Agomelatine
is a new chemical entity that is nearing approval for treatment of
depression. It was developed by Servier
Laboratories; they have entered into an agreement with Novartis
for commercialization of the product (Valdoxan®).This represents a new approach to the pharmaceutical treatment of depression. The putative mechanism of action is that it stimulates melatonin receptors, and blocks a subtype of serotonin 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 Takeda product, ramelteon (Rozerem®) 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 mirtazapine. Note that this action does not modulate the activity of serotonin. Rather, it indirectly 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 advance
the sleep phase, much like melatonin does. Because
agomelatine does not inhibit reuptake of serotonin, it should not cause
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 lack
of discontinuation (withdrawal) syndrome.
Premarketing human and animal studies (1 2 3 4 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 implicated 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.
Premarketing human and animal studies (1 2 3 4 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 implicated 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.
Brain & Behavior
Medicine & Health
Comments
Wouldn't it be great if more prescribing physicians would bestir themselves to provide this sort of information to the public on new medications? Thanks, Corpus.
One thought: Why is it that Agomelatine won't cause daytime sleepiness?
Posted by: Dirkh | November 26, 2007 4:56 AM
what do you mean by a "polarity switch"?
*goes off to read some*
Posted by: laura | November 26, 2007 2:45 PM
Polarity switch refers to switching from depression to mania or hypomania, or back the other way.
Melatonin is not directly sedating. What it does is change your biological clock so that your brain thinks it is time to go to sleep. If you want to stay awake, of if something demands your attention, you will stay awake.
It is important to keep in mind, however, that everyone is different. Unexpected things do happen. The pharmacology of the drug does not always tell us ahead of time what will happen to any individual when they take a drug.
Posted by: Joseph j7uy5 | November 26, 2007 4:31 PM
Here's an intriguing abstract on melatonin's effect on nighttime memory formation:
Science 16 November 2007:
Reports
Melatonin Suppresses Nighttime Memory Formation in Zebrafish
Oliver Rawashdeh, Nancy Hernandez de Borsetti, Gregg Roman,* Gregory M. Cahill
Memory processes are modulated by the biological clock, although the mechanisms are unknown. Here, we report that in the diurnal zebrafish both learning and memory formation of an operant conditioning paradigm occur better during the day than during the night. Melatonin treatment during the day mimics the nighttime suppression of memory formation. Training in constant light improves nighttime memory formation while reducing endogenous melatonin concentrations. Treatment with melatonin receptor antagonists at night dramatically improves memory. Pinealectomy also significantly improves nighttime memory formation. We adduce that melatonin is both sufficient and necessary for poor memory formation during the night.
Posted by: Dirkh | December 1, 2007 7:28 AM
Hi,
Thanks for this good article.
Posted by: oyunlar | March 7, 2008 6:59 PM
Wouldn't it be great if more prescribing physicians would bestir themselves to provide this sort of information to the public on new medications? Thanks, Corpus.
Posted by: youtube | March 28, 2008 5:05 AM
This is an important concern, one that deserves some consideration
Posted by: araba kiralama | April 1, 2008 6:11 PM
Treatment with melatonin receptor antagonists at night dramatically improves memory. Pinealectomy also significantly improves nighttime memory formation. We adduce that melatonin is both sufficient and necessary for poor memory formation during the night.
Posted by: Rize | April 14, 2008 7:30 AM
I was in an 8-week double-blind trial for agomelatine in Feb-Mar 07, then had a full year on 50 mg of this wonder drug. Far better than any SSRI I've taken with no side effrects of any kind, agomelatine gave me my sweetest year of vitality and health in the last decade.
But, of course, the trial ended, and I've now been off it for 5 weeks, and am beginning to feel myself slip back into depression. My sleep---perfect, refreshing 8 hours per night for a full year--is once again erratic and interrupted.
Any idea when this golden drop of sweetness will be approved for the market?
Posted by: zucchini189 | May 13, 2008 8:03 PM
Treatment with melatonin receptor antagonists at night dramatically improves memory. Pinealectomy also significantly improves nighttime memory formation. We adduce that melatonin is both sufficient and necessary for poor memory formation during the night.
Posted by: Karadeniz | June 20, 2008 3:55 PM
The melatonin receptor action is not new: the Takeda product, ramelteon (Rozerem®) also is an agonist at the MT1 and MT2 receptors. It is marketed as a nonaddictive sleep aid. :)
Posted by: oyunzamani | May 28, 2009 9:11 PM
A little confusing - does this drug result in weight loss? How would it go when combined with lexapro and respirdal? I have previously had a problem with occulogyric crisis (particularly in response to aropax) - will the drug cause this?
Posted by: Kath | February 5, 2011 3:53 AM
Kath, studies lasting up to ten months indicate that agomelatine is weight-neutral, causing neither weight gain nor weight loss. There is no reason to think that it could cause oculogyric crisis. As for interactions, here is the available information:
(;TLDR no interaction with Lexapro or Risperdal)
Potential interactions affecting agomelatine:
Agomelatine is metabolised mainly by cytochrome P450 1A2 (CYP1A2) (90%) and by CYP2C9/19 (10%). Medicinal products that interact with these isoenzymes may decrease or increase the bioavailability of agomelatine.
Fluvoxamine, a potent CYP1A2 and moderate CYP2C9 inhibitor markedly inhibits the metabolism of agomelatine resulting in a 60-fold (range 12-412) increase of agomelatine exposure.
Consequently, co-administration of Valdoxan with potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) is contraindicated.
Combination of agomelatine with oestrogens (moderate CYP1A2 inhibitors) results in a several fold increased exposure of agomelatine. While there was no specific safety signal in the 800 patients treated in combination with oestrogens, caution should be exercised when prescribing agomelatine with other moderate CYP1A2 inhibitors (e.g. propranolol, grepafloxacine, enoxacine) until more experience has been gained (see section 4.4).
Potential for agomelatine to affect other medicinal products:
In vivo, agomelatine does not induce CYP450 isoenzymes. Agomelatine inhibits neither CYP1A2 in vivo nor the other CYP450 in vitro. Therefore, agomelatine will not modify exposure to medicinal products metabolised by CYP 450.
Medicinal products highly bound to plasma protein:
Agomelatine does not modify free concentrations of medicinal products highly bound to plasma proteins or vice versa.
Posted by: Joseph j7uy5
| February 5, 2011 10:41 AM
It is important to keep in mind, however, that everyone is different. Unexpected things do happen. The pharmacology of the drug does not always tell us ahead of time what will happen to any individual when they take a drug.
sorryy
Posted by: Laptop | August 8, 2011 6:54 AM