Asenapine versus placebo for schizophrenia

Review question

Asenapine is a newer antipsychotic drug developed in the early-to-mid 1990s. The review looks at the effects of asenapine in the treatment of schizophrenia compared with placebo.


People with schizophrenia often have 'positive symptoms', such as hearing voices, seeing things (hallucinations) and strange beliefs (delusions). People also have 'negative symptoms', including loss of emotions, apathy, social withdrawal, lack of pleasure and difficulty speaking and communicating. Disorder of thoughts, anxiety and depression are common. The main treatment for these symptoms of schizophrenia is antipsychotic drugs, which are divided into older drugs (typical or first generation) and newer drugs (atypical or second generation). These drugs often have severe side effects, such as weight gain, muscle stiffness, involuntary shaking and tiredness. Asenapine is a newer antipsychotic drug developed in the 1990s. At present there are no systematic reviews assessing the effects of this drug.

Study characteristics

The review includes six trials with 1835 people. The trials randomised people with schizophrenia to receive either asenapine or placebo. Five of these trials had high rates of people leaving early and were sponsored by pharmaceutical companies.

Key results

There is some evidence that asenapine, when compared to placebo, improves the positive, negative and depressive symptoms of schizophrenia while having less risk of debilitating side effects.

Quality of the evidence

However, due to the low quantity and limited quality of evidence currently available, it remains difficult to recommend the use of asenapine for schizophrenia. There is a need for large-scale, longer-term follow up, and bias-free randomised controlled trials investigating the effects and safety of asenapine.

Ben Gray, Senior Peer Researcher, McPin Foundation.

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.

Read the full abstract...

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.


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

Search strategy: 

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.