Deborah Brauser

October 26, 2012

VIENNA, Austria — The new serotonin-norepinephrine reuptake inhibitor (SNRI) levomilnacipran is effective in treating patients with major depressive disorder (MDD), new research suggests.

A phase 3 randomized controlled trial (RCT) of more than 700 adults with MDD showed that those treated for 2 months with 40-mg, 80-mg, or 120-mg daily doses of levomilnacipran sustained release (SR) all showed significantly greater symptom improvements than those who received placebo.

Although the active medication overall was considered "generally well tolerated," common treatment-related adverse events (AEs) included nausea and hyperhidrosis (especially in the 80-mg dose).

Forest Laboratories announced in September that they had submitted a New Drug Application to the US Food and Drug Administration (FDA) for levomilnacipran in the treatment of MDD in adult patients.

"This was one of the pivotal trials done to test the efficacy and safety profile of this drug. And it was one that was submitted to the FDA," coinvestigator Jolan Terner-Rosenthal, PhD, senior medical science liaison at Forest Research Institute in Jersey City, New Jersey, told Medscape Medical News.

Dr. Jolan Terner-Rosenthal

"For depression, there's no one treatment that works for every patient. Our conversations with physicians, psychiatrists, and family practitioners have shown that they need more options. And levomilnacipran is an SNRI that's another option to help patients," added Dr. Terner-Rosenthal.

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

"One to Watch"

At this year's American Psychiatric Association (APA) annual meeting, the investigators presented several poster studies assessing levomilnacipran, which were commented on by 2 psychiatrists in blogs for Medscape Medical News.

Nassir Ghaemi, MD, professor of psychiatry at Tufts University School of Medicine and director of the Mood Disorders Program at Tufts Medical Center in Boston, Massachusetts, noted in his blog that among "some posters I found of interest" was 1 assessing this medication.

"A new antidepressant seems slated for probable FDA approval for MDD by the end of the year: levomilnacipran SR," he wrote at the time. "Two double-blind placebo-controlled RCTs for acute MDD were effective [and a] clear pattern of any specific side effects of concern was not seen."

Michael Thase, MD, professor of psychiatry at the University of Pennsylvania Perelman School of Medicine in Philadelphia, discussed levomilnacipran in his after-meeting video blog posting, titled, "Three Depression Therapies to Watch."

He noted that the antidepressant "closest to being introduced in the United States" is levomilnacipran, making it the fourth entry into the SNRI class of medications.

"I think it's now clear that this is an effective medication. That was established for the parent drug, milnacipran, outside of the United States," said Dr. Thase in his blog.

"I think the thing that distinguishes this from the other members of the SNRI class is that at a low therapeutic dose, the drug is much more of a norepinephrine reuptake inhibitor than a serotonin reuptake inhibitor, making it clearly different from venlafaxine, desvenlafaxine, and duloxetine," he added.

Significant Efficacy

For the current study, the researchers enrolled 724 patients diagnosed with MDD who were between the ages of 18 and 65 years.

The participants were randomly assigned to receive daily for 8 weeks either 40 mg (n = 181; 69% women; mean age, 42 years), 80 mg (n = 181; 62% women; mean age, 41 years), or 120 mg (n = 183; 59% women; mean age, 40 years) of levomilnacipran SR or placebo (n = 179; 61% women; mean age, 41 years). A total of 71% of the patients completed the study.

The primary outcome measure was total score change from baseline to end of treatment on the Montgomery-Ǻsberg Depression Rating Scale–Clinician Rated (MADRS-CR).

Secondary measures included total score change on the Sheehan Disability Scale (SD), safety, and tolerability. Post hoc analyses also assessed single-item changes on the MADRS-CR.

Results showed that compared with the group receiving placebo, significant improvements in MADRS-CR total score changes were found for the groups receiving levomilnacipran SR 40 mg (P = .019), 80 mg (P = .004), and 120 mg (P = .0005).

In addition, significantly greater improvements on the SDS were shown in those receiving levomilnacipran SR 80 mg and 120 mg (both P < .05) compared with placebo. The 120-mg group also showed significantly greater improvements on all 3 of the SDS disability dimensions: work, social life, and family life.

The post hoc analyses showed that all groups receiving levomilnacipran SR had significantly greater improvement on the MADRS item of apparent sadness than those receiving placebo.

Those receiving the 2 higher doses also showed significant improvement in reported sadness and inner tension, and the highest dose group alone showed significant improvement in reduced sleep, difficulty concentrating, and suicidal thoughts.

Adverse Events

Treatment-related AEs occurred in 76%, 83%, and 77% of the patients receiving the 40-mg, 80-mg, and 120-mg doses of levomilnacipran, respectively, and in 64% of the patients receiving placebo.

However, there were more than 3 times as many discontinuations due to AEs in the active medication groups (7% of the 40-mg group, 15% of the 80-mg group, 7% of the 120-mg group) than in the placebo group (2%)

Common adverse events reported from those receiving the active medication included nausea, constipation, heart rate increase, and hyperhidrosis.

Serious AEs were reported by 2 of the patients receiving the 40-mg dose of the active medication (chest pain and deep vein thrombosis in 1 and aggression in the other) and by 1 of the patients receiving the 80-mg dose (cytomegalovirus mononucleosis).

The investigators note that they are pleased with the overall results.

"Levomilnacipran demonstrated significant, dose-proportional improvement in depressive symptoms relative to placebo," they write.

"When you have 30% disability out there due to depression and other psychiatric disorders, anything that can potentially help patients is obviously important," added Dr. Terner-Rosenthal.

A "Me Too" Drug?

However, when asked for comment, 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, said he was not that impressed with this medication.

Dr. Robbert Verkes

"This antidepressant is effective. But when you look at the side-effect profile, I think it's a 'me too' drug. And I'm not excited," he told Medscape Medical News.

Dr. Verkes, who was not involved with this research, added that there are already several similar medications out there, and he is not sure there is need for another one.

"If they can show real benefits over the compounds we already have, then that would be interesting. But just being effective isn't really enough."

He further noted that the side effects found are "comparable with drugs we already know," and that he does not believe this is another good tool for the clinician's toolbox.

"I would say, put your efforts into something else, into something that we need. That said, this may be a good drug — and a perfectly adequate 'me too.' "

The study was funded by Forest Laboratories Inc and Pierre Fabre Médicament. Dr. Terner-Rosenthal is an employee of Forest Research Institute. Dr. Verkes has disclosed no relevant financial relationships.

25th European College of Neuropsychopharmacology (ECNP) Congress. Abstract P.2.c.020. Presented October 15, 2012.