Professor/Head of Department
Department of Biological Psychiatry
Medical University Innsbruck
Risperidone is a second-generation antipsychotic, the clinical benefit/risk profile of which has been extensively studied in psychiatric disorders ranging from autism to schizophrenia. (1) Recently, the manufacturers of risperidone have developed an aqueous suspension that contains the drug in a matrix of glycolic acid–lactate copolymer. This polymer, after having been slowly hydrolysed after intragluteal injection, releases risperidone into the bloodstream.
Biweekly injections of long-acting intramuscular risperidone (LAIR) lead to similar mean steady-state plasma concentrations and plasma areas-under-the-curve for both risperidone and 9-hydroxy-risperidone as oral risperidone, whereas mean peak concentrations of the active moiety are 25–32% lower with LAIR than with oral risperidone.(2) Serum concentrations of risperidone plus 9-hydroxy- risperidone appear to increase in a dose-dependent linear fashion between 25 and 75mg biweekly injections.(3) Brain dopamine 2 (D(2)) receptor occupancy, as assessed by (11)C-raclopride, also reveals dose dependency ranging from 25–72% at steady state reached after LAIR (25, 50 or 75mg). This corresponds to occupancy levels following treatment with 2–6mg oral risperidone.(4)
The development of LAIR has entailed placebo-controlled trials in which LAIR was compared with oral risperidone, as well as studies in which patients were switched from traditional depots or from oral antipsychotics to LAIR, generally with an observational period of 12 weeks. In addition to these studies, a one-year open clinical trial, post-hoc analyses and prescription audits have been carried out.
In the phase III trials, biweekly injections of LAIR (25, 50 and 75mg) were evaluated. As the studies did not reveal any efficacy advantages of 75mg injections over the two lower doses, and because of a suggested higher likelihood to develop extrapyramidal motor side-effects on the higher dose, the company decided not to market the 75mg injections, which explains why most analyses report results for the two lower doses only.
Schizophrenia patients (n=440) entered a four-arm study comparing the three doses of LAIR with placebo. Change scores on all three doses differed significantly from placebo for positive and negative syndrome scale (PANSS) total scores as well as the PANSS positive and negative subscales.(5) No unexpected adverse events (compared with the well-known safety profile of oral risperidone) were observed. The higher doses of risperidone induced more extrapyramidal side-effects (EPSs), although these were generally mild across dose groups. Both patients and investigators rated injection site pain as low.
In a second double-blind study, 640 patients with schizophrenia were prospectively treated with 1–6mg of oral risperidone for eight weeks.(6) Stable patients were then treated with either LAIR or continued on oral risperidone in a random fashion. Both groups demonstrated significant improvement over baseline on PANSS total and subscores. A noninferiority analysis demonstrated comparable efficacy. As in the study by Kane et al,(5) no unexpected adverse events were observed.
The safety and efficacy of switching from traditional depot neuroleptics (flupentixol decanoate, fluphenazine decanoate, haloperidol decanoate and zuclopenthixol decanoate) to LAIR were the main outcome variables of another 12-week study.(7) Before being switched, patients received two cycles of their original depot antipsychotic. Then they were given an initial dose of LAIR (25mg), which could be increased by 12.5mg, up to a maximum dose of 75mg. Again, PANSS scores decreased significantly during the 12-week study period. EPSs decreased compared with previous treatment.
Lindenmayer et al studied symptomatically stable schizophrenia patients switched from oral haloperidol, quetiapine or olanzapine to 25–50mg of biweekly LAIR.(8) Small but significant reductions in total PANSS scores were observed by the end of week 12. Again, switching to LAIR was reported to be safe and well tolerated.
In the only one-year trial of LAIR available to date, Fleischhacker et al assessed over 600 patients whose medication was changed from oral to LAIR.(9) Patients who were pretreated with 1–2mg of the oral drug were switched to 25mg LAIR, patients on 2–4mg received 50mg of LAIR, and patients originally on 4–6mg were given 75mg of LAIR biweekly. Sixty-five percent of patients completed the full trial, with significant improvements in PANSS total scores in each of the three groups.
The largest sample (1,876 patients suffering from schizophrenia or other psychoses) were enrolled in a large open, prospective trial in which patients were switched directly from their previous antipsychotic medication to 25–50mg biweekly LAIR.(10) Trial duration was six months, with 74% of patients remaining in the study. Reasons for dropping out were non‑compliance (38%), insufficient efficacy (33%) and side-effects (26%). A significant reduction of symptoms (measured by the total PANSS score and the PANSS subscales) was observed at endpoint. Clinical global impression (CGI) and global assessment of functioning (GAF), as well as patient satisfaction and quality of life (SF36), also improved. As observed in previous studies, the severity of extrapyramidal motor symptoms decreased during the six-month trial period.
A number of secondary analyses have been performed on the studies outlined above. An analysis of health-related quality of life(11) was performed using data from the placebo-controlled study.(5) The authors found significant improvements in some domains of the SF36 (bodily pain, general health, social functioning, role emotional and mental health) for patients on active treatment, compared with the placebo group. Interestingly, patients in the 25mg group reached normal SF36 values in a number of SF36 domains after three months of LAIR. These results are substantiated by quality-of-life data obtained from the one-year open clinical trial,(9) in which, using a similar methodology, sustained improvements in quality of life were also observed.(12) Importantly, these improvements were largely independent of changes in psychopathological symptoms, as assessed by the PANSS.
In post-hoc analyses, the one-year study sample(9) was differentiated into patients who were pretreated with either conventional depot antipsychotics,(13) oral conventional antipsychotics(14) or oral risperidone.(15) In all three subanalyses, as in the overall sample, PANSS total scores were improved at endpoint when compared with baseline, and extrapyramidal symptoms declined. These findings are most compelling with regard to the group of patients who were switched from stable doses of oral risperidone to LAIR. Although interesting, these results need to be reproduced in prospective clinical trials.
A retrospective analysis examining risk/benefit ratios of patients aged 65 or older confirmed safety and efficacy as determined in younger populations.(16) The one-year study also included patients suffering from schizoaffective disorders that were not included in the original report.(9) This sample, consisting of 110 patients, also showed significant PANSS total score improvements from baseline to endpoint. Scores on the PANSS subscales also decreased.(17)
A stringent tardive dyskinesia analysis from the schizophrenia sample participating in the one-year study is also available.(18) Five of 530 subjects (0.9%) without dyskinesia at baseline met predefined tardive dyskinesia criteria.
Finally, a part of the long-term sample was evaluated with regard to healthcare resource utilisation. The main findings included a significant decrease of hospitalisation days and outpatient consultations, which led to the hypothesis that LAIR will, in the long run, decrease healthcare costs for schizophrenia patients.(19)
Two reports from UK prescription audits complement the available evidence. Taylor et al evaluated prescriptions written for patients in the South London and Maudsley NHS Trust and reported a significant improvement of CGI scores compared with the pretreatment period.(20) They also found a considerable reduction in antipsychotic coprescriptions and judged LAIR as “moderately effective in clinical practice as judged by attrition from treatment”.
Patel et al attempted to find prognostic indicators for early discontinuation of LAIR and found that patients who were switched from an oral antipsychotic to LAIR were more likely to discontinue this drug than those who had previously been treated with a depot neuroleptic.(21) Whether this report was derived from the same sample as the one by Taylor et al20 is not clearly explained.
Risperidone is currently the only new-generation antipsychotic available as a sustained-release preparation. Available evidence suggests that it is an important addition to the therapeutic measures for the long-term management of schizophrenia patients. It may even have efficacy and safety advantages over oral risperidone.
Published reports stem almost exclusively from the development programme sponsored by the drug’s manufacturer. A number of issues need to be resolved in future studies, such as the pharmacokinetic properties of LAIR, which seem to make a prolongation of the injection interval to at least three, or maybe four, weeks possible. Furthermore, a double-blind, direct comparison of LAIR with conventional depot formulations with a main focus on (cost) effectiveness would provide an important additional perspective. Finally, the potential for dose increases in the case of symptoms resistant to 50mg injections and for dose decreases in the case of first episode or elderly patients needs to be explored further. Hopefully, positive results from such studies would help to overcome the reluctance of doctors and patients to use long-acting injectable medications, which provide considerable advantages in monitoring compliance in schizophrenic patients.
- Möller HJ. Expert Opin Pharmacother 2005;6:803-18.
- Eerdekens M, et al. Schizophr Res 2004;70:91-100.
- Castberg I, Spigset O. Ther Drug Monit 2005;27:103-6.
- Gefvert O, et al. Int J Neuropsychopharmacol 2005;8:27-36.
- Kane JM, et al. Am J Psychiatry 2003;160:1125-32.
- Chue P, et al. Eur Neuropsychopharmacol 2005;15:111-7.
- Turner M, et al. Int Clin Psychopharmacol 2004;19:241-9.
- Lindenmayer JP, et al. J Clin Psychiatry 2004;65:1084-9.
- Fleischhacker WW, et al. J Clin Psychiatry 2003;64:1250-7.
- Möller HJ, et al. Int Clin Psychopharmacol 2005;20:121-30.
- Nasrallah HA, et al. J Clin Psychiatry 2004;65:531-6.
- Fleischhacker WW, et al. Br J Psychiatry In press 2005.
- Lasser RA, et al. Eur Psychiatry 2004;19:219-25.
- van Os J, et al. Int Clin Psychopharmacol 2004;19:229-32.
- Lasser RA, et al. Int J Neuropsychopharmacol 2005;8:427-38.
- Lasser RA, et al. Int J Geriatr Psychiatry 2004;19:898-905.
- Lasser R, et al. J Affect Disord 2004;83:263-75.
- Gharabawi GM, et al. Schizophr Res 2005; epub ahead of print.
- Leal A, et al. Pharmacoepidemiol Drug Saf 2004;13:811-6.
- Taylor DM, et al. J Clin Psychiatry 2004;65:1076-83.
- Patel MX, et al. Int Clin Psychopharmacol 2004;19:233-9.