HOLLYWOOD, FLA. – The investigational antidepressant vortioxetine achieved a 55% remission rate in a large, double-blind study of patients with major depressive disorder switched to the drug after an inadequate response to one of a half-dozen approved selective serotonin reuptake inhibitors or selective norepinephrine reuptake inhibitors.
"I think it’s quite impressive to see a remission rate on the order of 55% in this difficult-to-treat population," Dr. Marianne Dragheim observed in presenting the study findings at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.
After all, in the landmark NIMH-sponsored sequential treatment alternatives to relieve depression, or STAR*D trial, in which citalopram nonresponders were switched to second-line treatment with sustained-release bupropion, extended-release venlafaxine, or sertraline, the mean remission rate after 12-14 weeks on the backup medication was just 31% (N. Engl. J. Med. 2006;354:1231-42), noted Dr. Dragheim of H. Lundbeck A/S, Valby, Denmark.
Vortioxetine is a first of its kind multimodal antidepressant. It is an inhibitor of the 5-hydroxytryptamine (5-HT) or serotonin transporter. In addition, vortioxetine is a 5-HT3, 5-HT7, and 5-HT10 receptor antagonist, a 5-HT1A receptor agonist, and a 5-HT1B receptor partial agonist.
Vortioxetine is currently under review at the Food and Drug Administration for possible marketing approval. The evidence submitted to the FDA includes seven positive studies, including four phase III randomized trials presented in May at the annual meeting of the American Psychiatric Association in San Francisco. The switching study Dr. Dragheim presented at the NCDEU meeting was completed so recently that it was not included in the FDA’s data package.
She reported on 501 European patients with major depressive disorder who responded inadequately to at least 6 weeks of monotherapy with citalopram, escitalopram, sertraline, paroxetine, venlafaxine, or duloxetine at approved doses. The study participants, all of whom wanted to change their antidepressant because of inadequate response, were randomized to 12 weeks of double-blind treatment with flexibly dosed vortioxetine at 10-20 mg/day or agomelatine at 25-50 mg/day. Agomelatine is approved as an antidepressant in the European Union and elsewhere in the world, but not in the United States.
The primary study endpoint was the change in scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) between baseline and week 8. From a baseline MADRS total score of 29, the vortioxetine group improved by a mean of 2.2 more points than the agomelatine group, a statistically significant difference.
In addition, the vortioxetine-treated patients fared significantly better in terms of numerous secondary endpoints. They had a mean 1.9-point greater improvement than did the agomelatine group at 8 weeks in the Hamilton Anxiety Rating Scale total score, a 0.3-point greater improvement on the Clinical Global Impression-Severity, and a 2.2-point bigger improvement on the Sheehan Disability Scale.
The week-8 response rate as reflected in at least a 50% improvement from baseline in MADRS score was 61.5% in the vortioxetine group and 47.3% with agomelatine.
Remission as defined by a MADRS score of 10 or less occurred in 40.5% of the vortioxetine group and 29.5% of the agomelatine group at week 8, and in 55.2% vs. 39.4%, respectively, at week 12 (P = .0002).
Study withdrawal because of adverse events occurred in 5.9% of the vortioxetine group, compared with 9.5% of patients on agomelatine. Nausea, reported by 16% of patients on vortioxetine, was the only side effect more common in patients on that drug; however, less than 1% of subjects on vortioxetine left the study because of nausea.
Vortioxetine is being developed jointly by H. Lundbeck and Takeda Pharmaceutical Co.Dr. Dragheim is a company employee.