Long-Acting Risperidone

Long-acting risperidone (Risperdal Consta™) is a novel, intramuscular formulation of the atypical antipsychotic risperidone, which has shown efficacy in the treatment of patients with schizophrenia.

Long-acting risperidone is pharmacokinetically equivalent to and causes less plasma drug concentration fluctuation than the oral formulation. This novel formulation is an aqueous suspension of microspheres comprising risperidone and a biodegradable copolymer. Significant release of risperidone from the microspheres begins 3 weeks after the first injection: thus, administration of another antipsychotic is necessary during this period only. Steady-state plasma concentrations are reached after the fourth injection. Elimination is complete 7–8 weeks after the last injection.

Long-acting risperidone 25 or 50mg every 2 weeks demonstrated significantly greater antipsychotic efficacy than placebo and equivalent efficacy to oral risperidone 2–6 mg/day in two randomised, double-blind, double-dummy, 12-week trials of patients with schizophrenia. Additionally, in one of these trials, improvements in health-related quality of life (HRQOL) were superior with long-acting risperidone than placebo.

Compared with baseline, improvements in the symptoms of schizophrenia in stable patients were significant with long-acting risperidone 25 or 50mg (12-month trial) and 25, 37.5 or 50mg (12-week trial) every 2 weeks, in two noncomparative, multicentre trials. Patient satisfaction with their medication and patient HRQOL mental health scores improved significantly in the 12-month trial.

Long-acting risperidone is generally well tolerated, with a low incidence of injection site pain and an otherwise similar profile of adverse effects to the oral formulation. The overall incidence of extrapyramidal disorders in clinical trials was low (≤ 10%) with similar, yet minimal, changes in extrapyramidal symptom severity between patients treated with long-acting risperidone, oral risperidone or placebo. Tardive dyskinesia was reported in the 12-month trial, in 0.7% of patients.

Risperidone is a potent serotonin 5-HT_2A and dopamine D₂ antagonist and has high affinity for α₁-adrenergic and dopamine D₄ receptors. The efficacy of risperidone against the negative symptoms of schizophrenia and lowered risks of extrapyramidal symptoms (EPS), relative to typical antipsychotics, may be attributable to serotonergic antagonism. Its efficacy against positive symptoms is likely to be attributable to dopaminergic antagonism, although the exact mechanisms are still unclear. Oral risperidone produces a marked and sustained increase in serum prolactin levels during short- and long-term treatment, although this does not appear to be directly correlated with prolactin-associated adverse events.

The long-acting formulation of risperidone is an aqueous suspension of carbohydrate-based microspheres that are gradually hydrolysed at the injection site, resulting in a significant release of risperidone 3 weeks after the first injection, followed by a gradual and sustained release of risperidone from weeks 4–6 after the first injection. Following regular administration every 2 weeks, steady state is reached after the fourth injection. Oral and long-acting risperidone are pharmacokinetically equivalent. The long-acting formulation of risperidone produces less fluctuation in plasma drug concentrations and a significantly lower peak steady-state plasma concentration than oral risperidone. Risperidone is highly bound to plasma proteins (≈90%).

Risperidone is metabolised by cytochrome P450 2D6 to the active metabolite 9-hydroxyrisperidone (9-OHRIS), subject to genetic polymorphism. Total body clearance in extensive (and poor) metabolisers of risperidone following administration of long-acting risperidone is 13.7 (3.3) L/h and of the active moiety (risperidone and 9-OHRIS) is 5.0 (3.2) L/h. Elimination is primarily renal and completed by 7–8 weeks after the last injection of long-acting risperidone. The pharmacokinetic profile of long-acting risperidone is similar in elderly and non-elderly patients.

Long-acting risperidone is an effective treatment for schizophrenia. The efficacy of long-acting risperidone was superior to that of placebo at a dosage of 25 or 50mg every 2 weeks (n = 283) and not significantly different from that of oral risperidone 2–6mg once daily at a dosage of 25–75mg every 2 weeks (n = 541), according to two well-designed 12-week trials. Total, positive and negative symptom scores from the Positive and Negative Syndrome Scale (PANSS) of patients treated with long-acting risperidone 25 or 50mg were significantly reduced from baseline and not significantly different from oral risperidone. In stable patients previously treated with conventional depot antipsychotics, symptom control (assessed by PANSS total scores) was improved during 12-weeks’ treatment with long-acting risperidone (25, 37.5 and 50mg) in a noncomparative trial (n = 166). In addition, most of the assessed health-related quality of life (HRQOL) domains of patients treated with long-acting risperidone for 12 weeks significantly improved from baseline to endpoint compared with placebo recipients.

In a noncomparative 12-month trial in symptomatically stable patients with schizophrenia (n = 322), long-acting risperidone 25 or 50mg every 2 weeks for 12 months improved schizophrenic symptoms as assessed by significant reductions in mean PANSS total, positive and negative symptom scores from baseline to endpoint. Additionally, both patient satisfaction with their medication and HRQOL mental health scores improved significantly from baseline after treatment with long-acting risperidone.

Long-acting risperidone 25 or 50mg every 2 weeks is generally well tolerated as evidenced by two well-designed 12-week trials and two noncomparative trials (12 weeks and 12 months). The most common (incidence ≥10%) treatment-emergent adverse events (in any long-acting risperidone treatment group) included insomnia, psychosis, headache, agitation, dizziness, rhinitis and pain in a 12-week trial and hyperkinesia, headache, depression, anxiety, insomnia, psychosis and rhinitis in a 12-month trial. Tardive dyskinesia was reported with a low incidence (0.7%) in the 12-month trial.

Changes in EPS severity (assessed by Extrapyramidal Symptom Rating Scale [ESRS] scores) from baseline were similar in patients receiving longacting or oral risperidone and minimal in patients receiving placebo or long-acting risperidone. Over the short term, long-acting risperidone improved parkinsonism and dyskinesia symptoms (ESRS subscale) relative to baseline in a noncomparative trial. Long-acting risperidone 25 or 50mg every 2 weeks maintained a low severity of EPS in a 12-month noncomparative trial.

Injection site pain is usually infrequent and mild. Patients receiving long-acting risperidone generally experienced a small mean bodyweight gain (0.5kg) over 12 weeks, similar to that with oral risperidone (0.3kg), but a larger increase over a 12-month period (≈2kg). Changes in laboratory tests or electrocardiogram results in patients receiving long-acting risperidone were not clinically relevant and changes in cardiovascular measures were not significantly different to placebo recipients. Treatment-emergent orthostatic hypotension has been observed in 2% of patients receiving long-acting risperidone in a 12-week trial.

Long-acting risperidone 25 or 50mg once every 2 weeks significantly reduced hospitalisation rates and use of day or night clinics from baseline to endpoint over 1 year according to results from a noncomparative, multicentre trial (n = 397). Reductions in the number of hospitalisations, the number of episodes of institutional care and the cumulative duration of hospitalisation were reported in patients after switching to long-acting risperidone in a mirror-image study in Sweden (n = 92). Preliminary data from pharmacoeconomic studies suggest that long-acting risperidone may be more cost effective than oral olanzapine and depot haloperidol in patients with schizophrenia (French model) and offer cost savings relative to both depot haloperidol and oral olanzapine in patients with schizophrenia at high risk of noncompliance (Dutch model) and relative to oral olanzapine in patients with schizophrenia (German model).

The recommended dosage of long-acting risperidone is 25mg (maximum 50mg) every 2 weeks by intramuscular gluteal injection. Treatment with an antipsychotic should be continued for the first 3 weeks of long-acting risperidone treatment, with any dose adjustment of long-acting risperidone considered only at 4-weekly intervals. In patients with hepatic or renal impairment and in the elderly, the recommended dosage is 25mg every 2 weeks.