New Developments in Long-Acting Injectable Antipsychotic Drugs: An Expert Interview With Peter J. Weiden, MD

Peter J. Weiden, MD


June 12, 2008

Editor's Note

Second-generation antipsychotic drugs are widely used for treatment of psychotic disorders, but only risperidone comes in a depot formulation. Depot medications are an important component of the psychiatric pharmacopoeia because of the high rate of treatment nonadherence in patients with chronic mental illness, and more options may soon become available. To learn about research in this field, Medscape's Randall F. White, MD, spoke to Peter J. Weiden, MD, professor of psychiatry at the University of Illinois at Chicago.

Medscape: What is your view of the role of long-acting injectable medications in psychiatry?

Dr. Weiden: This will be one of the next big developments in the coming 5 to 10 years. A key message that I came away with from this year's meeting of the American Psychiatric Association (APA) is that a lot of research is taking place with the second-generation antipsychotics (SGAs), especially with long-acting preparations. In the next few years, we're going to be hearing and learning a lot more about options among the long-acting SGAs.

Medscape: Injectable risperidone microspheres are now commonly used for treating chronic schizophrenia. What new research with this SGA for this indication did you encounter at the recent APA annual meeting?

Dr. Weiden: Several longitudinal observational trials are underway in Europe with patients with schizophrenia receiving risperidone microspheres. By the way, in Europe, risperidone microspheres are available at a dose of 75 mg as well as in doses of 12.5, 25, and 50 mg, which are available in the United States. Having said that, practice in Europe is similar to practice in North America.

A research poster presented data on the effectiveness of switching people with schizophrenia to long-acting risperidone microspheres early in their illness.[1] They were not quite first-episode patients, but they were not chronic patients. The investigators found that the injectable agent was acceptable by this patient population, and the relapse rate at 6 months was 28%, which is good for such patients.

Medscape: How many subjects were in the study?

Dr. Weiden: This is an interim report of a continuing multicenter trial in Belgium. The researchers reported on 61 subjects who had been followed for up to 6 months. The mean subject age was 31.7 years, and enrollment criteria included a documented history of fewer than 4 psychotic episodes.

Long-acting preparations have tended to be reserved for patients late in their course of illness, when they become treatment resistant. The importance of this trial with long-acting risperidone, and I think this can be generalized to any long-acting SGA, is that it is acceptable to administer early in the course of illness. It provides the efficacy, relapse prevention, and improvement in symptoms over time that you see with other antipsychotics.

The problem in this study is the lack of a group treated with a comparator. The reader is left to guess, but based on my knowledge of how early episode patients respond, it looks like the response we would expect from an effective antipsychotic. I think, however, that the take-home message is more about acceptability of the depot medication in this population than about efficacy per se.

Medscape: Does any research examine the application of risperidone microspheres in other disorders?

Dr. Weiden: Yes. In a small open-label study from Barcelona, Spain, long-acting risperidone was given as adjunctive treatment to 14 patients with bipolar disorder and 8 with schizoaffective disorder.[2] Adding long-acting risperidone reduced symptoms.

Another study looked at adjunctive risperidone microspheres for treatment-refractory bipolar disorder.[3] Although this application is off-label, it is consistent with an application to the US Food and Drug Administration (FDA) submitted in April 2008 for approval of long-acting risperidone as adjunctive treatment for highly relapsing bipolar disorder.

Medscape: Paliperidone is available as an oral antipsychotic, and phase 3 trials are underway for an injectable depot formulation. Can you mention the research presented on this medication?

Dr. Weiden: Yes, I would like to discuss 2 studies. One was a 9-week placebo-controlled study with different doses of a long-acting version of paliperidone compared with placebo.[4] The investigators initiated treatment with an oral run-in of paliperidone for 1 week, and then used what they called a 50-mg-equivalent monthly injection or a 100-mg-equivalent monthly injection. This is a pivotal trial.

Medscape: So the data will be submitted to the FDA?

Dr. Weiden: I would presume so. The Positive and Negative Syndrome Scale (PANSS) total and factor scores improved from baseline to endpoint significantly more than with placebo.

Medscape: I'm not sure I understand the concept of 50-mg and 100-mg equivalents.

Dr. Weiden: There is actually more paliperidone than 50 mg or 100 mg in the injectable palmitate formulation, but those are the researchers' estimated doses because of variable bioavailability. The bottom line is that the medication is effective, but the dose ranges still need to be better understood or at least explained.

Medscape: Yet in the course of a chronic illness, 9 weeks isn't that long.

Dr. Weiden: Yes. In another study, 849 patients were randomized to flexible dosing by a clinician.[5] They received either 25-mg, 50-mg, or 100-mg equivalents for 9 weeks. Following this, they received a fixed dose for 12 weeks, and then the 410 subjects who remained in the study entered a maintenance phase, in which they were randomized to placebo or active treatment for 24 weeks.

This study was a hybrid of dose-finding and relapse prevention. And it appears that paliperidone palmitate will be an effective medication in terms of relapse prevention; it separated out from placebo quite quickly.

One can argue about whether risperidone or paliperidone is better, given that paliperidone is a metabolite of risperidone. Let's just bypass that argument and ask the question, what are the potential advantages of paliperidone palmitate over risperidone microspheres? I can think of 2. One is that paliperidone palmitate is administered every 4 weeks, whereas risperidone microspheres are administered every 2 weeks. The second is that paliperidone palmitate will not need refrigeration, so it will be convenient for the clinician to store on site.

I'd like to mention that some pharmacokinetic studies were presented that examined whether long-acting paliperidone and risperidone can be injected into the deltoid muscle.[6] It's presently an off-label use of risperidone microspheres, but it appears that the pharmacokinetics might permit deltoid injection. I nevertheless wouldn't recommend it to clinicians at this time.

Medscape: Iloperidone is a new antipsychotic agent that is undergoing review by the FDA. Can you briefly describe its mechanism of action or its pharmacology?

Dr. Weiden: Iloperidone is a mixed dopamine D2, serotonin 5-HT2A antagonist, a member of what I call the "-done" family, including risperidone and ziprasidone. It's still a different antipsychotic from those; it has a high affinity for 5-HT2A and adrenergic alpha-1 receptors and low affinity for serotonin 5-HT1A, dopamine D-1, and histamine receptors.[7]

Iloperidone had an active phase 3 clinical trial program in the late 90s when it was owned by Novartis. It is now owned by Vanda, which has done another phase 3 pivotal trial comparing iloperidone with placebo and, as an active comparator, with ziprasidone.[8] The data are under review by the FDA, and the drug may be approved as early as this summer or fall.

Medscape: Would you comment on research on the long-acting form of this agent?

Dr. Weiden: The interesting fact is that a long-acting version of the medication has been developed, which is unusual for an antipsychotic before its initial FDA approval. A microsphere formulation was tested for safety and pharmacokinetics during 2000 to 2002. If the oral version gains FDA approval, it would not take much time to proceed with phase 3 trials for the injection. A long-acting injectable form of iloperidone may be available within the near term.

In the open-label trial presented at the APA conference that was based on data from 2002, 64 subjects received oral iloperidone for 21 days; 20 received placebo.[9] The patients then received at least 2 cycles of injections every 28 days. The depot formulation appeared safe and well tolerated.

If approved, iloperidone will have the advantage of being a 4-week medication. It would clearly need to go through extensive phase 3 testing, but having it already in a depot formulation with some safety data is very promising because that tends to be the Achilles heel of this development process. Many antipsychotic agents aren't amenable to depot formulation. The difficulty of this process is illustrated by long-acting olanzapine, which was recently dis-approved by the FDA because it caused intense sedation.

In my view, the big news is that at least 2 long-acting SGAs that can be given in 28-day cycles are in testing and may be clinically available in the next few years.

Medscape: My final question is, do you find that any generational disparities exist in the use of injectable antipsychotics?

Dr. Weiden: I think this should be a wake-up call for all of us because when long-acting injections became available in the 60s, they were underused, at least in the United States. It took many years to train clinicians to use these agents.

Medscape: You're talking about fluphenazine decanoate.

Dr. Weiden: I'm talking about the first-generation depot medications, yes. Long-acting SGAs have the advantage of causing less extrapyramidal symptoms -- and we can debate whether they're better drugs. I think they are -- and of a depot formulation, which can help prevent nonadherence among patients who are cognitively impaired or who lack insight.

These advantages will be reversed, to an extent, by doctors who lack the skill to use them, because it's junior physicians who work in community mental health clinics. Depot medications have not been as much a part of their training as it would have been 20 years ago.

Clinicians will need to understand the indications for these agents and the techniques used to start treatment with them, dose them, and inject them. What I learned at this APA meeting is that the time for teaching these skills is now.


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