Deborah Brauser

October 10, 2013

BARCELONA, Spain ― Lurasidone used alone and adjunctively offers significant improvement in core symptoms of bipolar depression, new research suggests.

Joseph R. Calabrese, MD, from the Department of Psychiatry at Case Western Reserve University in Cleveland, Ohio, presented unpublished data from 2 large phase 3 studies here at the 26th European College of Neuropsychopharmacology (ECNP) Congress.

The 340-person PREVAIL 1 trial showed that those who received 20 to 120 mg of lurasidone plus lithium or valproate for 6 weeks had significantly better scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) than the placebo group. There were also significantly more responders in the active treatment group.

"As early as week 3 and at each and every time point thereafter, lurasidone used adjunctively was efficacious," said Dr. Calabrese.

"Lurasidone also doesn't have the metabolic burden, and there's no significant change in body weight, which makes it so much easier for patients to use. Efficacy in the absence of metabolic burden is huge."

The 485-person PREVAIL 2 trial, which evaluated lurasidone as montherapy, also showed significant efficacy.

These findings contributed to the recent approval by the US Food and Drug Administration of 20- to 120-mg/day doses of the medication for adults with bipolar depression, which was reported by Medscape Medical News.

Results

Dr. Calabrese noted that the search for effective interventions for this patient population is very important to him.

"It is this phase of the illness where our patients live the majority of their symptomatic lives, and it is this phase where people kill themselves. This is why I have specifically focused on this phase, and I will finish the rest of my career working to develop new treatments for bipolar depression," he told Medscape Medical News.

His presentation, entitled "New Developments in the Pharmacotherapy of Bipolar Disorders," was given to a packed auditorium of meeting attendees.

"No pharmacotherapy has [before] received approval for short-term adjunctive treatment of bipolar depression. Monotherapy designs have generated good internal validity but appear to inflate therapeutic effect size," he said.

PREVAIL 1's primary outcome measure was the MADRS, which showed a significant symptom score decrease between baseline and the 6-week end point for lurasidone compared with placebo (-17.1 vs - 13.5, respectively; P < .01).

The responder rate (50% or more reduction from baseline on the MADRS) was 57% vs 42%, respectively (P < .01); the number to treat for response was 7, and the number to harm was 100. Remission rates were 50% vs 35% (P < .01).

Between-group differences in number of adverse event (AE) discontinuations were not significant (7.9% of those receiving lurasidone vs 6% of those receiving placebo).

The most common treatment-related AEs were nausea (17.5% vs 11%, respectively), headache (10.4% vs 12.3%), and somnolence (8.7% vs 4.3%).

There were no statistically significant or clinically significant between-group differences in metabolic parameters such as weight, body mass index, or cholesterol, triglyceride, and glucose levels.

Monotherapy Data

In the PREVAIL 2 monotherapy trial, participants were randomly assigned to receive 20- to 60-mg doses of lurasidone (n = 161), 80- to 120-mg doses of lurasidone (n = 162), or placebo (n = 162).

Both of the lurasidone groups had mean MADRS score changes at week 6 of -15.4 vs -10.7 for the placebo group (P < .001 for both). In addition, both doses of the active treatment showed efficacy by week 2.

The responder rate for the higher dose of lurasidone was 51% vs 53% for the lower dose and 30% for placebo (P < .001). The number to treat was 5 for each of the lurasidone doses.

Remission rates were 40% vs 42% and 25%, respectively (P < .01).

Dr. Joseph Calabrese

"I think the take-home message from this trial is that the higher dose is no more effective than the lower dose. So like every single atypical antipsychotic agent studied in bipolar depression, it isn't necessary to use the doses that work in the treatment of schizophrenia," said Dr. Calabrese.

The most common treatment-related AEs for the group receiving high-dose lurasidone were nausea (17%), somnolence (14%), and akathesia (11%).

Although the most common AE for the group receiving lower-dose lurasidone was also nausea (10%), it was not significantly different from placebo (8%). Somnolence was reported by 7% of both the lower-dose lurasidone and placebo groups, and akathesia was reported by 8% and 2%, respectively.

A total of 3% of those receiving the higher dose dropped out because of akathesia vs 0.% of those receiving the lower dose.

"Again, no advantage here for the higher dose in efficacy, but a small yet clinically significant disadvantage from a side-effect tolerability perspective," said Dr. Calabrese.

"I would suggest that clinicians add lurasidone to the regimen of medicine they're already prescribing. After they find out it's well tolerated and they begin to see improvement, then begin peeling off other medicines. That way it's a conservative approach."

Full results from PREVAIL 1 and 2 are currently in press.

Disappointing Armodafinil Studies

Dr. Calabrese also discussed data from 3 recent studies that assessed armodafinil for bipolar depression. Unfortunately, only 1 of the 3 had significantly positive results, which means development of the drug will be discontinued.

"This is troubling because as a field, we need everything we can get," he said.

All of the multicenter randomized control trials ran for 8 weeks, but they had some unique design features. Because armodafinil has shown no efficacy for mania, there was a need to use multiple agents approved for mania, "which complicated the studies," reported Dr. Calabrese.

In fact, 19 different combinations/regimens on placebo and 17 different combinations/regimens on armodafinil 150 mg were included.

"Armodafinil is a weak dopamine reuptake inhibitor and [was] evaluated using a more inclusive design, allowing lithium, valproate, lamotrigine, aripiprazole, olanzapine, ziprasidone, or risperidone, which would be expected to deflate effect size," Dr. Calabrese wrote in his presentation abstract.

The primary efficacy measure for the 1 positive study was the 30-item IDS-C. Results showed that the group receiving 150 mg of armodafinil had a significant improvement on the IDS-C after 8 weeks compared with the placebo group (P = .01), as well as responder rates of 46% vs 34% (P = .01). However, the effect size was only 0.28.

"Again, all of those adjunctive treatments were whittling away at the effect size," said Dr. Calabrese to meeting attendees.

"These types of studies are important from a scientific perspective because they tell us where to go in the future, but we need compounds that we can use and that show efficacy. It's important to follow up on these leads, but in the meantime, we have to develop medications," he added.

More Compounds in the Pipeline

"I believe this presentation was one of the highlights of the entire meeting," session moderator Eduard Vieta, MD, PhD, professor of psychiatry at the University of Barcelona in Spain and a department head at the University Hospital of Barcelona, told Medscape Medical News.

Dr. Eduard Vieta

"Dr. Calabrese introduced new data showing the efficacy of new strategies. One was lurasidone, which is a second-generation antipsychotic with a mechanism of action that is quite interesting. And it was shown to be effective and quite safe in bipolar depression, which is an area of huge unmet need," he said.

Dr. Vieta, who was not involved with the research, noted that it was also interesting to see the results from the armodafinil studies.

"These results were mixed. There were some positive outcomes, but unfortunately, the primary outcome failed on 2 of 3 of the studies. And this is why armodafinil is very unlikely to be approved for this use," he said.

Looking to the future, he noted that although many companies are dropping their central nervous system research, "there is still a lot of hope because there are several compounds in phase 2 at the moment that look very promising."

"Hopefully, in 3 to 4 years we'll have another session on this topic with a lot of new and exciting data," smiled Dr. Vieta.

26th European College of Neuropsychopharmacology (ECNP) Congress. Symposium S.05.02. Presented October 6, 2013.

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