Antidepressant Targets Circadian Cycle, Has Fewer Side Effects

PARIS — Two clinical trials have found agomelatine, an investigational drug targeting dysfunction in circadian rhythm, to be as effective as venlafaxine in treating major depressive disorder, but with fewer side effects.

In particular, sexual dysfunction occurred at significantly lower rates in patients who remitted on agomelatine, compared with those who remitted on venlafaxine (Effexor), Dr. Sidney H. Kennedy said at the annual congress of the European College of Neuropsychopharmacology.

He also presented a pooled analysis from three placebo-controlled trials that showed agomelatine's sexual side-effect profile to be similar to placebo and better than that of selective serotonin reuptake inhibitors (SSRIs).

Servier, a French pharmaceutical firm, sponsored the studies. It is seeking approval of agomelatine for major depressive disorder in Europe and has licensed the new agent to Novartis for development in the United States.

If approved, agomelatine could become the first melatonergic antidepressant. It is an agonist of the melatonin 1 and melatonin 2 receptors and also has antagonist properties against the serotonergic 5-HT_2C receptors. Other analyses have shown that it improves sleep quality.

“Its mechanisms appear to be normalizing a disruptive circadian rhythm,” said Dr. Kennedy, psychiatrist-in-chief at the University Health Network in Toronto and a professor of psychiatry at the University of Toronto.

Both agomelatine-venlafaxine trials were randomized, double-blind, and parallel-group studies conducted in multiple countries. Patients ranged in age from 18 to 60 years and met criteria for major depressive disorder in the studies, reported by Dr. Kennedy with Dr. Christian Guilleminault of Stanford (Calif.) University.

The first study randomized 165 patients to agomelatine and 167 to venlafaxine IR. Patients started on 25 mg/day of agomelatine or 75 mg/day of venlafaxine. If they did not improve over 2 weeks, the doses could be increased to 50 mg/day of agomelatine or 150 mg/day of venlafaxine.

After 6 weeks, 76.4% of the agomelatine group and 70.6% of the venlafaxine cohort had responded to treatment. In both groups, total Hamilton Rating Scale for Depression scores fell from about 26 points to about 9 points. Responders were allowed to stay on their study drug for 6 months, at which point the investigators found a statistically significant benefit for agomelatine in Clinical Global Impression-Improvement scores.

The second study randomized 137 patients to agomelatine and 140 to venlafaxine IR. Doses were fixed at 50 mg/day of agomelatine and 75 mg daily of venlafaxine IR, which increased after 2 weeks to 150 mg/day. Dr. Kennedy and Dr. Guilleminault reported the remission rates were similar at 12 weeks: 73% on agomelatine and 67% on venlafaxine. Total scores on the Montgomery-Asberg Depression Rating Scale fell from 27.9 points to about 10 points in both groups.

Combined data from both trials showed fewer patients on agomelatine withdrew because of adverse events, compared with those on venlafaxine: 4.3% vs. 13.2%, respectively, at 6 weeks and 2.2% vs. 8.6%, respectively, at 12 weeks. The most frequent adverse events at 6 weeks in 303 patients on agomelatine included psychiatric disorders (1.7%), nervous system disorders (1%), and gastrointestinal disorders (0.7%).

The sexual function data, reported by Dr. Kennedy with Beata S. Eisfeld of the University of Toronto, showed 80% of people who remitted on agomelatine had no dysfunction in drive-desire/arousal or orgasm, compared with 58.8% and 53%, respectively, on venlafaxine. In the pooled placebo-controlled data, 3.2% of 1,120 patients on agomelatine, 2.6% of 998 patients on placebo, and 10.8% of 567 patients on an SSRI had “at least one emergent sexual dysfunction event.”

In particular, sexual dysfunction occurred at significantly lower rates in patients who remitted on agomelatine. DR. KENNEDY

PARIS — Two clinical trials have found agomelatine, an investigational drug targeting dysfunction in circadian rhythm, to be as effective as venlafaxine in treating major depressive disorder, but with fewer side effects.

In particular, sexual dysfunction occurred at significantly lower rates in patients who remitted on agomelatine, compared with those who remitted on venlafaxine (Effexor), Dr. Sidney H. Kennedy said at the annual congress of the European College of Neuropsychopharmacology.

He also presented a pooled analysis from three placebo-controlled trials that showed agomelatine's sexual side-effect profile to be similar to placebo and better than that of selective serotonin reuptake inhibitors (SSRIs).

Servier, a French pharmaceutical firm, sponsored the studies. It is seeking approval of agomelatine for major depressive disorder in Europe and has licensed the new agent to Novartis for development in the United States.

If approved, agomelatine could become the first melatonergic antidepressant. It is an agonist of the melatonin 1 and melatonin 2 receptors and also has antagonist properties against the serotonergic 5-HT_2C receptors. Other analyses have shown that it improves sleep quality.

“Its mechanisms appear to be normalizing a disruptive circadian rhythm,” said Dr. Kennedy, psychiatrist-in-chief at the University Health Network in Toronto and a professor of psychiatry at the University of Toronto.

Both agomelatine-venlafaxine trials were randomized, double-blind, and parallel-group studies conducted in multiple countries. Patients ranged in age from 18 to 60 years and met criteria for major depressive disorder in the studies, reported by Dr. Kennedy with Dr. Christian Guilleminault of Stanford (Calif.) University.

The first study randomized 165 patients to agomelatine and 167 to venlafaxine IR. Patients started on 25 mg/day of agomelatine or 75 mg/day of venlafaxine. If they did not improve over 2 weeks, the doses could be increased to 50 mg/day of agomelatine or 150 mg/day of venlafaxine.

After 6 weeks, 76.4% of the agomelatine group and 70.6% of the venlafaxine cohort had responded to treatment. In both groups, total Hamilton Rating Scale for Depression scores fell from about 26 points to about 9 points. Responders were allowed to stay on their study drug for 6 months, at which point the investigators found a statistically significant benefit for agomelatine in Clinical Global Impression-Improvement scores.

The second study randomized 137 patients to agomelatine and 140 to venlafaxine IR. Doses were fixed at 50 mg/day of agomelatine and 75 mg daily of venlafaxine IR, which increased after 2 weeks to 150 mg/day. Dr. Kennedy and Dr. Guilleminault reported the remission rates were similar at 12 weeks: 73% on agomelatine and 67% on venlafaxine. Total scores on the Montgomery-Asberg Depression Rating Scale fell from 27.9 points to about 10 points in both groups.

Combined data from both trials showed fewer patients on agomelatine withdrew because of adverse events, compared with those on venlafaxine: 4.3% vs. 13.2%, respectively, at 6 weeks and 2.2% vs. 8.6%, respectively, at 12 weeks. The most frequent adverse events at 6 weeks in 303 patients on agomelatine included psychiatric disorders (1.7%), nervous system disorders (1%), and gastrointestinal disorders (0.7%).

The sexual function data, reported by Dr. Kennedy with Beata S. Eisfeld of the University of Toronto, showed 80% of people who remitted on agomelatine had no dysfunction in drive-desire/arousal or orgasm, compared with 58.8% and 53%, respectively, on venlafaxine. In the pooled placebo-controlled data, 3.2% of 1,120 patients on agomelatine, 2.6% of 998 patients on placebo, and 10.8% of 567 patients on an SSRI had “at least one emergent sexual dysfunction event.”

In particular, sexual dysfunction occurred at significantly lower rates in patients who remitted on agomelatine. DR. KENNEDY

PARIS — Two clinical trials have found agomelatine, an investigational drug targeting dysfunction in circadian rhythm, to be as effective as venlafaxine in treating major depressive disorder, but with fewer side effects.

In particular, sexual dysfunction occurred at significantly lower rates in patients who remitted on agomelatine, compared with those who remitted on venlafaxine (Effexor), Dr. Sidney H. Kennedy said at the annual congress of the European College of Neuropsychopharmacology.

He also presented a pooled analysis from three placebo-controlled trials that showed agomelatine's sexual side-effect profile to be similar to placebo and better than that of selective serotonin reuptake inhibitors (SSRIs).

Servier, a French pharmaceutical firm, sponsored the studies. It is seeking approval of agomelatine for major depressive disorder in Europe and has licensed the new agent to Novartis for development in the United States.

If approved, agomelatine could become the first melatonergic antidepressant. It is an agonist of the melatonin 1 and melatonin 2 receptors and also has antagonist properties against the serotonergic 5-HT_2C receptors. Other analyses have shown that it improves sleep quality.

“Its mechanisms appear to be normalizing a disruptive circadian rhythm,” said Dr. Kennedy, psychiatrist-in-chief at the University Health Network in Toronto and a professor of psychiatry at the University of Toronto.

Both agomelatine-venlafaxine trials were randomized, double-blind, and parallel-group studies conducted in multiple countries. Patients ranged in age from 18 to 60 years and met criteria for major depressive disorder in the studies, reported by Dr. Kennedy with Dr. Christian Guilleminault of Stanford (Calif.) University.

The first study randomized 165 patients to agomelatine and 167 to venlafaxine IR. Patients started on 25 mg/day of agomelatine or 75 mg/day of venlafaxine. If they did not improve over 2 weeks, the doses could be increased to 50 mg/day of agomelatine or 150 mg/day of venlafaxine.

After 6 weeks, 76.4% of the agomelatine group and 70.6% of the venlafaxine cohort had responded to treatment. In both groups, total Hamilton Rating Scale for Depression scores fell from about 26 points to about 9 points. Responders were allowed to stay on their study drug for 6 months, at which point the investigators found a statistically significant benefit for agomelatine in Clinical Global Impression-Improvement scores.

The second study randomized 137 patients to agomelatine and 140 to venlafaxine IR. Doses were fixed at 50 mg/day of agomelatine and 75 mg daily of venlafaxine IR, which increased after 2 weeks to 150 mg/day. Dr. Kennedy and Dr. Guilleminault reported the remission rates were similar at 12 weeks: 73% on agomelatine and 67% on venlafaxine. Total scores on the Montgomery-Asberg Depression Rating Scale fell from 27.9 points to about 10 points in both groups.

Combined data from both trials showed fewer patients on agomelatine withdrew because of adverse events, compared with those on venlafaxine: 4.3% vs. 13.2%, respectively, at 6 weeks and 2.2% vs. 8.6%, respectively, at 12 weeks. The most frequent adverse events at 6 weeks in 303 patients on agomelatine included psychiatric disorders (1.7%), nervous system disorders (1%), and gastrointestinal disorders (0.7%).

The sexual function data, reported by Dr. Kennedy with Beata S. Eisfeld of the University of Toronto, showed 80% of people who remitted on agomelatine had no dysfunction in drive-desire/arousal or orgasm, compared with 58.8% and 53%, respectively, on venlafaxine. In the pooled placebo-controlled data, 3.2% of 1,120 patients on agomelatine, 2.6% of 998 patients on placebo, and 10.8% of 567 patients on an SSRI had “at least one emergent sexual dysfunction event.”

In particular, sexual dysfunction occurred at significantly lower rates in patients who remitted on agomelatine. DR. KENNEDY