NPC Archive Item: Long-acting injectable risperidone no better than oral antipsychotics in unstable schizophrenia

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6th April 2011

A study has found that, in high-risk patients with schizophrenia and schizoaffective disorder, long-acting injectable risperidone did not significantly improve time to hospitalisation, psychiatric symptoms, quality of life or functioning, compared with oral antipsychotics. Patients who received long-acting risperidone▼ had more adverse events including local injection site reactions, headache, and extra-pyramidal signs and symptoms.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Healthcare professional should follow NICE guidance on the management of patients with schizophrenia. NICE advises that depot or long-acting antipsychotics may be given after an acute episode of schizophrenia if the patient prefers, and to avoid covert non-adherence to oral medication. The choice of antipsychotic should be made in partnership with the person (and carer if appropriate) taking into account the relative potential of individual antipsychotics to cause extrapyramidal side effects, metabolic side effects (such as weight gain), and other side effects. A patient decision aid is available in the schizophrenia eLearning materials that include a chart of the relative side effect profiles of different antipsychotics. This may be helpful when considering which antipsychotic is most appropriate for a person to try first.

What is the background to this?
Three randomised controlled trials (RCTs) have shown no advantage of long-acting injectable risperidone over oral treatment in patients with clinically stable schizophrenia. This study tested the hypothesis that long-acting injectable risperidone would be superior in reducing the risk of hospitalisation for up to two years, compared with a psychiatrist’s choice of an oral antipsychotic, in patients with unstable disease, who had been hospitalised within the previous two years or were at risk of being hospitalised.

What does this study claim?
The rate of hospitalisation after randomisation was not significantly lower among patients who received long-acting injectable risperidone than among those who received oral antipsychotics (39% after 10.8 months vs. 45% after 11.3 months, respectively; hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.63 to 1.20, P=0.39). Psychiatric symptoms, quality of life, and scores on the Personal and Social Performance scale of global functioning, were also not significantly improved with long-acting injectable risperidone, compared with control treatments. Patients who received long-acting injectable risperidone reported more injection site reactions, headache, and extra-pyramidal signs and symptoms.

So what?
The study does have some limitations. Firstly, 12% of control patients received long-acting injectable risperidone an average of 5 months into the trial, which may have biased the results in favour of oral treatment. Secondly, the dose of the long-acting preparation may have been inadequate in some patients. Thirdly, decisions regarding hospitalisation were unblinded and, fourthly, the trial included older, primarily male veterans so the results may not be generalisable to other populations. Finally, due to recruitment difficulties, the study included fewer patients than originally planned and may not have been sufficiently powered to exclude modest differences between the treatment and control groups.

Nevertheless, these findings are consistent with those of the three RCTs that showed no difference between long-acting injectable risperidone and oral risperidone in patients with stable schizophrenia. All these trials support NICE guidance, which advises that long-acting preparations should only be used in limited circumstances, i.e. in patients who would prefer such treatment after an acute episode, or where avoiding covert non-adherence (either intentional or unintentional) to antipsychotic medication is a clinical priority within the treatment plan.

Study details
Rosenheck RA, et al. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N Engl J Med 2011;364:842–51

Design: RCT with up to two years follow-up


Patients: 369 patients in the Veterans Affairs (VA) system with schizophrenia or schizoaffective disorder. 40% were hospitalised at randomization, 55% were hospitalised within the previous 2 years, and 5% were at risk for hospitalisation.


Intervention and comparison: Patients were randomised to 25–50 mg of long-acting injectable risperidone every two weeks or to a psychiatrist’s choice of an oral antipsychotic.


Outcomes: The primary end point was hospitalisation in a VA or non-VA psychiatric hospital. Symptoms, quality of life, and functioning were assessed in blinded videoconference interviews.


Results: With a mean follow-up of 11.3 and 10.8 months, respectively, 81 of 182 (45%) patients receiving oral medication and 72 of 187 (39%) receiving long-acting injectable risperidone were hospitalised. Long-acting injectable risperidone was not superior to oral treatment with respect to the time to hospitalisation (HR 0.87, 95%CI 0.63 to 1.20, P=0.39). An analysis that excluded the 21 subjects who switched from an oral antipsychotic to long-acting injectable risperidone provided similar results (HR 1.00, 95%CI 0.71 to 1.40), as did an analysis that was adjusted for covariates (HR 0.82, 95%CI 0.59 to 1.13). Long-acting injectable treatment was not superior to oral treatment in the duration of adherence to the randomized treatment (P=0.19). There was also no significant difference between the groups in multiple standard measures of symptoms, quality of life, side effects, or service use.

Patients who received long-acting injectable risperidone had more “general disorders and administration site conditions” (injection-related pain or induration) (P=0.04) and “nervous system disorders” (headache and extrapyramidal signs and symptoms) (P<0.001).


Sponsorship: The study was supported by the Veterans Affairs Cooperative Studies Program and an unrestricted grant from Ortho-McNeil Janssen Scientific Affairs
More information on schizophrenia can be found in the eLearning materials on the NPC website.

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