Risperidone versus placebo for people with schizophrenia


Risperidone was one of the first “atypical” antipsychotics to appear in the early 1990s. As a serotonin/dopamine receptor antagonist, it binds to D2 and D3 receptors with 50 and 20 times greater affinity than clozapine and is only 2-3 times less potent than haloperidol (Leyson et al, 1994).

In 2007, risperidone became off license and has emerged as the new standard care comparator for schizophrenia. Much of the current evidence for the use of risperidone is based on comparisons to older drugs with poor side effect profiles, such as haloperidol (Hunter et al, 2003).

However, comparing risperidone to other antipsychotics underestimates the importance of the placebo effect. With placebo effects accounting for up to 33% of clinical improvement (Benson and Friedman, 1996), many researchers feel that only by comparison to placebo can a rationalised therapeutic approach be developed (Vallance, 2006).

Cochrane reviews to date have evaluated the efficacy of risperidone for schizophrenia by comparing it with “typical” and other “atypical” antipsychotics. The subject of today’s blog is a Cochrane review (Rattehalli et al, 2016) that compares the efficacy of risperidone to that of placebo.

This Cochrane review aimed to determine the clinical effects and safety of risperidone compared with placebo for people with schizophrenia.

This Cochrane review aimed to determine the clinical effects and safety of risperidone compared with placebo for people with schizophrenia.


Searches were conducted in the Cochrane Schizophrenia Group’s trial register, which is the best place in the world to find schizophrenia trials. Studies were included that had been published up to October 2015.

All randomised controlled trials (RCTs) comparing oral risperidone with placebo treatments for people with schizophrenia or schizophrenia-like psychoses were included. All references of reports for included trials were also searched for further relevant studies. Participants were over the age of 17 with schizophrenia or other types of schizophrenia-like psychoses.


In total, 763 citations were identified (after removal of duplicates). Fourteen studies with 24 references were awaiting further assessment due to lack of reviewer agreement and/or lack of full-text. One study was still ongoing. Overall this resulted in 15 studies with 56 references and 2,428 participants being included in the data and analysis.

The main findings of this review comparing risperidone with placebo for schizophrenia were:

  • Patients in the risperidone group were more likely to achieve a significant clinical improvement (36% risk reduction in not achieving clinically significant improvement in psychotic symptoms). This effect was still present even when 3 studies were removed due to a high attrition rate
  • Patients receiving risperidone were more likely to have shown a significant improvement on the clinical global impression scale (Guy, 1976)
  • The risperidone group achieved a greater reduction on the brief psychiatric rating scale (Overall and Gorham, 1962) and on the positive and negative syndrome scale (Kay et al, 1968)
  • The risperidone group were less likely to leave the study early
  • The incidence of side effects was significantly higher in the risperidone group, with the risperidone group 1.56 times more likely to experience extrapyramidal side effects (1.56), akathisia (2.58), hypertonia (2.98) and parkinsonism (7.64)


This Cochrane review has shown that overall risperidone has a positive effect on the metal state of people with schizophrenia, however the data on which this is based is of low quality.

In particular, mental state and global state outcomes favoured risperidone, however when used alone the relationship between these measures and meaningful clinical improvement is unclear.

It is also concerning that while clinicians and patients may be reassured by the side effect profile of risperidone compared to “typical” antipsychotics, when compared to placebo the incidence of side effects in risperidone is significantly greater.  Even more concerning is that due to poor reporting, the adverse effects of risperidone compared to placebo could be under estimated.

In conclusion, this Cochrane review shows that there is low quality evidence that supports the efficacy of risperidone compared to placebo. However, based on the same low quality evidence, it is unclear if the benefits of treatment outweigh the harm.

At present there is insufficient evidence from this review to support the use of risperidone over placebo. More independent, high quality and longer duration RCTs are required in order to allow clinicians and patients to be confident in the evidence for the use of risperidone in the treatment of schizophrenia.

Strengths and limitations

  • Overall, the quality of evidence was poor
  • Pharmaceutical companies funded 8 of the 15 studies
  • Although all studies were reported as randomised, the method of randomisation was not always clear which could potentially lead to selection bias. Indeed the reviewers had concerns about sequence generation and allocation concealment in over half the included studies
  • All studies were reported to be double blind, but again how this was achieved wasn’t always described, which made the assessment of observation bias by the authors difficult
  • Some studies did not consider the analysis of data from participants who left the study early leaving them at high risk of attrition bias
  • The authors also highlighted the issue of multiple publications and the risk of bias that this brings, with a large number being identified during this study
  • In addition to the risk of different forms of bias in many studies, much of the data could not be used due to poor reporting.

The authors highlight that in addition to low quality data the applicability of the review is also limited. All of the 15 studies included were of short duration (between 8 and 16 weeks), thus the results of this review cannot be applied to the long term use of risperidone. Also, while studies were conducted in both primary and secondary care settings, most were conducted in high income countries.  Thus the application of the findings outside these settings is limited.


  • The atypical antipsychotic risperidone has emerged as the new standard care comparator for new therapeutics in schizophrenia despite a lack of evidence demonstrating superior efficacy when compared to placebo
  • This Cochrane review shows that, based on the evidence available, risperidone has greater efficacy in causing clinical improvements in patients with schizophrenia compared to placebo
  • However, the incidence of side effects, including extrapyramidal symptoms, in patients in the risperidone group are significantly greater than those in the placebo group
  • In addition, the quality of evidence is poor, meaning that based on the evidence available, it is unclear if the benefits of risperidone outweigh the risks
  • At present there is insufficient evidence to support the use of risperidone over placebo
  • Further, independent and high quality research is needed in this area. Future RCTs must be of longer duration and be well planned, well conducted and well reported in order to provide a solid evidence base for the treatment of schizophrenia.
At present there is insufficient evidence to support the use of risperidone over placebo.

This review suggests that there is insufficient evidence to support the use of risperidone over placebo in schizophrenia.


Primary paper

Rattehalli RD, Zhao S, Li BG, Jayaram MB, Xia J, Sampson S. Risperidone versus placebo for schizophrenia. Cochrane Database of Systematic Reviews 2016, Issue 12. Art. No.: CD006918. DOI: 10.1002/14651858.CD006918.pub3.

Other references

Benson H, Friedman R (1996) Harnessing the power of the placebo effect and renaming it “remembered wellness”. Annual Review of Medicine 1996;47:193–9. (PubMed Abstract)

Guy U. ECDEU assessment manual for psychopharmacology (1976). Revised. Rockville: National Institute of Mental Health,

Hunter RH, Joy CB, Kennedy E et al (2003) Risperidone versus typical antipsychotic medication for schizophrenia (PDF). Cochrane Database of Systematic Reviews 2003, Issue 2. CD000440

Kay SR, Opler LA, Fiszbein A (1986) Positive and Negative Syndrome Scale (PANSS) Manual. North Tonawanda, NY: Multi-Health Systems, 1986.

Leysen JE, Janssen PM, Megens AA et al (1994) Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity. Journal of Clinical Psychiatry 1994;55(Suppl):5–12. (PubMed Abstract)

Overall JE, Gorham DR (1962) The Brief Psychiatric Rating Scale (PDF). Psychological Reports 1962;10:799–812.

Vallance AK. Something out of nothing: the placebo effect (PDF). Advances in Psychiatric Treatment 2006;12:287–96.

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Joanne Wallace

Joanne Wallace is a graduate entry Medical Student at The University of Warwick. Previously she worked in medical research after completing a degree in Biomedical Science at The University Of Sheffield and a PhD at Newcastle University. Her PhD and postdoctoral work focused on the pathology of cognitive dysfunction in animal models of psychiatric disorders and Alzheimer’s disease. Her interests include early behavioural or biomarkers of prodromal psychiatric disease and how these can be targeted for treatments and how knowledge of underlying pathology can be utilised in the diagnosis and treatment of psychiatric disease and dementia.

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