Antipsychotics: Injectables vs Orals

Jeffrey A. Lieberman, MD


April 07, 2011

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Hello, this is Dr. Jeffrey Lieberman of Columbia University speaking to you today for Medscape. Today I want to discuss a paper that recently appeared in The New England Journal of Medicine[1] that reported a rather surprising event. This was a study comparing the use of long-acting injectable risperidone with oral risperidone, reported by the Yale group led by Bob Rosenheck.

The hypothesis was that in the treatment of unstable patients with schizophrenia, long-acting injectable medication would result in a greater degree of improvement, stability and lower rates of relapse, and specifically rehospitalization (the primary outcome variable).

This is an intuitive hypothesis empirically supported by previous data. It would also have advanced our knowledge in terms of an evidence base for using long-acting injectable medication.

The result that was reported, however, was that no difference was seen between the long-acting injectable risperidone vs oral risperidone. A slight numerical difference in the percentage of people who were rehospitalized in the course of the 2-year follow-up study was observed in patients who received oral risperidone (45%) vs those who received the long-acting injectable medication (39%). Moreover, the duration of survival before hospitalization was slightly longer for the long-acting injectable group (11.3 months vs 10.8 months).

Frankly I was surprised when I read this because I've been an advocate of using long-acting injectable medication more than we do generally in the United States. Adherence is one of the major problems in managing people with schizophrenia, and we know that nonadherence results in symptom exacerbation and complications, including hospitalization. However, this assumption was not supported by the findings.

As they say in sports, when you have an underdog that beats the favored team and achieves an upset, that's why you have to play the game. This is why these studies have to be done: to verify or to disprove our assumptions.

Even though this study failed to find a difference supporting the superior efficacy of long-acting injectable medication in unstable people with schizophrenia for time to hospitalization,(the primary outcome variable) as well as for the other outcome variables (which included improvement in symptoms, quality of life, and amount of services used), this doesn't necessarily mean that long-acting injectable medication isn't useful in noncompliant or unstable patients. The best therapy must be evaluated on a patient-by-patient basis until we have further studies that give us more definitive answers.

The other notable aspect of this study is that long-acting injectable risperidone is a different formulation than most of the long-acting injectable medication that are either decanoates or palmitates; they're esterified formulations as opposed to risperidone, which is a microsphere preparation (a medication incorporated into little beads that are injected in solution and given parenterally into the muscle).

It could be that the formulation of this medication resulted in a greater degree of side effects or site of injection irritation that could have mitigated the superior efficacy. We don't know whether the results are fully generalizable to the other long-acting injectable medications that are esterified formulations, where the level of irritation or associated side effects may be less.

This is all the more reason that we need to have more comparative effectiveness studies which compare the effectiveness of one marketed treatment with another marketed treatment, including when there are different formulations.

The United States has established a new agency, the acronym for which is PCORI [Patient-Centered Outcomes Research Institute], which is supposed to oversee the formulation of a funding policy for comparative effectiveness studies. This program will be administered either through the Association for Healthcare Research and Quality or the National Institutes of Health in all likelihood. But it is really geared to support comparative effectiveness studies to let us know which marketed treatments work well.

In this case, we study the effects of 2 treatments that have been promoted in different formulations and find no difference. Perhaps it's a surprising result, but it's published in The New England Journal of Medicine. It's a valid study, so once again it cautions us about having assumptions that are unverified.

We have to wait for further studies to be done that compare the effectiveness of other long-acting injectable medications with oral medication and with newer forms of long-acting injectable medication, or paliperidone palmitate with older forms of long-acting injectable medication, such as haloperidol or fluphenazine decanoate.

So stay tuned, and hopefully these studies will be forthcoming. For Medscape, this is Dr. Jeffrey Lieberman of Columbia University saying thank you and see you next time.