Deborah Brauser

October 18, 2012

VIENNA, Austria — The experimental multimodal antidepressant Lu AA21004 (vortioxetine) is effective and well tolerated in the treatment of elderly patients with recurrent major depressive disorder (MDD), new research suggests.

A double-blind, randomized controlled trial (RCT) of more than 450 elderly adults with MDD from 7 countries showed that those treated with Lu AA21004 showed significantly greater improvement on several depression rating scales and cognitive tests compared with those who received placebo.

In addition, the only adverse event that occurred at a higher incidence with the experimental medication than with placebo was nausea.

"We found that this is an effective antidepressant in older people, with clear separation between the vortioxetine group and the placebo group on standard depression measures," lead author Cornelius Katona, MD, FRCPsych, from the Department of Mental Health Sciences at the University College London in the United Kingdom, told Medscape Medical News.

"Several similarly designed studies of antidepressants in old age have proved negative. This is 1 of relatively few recent studies where it shows a new antidepressant to be effective. And we found that it was extremely well tolerated and had a very nice effect on cognition," said Dr. Katona.

Dr. Cornelius Katona

Takeda Pharmaceutical and Lundbeck recently jointly announced that they had submitted a New Drug Application to the US Food and Drug Administration and a marketing authorization application to the European Medicines Agency for this medication in the treatment of MDD in adult patients.

"As, and when, this drug becomes available, I think it will be a very interesting drug to consider — especially because it has a novel mode of action," said Dr. Katona.

The study was presented here at the 25th European College of Neuropsychopharmacology (ECNP) Congress.

Multicountry Study

Lu AA21004 is a bis-arylsulfanyl amine compound that is "thought to work through a combination of 2 pharmacological modes of action: 5-HT reuptake inhibition and receptor activity," write the investigators.

"In vitro studies indicate that [it] is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist, and inhibitor of the 5-HT transporter," they add

At the American Psychiatric Association 2011 Annual Meeting, and reported at the time by Medscape Medical News, an RCT of more than 500 adult patients of all ages with MDD from 4 continents showed that those who received 1-, 5-, or 10-mg doses of Lu AA21004 had significantly reduced symptoms over 8 weeks compared with those who received placebo.

However, a second RCT presented at the event with 600 patients from the United States showed no significant between-group differences in depression symptoms for those receiving 5 mg of the active treatment or placebo for 6 weeks.

At the time, coinvestigator Michael Thase, MD, professor of psychiatry at the University of Pennsylvania School of Medicine in Philadelphia, said that he was not sure whether the latter study failed because of the dose assessed or because of the stringent rules in place for drug studies in this country.

"Our [multicountry] trial gives us reason to believe we're on the right track with this multiaction agent," he told Medscape Medical News at the time.

According to a release, Lundbeck has since reported positive results from 3 phase 3 clinical trials, including 2 in the United States, showing significantly greater improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS) for patients receiving Lu AA21004 than for those receiving placebo.

The release states that "more than 5,000 study subjects have been exposed to Vortioxetine worldwide."

Recurrent Depression

For the current study, the investigators sought to assess the efficacy and tolerability of 5 mg/day of the medication in an elderly population.

A total of 452 patients older than 64 years (mean age, 70.6 years) were enrolled in the trial. All had a clinical diagnosis of MDD and were in the midst of a current major depressive episode (MDE) that had lasted at least 4 weeks.

Other inclusion criteria included having had at least 1 previous MDE before the age of 60 years and having a current MADRS total score of more than 25.

The participants were randomly assigned to receive for 8 weeks either the 5 mg/day of Lu AA21004 (n = 156; 69% women), 60 mg/day of duloxetine (active reference; n = 151; 66% women), or placebo (n = 145; 62% women).

The primary outcome measure was change from baseline to week 8 on the 24-item Hamilton Depression Rating Scale (HAM-D24). A "response" was defined as at least 50% improvement from baseline.

The Rey Auditory Verbal Learning Test (both acquisition and delayed recall components) and the Digital Symbol Substitution Test were used to assess cognitive performance.

Results showed that, compared with the patients receiving placebo, the patients receiving Lu AA21004 had a significantly greater improvement from baseline to week 8 on the HAM-D24 (P = .0011; mean difference from placebo, 3.3 points). They also had greater improvement at week 6 than did the placebo group (P = .02; mean difference from placebo, 2.1 points).

In addition, there were significantly more HAM-D24 responses for the Lu AA21004 group than for the placebo group (53.2% vs 35.2%, respectively; P < .05) and more HAM-D17 remissions (29.2% vs 19.3%, respectively; P < .05).

Favorable Side-Effect Profile

Those treated with the experimental medication also had higher scores on cognition tests of speed processing, verbal learning, and memory than those treated with placebo.

The patients treated with duloxetine also had greater improvements on the HAM-D24 than those receiving placebo (mean difference from placebo, 5.5 points).

Study discontinuation rates due to treatment-related adverse events were 5.8% of those receiving Lu AA21004, 9.9% for those receiving duloxetine, and 2.8% of those receiving placebo.

Nausea was the only adverse event, with a significantly higher incidence after treatment with Lu AA21004 than after receiving placebo (21.8% vs 8.3%, respectively).

For the duloxetine patients, there was a significantly higher incidence of nausea, fatigue, dry mouth, constipation, hyperhidrosis, and somnolence than for those receiving placebo.

Serious adverse events were reported by 4 of the placebo patients, 1 of the Lu AA21004 patients, and 1 of the duloxetine patients. No deaths were reported during the study.

"No clinically relevant changes over time or differences between treatment groups were seen in clinical laboratory test results, vital signs weight or ECG parameters," report the investigators.

"Older people are more likely to have other medications and other conditions, which tend to make drugs less well tolerated and more dangerous. So this very good side-effect profile is particularly important," added Dr. Katona.

Still, he pointed out that "one has to remember that this is the lowest effective dose. It's likely that the range of doses that will be recommended as and when the drug is licensed will be between 5 mg and 20 mg."

Novel Mechanism

"This medication is exciting because of its mechanism," Robbert J. Verkes, MD, PhD, from the Unit for Clinical Psychopharmacology in the Department of Psychiatry at the Radboud University Medical Center in Nijmegen, the Netherlands, told Medscape Medical News.

Dr. Robbert Verkes

"That makes it quite interesting and not a 'me too' drug. It may add something," said Dr. Verkes, who was not involved with this research.

He also noted that the side-effect profile was interesting, especially in comparison with duloxetine.

"So we should keep an eye on this new compound. Of course, we need more than 1 study. But because this is a new mechanism, maybe patients who do not show a response on classical antidepressants, reuptake inhibitors, may show response on this new one."

The study was funded by L. Lundbeck A/S as part of a joint clinical development program with Takeda Pharmaceutical Company. Dr. Verkes has disclosed no relevant financial relationships.

25th European College of Neuropsychopharmacology (ECNP) Congress. Abstract P.2.c.015. Presented October 15, 2012.