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Letter to the Editor

Reply to Cost and Cost-Effectiveness in a Randomized Trial of Long-Acting Risperidone for Schizophrenia

Paul G. Barnett, PhD, and Robert A. Rosenheck, MD

Published: October 15, 2012

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See original letter by Alphs, et al.

Drs Barnett and Rosenheck Reply

To the Editor: We have reported the first economic evaluation of long-acting injectable (LAI) risperidone using data from a clinical trial.1 We believe that trial fairly evaluated this medication for treatment of unstable schizophrenia and schizoaffective disorder.

The treatment groups were equivalent. They did not differ in any of 5 measures of severity of illness. Each group had a baseline measure of psychiatric hospital use that was significantly greater than that of the other group. At the time of randomization, the LAI risperidone group was more likely to be in the psychiatric hospital. In the year preceding randomization, the oral antipsychotic group spent more days in the psychiatric hospital (mean of 25.7 days vs 20.9 days for LAI risperidone, P < .01). This does not mean that randomization failed. Nevertheless, we compared the groups’ costs while controlling for baseline differences, including psychiatric hospitalization at randomization. The results were unaffected: total costs incurred by the treatment groups were not significantly different. Results were also unaffected when we excluded the cost of psychiatric stays underway at randomization. Costs excluding this care were $13,829 per quarter for LAI risperidone versus $13,616 for oral antipsychotics (P = .937).

Some patients assigned to oral agents switched to LAI risperidone. The converse was also true. The majority of patients received their intended treatment, and the intent-to-treat analysis found no evidence that random assignment to LAI risperidone prevented hospitalization. Our 2 publications1,2 do report different amounts of crossover treatment. Our first article2 reported information on medication use gathered by site staff on case-report forms. The economic study1 supplemented this with comprehensive information from the US Department of Veterans Affairs pharmacy database. Although we describe these sources in the methods section of each article, we should have been more explicit in stating that the results were different and why this was so.

We conducted an "on treatment" analysis and found no significant association between the number of LAI risperidone injections received and the cost of subsequent psychiatric hospitalizations. A contamination-adjusted intent-to-treat analysis to control for selection bias, using randomization as the instrumental variable, yielded the same result.

The intensity of care received by trial participants was affected very little, if at all, by the monthly visits specified in the protocol. A minimum of 1 visit per month is not an unusual intensity of care for patients at risk for a psychiatric hospital stay. Study participants entered the study as intense users of care, with 54 visits in the year prior to randomization. They had 66 visits per year during the trial. The acute instability that made them eligible for the trial may account for much of this increase in service use.

It has been hypothesized that the extra cost of injectable antipsychotic medications like LAI risperidone will be offset by reduced psychiatric hospitalization costs. We determined that patients randomly assigned to LAI risperidone had higher medication cost, but we found no significant offset.

This study was not designed to show the equivalence of LAI risperidone and oral antipsychotics. Its findings were consistent with 4 previous trials that found no significant superiority for LAI risperidone as compared to oral agents.3-6 A fifth trial that found an advantage to LAI risperidone may have used less-than-optimal doses of the oral comparator.7

Adoption of a more costly medication can be justified only if it increases value. We found that LAI risperidone increased pharmaceutical costs without offsetting other costs or generating any therapeutic benefit. Health care sponsors will be hard-pressed to include LAI risperidone in their formulary when it cannot show a significant benefit in repeated trials.


1. Barnett PG, Scott JY, Krystal JH, et al; CSP 555 Research Group. Cost and cost-effectiveness in a randomized trial of long-acting risperidone for schizophrenia. J Clin Psychiatry. 2012;73(5):696-702. doi:10.4088/JCP.11m07070 PubMed

2. Rosenheck RA, Krystal JH, Lew R, et al; CSP555 Research Group. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N Engl J Med. 2011;364(9):842-851. doi:10.1056/NEJMoa1005987 PubMed

3. Bai YM, Chen TT, Chen JY, et al. Equivalent switching dose from oral risperidone to risperidone long-acting injection: a 48-week randomized, prospective, single-blind pharmacokinetic study. J Clin Psychiatry. 2007;68(8):1218-1225. doi:10.4088/JCP.v68n0808 PubMed

4. Chue P, Eerdekens M, Augustyns I, et al. Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. Eur Neuropsychopharmacol. 2005;15(1):111-117. doi:10.1016/j.euroneuro.2004.07.003 PubMed

5. Keks NA, Ingham M, Khan A, et al. Long-acting injectable risperidone v olanzapine tablets for schizophrenia or schizoaffective disorder: randomised, controlled, open-label study. Br J Psychiatry. 2007;191(2):131-139. doi:10.1192/bjp.bp.105.017020 PubMed

6. Macfadden W, Ma YW, Thomas Haskins J, et al. A prospective study comparing the long-term effectiveness of injectable risperidone long-acting therapy and oral aripiprazole in patients with schizophrenia. Psychiatry (Edgmont). 2010;7(11):23-31. PubMed

7. Gaebel W, Schreiner A, Bergmans P, et al. Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: results of a long-term, open-label, randomized clinical trial. Neuropsychopharmacology. 2010;35(12):2367-2377. doi:10.1038/npp.2010.111 PubMed

Paul G. Barnett, PhD

Robert A. Rosenheck, MD

Author affiliations: Health Economics Resource Center, VA Cooperative Studies Program, VA Palo Alto Health Care System, Menlo Park; and Department of Health Research & Policy, Stanford University Medical School, Palo Alto (Dr Barnett), California; and Veterans Affairs Connecticut Health Care System, West Haven; and Yale School of Medicine, New Haven (Dr Rosenheck), Connecticut.

Potential conflicts of interest: Dr Rosenheck has received research support from Eli Lilly, Janssen, AstraZeneca, and Wyeth; has been a consultant to GlaxoSmithKline, Bristol-Myers Squibb, Organon, and Janssen; and has provided expert testimony for the plaintiffs in UFCW Local 1776 and Participating Employers Health and Welfare Fund et al v Eli Lilly and Company, for the respondent in Eli Lilly Canada Inc v Novapharm Ltd and Minister of Health, and for the Patent Medicines Prices Review Board, Canada, in the matter of Janssen Ortho Inc and Risperdal Consta. Dr Barnett reports no potential conflict of interest.

Funding/support: The study discussed [J Clin Psychiatry 2012;73(5):696-702] was supported by the Veterans Affairs Cooperative Studies Program, and an unrestricted grant and Risperdal Consta were provided by Ortho-McNeil Janssen Scientific Affairs, LLC.

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