Current Psychiatry Reports

, Volume 13, Issue 4, pp 243–244

What Can We Expect From Long-Acting Formulations for Schizophrenia?


    • Division of Translational Neuroscience, Department of PsychiatryUniversity of Pennsylvania

DOI: 10.1007/s11920-011-0206-2

Cite this article as:
Siegel, S.J. Curr Psychiatry Rep (2011) 13: 243. doi:10.1007/s11920-011-0206-2

Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia—a critical systematic review and meta-analysis of randomised long-term trials. Schizophr Res 2011; 127:83–92.

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

Rating: •• Of major importance.

Introduction: The advantages of depot formulations for improved medication adherence, and therefore improved clinical outcomes, have been consistently demonstrated over the past three decades. For example, a recent meta-analysis of 10 studies that met rigorous criteria for inclusion based on quality and duration suggested overwhelming support for this hypothesis. However, another recent high-profile article by Rosenheck and colleagues in The New England Journal of Medicine seems to contradict the superiority of depot formulations over oral medication. Therefore, the current report reviews the design and data in the Rosenheck et al. clinical trial and compares and contrasts these data with the aforementioned meta-analysis by Leucht and colleagues.

Aims: The aim of the study by Rosenheck et al. in The New England Journal of Medicine was to compare the long-acting injectable risperidone (Risperdal Consta; Ortho-McNeil-Janssen Pharmaceuticals, Titusville, NJ) with the treating physician’s oral formulation of choice in schizophrenia patients in the Veterans Affairs (VA) system.

Methods: A total of 382 patients were randomly assigned, 369 of whom were observed for 2 years. The primary end point was the rate of hospitalization. Secondary measures included psychiatric symptoms, quality of life, and scores on the Personal and Social Performance scale of global functioning. Side effects were also evaluated.

Results: The rate of hospitalization was not significantly different among groups. A total of 39% of participants in the injectable group were hospitalized (mean time to admission, 10.8 months), compared with 45% of the orally treated group (mean time to admission, 11.3 months). Secondary outcome measures were also not significantly different among groups. Similarly, there was no significant difference in overall side effects, but the injection group had more motor side effects and injection site reactions.

Discussion: The study by Rosenheck and colleagues was designed to detect differences among two efficacious treatments. As such, it may be best characterized as a noninferiority study, which typically requires very large cohorts of participants—exceeding that in the Rosenheck et al. report—to detect statistical significance. Interestingly, the Rosenheck et al. study noted that it was originally planned for 600 patients to have sufficient power to detect meaningful differences but was later resized to a smaller number of participants due to recruiting problems. Despite this limitation in sufficient power, the authors concluded that there is no evidence for superiority of Risperdal Consta over an uncontrolled mixture of oral medications. Alternatively, to address the limitation in sample size for such noninferiority studies, a recent meta-analysis of 1,700 participants demonstrated that depot antipsychotics are significantly superior for treatment of relapse (P < 0.0009) relative to oral medication. The larger study by Leucht and colleagues also found that depot medications were superior for dropouts due to lack of efficacy, and close to significantly superior for all dropouts (P = 0.06). However, there were some similarities among the recent small study and the larger meta-analysis. The Leucht et al. meta-analysis also found that rehospitalization was not different among treatments (P = 0.1), suggesting that hospitalization per se does not capture all measures of relapse. Additionally, both studies found a lack of differences among groups with regard to adverse events.

The authors of the recent New England Journal of Medicine study noted several other major limitations to their work that further reduce generalizability, or perhaps even utility of their finding in clinical practice. For example, physicians were not blinded to study condition, and the authors admitted that this likely biased the treating physician’s decisions regarding level of care. Additionally, 12% of the oral group switched to depot medication during the study. Although the authors analyzed the data with and without these participants, it may have been more accurate to consider them as having failed the oral treatment at time of switch, rather than carrying them forward as depot or merely excluding them. For example, if that 12% had been considered treatment failures in the oral arm, it would have increased the variance between treatments arms from a difference of 6% (39% treatment failures on depot, 45% treatment failures on oral) to a difference of 18% (39% depot vs 57% oral). Thus, a large proportion of oral patients who may have been hospitalized due to poor outcome in the initial months were carried forward as if the oral medication had worked, when in fact they were receiving benefits of depot to remain out of hospital. This would have increased the oral failure rate significantly, and likely would have altered the final conclusions and interpretation.

Further limitations for relevance to most psychiatric practice result from the study population as well as the environment in which the Rosenheck et al. study was conducted. Specifically, hospitalization rates and criteria for older male VA patients may not be representative of the general population. Indeed, the mission of the VA system is quite different than that of the general medical community. Whereas the criteria for inpatient hospitalization among the general medical environment are quite restrictive and related to severe deterioration or danger, the criteria in the VA tend to incorporate a broader mission to care for and look after the veteran population. As such, it is likely that admission criteria for the current study are considerably weaker than would be the case in the community. It is also imperative to view this study within the constraints of its scope and not generalize to other long-acting formulations. For example, Risperdal Consta is a biweekly formulation, whereas all other long-acting formulations last at least 1 month, and all other formulations can be given using smaller needles with a lower volume of injection.

Taken together, data from the two studies discussed above suggest a significant benefit to long-acting formulations in general. However, they also suggest that rehospitalization may not reflect overall improvements in symptoms and quality of life afforded from depot formulations relative to oral. Furthermore, 2-week formulations may not be sufficiently long to provide the level of benefit seen with monthly injections. As such, the data in the Rosenheck et al. study should be seen as preliminary data suggesting that Risperdal Consta may not be cost-effective for reducing inpatient hospital days in the VA system.


The recent study by Rosenheck et al. questions conventional wisdom regarding the superiority of depot formulations. Although there is always merit to challenging clinical assumptions with rigorous data-based studies, the large number of limitations in design and interpretation of the underpowered Rosenheck et al. study obviate the ability to address these questions appropriately. Alternatively, the question of noninferiority among two effective treatments is more rigorously addressed in a Cochrane review–style meta-analysis as performed by Leucht and colleagues. Therefore, the superiority of depot formulations across a broad range of outcome measures should not be discounted by the relatively small open study of Risperdal Consta.


Dr. Siegel has served as a consultant for NuPathe and Merck & Co., has received royalties from NuPathe, has received payment for leading a discussion group from Merck & Co., and has had travel expenses covered by Merck & Co.

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© Springer Science+Business Media, LLC 2011