Melatonin Agonist Shows Benefits in Treating Bipolar Depression


Paula Moyer, MA



June 21, 2005 (Pittsburgh) — Patients with bipolar depression may get
relief from the adjunctive use of agomelatine (Valdoxan), according to
U.S. and French investigators who presented their findings here at the
Sixth International Congress on Bipolar Disorder.

"This is the first melatoninergic antidepressant, and it may fill a need
in bipolar depression," said Joseph R. Calabrese, MD, in an interview.
"Others have not shown benefit, and we think that agomelatine may work
because it has a different mechanism of action."

The new agent works on the melatonin 1 and melatonin 2 receptors and
also has 5-HT2c antagonist properties, as do selective serotonin
reuptake inhibitors (SSRIs), said Dr. Calabrese, a professor of
psychiatry, at Case Western Reserve University, Cleveland, Ohio. He
added that the hope is that a melatoninergic agent would be less likely
to cause hypomania and rapid cycling than are SSRIs.

The expectation is that agomelatine would be used in an adjunctive
manner along with a mood stabilizer, according to Dr. Calabrese, who was
the coinvestigator. The lead investigator was Judith D. Guelfi, MD, a
consultant psychiatrist in the Psychiatric Clinic at Hôpital Sainte-Anne
in Paris, France.

The investigators were interested in agomelatine's potential to treat
bipolar depression because it has been shown to be effective in treating
major depressive disorder. The drug has been submitted for approval to
the European Agency for the Evaluation of Medical Products, and approval
is expected in early to mid-2006.

Therefore, in an initial study, Drs. Guelfi and Calabrese recruited 21
patients with bipolar I disorder who were experiencing a major
depressive episode to see if adjunctive treatment with agomelatine in
addition to a mood stabilizer would improve their symptoms. The
investigators used the Hamilton Rating Scale for Depression-17
(HAM-D17), and eligible patients had a score of at least 18, and a
response was defined as a reduction of at least 50% in the HAM-D17
score, and remission was defined as a HAM-D17 score of no more than 6.

All patients received 0.25 mg of agomelatine daily during an initial
six-week acute period, in which 47% of patients responded during the
first week of treatment, and in which 85% had responded by the end of
the acute phase. Afterward, 19 patients continued for an extension phase
from weeks 6 to 52; 11 patients completed the study. Among those who
continued, 10 were in remission by the end of the study. Among the eight
discontinuations, two were for lack of efficacy, three were for adverse
events, and of the remaining three, one had recovered by week 18 and did
not feel the need for ongoing therapy, one had withdrawn consent, and
one had poor compliance. Fifteen adverse events occurred, including two
manic or hypomanic episodes. Generally, though, treatment was well
tolerated, with an average Young Mania Rating Scale score that was 4 at
onset and declined throughout the study period to 2 by the study's end.

"We were looking for a signal that agomelatine could be effective in
bipolar depression, and we think the findings warrant further study,"
said Dr. Calabrese. "We would anticipate that agomelatine would be used
as an adjunctive therapy." However, Dr. Calabrese cautioned that larger
studies would be needed that replicated these findings to make a more
definitive statement.

Sixth ICBD: Abstract P163. Presented June 17, 2005

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