Asenapine for the Treatment of Psychotic Disorders

Abstract

Objective:

A systematic review was conducted to examine the efficacy, tolerability, and acceptability of asenapine compared with other antipsychotics in the treatment of psychotic disorders.

Methods:

Four databases, 8 trial registries, and conference presentations were searched for randomized clinical trials of asenapine versus any comparator for the treatment of any psychotic illness. Primary outcome measures were changes in the Positive and Negative Syndrome Scale (PANSS) total score and the incidence of withdrawal due to adverse effects.

Results:

Eight randomized clinical trials, encompassing 3765 patients, that compared asenapine with placebo (n = 5) and olanzapine (n = 3) were included. No differences were found between asenapine and olanzapine in terms of changes to PANSS total or PANSS negative subscale scores. Patients taking asenapine were more likely to experience worsening schizophrenia and/or psychosis than were those taking olanzapine. No differences were found between asenapine and olanzapine in rates of discontinuation due to adverse drug reactions or lack of efficacy, but those taking asenapine had higher rates of withdrawal for any reason than those taking olanzapine. Asenapine caused less clinically significant weight gain or increases in triglycerides than olanzapine and was more likely to cause extrapyramidal symptoms than olanzapine. In comparison to placebo, either no difference or superiority was demonstrated in favour of asenapine on all efficacy measures.

Conclusion:

The current evidence is limited, as asenapine has been compared only with placebo or olanzapine. In the randomized clinical trials analysed, asenapine was similar or superior to placebo and similar or inferior to olanzapine on most efficacy outcomes. While asenapine demonstrated fewer adverse metabolic outcomes than olanzapine, rates of extrapyramidal symptom–related adverse effects were higher.

Affecting approximately 1% of the population, schizophrenia is associated with significant social and occupational dysfunction.¹ Various antipsychotic agents have been developed since the 1950s that have radically improved treatment of the positive symptoms of this disorder.² However, negative and cognitive symptoms are more difficult to treat and respond poorly to currently available treatment options.²

While several new antipsychotics (such as asenapine, lurasidone, and iloperidone) have been developed in recent years, data are lacking that compare the efficacy and safety of these agents with established therapies in the treatment of psychotic disorders, making the decision to use the new agents difficult.

Asenapine (ASP) is the only antipsychotic available on the Canadian market for sublingual use, allowing for a more rapid onset of action than antipsychotics that are absorbed enterally.^3,4 This could allow for a faster de-escalation of acute psychosis and improve adherence with medication in patients who, for a variety of reasons, may be unwilling to swallow medications.⁵ ASP is also of interest due to its broad range of receptor affinities, possibly enhancing its efficacy against negative and cognitive symptoms of schizophrenia.⁶

Available reviews on this topic are limited in several ways. Szegedi et al⁷ conducted a meta-analysis of placebo-controlled trials of 6 weeks’ duration and a multiple treatment meta-analysis to inferentially compare the relative efficacy of ASP to other antipsychotics, although direct comparisons may or may not have been performed.⁸ This meta-analysis did not study the long-term safety and efficacy of ASP, and a direct comparison between ASP and other agents was not provided. Instead, the investigators incorporated their results for ASP into a previously published review by Leucht et al.⁹ in order to compare its efficacy with that of other available antipsychotics.⁷ A systematic review and meta-analysis by DeHert et al.¹⁰ compared ASP, iloperidone, lurasidone, and paliperidone for metabolic adverse effects only. Leucht et al.¹¹ conducted a multiple-treatments meta-analysis including both direct and indirect comparisons of 15 different antipsychotics in patients requiring acute treatment. This review excluded the patients with primarily negative symptoms of schizophrenia, patients with concurrent medical illnesses, patients with treatment refractory disease, and those who were clinically stable.¹¹

The current review was conducted to examine the efficacy, tolerability, and acceptability of ASP in comparison to other currently available antipsychotics in the short- and long-term treatment of both acute and clinically stable psychotic disorders, in order to identify patient populations most likely to benefit from this medication.

Methods

Protocol and Registration

Methods of this review were specified in advance, and the protocol was registered with PROSPERO (CRD42014008970).

Search Strategy

Medline, EMBASE, PsychInfo, the Cochrane Central Register of Controlled Trials, and the Cochrane Schizophrenia Group Trials Registry were searched (2013 Oct 13) using the terms asenapine, asenapine maleate, Saphris®, and Sycrest®. No limits were placed on this search, and there were no language restrictions. Eight clinical trial registries and electronically available conference materials from the American Psychiatric Association, World Psychiatric Association, and Canadian Psychiatric Association (2009-2013) were searched for unpublished literature. Clinical experts, and the manufacturer of ASP, Lundbeck Canada, were also contacted to request unpublished trials. Reference lists of included and excluded articles were hand searched for randomized clinical trials matching the inclusion criteria.

Eligibility Criteria

Randomized clinical trials, regardless of publication status or language, were eligible for inclusion. We included patients of any age or disease severity (meeting criteria for the diagnosis of acute or chronic schizophrenia, psychosis, schizoaffective disorder, schizophreniform disorder, and other psychotic disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV], DSM-IV Text Revision [DSM-IV-TR], and/or ICD-10 Classification of Mental and Behavioural Disorders). Relevant interventions were ASP (any dosage form and dosing regimen) compared with any typical or atypical antipsychotic (any dosage form or dosing regimen) or placebo (PLC). The primary efficacy outcome measure was a change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score. The primary safety outcome was the rate of discontinuation due to adverse effects. A list of secondary outcome measures can be found in Table 1.

Table 1.

Secondary and post hoc outcomes.

Secondary efficacy outcomes

Rates (in percentage) of PANSS total responders Changes in PANSS subscale scores (PANSS positive, PANSS negative, and PANSS psychopathology) Changes in PANSS Marder subscale scores (PANSS Marder positive, PANSS Marder negative, PANSS Marder disorganized thought, PANSS Marder hostility and excitement, and PANSS Marder anxiety and depression) Rates (in percentage) of responders to the Clinical Global Impression–improvement scale (CGI-I) Changes in the Clinical Global Impression–severity scale (CGI-S) Changes in the Negative Symptom Assessment–16 (NSA-16) scale Changes in the Global Assessment of Functioning (GAF) scale Changes in the Brief Psychiatric Rating Scale (BPRS) Time required to achieve a response Time required to achieve remission Duration of time in remission Relapse rates

Secondary tolerability outcomes

Effect on cardiovascular function, such as incidence of QTc prolongation (≥500 ms), changes from baseline in the QTc interval, and orthostasis Effect on weight, such as incidence of clinically significant weight gain (reported as ≥7% increase in body weight from baseline), incidence of clinically significant weight loss (reported as ≥7% decrease in body weight from baseline), and change in weight from baseline Rates of metabolic derangements, such as changes from baseline in fasting blood glucose, changes from baseline in triglycerides, and new-onset metabolic syndrome Incidence of movement disorders, such as incidence of any reported extrapyramidal symptoms, akathisia, and rigidity of any kind; dystonic reactions; and parkinsonism Improvements in several scales that measure extrapyramidal symptoms were also included as secondary tolerability outcomes and include changes from baseline in each of the following scales: Barnes Akathisia Rating Scale (BARS), Simpson Angus Scale (SAS), Extrapyramidal Symptom Rating Scale (ESRS), and Abnormal Involuntary Movement Scale (AIMS). Laboratory changes, such as incidence of hyperprolactinemia, changes from baseline in serum prolactin levels, agranulocytosis, and other reported significant hematologic abnormalities Incidence of neuroleptic malignant syndrome Incidence of anticholinergic effects Effect on sleep Incidence of seizures Behavioural changes, such as incidence of agitation and of anxiety Rates of all-cause mortality

Secondary acceptability outcomes

Patient perspective on efficacy, ease of use, and improvement in quality of life as demonstrated with the use of several scales, including the Glasgow Antipsychotic Side Effect Scale (GASS), Patient Reported Outcomes (PRO), Drug Attitude Inventory (DAI) scale, Personal Evaluation of Transitions in Treatment (PETiT), Quality of Life Enjoyment and Satisfaction (Q-LES-12), Subjective Well-being under Neuroleptic Treatment (SWN) scale, and the physical and mental component scales of the Medical Outcomes Study 12-item Short Form (SF-12) Adherence rates Rates of all-cause discontinuation Rate of discontinuation due to adverse effects or a lack of efficacy Time to admission and readmission to hospital Length of stay in hospital Patient’s reintegration into society (and/or workforce) Patient engagement in services Cost-effectiveness, including cost to the patient as well as the health care system

Post hoc outcomes

Incidence of any adverse drug reaction Incidence of severe adverse effects Changes in aspartate aminotransferase Changes in alanine aminotransferase

PANSS = Positive and Negative Syndrome Scale.

Data Extraction

Data extraction was performed in duplicate by 2 authors (C.O. and S.D.). When trials used both mixed model of repeated measures and last observation carried forward to impute missing data, the former was used; if only last observation carried forward was used for missing data imputation, this was used as the data source. For trials in which patients were assigned to 5-mg BID or 10-mg BID arms, the 10-mg BID arm was selected for primary comparison, as this is the maximum recommended dose of ASP for the indications in question. For trials that included more than 2 arms, only data from the arms for which the trial was powered were extracted for this review (to avoid unit-of-analysis errors).¹²

Statistical Analysis

A random effects model was used to combine outcomes, using Review Manager 5.2.¹³ Odds ratios with 95% confidence intervals were calculated for dichotomous outcomes, and weighted mean difference was used to report continuous outcomes. Results were subdivided based on the comparator. We used the I² statistic in Review Manager to assess heterogeneity, as described in the Cochrane Handbook.¹⁴

Risk of Bias Assessment

The risk of bias from the included trials was assessed using the Cochrane risk of bias assessment tool.¹⁴ All trials were randomized and double-blinded, but methods of randomization and allocation concealment were not mentioned. Additional sources of bias include the fact that all included articles were written in English and were sponsored by the manufacturers of ASP. Reporting bias was also possible as all trials reported frequent adverse reactions, omitting rare but potentially serious adverse effects. In addition, very few of the trials obtained through the initial search were available in published form, and very few of the unpublished trials were obtained from either the manufacturer or the authors. Publication bias may be present, and we speculate that some negative trials may be missing from our review. The decision was made by the authors not to include a funnel plot as it is very difficult to show true asymmetry when fewer than 10 articles are included.¹⁵ There was also significant attrition in all studies, as shown by high withdrawal rates. The majority of the authors were current employees or representatives of the manufacturer of ASP. See Figure 1 for more details.

Figure 1.

Cochrane risk of bias assessment.

Results

The search yielded 742 citations, of which 8 articles (3765 patients) met inclusion criteria.^16–23 See the flow diagram in Figure 2 for additional details regarding trial selection and Table 2 for characteristics of the included studies. Table 3 lists the excluded trials and reasons for exclusion. Of the 8 trials included, 5 were placebo-controlled and 3 compared ASP with olanzapine (OZP). No unpublished studies were obtained from either the manufacturer or the expert authors. Data for the unpublished study 41021 were obtained through the FDA website and an Australian government document. All patients included had a diagnosis of either DSM-IV schizophrenia or schizoaffective disorder.

Figure 2.

Study selection.

Table 2.

Characteristics of included trials.

Identifier	Duration	Participants and methods	Psychotic illnesses included	Interventions	Number randomized in each group	Primary efficacy outcome
Trial 41021	6 weeks	Adultsa Randomized, blinded, and placebo-controlled	DSM-IV acute schizophrenia	ASP 5 mg BID ASP 5 mg BID × 1 day and then 10 mg BID OZP 10 mg daily × 7 days and then 15 mg daily PLC	ASP 5 mg: 102 ASP 10 mg: 96 OZP: 95 PLC: 93	Change from baseline in PANSS total score
Buchanan 2012 (EH)b	26 weeks	≥18 years old and stable on current therapy Randomized, double-blinded	DSM-IV schizophrenia (clinically stable disease)	ASP 5-10 mg BID OZP 5-20 mg daily	ASP: 241 OZP: 240	Change in NSA-16 total score
Buchanan 2012 (WH)b	26 weeks	≥18 years old and stable on current treatment Randomized, double-blinded	DSM-IV schizophrenia (clinically stable disease)	ASP 5-10 mg BID OZP 5-20 mg daily	ASP: 244 OZP: 224	Change in NSA-16 total score
Chapel 2009	16 days	≥18 years olda Randomized, double-blinded, placebo-controlled, dose-escalating trial	DSM-IV schizophrenia or schizoaffective disorder (clinically stable disease)	ASP 5 mg BID × 10 days and then 10 mg BID × 6 days ASP 15 mg BID × 10 days and then 20 mg BID × 6 days QTE 375 mg BID × 16 days PLC × 16 days	ASP 5/10 mg: 38 ASP 15/20: 38 QTE: 37 PLC: 35	Time-matched change from baseline in QTc with ASP vs. PLC
Kane 2010	6 weeks	≥18 years olda Randomized, double-blinded, placebo-controlled trial	DSM-IV schizophrenia with acute exacerbation	ASP 5 mg BID ASP 10 mg BID HDL 4 mg BID PLC	ASP 5 mg: 114 ASP 10 mg: 106 HDL: 115 PLC: 123	Change from baseline in PANSS total score
Kane 2011	26 weeks	≥18 years old, stable on current treatment Randomized, double-blinded, placebo-controlled trial	DSM-IV schizophrenia (clinically stable disease)	ASP: 5-10 mg BID PLC	ASP: 194 PLC: 192	Time to relapse or impending relapse
Potkin 2007	6 weeks	≥18 years old with acute decompensation either on or off antipsychotics Randomized, double-blinded, double-dummy, placebo-controlled trial	DSM-IV acute schizophrenia	ASP: 1 mg BID on day 1, 2 mg BID on day 2, 3 mg BID on day 3, 4 mg BID on day 4, and then 5 mg BID onwards RIS: 1 mg BID on day 1, 2 mg BID on day 2, and then 3 mg BID onwards PLC	ASP: 60 RIS: 60 PLC: 62	Change from baseline in PANSS total score
Schoemaker 2010	52 weeks	≥18 years old inpatients or outpatients either on treatment or treatment naïve Randomized, double-blinded, double-dummy trial	DSM-IV schizophrenia or schizoaffective disorder (unstable disease)	ASP: 5 mg BID × 1 week and then 5 mg BID or 10 mg BID OZP: 10 mg daily × 1 week and then 10 or 20 mg daily	ASP: 908 OZP: 311	Change from baseline in PANSS total score

ASP = asenapine; BID = twice daily; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; HDL = haloperidol; NSA-16 = Negative Symptoms Assessment–16; OZP = olanzapine; PANSS = Positive and Negative Syndrome Scale; PLC = placebo; QTE = quetiapine; RIS = risperidone.

^aIt is unclear from the trial whether patients were on or off antipsychotics at the time of study entry.

^bThis paper included results from 2 core trials, one performed in the Eastern hemisphere (EH) (including 15 countries in Europe, South Africa, and Australia) and the other in the Western hemisphere (WH) (including 5 countries in North and South America).

Table 3.

Trials excluded from the review with reasons for exclusion.

Study	Rationale for exclusion
Agarkar S, Anthony D, Ferrando S. Risk of akathisia associated with atypical antipsychotics [letter to the editor]. J Neuropsychiatry Clin Neurosci. 2013;25(1):E46-E47.	Not an RCT
Angersbach D. A new antipsychotic drug in development: asenapine for acute treatment of schizophrenia. Psychopharmakotherapie. 2008;15(2):97-98.	Not an RCT
Awad AG, Voruganti LN. The impact of newer atypical antipsychotics on patient-reported outcomes in schizophrenia. CNS Drugs. 2013;27(8):625-636.	Not an RCT
Beach SR, Celano CM, Noseworthy PA, et al. QTc prolongation, torsades de pointes and psychotropic medications. Psychosomatics. 2013;54(1):1-13.	Not an RCT
Berger A, Kushkuley S, Sanders K, et al. Clinical outcomes and economic costs of second generation antipsychotics in patients with chronic schizophrenia or schizoaffective disorders [conference abstract]. Value Health. 2011;14(3):A190.	Not an RCT
Bou Khalil R. Atypical antipsychotic drugs, schizophrenia, and metabolic syndrome in non-Euro-American societies. Clin Neuropharmacol. 2012;35(3):141-147.	Not an RCT
Catts SV. The place of asenapine in the treatment of schizophrenia and bipolar disorder. Med Today. 2012;13(7):59-61.	Not an RCT
Cazorla P, Mackle M, Zhao J, et al. Safety and tolerability of switching to asenapine from other antipsychotic agents in stable patients with persistent negative symptoms. Neuropsychiatr Dis Treat. 2012;8:247-257.	Not an RCT
Cazorla P, Mackle M, Zhao J, et al. Safety and tolerability of switching to asenapine from other antipsychotic agents: pooled results from two randomized multicenter trials in stable patients with persistent negative symptoms in schizophrenia. Neuropsychiatr Dis Treat. 2012;8:247-257.	Not an RCT
Cazorla P, Zhoa J, Szegedi A. Incidence, onset and duration of treatment emergent somnolence with asenapine in patients with schizophrenia or bipolar disorder. J Pharm Pract. 2011;24(2):254-255.	Not an RCT
Cetin M. Asenapine: a novel hope in the treatment of schizophrenia and manic and mixed episodes of bipolar 1 disorder. Bull Clin Psychopharmacol. 2013;23(1):99-106.	Not an RCT
Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence based medicine approach. CNS Drugs. 2013;27(11):879-911.	Not an RCT
Citrome L. A systematic review of meta-analyses of the efficacy of oral atypical antipsychotics for the treatment of adult patients with schizophrenia. Expert Opin Pharmacother. 2012;13(11):1545-1573.	Not an RCT
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. Int J Clin Pract. 2009;63(12):1762-1784.	Not an RCT
De Hert M, Dobbelawere M, Sheridan EM, et al. Body weight and metabolic adverse effects of asenapine, iloperidone, lurasidone and paliperidone in the treatment of schizophrenia and bipolar disorder: a systematic review and exploratory meta-analysis. CNS Drugs. 2012;26(9):733-759.	Not an RCT
De Hert M, Dobbelaere M, Sheridan EM, et al. Metabolic and endocrine adverse effects of second generation antipsychotics in children and adolescents: a systematic review of randomized, placebo controlled trials and guidelines for clinical practice. Psiquiatria Biologica. 2011;18(3):89-104.	Not an RCT
De Hert M, Guiraud-Diawara A, Marre C. Comparison of metabolic syndrome incidence among schizophrenia patients treated with asenapine versus olanzapine. Eur Psychiatry. 2013;28	Not an RCT
Dubovsky SL, Frobose C, Phiri P, et al. Asenapine: short term tolerability, safety and pharmacokinetic profile in older patients with psychosis. Int J Geriatr Psychiatry. 2012;27(5):472-482.	Not an RCT
Friberg LE, De Greef R, Kerbusch T, et al. Modeling and simulation of the time course of asenapine exposure response and dropout patterns in acute schizophrenia. Clin Pharmacol Ther. 2009;86(1):84-91.	Not an RCT
Gao K, Mackle M, Cazorla P, et al. Comparison of somnolence associated with asenapine, olanzapine, risperidone and haloperidol relative to placebo in patients with schizophrenia or bipolar disorder. Neuropsychiatr Dis Treat. 2013;9:1145-1157.	Not an RCT
Ivanov I, Charney A. Treating pediatric patients with antipsychotic drugs: balancing benefits and safety. Mount Sinai J Med. 2008;75(3):276-286.	Not an RCT
Janicak PG, Rado JT. Recent second generation antipsychotics implications for treating elderly patients with schizophrenia. Psychopharm Review. 2012;47(8):57-64.	Not an RCT
Janicak PG, Rado JT. Asenapine: a review of the data. Psychopharm Review. 2009;44(12):89-94.	Not an RCT
Jarskog LF. Advantages and limitations of newer antipsychotics: evidence from large comparative trials. Clin Schizophr Relat Psychoses. 2012;6(3):113-114.	Not an RCT
Johnsen E, Kroken RA. Drug treatment developments in schizophrenia and bipolar mania: latest evidence and clinical usefulness. Ther Adv Chronic Dis. 2012;3(6):287-300.	Not an RCT
Kirson NY, Weiden PJ, Yermakov S, et al. Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: synthesizing results across different research designs. J Clin Psychiatry. 2013;74(6):568-575.	Not an RCT
Kumar A, Narayan M, Raja H, et al. Asenapine versus typical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2012;(11):CD010230.	Not an RCT
La Torre A, Conca A, Duffy D, et al. Sexual dysfunction related to psychotropic drugs: a critical review part II: antipsychotics. Pharmacopsychiatry. 2013;46(6):201-208.	Not an RCT
Lachaine J, Beauchemin C, Mathurin K, et al. Cost effectiveness of asenapine in the treatment of schizophrenia in Canada [conference abstract]. Value Health. 2012;15(4):A88.	Not an RCT
Leucht S, Cipriani A, Spineli, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple treatments meta-analysis. Lancet. 2013;382(9896):951-962.	Not an RCT
Marder SR. Newer antipsychotics and the differences between clinical experiences and clinical trials. CNS Spectrums. 2007;12(11):812-815.	Not an RCT
Mcdonagh M, Peterson K, Carson S, et al. Atypical antipsychotic drugs: drug class review. Oregon Health and Sciences University, July 2010.	Not an RCT
Minassian A, Young JW. Evaluation of the clinical efficacy of asenapine in schizophrenia. Expert Opin Pharmacother. 2010;11(12):2107-2115.	Not an RCT
Potkin SG. Optimising short and long term schizophrenia treatment [conference abstract]. Eur Neuropsychopharmacol. 2012;22:S446.	Not an RCT
Potkin SG, Phiri P, Zhoa J, et al. A pooled analysis of the effects of asenapine on the persistent negative symptoms of schizophrenia. Neuropsychopharmacology. 2010;35:S213.	Not an RCT
Preda A, Faziola L. Asenapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010;(12):CD008902.	Not an RCT
Prohn M, De Greef R, Chapel S, et al. Population pharmacokinetics of asenapine in patients with schizophrenia or bipolar disorder [conference abstract]. Eur Neuropsychopharmacol. 2009;19:S542-S543.	Not an RCT
Scarff JR, Casey DA. Newer oral atypical antipsychotic agents: a review. P T. 2011;26(12):832-841.	Not an RCT
Schimmelmann BG, Schmidt SJ, Carbon M, et al. Treatment of adolescents with early onset schizophrenia spectrum disorders: in search of a rational, evidence-informed approach. Curr Opin Psychiatry. 2013;26(2):219-230.	Not an RCT
Shoemaker J, Naber D, Vrijland P, et al. Long term assessment of asenapine vs olanzapine in patients with schizophrenia or schizoaffective disorder: erratum. Pharmacopsychiatry. 2011;44(7):343.	Not an RCT
Shoemaker J, Stet L, Vrijland P, et al. Long term efficacy and safety of asenapine or olanzapine in patients with schizophrenia or schizoaffective disorder: an extension study. Pharmacopsychiatry. 2012;45(5):196-203.	Not an RCT
Shulman M, Njoku IJ, Manu P. Thrombotic complications of treatment with antipsychotic drugs. Minerva Med. 2013;104(2):175-184.	Not an RCT
Stoner SC, Pace HA. Asenapine: a clinical review of a second generation antipsychotics. Clin Ther. 2012;34(5):1023-1040.	Not an RCT
Szegedi A, Verweij P, Van Duijnhoven, et al. Meta-analyses of the efficacy of asenapine for acute schizophrenia: comparisons with placebo and other antipsychotics. J Clin Psychiatry. 2012;73(12):1533-1540.	Not an RCT
Tarazi FI. The preclinical profile of asenapine: clinical relevance for the treatment of schizophrenia and bipolar mania. Expert Opin Drug Discov. 2013;8(1):93-103.	Not an RCT
Timpe EM, Chopra RA. Asenapine: a novel atypical antipsychotic agent for schizophrenia and bipolar disorder. J Pharm Technol. 2010;26(6):352-361.	Not an RCT
Zhao J, Cazorla P, Schoemaker J, et al. Weight change and metabolic effects of asenapine in placebo or olanzapine controlled studies. Eur Psychiatry. 2011;26.	Not an RCT
Buchanan RW, Panagides J, Zhao J, et al. Asenapine versus olanzapine in people with persistent negative symptoms of schizophrenia. J Clin Psychopharmacol. 2012;32(1):36-45.	Duplicate
Citrome L. A systematic review of meta-analyses of the efficacy of oral atypical antipsychotics for the treatment of adult patients with schizophrenia. Expert Opin Pharmacother. 2012;13(11):1545-1573.	Duplicate
Cazorla P, Zhoa J, Szegedi A. Incidence, onset and duration of treatment emergent somnolence with asenapine in patients with schizophrenia or bipolar disorder. J Pharm Pract. 2011;24(2):254-255.	Duplicate
De Hert M, Dobbelawere M, Sheridan EM, et al. Body weight and metabolic adverse effects of asenapine, iloperidone, lurasidone and paliperidone in the treatment of schizophrenia and bipolar disorder: a systematic review and exploratory meta-analysis. CNS Drugs. 2012;26(9):733-759.	Duplicate
Dubovsky SL, Frobose C, Phiri P, et al. Asenapine: short term tolerability, safety and pharmacokinetic profile in older patients with psychosis. Eur Neuropsychopharmacol. 2010;20:S489-S490.	Duplicate
Dubovsky SL, Frobose C, Phiri P, et al. Asenapine: short term tolerability, safety and pharmacokinetic profile in older patients with psychosis [conference abstract]. ECNP Congress, Amsterdam, the Netherlands, 2010 Aug 28–Sep 1.	Duplicate
Dubovsky SL, Frobose C, Phiri P, et al. Asenapine: short term tolerability, safety and pharmacokinetic profile in older patients with psychosis. Schizophr Res. 2010;117(2-3):263-264.	Duplicate
Dubovsky SL, Frobose C, Phiri P, et al. Asenapine: short term tolerability, safety and pharmacokinetic profile in older patients with psychosis. Schizophr Res. 2010;117(2-3):263-264.	Duplicate
Kane JM, Cohen M, Zhao J, et al. Efficacy and safety of asenapine in a placebo and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. J Clin Psychopharmacol. 2010;30(2):106-115.	Duplicate
Kane JM, Mackle M, Snowadami L, et al. A randomized placebo controlled trial of asenapine for the prevention of relapse of schizophrenia after long-term treatment. J Clin Psychiatry. 2011;72(3):349-355.	Duplicate
Kane JM, Cohen M, Zhao J, et al. Efficacy and safety of asenapine in a placebo and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. J Clin Psychopharmacol. 2010;30(2):106-115.	Duplicate
Kane JM, Cohen M, Zhao J, et al. Efficacy and safety of asenapine in a placebo and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. J Clin Psychopharmacol. 2010;30(2):106-115.	Duplicate
Kane JM, Mackle M, Snowadami L, et al. Double blind, placebo controlled trial of asenapine in prevention of relapse after long term treatment of schizophrenia. Int J Neuropsychopharmacol. 2010;13:223.	Duplicate
Kane JM, Mackle M, Snowadami L, et al. A randomized placebo controlled trial of asenapine for the prevention of relapse of schizophrenia after long-term treatment. J Clin Psychiatry. 2011;72(3):349-355.	Duplicate
Kirson NY, Weiden PJ, Yermakov S, et al. Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: synthesizing results across different research designs. J Clin Psychiatry. 2013;74(6):568-575.	Duplicate
Landbloom R, Zhao J, Cazorla P, et al. Weight change and metabolic effects of asenpine in placebo or olanzapine controlled studies. Bipolar Disord. 2011;13:65.	Duplicate
Mackle M, Snowadami L, Zhao J, et al. Double blind placebo controlled trial of asenapine in prevention of relapse after long-term treatment of schizophrenia [conference abstract]. Eur Neuropsychopharmacol. 2009;19:S543.	Duplicate
Cazorla P, Mackle M, Zhao J, et al. Safety and tolerability of switching to asenapine from other antipsychotic agents in stable patients with persistent negative symptoms. Neuropsychiatr Dis Treat. 2012;8:247-257.	Duplicate
Cazorla P, Mackle M, Zhao J, et al. Safety and tolerability of switching to asenapine from other antipsychotic agents in stable patients with persistent negative symptoms. J Pharm Pract. 2012;25(2):266.	Duplicate
Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo and risperidone controlled trial. J Clin Psychiatry. 2007;68:1492-1500.	Duplicate
Potkin SG, Phiri P, Szegedi A, et al. Long-term effects of asenapine or olanzapine in patients with persistent negative symptoms of schizophrenia: a pooled analysis. Schizo Res. 2013;150(2-3):442-449.	Duplicate
Potkin SG, Phiri P, Zhao J, et al. A pooled analysis of the effects of asenapine on the persistent negative symptoms of schizophrenia. Eur Psychiatry. 2011;26.	Duplicate
Potkin S, Phiri P, Zhao J, et al. A pooled analysis of the effects of asenapine on the persistent negative symptoms of schizophrenia [conference abstract]. Neuropsychopharmacology. 2010;35:S213.	Duplicate
Shoemaker J, Naber D, Vrijland P, et al. Long term assessment of asenapine vs olanzapine in patients with schizophrenia or schizoaffective disorder. Pharmacopsychiatry. 2010;43(4):138-146.	Duplicate
Shoemaker J, Naber D, Vrijland P, et al. Long term assessment of asenapine vs olanzapine in patients with schizophrenia or schizoaffective disorder. Pharmacopsychiatry. 2010;43(4):138-146.	Duplicate
Shoemaker J, Naber D, Vrijland P, et al. Long term assessment of asenapine vs olanzapine in patients with schizophrenia or schizoaffective disorder: erratum. Pharmacopsychiatry. 2011;44(7):343	Duplicate
Shoemaker J, Stet L, Vrijland P, et al. Safety and efficacy of long-term asenapine versus olanzapine in schizophrenia or schizoaffective disorder patients. Eur Psychiatry. 2010;25.	Duplicate
Shoemaker J, Stet L, Vrijland P, et al. Long term efficacy and safety of asenapine or olanzapine in patients with schizophrenia or schizoaffective disorder: an extension study. Pharmacopsychiatry. 2012;45(5):196-203.	Duplicate
Shoemaker J, Stet L, Vrijland P, et al. Long term efficacy and safety of asenapine or olanzapine in patients with schizophrenia or schizoaffective disorder. J Pharm Pract. 2010;23(2):162	Duplicate
Dubovsky SL, Frobose C, Phiri P, et al. Asenapine: short term tolerability, safety and pharmacokinetic profile in older patients with psychosis. Int J Geriatr Psychiatry. 2012;27(5):472-482.	Duplicate
Szegedi A, Verweij P, Van Duijnhoven, et al. Meta-analyses of the efficacy of asenapine for acute schizophrenia: comparisons with placebo and other antipsychotics. J Clin Psychiatry. 2012;73(12):1533-1540.	Duplicate
Szegedi A, Verweij P, Van Duijnhoven, et al. Meta-analyses of the efficacy of asenapine for acute schizophrenia: comparisons with placebo and other antipsychotics. J Clin Psychiatry. 2012;73(12):1533-1540.	Duplicate
Szegedi A, Verweij P, Van Duijnhoven, et al. Meta-analyses of the efficacy of asenapine for acute schizophrenia: comparisons with placebo and other antipsychotics. J Clin Psychiatry. 2012;73(12):1533-1540.	Duplicate
Szegedi A, cazorla P, Zhao J. Incidence, onset and duration of treatment-emergent somnolence with asenapine in adult patients with schizophrenia or bipolar disorder [conference abstract]. Eur Neuropsychopharmacol. 2011;21:S502-S503.	Duplicate
Zhao J, Cazorla P, Schoemaker J, et al. Weight change and metabolic effects of asenapine in placebo or olanzapine controlled studies [conference abstract]. Neuropsychopharmacology. 2010;35:S322-S323.	Duplicate
Meltzer H, Cohen M, Snowadami, L, et al. Long term safety and maintenance of effect of asenapine in patients with acute exacerbation of schizophrenia [conference abstract]. Eur Neuropsychopharmacol. 2009;19:S536-S537.	Full text not provided by author
Harrigan EP, Miceli JJ, Anziano R, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol. 2004;24(1):62-69.	Asenapine was not included
Alexander W. New Atypical agents and virtual reality with drug therapy. American Psychiatric Association. P T. 2008;33(6):364-367.	Wrong diagnosis studied
Boyda HN, Procyshyn RM, Pang CC, et al. Metabolic side effects of the novel second generation antipsychotic drugs asenapine and iloperidone: a comparison with olanzapine. PLoS One. 2013;8(1):e53459.	Not performed in human subjects

RCT = randomized clinical trial. Full text screening was performed in duplicate by C.O. and S.D.

Efficacy Outcomes

PANSS

Patients were considered to be PANSS responders if they achieved a ≥30% decrease in their PANSS total score from baseline at the end of the study. Results favoured ASP over PLC in terms of both change in PANSS total score (OR –8.98; 95% CI, –12.73 to –5.23) (Figure 3) and percentage of PANSS responders (OR 1.88; 95% CI, 1.24 to 2.84), No differences were found between ASP and PLC in terms of changes to the 3 PANSS subscale scores. No differences were noted between ASP and OZP in terms of changes to PANSS total (Figure 3), nor were there any differences between ASP and OZP in changes to PANSS negative subscale scores. In addition, ASP was found to be inferior to OZP regarding changes to PANSS positive and PANSS psychopathology subscale scores, with differences of 0.94 (95% CI, 0.46 to 1.42) and 1.38 (95% CI, 0.51 to 2.25), respectively. Both the ASP vs. PLC and the ASP vs. OZP comparisons demonstrated considerable heterogeneity (82% and 78%, respectively) for the outcome change in PANSS total score.

Figure 3.

Changes in PANSS total score.

Clinical Global Impression (CGI)

Schoemaker et al.²⁰ and Kane et al.¹⁷ considered CGI improvement scale (CGI-I) responders to be those with a CGI-I score of 1 (very much improved) or 2 (much improved) at study end. ASP was superior to PLC on improvement in CGI severity scale (CGI-S) scores, while no difference was observed between ASP and OZP in this outcome. There was no difference in the rates of CGI-I responders between those randomized to ASP and those randomized to PLC. ASP was inferior to OZP in this outcome (OR 0.66; 95% CI, 0.52 to 0.84).

Worsening schizophrenia and/or psychosis

Rates of worsening schizophrenia and/or psychosis did not differ between ASP and PLC. However, compared with those randomized to OZP, more patients randomized to ASP experienced this outcome (OR 1.38; 95% CI, 1.05 to 1.82). Refer to Table 4 for a summary of efficacy results.

Table 4.

Summary table of efficacy outcomes.

Outcome	ASP vs. PLC	ASP vs. OZP	ASP 10 mg BID vs. 5 mg BID
Changes to PANSS total	Favours ASP (greater reduction with ASP) WMD: –8.98 (95% CI, –12.73 to –5.23)	No difference WMD: 3.05 (95% CI, –0.46 to 6.56)
Changes to PANSS negative	No difference WMD: –0.1 (95% CI, –1.25 to 1.05)	No difference WMD: –0.23 (95% CI, –1.02 to 0.55)
Changes to PANSS Marder negative	Favours ASP (greater reduction with ASP) WMD: –1.54 (95% CI, –2.25 to –0.84)	No difference WMD: 0.22 (95% CI, –1.14 to 1.57)	No difference WMD: 0 (95% CI, –1.38 to 1.38)
Worsening schizophrenia	No difference OR 0.7 (95% CI, 0.22 to 2.26)	Favours OZP (lower incidence with OZP) OR 1.38 (95% CI, 1.05 to 1.82)	No difference OR 3.3 (95% CI, 0.9 to 12.7)
Changes to CGI-S	Favours ASP (greater reduction with ASP) WMD: –0.46 (95% CI, –0.78 to –0.14)	No difference WMD: 0.22 (95% CI, 0.00 to 0.44)	No difference WMD: 0.1 (95% CI, –0.18 to 0.38)
Rates of CGI-I responders	No difference WMD: 1.54 (95% CI, 0.90 to 2.64)	Favours OZP WMD: 0.66 (95% CI, 0.52 to 0.84)

ASP = asenapine; BID = twice daily; CGI-I = Clinical Global Impression–improvement scale; CGI-S = Clinical Global Impression–severity scale; OR = odds ratio; OZP = olanzapine; PANSS = Positive and Negative Syndrome Scale; PLC = placebo; WMD = weighted mean difference.

Withdrawals

Rates of either withdrawal for any reason or withdrawal due to adverse effects were no different between patients receiving ASP and those receiving PLC (Figure 4). ASP-treated patients had lower rates of withdrawal due to lack of efficacy than those taking PLC (OR 0.37; 95% CI, 0.20 to 0.69). When ASP was compared with OZP, no difference was shown for rates of discontinuation due to adverse drug reactions (ADRs) (Figure 4) or lack of efficacy, but ASP had higher rates of overall withdrawal (OR 2.06; 95% CI, 1.71 to 2.49).

Figure 4.

Rates of withdrawal due to adverse effects.

Safety and Tolerability Outcomes

Adverse effects

No differences were found between ASP and either PLC or OZP in rates of “any ADR.” Higher rates of serious ADRs were demonstrated in those receiving ASP compared with OZP (OR 1.84; 95% CI, 1.36 to 2.47). Trials did not specify which serious adverse effects occurred.

Effect on sleep

Rates of insomnia were comparable between ASP and PLC, whereas patients randomized to ASP were more likely to report this adverse effect than those randomized to OZP (OR 1.46; 95% CI, 1.13 to 1.90). Rates of sedation were similar between ASP and both comparators.

Metabolic adverse effects

The incidence of clinically significant weight gain was greater with ASP compared with PLC (OR 3.58; 95% CI, 1.13-11.31). Those taking ASP were less likely to have reported this outcome than those randomized to OZP (OR 0.35; 95% CI, 0.27 to 0.44). Changes from baseline in triglyceride values were similar between ASP and PLC. Based on results from 1 trial, patients receiving ASP had less change in triglyceride than OZP-treated patients (OR –0.45; 95% CI, –0.71 to –0.19). No significant differences were found between ASP and either comparator in changes in fasting blood glucose or new-onset National Cholesterol Education Program metabolic syndrome.¹⁶

Extrapyramidal symptoms (EPS)

No differences were found between ASP and PLC in reported rates of EPS. Patients randomized to ASP were more likely to experience EPS and akathisia than were patients taking OZP: OR 2.06 (95% CI, 1.38 to 3.06) and OR 2.27 (95% CI, 1.45 to 3.55), respectively. No differences were noted between groups in changes to any of the EPS rating scales: Simpson Angus scale, Abnormal Involuntary Movement Scale, Extrapyramidal Symptoms Rating Scale, or Barnes Akathisia Rating Scale.

Patient Acceptance and Quality of Life Outcomes

Very few trials measured patient-reported outcomes, such as improvements in quality of life and subjective well-being while receiving neuroleptics. Schoemaker et al.²⁰ reported both patients’ and investigators’ subjective impressions of improvement of the patients’ disease condition in comparison to when they were taking previous neuroleptics. Those taking ASP were less likely to be considered “much improved” by the investigator than those receiving OZP (OR 0.65; 95% CI, 0.45 to 0.93).

Refer to Table 5 for a summary of additional clinically relevant results.

Table 5.

Summary of clinically important outcomes.

Outcome	No. of trials reporting the outcome	Total no. of patients in trials	Effects	Odds ratio (95% CI) or mean difference (95% CI)
Asenapine vs. placebo
Changes to PANSS total	3	689	Favours ASP (greater reduction with ASP)	–8.98 (–12.73 to –5.23)
Changes to CGI-S	2	609	Favours ASP (greater reduction with ASP)	–0.46 (–0.78 to –0.14)
Changes to PANSS negative	1	189	No difference	–0.1 (–1.25 to 1.05)
Changes to PANSS Marder negative	2	609	Favours ASP (greater reduction with ASP)	–1.54 (–2.25 to –0.84)
Incidence of discontinuation due to adverse effects	3	736	No difference	0.53 (0.20 to 1.42)
Incidence of all adverse effects	3	736	No difference	0.91 (0.60 to 1.39)
Incidence of serious adverse effects	3	736	No difference	0.75 (0.24 to 2.30)
Clinically significant increases in body weight (≥7% of baseline)	3	736	Favours PLC (lower incidence with PLC)	3.58 (1.13 to 11.31)
Incidence of reported akathisia	2	615	No difference	2.62 (0.87 to 7.87)
Incidence of patients reporting any EPS symptoms	2	615	No difference	1.21 (0.40 to 3.67)
Incidence of sedation	1	229	No difference	1.42 (0.42 to 4.78)
Incidence of insomnia	3	736	No difference	0.91 (0.40 to 2.06)
Worsening schizophrenia	3	736	No difference	0.7 (0.22 to 2.26)
Agitation	3	736	Favours ASP (lower incidence with ASP)	0.54 (0.3 to 0.97)
Asenapine vs. olanzapine
Changes to PANSS total	4	2242	No difference	3.05 (–0.46 to 6.56)
Changes to CGI-S	3	2051	No difference	0.22 (0.00 to 0.44)
Changes to PANSS negative	3	1076	No difference	–0.23 (–1.02 to 0.55)
Changes to PANSS Marder negative	3	2051	No difference	0.22 (–1.14 to 1.57)
Incidence of discontinuation due to adverse effects	3	1647	No difference	1.20 (0.57 to 2.51)
Incidence of all adverse effects	3	2148	No difference	1.05 (0.78 to 1.40)
Incidence of serious adverse effects	3	2168	Favours OZP (lower incidence with OZP)	1.84 (1.36 to 2.47)
Clinically significant increases in body weight (≥7% of baseline)	3	2168	Favours ASP (lower incidence with ASP)	0.35 (0.27 to 0.44)
Incidence of reported akathisia	3	2168	Favours OZP (lower incidence with OZP)	2.27 (1.45 to 3.55)
Incidence of patients reporting any EPS symptoms	3	2168	Favours OZP (lower incidence with OZP)	2.06 (1.38 to 3.06)
Incidence of sedation	3	2168	No difference	0.82 (0.59 to 1.16)
Incidence of insomnia	3	2168	Favours OZP (lower incidence with OZP)	1.46 (1.13 to 1.90)
Worsening schizophrenia	3	2168	Favours OZP (lower incidence with OZP)	1.38 (1.05 to 1.82)
Agitation	2	949	No difference	2.7 (0.82 to 8.95)
Asenapine 10 mg vs. asenapine 5 mg
Changes to PANSS total	ND	ND	ND	ND
Changes to CGI-S	1	214	No difference	0.1 (–0.18 to 0.38)
Changes to PANSS negative	ND	ND	ND	ND
Changes to PANSS Marder negative	1	214	No difference	0 (–1.38 to 1.38)
Incidence of discontinuation due to adverse effects	1	217	No difference	2.2 (0.7 to 6.7)
Incidence of all adverse effects	1	217	No difference	1.7 (0.92 to 3)
Incidence of serious adverse effects	1	217	No difference	1.38 (0.49 to 3.84)
Clinically significant increases in body weight (≥7% of baseline)	1	217	No difference	0.7 (0.19 to 2.5)
Incidence of reported akathisia	1	217	No difference	2.3 (0.85 to 6.4)
Incidence of patients reporting any EPS symptoms	1	217	No difference	1.2 (0.6 to 2.5)
Incidence of sedation	1	217	No difference	0.9 (0.31 to 2.58)
Incidence of insomnia	1	217	No difference	0.9 (0.45 to 1.7)
Worsening schizophrenia	1	217	No difference	3.3 (0.9 to 12.7)
Agitation	1	217	No difference	0.71 (0.3 to 1.95)

ASP, asenapine; CGI-S, Clinical Global Impression–severity scale; EPS, extrapyramidal symptoms; ND, no data; OZP, olanzapine; PANSS, Positive and Negative Syndrome Scale; PLC, placebo.

Additional Analyses

Two post hoc subgroup analyses were conducted, one comparing ASP 5-mg BID and 10-mg BID dosing and the other including only long-term trials (those ≥26 weeks long).

ASP 5 mg BID vs. 10 mg BID

No statistically significant differences were found for efficacy, rates of withdrawal, or tolerability outcomes between the 2 doses.

Long-term trials

Four trials were included in this analysis.^16,18,20 Trials with PLC comparator showed comparable results when limited to long-term trials. All trials with OZP comparator were long-term trials, so there was no change to those results.

Discussion

This review demonstrates that the current evidence for the use of ASP in psychotic disorders is limited. A total of 8 trials were included in this review: 5 were placebo-controlled and 3 compared ASP with OZP.

The results demonstrate that ASP 10 mg BID was superior to PLC on several efficacy outcomes but was not superior to OZP. ASP’s purported enhanced activity against negative and cognitive symptoms of schizophrenia was not confirmed by the results of this review. Nor was enhanced adherence with ASP demonstrated. In addition, patients taking ASP were more likely to withdraw from clinical trials, suggesting that adherence to ASP in the clinical setting may be inferior to OZP.

Second-generation antipsychotics have a documented adverse impact on the patient’s metabolic profile.² Results from this review favoured ASP over OZP in this regard, which suggests that ASP may be advantageous in patients at higher risk of cardiovascular morbidity and mortality.

ASP demonstrated a similar propensity towards sedation as both PLC and OZP, a surprising finding considering the well-known sedative effects of OZP. A lack of power to detect a difference in rates of sedation may be at play, reducing our ability to detect a significant difference when results were combined for this meta-analysis.

Rates of EPS were lower with OZP than ASP and comparable between ASP and PLC. The authors believe that these findings may be due to the number and duration of trials included in this review. Some forms of EPS may occur months to years after the initiation of an antipsychotic. All trials comparing ASP and OZP were long-term trials, while only 1 placebo-controlled trial was a long-term trial. It is possible that with time, a significant difference favouring PLC would have been detected for this adverse effect; however, the majority of the placebo-controlled studies included were likely too short in duration to reveal a significant difference in this outcome.

No conclusions can be drawn about the impact of oral hypoesthesia, a common adverse effect reported with ASP,⁵ since only 1 placebo-controlled trial reported on this outcome.¹⁷

The subgroup analysis comparing ASP 5 mg BID and 10 mg BID demonstrated no differences in efficacy, withdrawals, or tolerability outcomes between the 2 doses. Although not powered for this comparison, these findings suggest that the efficacy of ASP is not dose-dependent and that dose escalation is not warranted.

The strengths of this review include the fact that it was conducted in accordance with PRISMA (Table 6) and Cochrane guidelines and was registered a priori.^14,24 The breadth of the search strategy ensured that all relevant articles matching the inclusion criteria were found. All study selection and data extraction were done in duplicate, thus minimizing the risk of bias.²⁵

Table 6.

PRISMA checklist.

Section/topic	#	Checklist item	Reported on page #
Title
Title	1	Identify the report as a systematic review, meta-analysis, or both.	1
Abstract
Structured summary	2	Provide a structured summary including, as applicable, background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.	2
Introduction
Rationale	3	Describe the rationale for the review in the context of what is already known.	5
Objectives	4	Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).	7
Methods
Protocol and registration	5	Indicate whether a review protocol exists and whether and where it can be accessed (e.g., Web address); if available, provide registration information including registration number.	6
Eligibility criteria	6	Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.	7
Information sources	7	Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.	6
Search	8	Present full electronic search strategy for at least 1 database, including any limits used, such that it could be repeated.	6
Study selection	9	State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).	7
Data collection process	10	Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.	7
Data items	11	List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.	Table 1
Risk of bias in individual studies	12	Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level) and how this information is to be used in any data synthesis.	8
Summary measures	13	State the principal summary measures (e.g., risk ratio, difference in means).	8
Synthesis of results	14	Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.	8

There are some limitations of this review. All included trials had strict inclusion and exclusion criteria such as the exclusion of those with concurrent psychiatric illnesses, including substance abuse, which may limit generalizability of the results to a broad patient population. All patients were included in this meta-analysis regardless of whether patients were treated as inpatient or outpatient and whether they were in florid psychosis or had stable disease. This may explain the heterogeneity observed in this review, such as in the change in PANSS total score with an I² of 95.3%. Trials handled missing data inconsistently, resulting in the combination of results obtained from either mixed model of repeated measures or last observation carried forward in the meta-analysis. This contributes further to the heterogeneity of results. Thirteen potentially eligible trials were unobtainable from authors and/or the manufacturer of ASP despite repeated requests. This large source of unknown data could have a significant effect on the outcomes reported in this review.

Conclusions

Insufficient evidence is available to make recommendations on preference of ASP over other antipsychotic medications in the treatment of psychotic disorders. Results from the included trials suggest that ASP is either comparable to or inferior to OZP for the majority of efficacy, tolerability, and acceptability outcomes. ASP demonstrated a safer metabolic profile than OZP with a trend towards less sedation; ASP was more likely than OZP to lead to EPS. With this in mind, ASP may be a treatment choice for those who cannot tolerate the sedative effects of OZP, such as drivers and night shift workers, as well as those who are at high risk of metabolic adverse effects.

ASP should also be considered an option in patients who will be able to follow the prescribed administration instructions.

There is a need for well-designed, randomized clinical trials that are adequately powered to compare the efficacy and acceptability of ASP with active comparators other than OZP. The outcome measures that are clinically relevant and merit further study include quality of life, cost, adherence with medication, and length of hospitalization. The comparisons of different doses of ASP may be beneficial in order to determine whether dosing flexibility affects treatment efficacy and safety.