011458.
doi: 10.1002/14651858.CD011458.pub2.

Asenapine versus placebo for schizophrenia

Alistair Hay  1 , Amy Byers, Marco Sereno, Manpreet Kaur Basra, Snigdha Dutta
Affiliations
Meta-Analysis

Asenapine versus placebo for schizophrenia

Alistair Hay et al. Cochrane Database Syst Rev. .

Abstract

Background: Schizophrenia is a highly prevalent and chronic disorder that comprises a wide range of symptomatology. Asenapine is a recently developed atypical antipsychotic that is approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia.

Objectives: To determine the clinical effects of asenapine for adults with schizophrenia or other schizophrenia-like disorders by comparing it with placebo.

Search methods: We searched the Cochrane Schizophrenia Group's Trials Register (July 04, 2014) which is based on regular searches of MEDLINE, EMBASE, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and registries of clinical trials. There are no language, date, document type, or publication status limitation for inclusion of records into the register. We inspected references of all included studies for further relevant studies.

Selection criteria: Our review includes randomised controlled trials (RCTs) comparing asenapine with placebo in adults (however defined) with schizophrenia or related disorders, including schizophreniform disorder, schizoaffective disorder and delusional disorder, again, by any means of diagnosis.

Data collection and analysis: We inspected citations from the searches and identified relevant abstracts, and extracted data from all included studies. For binary data we calculated risk ratio (RR) with 95% confidence intervals (CI), and for continuous data we calculated mean differences (MD). We used the GRADE approach to produce a 'Summary of findings' table which included our outcomes of interest, where possible. We used a fixed-effect model for our analyses.

Main results: We obtained and scrutinised 41 potentially relevant records, and from these we could include only six trials (n = 1835). Five of the six trials had high risk of attrition bias and all trials were sponsored by pharmaceutical companies. Results showed a clinically important change in global state (1 RCT, n = 336, RR 0.81, 95% CI 0.68 to 0.97, low-quality evidence) and mental state (1 RCT, n = 336, RR 0.72, 95% CI 0.59 to 0.86, very low-quality evidence) at short-term amongst people receiving asenapine. People receiving asenapine demonstrated significant reductions in negative symptoms (1 RCT, n = 336, MD -1.10, 95% CI -2.29 to 0.09, very low-quality evidence) at short-term. Individuals receiving asenapine demonstrated significantly fewer incidents of serious adverse effects (1 RCT, n = 386, RR 0.29, 95% CI 0.14 to 0.63, very low-quality evidence) at medium-term. There was no clear difference in people discontinuing the study for any reason between asenapine and placebo at short-term (5 RCTs, n = 1046, RR 0.91, 95% CI 0.80 to 1.04, very low-quality evidence). No trial reported data for extrapyramidal symptoms or costs.

Authors' conclusions: There is some, albeit preliminary, evidence that asenapine provides an improvement in positive, negative, and depressive symptoms, whilst minimising the risk of adverse effects. However due to the low-quality and limited quantity of evidence, it remains difficult to recommend the use of asenapine for people with schizophrenia. We identify a need for large-scale, longer-term, better-designed and conducted randomised controlled trials investigating the clinical effects and safety of asenapine.

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Conflict of interest statement

Alistair Hay – none known.

Amy Byers – none known.

Marco Sereno – none known.

Manpreet Basra – none known.

Snigdha Dutta – none known.

Figures

1
1
Chemical structure of asenapine
2
2
Study flow diagram.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 1 Global state: 1. No clinically important change (CGI‐I) ‐ short‐term (up to 12 weeks).
1.2
1.2. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 2 Global state: 2. Average change score (CGI‐S, high=poor).
1.3
1.3. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 3 Global state: 3. Relapse ‐ medium‐term (13 to 26 weeks).
1.4
1.4. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 4 Global state: 4. Use of any concomitant medication.
1.5
1.5. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 5 Global state: 5. Use of specific concomitant medication.
1.6
1.6. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 6 Mental state: 1. No clinically important change (PANSS) ‐ short‐term.
1.7
1.7. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 7 Mental state: 2. Average change in total score (baseline‐to‐endpoint) (PANSS, high=poor).
1.8
1.8. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 8 Mental state: 3. Average change score (baseline‐to‐endpoint) (various scales, high=poor).
1.9
1.9. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 9 Adverse effects: 1. Incidence of serious adverse effects.
1.10
1.10. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 10 Adverse effects: 2. Incidence of any adverse effects.
1.11
1.11. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 11 Adverse effects: 3. Incidence of adverse effects by severity ‐ short‐term.
1.12
1.12. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 12 Adverse effects: 4. Specific adverse effects ‐ 4.1. Cardiovascular: incidence ‐ short‐term.
1.13
1.13. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 13 Adverse effects: 4. Specific adverse effects ‐ 4.2. Gastrointestinal: incidence ‐ short‐term.
1.14
1.14. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 14 Adverse effects: 4. Specific adverse effects ‐ 4.3. Metabolic: incidence.
1.15
1.15. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 15 Adverse effects: 4. Specific adverse effects ‐ 4.4. Metabolic: average change in prolactin levels (μg/L) (baseline‐to‐endpoint) ‐ short‐term.
1.16
1.16. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 16 Adverse effects: 4. Specific adverse effects ‐ 4.5. Metabolic: average change in weight (kg) (baseline‐to‐endpoint).
1.17
1.17. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 17 Adverse effects: 4. Specific adverse effects ‐ 4.6. Other specific adverse effects: incidence.
1.18
1.18. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 18 Adverse effects: 5. Extrapyramidal symptoms ‐ 5.1 Incidence.
1.19
1.19. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 19 Adverse effects: 5. Extrapyramidal symptoms ‐ 5.2. Average change (baseline‐to‐endpoint) (various scales, high=poor) ‐ short‐term.
1.20
1.20. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 20 Adverse effects: 6. Incidence of death (for any reason) ‐ short‐term.
1.21
1.21. Analysis
Comparison 1 ASENAPINE versus PLACEBO, Outcome 21 Leaving the study early.
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Update of

References

References to studies included in this review

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Kane 2010 {published data only}
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Kane 2011 {published data only}
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NCT00151424 {published data only}
    1. Citrome L. Asenapine for schizophrenia and bipolar disorder: A review of the efficacy and safety profile for this newly approved sublingually absorbed second‐generation antipsychotic. The International Journal of Clinical Practice 2009;63:1762‐84. - PubMed
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NCT00156117 {published data only}
    1. Citrome L. Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second‐generation antipsychotic. The International Journal of Clinical Practice 2009;63:1762‐84. - PubMed
    1. Leucht S, Zhao J. Early improvement as a predictor of treatment response and remission in patients with acute schizophrenia: effects of asenapine. European Neuropsychopharmacology 2013; Vol. 23:S470.
    1. Leucht S, Zhao J. Early improvement as a predictor of treatment response and remission in patients with schizophrenia: a pooled, post‐hoc analysis from the asenapine development program. Journal of Psychopharmacology 2014;28:387‐94. - PubMed
    1. NCT00156117. A multicenter, randomized, double‐blind, fixed‐dose, 6‐week trial of the efficacy and safety of asenapine compared with placebo using olanzapine positive control in subjects with an acute exacerbation of schizophrenia. http://clinicaltrials.gov/show/NCT00156117 2005.
    1. Potkin SG, Kane JM, Emsley RA, Naber D, Panagides J. Asenapine in schizophrenia: an overview of clinical trials in the Olympia program. Society of Biological Psychiatry, 63rd Annual Scientific Convention and Meeting, May 1‐3, 2008, Washington, DC. 2008.
Potkin 2007 {published data only}
    1. Citrome L. Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second‐generation antipsychotic. The International Journal of Clinical Practice 2009;63:1762‐84. - PubMed
    1. Fleming K, Potkin SG, Binneman B, Keller D, Alphs L, Panagides J. Effects of asenapine on cognitive function in acute schizophrenia: a placebo‐ and risperidone‐controlled trial. European Neuropsychopharmacology 2007;17(Suppl 4):S466.
    1. Potkin S, Fleming K, Binneman B, Keller DS, Alphs L, Panagides J. Asenapine improves cognitive function in acute schizophrenia: a placebo‐ and risperidone‐ controlled trial. Proceedings of the 160th Annual Meeting of the American Psychiatric Association; 2007 May 19‐24; San Diego, CA. 2007.
    1. Potkin S, Fleming K, Binneman B, Keller S. Asenapine cognitive function effects in acute schizophrenia: a placebo‐and risperidone‐controlled trial. Schizophrenia Bulletin 2007;33(2):454.
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References to studies excluded from this review

Castle 2013 {published data only}
    1. Castle D, Jensen JKS. Management of depressive symptoms in schizophrenia: a pooled, post hoc analysis from the asenapine development program. (Manuscript submitted for peer‐review, journal not currently known).
    1. Castle D, Jensen JKS. Management of depressive symptoms in schizophrenia: a pooled, post hoc analysis from the asenapine development program. European Neuropsychopharmacology 2013;23:S502‐3.
Cazorla 2008 {published data only}
    1. Cazorla P, Panagides J, Alphs L, Kouassi A, Buchanan R. Asenapine versus olanzapine in patients with predominant, persistent negative symptoms of schizophrenia. American Psychiatric Association, 161st Annual Meeting, May 3‐8, 2008, Washington, DC. 2008.
    1. Cazorla P, Panagides J, Alphs L, Kouassi A, Buchanan R, Szegedi A. Asenapine versus olanzapine in patients with predominant, persistent negative symptoms of schizophrenia. International Journal of Neuropsychopharmacology 2008;11(Suppl 1):138‐9.
NCT00156065 {published data only}
    1. Meltzer H, Cohen M, Snow‐Adami L, Mackle M, Zhao J, Szegedi A, et al. Long‐term safety and maintenance of effect of asenapine in patients with acute exacerbation of schizophrenia. European Neuropsychopharmacology 2009;19:S536‐S537.
    1. NCT00156065. A multicenter, double‐blind, flexible dose, long‐term extension trial of the safety and maintenance of effect of asenapine using a haloperidol positive control in subjects who complete protocol 041023. http://clinicaltrials.gov/show/NCT00156065 2005.
NCT01142596 {published data only}
    1. NCT01142596. Long‐term extension trial of asenapine in subjects with schizophrenia (study p06125). http://clinicaltrials.gov/show/NCT01142596 2010.
NCT01190254 {published data only}
    1. NCT01190254. Fixed dose efficacy and safety study of asenapine for the treatment of schizophrenia in adolescents (study p05896). http://clinicaltrials.gov/show/NCT01190254 2010.
The National Horizon Scanning Centre 2010 {published data only}
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References to studies awaiting assessment

NCT00156091 {published data only}
    1. NCT00156091. A multicenter, double‐blind, flexible‐dose, long‐term extension trial of the safety and maintenance of effect of asenapine using olanzapine positive control in subjects who complete protocols 041021/041022. http://clinicaltrials.gov/show/NCT00156091 2005.
NCT01098110 {published data only}
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References to ongoing studies

NCT01617187 {published data only}
    1. NCT01617187. A study of the efficacy and safety of asenapine in participants with an acute exacerbation of schizophrenia (p05688 am2). http://clinicaltrials.gov/show/NCT01617187 2012.

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