Deborah Brauser

May 11, 2012

May 11, 2012 (Philadelphia, Pennsylvania) — Intramuscular depot aripiprazole is a safe and tolerable option for long-term maintenance treatment of schizophrenia, according to several presentations from a new large trial presented here at the American Psychiatric Association's (APA's) 2012 Annual Meeting.

During efficacy analysis, investigators found that adult outpatients receiving once-monthly intramuscular injections of aripiprazole had a significantly greater delay in time to relapse and a significantly lower rate of relapse compared with the participants who received placebo.

"The efficacy was very, very good, which wasn't a major surprise," lead author John M. Kane, MD, chair of psychiatry at the Zucker Hillside Hospital in Glen Oaks, New York, and from the Hofstra North Shore–Long Island Jewish School of Medicine in Glen Oaks, told Medscape Medical News.

Dr. John Kane

"What was a bit of a surprise was that the study was positive very quickly. There was a robust finding before the study was even over," said Dr. Kane.

He reported that the significant efficacy led to the early discontinuance of the trial, based on predetermined criteria. This allowed patients to end their prolonged exposure to placebo.

In presentations on safety and tolerability issues, investigators found that most treatment-related adverse events (AEs) were mild or moderate, with serious AEs reported by only 4% of the aripiprazole group and by 7% of the placebo group.

"I think to have another long-acting injectable formulation, in this case of a drug that has been particularly well-tolerated and is, in my opinion, a go-to drug particularly in early-phase patients, where you want to minimize the risks of any adverse effects that might impact their health or their long-term outcome, is a very valuable addition," said Dr. Kane.

"Long-acting injectable drugs in general are a very important treatment modality underutilized in the United States. So having another formulation will also hopefully help us in terms of increasing the general utilization of these drugs."

The primary efficacy results were also published in the May issue of the Journal of Clinical Psychiatry.

Adherence Key

"Long-term disease management is the ultimate goal of treating the nearly 2.2 million adults living with schizophrenia in the US," said Dr. Kane.

"Every relapse a patient experiences can cause further erosion of his or her mental and physical health," he added.

The current preferred way of treating schizophrenia is with the long-term use of antipsychotics, making medication adherence "an important element in treatment success," write the investigators.

They note that long-acting injectable antipsychotics "have the potential to improve adherence" because they eliminate the need to take a medication daily.

As reported at the time by Medscape Medical News, Dr. Kane and colleagues published study results in the American Journal of Psychiatry in 2010 showing that long-acting injectable olanzapine (given every 2 weeks) was as safe and effective as its daily oral formulation for maintenance treatment of schizophrenia. That study included more than 1000 adult outpatients.

For the current study, the researchers sought to compare the safety and efficacy of injectable aripiprazole, which is a dopamine partial agonist, against placebo.

"Aripiprazole-intramuscular-depot is administered as a suspension into the gluteal muscle resulting in sustained concentrations of aripiprazole for more than 1 month, with the achieved steady-state concentrations being comparable to those of the once-daily oral aripiprazole formulation," write the investigators.

In the current study, 403 outpatients between the ages of 18 and 60 years with schizophrenia were randomly assigned in a ratio of 2:1 to receive 300 or 400 mg of aripiprazole intramuscular depot (n = 269; 60.2% men; mean age, 40.1 years) or matching placebo (n = 134; 59% men; mean age, 41.7 years) for a planned 52-week maintenance treatment period.

Previously, all participants not already receiving oral aripiprazole were switched to monotherapy with the medication (10 - 30 mg/day) during a 4- to 6-week conversion phase. This was followed by a 4- to 12-week oral stabilization phase, and then a depot stabilization phase. In the latter phase, the patients received injections of aripiprazole every 4 weeks for 3 months, along with the oral formulation for the first 2 weeks.

Only after meeting stability criteria at that endpoint were patients allowed to move into phase 4, which consisted of randomization. All participants "had been ill an average of 14 years," reported Dr. Kane.

The primary outcome measure for phase 4 analyses was time to impending relapse, which included clinical worsening, as shown by a score of ≥5 on the Clinical Global Impressions–Severity (CGI-S) scale; increases in combined scores from the Positive and Negative Syndrome Scale (PANSS); hospitalization; violent behavior; or a score of ≥4 on part 2 of the CGI Scale for Severity of Suicidality (CGI-SS).

Measures to assess safety and tolerability included shifts in metabolic parameters and weight, and score changes on the extrapyramidal symptom rating scale, the Abnormal Involuntary Movement Scale (AIMS), the Simpson-Angus Scale (SAS), and the Barnes Akathisia Rating Scale (BARS).

In addition, 2 interim analyses were planned by an Independent Data Monitoring Committee (IDMC), with the first scheduled to be conducted after 64 events of impending relapse. The IDMC could choose to end the trial if efficacy was shown at a level of at least .001.

Minimal Impact on Weight

At the first interim analysis and at final analysis, patients receiving injectable aripiprazole had a significantly greater delay in time to impending relapse than did those receiving placebo (P < .0001 for both analysis periods).

The rate of impending relapse was also significantly lower for the treatment group at final analysis (10.0% vs 39.6%, respectively; hazard ratio [HR], 5.0; 95% confidence interval [CI], 3.15 - 8.02; P < .0001).

CGI-S scores were significantly better for those receiving aripiprazole than for those receiving placebo (P < .0001).

Although the mean PANSS total score was maintained for the aripiprazole group, the scores worsened significantly for the placebo group (mean change, 1.4 vs 11.6; P < .0001).

Most treatment-related AEs were considered to be mild or moderate. Serious AEs were reported by 4.1% of those receiving aripiprazole and by 6.7% of those receiving placebo.

AEs reported by more than 5% of the participants were insomnia (10% of the aripiprazole group vs 9% of the placebo group), tremor (5.9% vs 1.5%), headache (5.9% vs 5.2%), anxiety (5.9% vs 7.5%), and akathisia (5.6% vs 6.0%).

Injection-site pain was reported by 3.0% of those receiving aripiprazole and 3.7% of those receiving placebo. Weight gain, defined as an increase of >7% from baseline, was found in 6.4% of the aripiprazole group and 5.2% of the placebo group.

"Minimal mean changes in weight of patients were observed throughout all study phases," report the researchers. "There were no unusual shifts in laboratory values or fasting metabolic parameters."

Under FDA Review

Rates of discontinuance due to treatment-related AEs were 7.1% and 13.4% for the aripiprazole and placebo groups, respectively.

According to Robert D. McQuade, PhD, executive vice president of Global Medical, Regulatory Affairs, and Scientific Alliances at Otsuka Pharmaceuticals, this formulation of aripiprazole was filed for approval with the US Food and Drug Administration (FDA) last fall. It is currently under FDA review.

"If approved, aripiprazole-IM-depot offers a new long-acting antipsychotic treatment option in schizophrenia with a different risk-benefit profile than currently available options," write the investigators.

"I think this is a particularly important part of the toolkit because of its favorable tolerability. We're not seeing enormous differences between these medications in efficacy. So when we're choosing, I do think we need to focus on tolerability because that's often what will determine long-term outcome," said Dr. Kane.

Dr. McQuade reported that this patient population had the option of enrolling in another study that will continue to collect long-term safety data.

Unique Mechanism of Action

"The development and demonstration of efficacy for the FDA approval of aripiprazole is a welcome development and gives us one more treatment option in terms of its long-acting formulation," Jeffrey Lieberman, MD, professor and chair of psychiatry at Columbia University College of Physicians and Surgeons, and psychiatrist-in-chief of the New York–Presbyterian Hospital at Columbian University Medical Center in New York City, told Medscape Medical News.

Dr. Jeffrey Lieberman

Dr. Lieberman, who was not involved with this study, is also president-elect of the APA. He agreed that adherence is one of the biggest problems in treating people with schizophrenia and related psychotic disorders.

"The vast majority of relapses that occur and exacerbations that occur are because of stopping or not consistently taking medication. As a result, modes of treatment delivery involving long-acting forms of the medications have been developed," he explained.

He noted that risperidone, paliperidone, and olanzapine have all now been formulated into long-acting forms, but that aripiprazole works in a different way.

"All of the antipsychotic drugs act by modulated dopamine neurotransmission of the dopamine-2 receptor, but they do it by slightly different ways pharmacodynamically. Aripiprazole is the only one that does it by partial dopamine-2 receptor agonism," he explained.

"So in that sense, it's not just another option, but it's another option with this unique mechanism of action."

Welcome, But Not Surprising

Still, Dr. Lieberman said that this study performed as expected: that IM depot aripiprazole is an effective medication for maintaining patients who have been stabilized on oral antipsychotic treatment.

"There's been no antipsychotic that's been developed that works acutely that hasn't been effective on a maintenance basis. So there are no surprises here whatsoever. In fact, the surprise would have been if it didn't work," said Dr. Lieberman.

He noted that even though this study had the type of design traditionally used for FDA registration, "it really isn't that helpful to clinicians."

"It's helpful for regulatory purposes because the FDA wants to see that a drug is active and better than an inactive treatment. But clinicians don't really care about that."

Dr. Lieberman said that what everyone really wants to know is how a medication compares with others.

"Is it comparably effective? Or more effective than active comparators that are currently being marketed and are the current standard of care?" he asked.

"And frankly, we're looking for less 'me too' treatments, which are more of the same. What we need are drugs that offer more than incremental value in terms of better efficacy and less side effects."

Overall, he said that the long-action formulation of injectable aripiprazole is "another welcome option," especially because of its unique pharmacodynamic mechanism of action.

However, "It would be good to know how it compares to the other long-acting injectable forms of medication in terms of how it should be used in clinical practice. These articles, although they're important from a regulatory standpoint, offer sort of little in the way of new and interesting news," he concluded.

This study was supported by Otsuka Pharmaceuticals Development & Commercialization, which manufacturers the study drug in partnership with H. Lundbeck A/S. Dr. Kane reported having been a consultant to Otsuka. Dr. Lieberman has disclosed no relevant financial relationships.

The American Psychiatric Association's 2012 Annual Meeting. Abstract #NR4-47, NR6-41. Presented May 6 and May 7, 2012.