COMMENTARY

The Year in Psychiatry: Studies Not to Miss From 2011

Christoph U. Correll, MD; Maren Carbon, MD

Disclosures

November 23, 2011

In This Article

Long-acting Injectable Risperidone vs Oral Antipsychotics

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;364:842-851.

At least 40% of psychiatric patients are only partially compliant with their antipsychotic prescription, and this factor substantially contributes to high hospitalization rates and to the observed morbidity and mortality in this population. Thus, studying the efficacy of ways to increase adherence in chronic, unstable schizophrenia in close to real-world conditions is an important goal. Long-acting injectable antipsychotics (LAIs) are one tool to improve medication adherence. Moreover the constant medication delivery typically results in reduced peak-level related adverse effects.

In this study, Rosenheck and colleagues included 369 chronic, predominantly male VA patients (91% male, mean age: 51 years, mean disease duration ~ 23 years, 37% with active comorbid substance abuse, 40% hospitalized at randomization, 55% hospitalized within the previous 2 years) with schizophrenia or schizoaffective disorder. Study subjects were randomly assigned to receive either their usual antipsychotic treatment or to receive 2-weekly injections of long-acting injectable risperidone (LAI-RIS), plus whichever psychotropic medication was considered necessary, except for clozapine. Time to hospitalization was the primary study endpoint; PANSS scores were the key secondary endpoint, assessed via remote centralized ratings to reduce the chance of unblinding and increase rater precision.

During the follow-up period of up to 2 years, time to hospitalization (P = .39) and time to all-cause discontinuation ( = .19) did not differ significantly across the 2 treatment groups. After 10.8 months and 11.3 months, respectively, the rate of hospitalization after randomization was 39% among patients receiving RIS-LAI and 45% among those receiving oral antipsychotics (hazard ratio: 0.87; 95% CI, 0.63 1.20). Moreover, neither psychiatric symptoms, nor quality-of-life scores on the Personal and Social Performance scale of global functioning, nor neurologic side effects differed among the 2 groups. Conversely, patients on RIS-LAI reported more adverse events at the injection site and more extrapyramidal symptoms.

The fact that 39% of the patients on LAI medication were rehospitalized within less than 1 year suggests that the study population was at enormous risk for hospitalization for reasons other than nonadherence. This rate represented only a 5% absolute and 11% relative reduction in risk compared with oral medication, which was not statistically significant. Of note, these data suggest that there is a population of patients who will require rehospitalization despite guaranteed medication delivery, although it is important to note that those patients receiving LAIs only received an average of 1.5 injections per month, rather than the 2 injections per month that would be expected if the recommended injection interval was followed (indicating that adherence with LAI was also not optimal). Moreover, 50% of the LAI doses beyond week 6 consisted of 25 mg or 37.5 mg, which could arguably have been too low. In addition, no aspects of medication history contributed to study inclusion. It is rather likely that a substantial proportion of the LAI-RIS group had already experienced a treatment period of oral risperidone and that some had relapsed despite this reliable intake of this medication. The likelihood to respond to LAI-RIS would be minimal in these subjects. Taken together, these data raise the issue that a randomized controlled trial may not be the optimal design to test the effect of long-acting antipsychotics, as participating patients are selected to be more compliant than patients unwilling to agree to take part in a randomized trial. In this regard, pharmacoepidemiologic and database studies may add relevant information about more generalizable, real-world samples.

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