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is a new chemical entity that is nearing approval for treatment of
depression. It was developed by
Laboratories; they have entered into an agreement with
for commercialization of the product (
rel="tag">Valdoxan®).
This represents a new approach to the pharmaceutical treatment of
depression. The putative mechanism of action is that it
stimulates
href="http://en.wikipedia.org/wiki/Melatonin">melatonin
receptors, and blocks a subtype of
receptor. Specifically, it has agonist properties at the MT1
and MT2 receptors, and antagonist properties at the 5HT-2c receptors
(5HT is shorthand for 5-hydroxytryptamine, another name for serotonin).
The melatonin receptor action is not new: the
product,
rel="tag">ramelteon (
also is an agonist at the MT1 and MT2 receptors. It is
marketed as a nonaddictive sleep aid.
Likewise, the antagonist activity at the 5HT-2c receptor is not new.
Many other antidepressants do that as well, such as
nefazodone
and
rel="tag">mirtazapine. Note that this
action does not
modulate the activity of serotonin. Rather, it
increases
the activity of frontocortical dopaminergic and adrenergic pathways.
What is new is that agomelatine is the first drug to have this
particular combination of receptor activities.
The action at the melatonin receptors should result in
improved sleep,
without causing somnolence during the daytime. What is does,
is
the sleep phase, much like melatonin does. Because
agomelatine does not inhibit reuptake of serotonin, it should
sexual dysfunction,
nausea, or agitation. In fact, the antagonist activity at the
5HT-2c receptor might prevent the sexual dysfunction caused by SSRIs,
if used in combination. One study indicated a
of discontinuation (withdrawal) syndrome.
Premarketing human and animal studies (
3
5)
indicate that agomelatine should be beneficial for treatment of
depression, and that it should alleviate some anxiety symptoms.
Sharp-eyed readers will be wondering about the effect on weight.
Blockade of the 5HT-2c receptor has been
in weight gain associated with some atypical
antipsychotics. However, I was not able to find any
indication that agomelatine will share this problem.
I must say I will be glad to see this product on the market.
However, as with any new product, I would use it sparingly in
the first six months after it reaches the pharmacy shelves.
During that period, I would use it for persons who have
demonstrated a lack of response to multiple adequate trials of other
antidepressants.
The reason to be cautious, is that it is common for drugs to be
released with great fanfare, often with unrealistic expectations about
lack of particular adverse effects. The thing is, you never
really know about the incidence of adverse effects until the drug has
been given to tens of thousands, if not millions, of persons.
Once the drug has been on the market for a while, say about a year, it
might be worth trying it for off-label things, such as anxiety.
I suspect it may find a role in treatment of insomnia even in
the absence of a mood disorder.
One thing everyone will be watching for is the possibility that
agomelatine, like other antidepressants, could provoke a polarity
switch. I don’t have a specific reason to worry about this,
but since nobody understands why it happens, it is impossible to
anticipate the risk based upon the pharmacology of the drug.
Premarketing studies generally are done in carefully selected
patients, so they do not tell you what will happen in a broader
population.
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