"New and Improved" Antidepressant - Agomelatine

[elisa]

Just wondering why they didn't follow the discontinuation period for more than 1 week????
http://www.presseportal.de/story.htx?nr=740512

Amsterdam, The Netherlands (ots/PRNewswire) -

- Valdoxan(R) (agomelatine) Provides Antidepressant Efficacy With
the Additional Clinical Benefit of Sleep Improvement With no Effect
on Daytime Vigilance

The first melatonergic antidepressant, Valdoxan(R) (agomelatine),
offers an innovative new approach to the treatment of depression.
Valdoxan combines antidepressant efficacy, even in severely depressed
patients, with an extremely favourable side-effect profile and has
the additional benefit of sleep regulation in depressive patients,
according to new data presented at the 18th Congress of the European
College of Neuropsychopharmacology (ECNP) today. The ability of
Valdoxan to relieve depressive patients' sleep disruption without
affecting daytime vigilance is a key advantage for an antidepressant
medicine as sleep complaints are a very common and disabling feature
of depression.

Antidepressant efficacy and additional clinical benefits

Valdoxan was shown to be an effective antidepressant, by reducing
the initial HAMD score to a similar extent to that of the selective
serotonin reuptake inhibitor (SSRI) paroxetine and significantly
greater than placebo (1). Results from two other clinical trials
presented in Amsterdam show that Valdoxan also has a similar efficacy
to the serotonin noradrenergic reuptake inhibitor (SNRI) venlafaxine,
but not the often observed side-effects associated with the SNRI.
Preliminary results of a specific study comparing Valdoxan (25 - 50
mg / day) with venlafaxine (75 - 150 mg / day) in depressed patients
showed that Valdoxan had a similar antidepressant effect. However,
Valdoxan treatment resulted in significantly better and earlier
improvement in initiating sleep (p<0.001). In addition, a
polysomnography study in depressed patients showed that Valdoxan 25
mg had a beneficial effect on sleep architecture.

"In addition to its effective antidepressant properties, Valdoxan
is the only antidepressant to have a specific action on circadian
rhythms", says Dr Raymond Lam from the Department of Psychiatry,
University of British Columbia, Canada. "It can relieve sleep
complaints in depressed patients without residual impairment and thus
appears to be an innovative, new pharmacological treatment for
depression."

Further studies versus placebo and comparators have confirmed the
antidepressant efficacy of Valdoxan in adults of all ages, including
elderly depressed patients.(1, 2) In addition, Valdoxan has shown
particularly interesting results in severely depressed patients; its
antidepressant efficacy increased as the severity of the depression
increased, including in patients with a HAMD>30, therefore providing
clear patient benefits.

Excellent side-effect profile

Valdoxan has an innovative pharmacological profile; it is the
first melatonergic antidepressant acting as a MT1 and MT2 receptor
agonist with additional 5-HT2C receptor antagonist properties. Due to
this unique mode of action, it does not show the typical side effects
found with SSRIs and SNRIs, in particular sexual dysfunction and drug
discontinuation symptoms(i), two common side-effects that patients
find particularly troubling.

A trial comparing Valdoxan with venlafaxine showed comparable
antidepressant efficacy of both treatments, but significantly less
sexual dysfunction with Valdoxan. In addition, a placebo-controlled,
double-blind study comparing Valdoxan with paroxetine showed that,
after one week of treatment discontinuation, no signs of
discontinuation symptoms were seen in the Valdoxan group compared to
significant discontinuation symptoms in the paroxetine group.(3)

A new and effective approach to depression treatment

Patient acceptability of antidepressants is a major concern and is
still one of the unmet needs in treating depression. Special emphasis
has been given to the acceptability of Valdoxan throughout its
clinical development programme, in particular its effect on sexual
dysfunction and drug discontinuation symptoms.

Valdoxan was discovered and developed by Servier. The drug is
currently in Phase III trials and a registration dossier for an
indication in major depressive disorder (MDD) was submitted to the
European Regulatory Agency (EMEA) in 2005.

(i) Discontinuation symptoms occur when treatment with certain
antidepressants (mainly SSRIs and SNRIs) is stopped. They can include
nausea, headache, dizziness, sleep disturbances, anxiety and
irritability.

[Delynbetter]

Just wondering why they didn't follow the discontinuation period for more than 1 week????

Oh, you know that answer! Those are when the results appear that they don't want anyone to know about!

[elisa]

Originally Posted by notdelynwell

Oh, you know that answer! Those are when the results appear that they don't want anyone to know about!

Exactly!!

[Sage]

Amsterdam is the LAST place on earth that I would trust studies of a drug!!!

[elisa]

Originally Posted by Sage

Amsterdam is the LAST place on earth that I would trust studies of a drug!!!

For me it would be Denmark, the country where the antidepressants were "born".

Clinical trials are conducted and paid for by pharmaceutical companies so it doesn't really matter where the studies originate from or where it was published.

[Buxy`s Back]

when are these peeps gonna stop trying to play god ,,,im sooooo damn angry

[zappelina]

The sad truth is they will never stop trying to play god and I know which god they worship, his name is mammon!

[sheacarney]

a placebo-controlled, double-blind study comparing Valdoxan with paroxetine showed that, after one week of treatment discontinuation, no signs of discontinuation symptoms* were seen in the agomelatine group compared to significant discontinuation symptoms in the paroxetine group.2

WOW!!!!! Now THERE'S a longitudinal study if I've ever seen one! One week of treatment and no discontinuation syndrome??? BRAVO! Of couse, the poor people who took the Paxil didn't do too well........anyone surprised?

-Shea

PS-Valdoxan is a new melatonin agonist. It will help the depressed get some sleep. I'm sure insomnia would never occur following discontinuation.

[sheacarney]

Oh, wait, perhaps they mean one week following discontinuation................another long term study, by Big Pharma standards.

GET THOSE DRUGS OUT THERE!!!!

[genevieve]

you know what makes me laugh the more?
when I see a study that goes like this
"there has not been any evaluation for this drug in a long term study (more than 10 weeks)"

they consider 10 weeks long term!!!! when we know most people on AD stay on them for years!!! often 5 years or more!!!!

hum...what a nice bunch of guinea pigs we are!

[rdjanis]

That is exactly it, they market to the public and use the public as guinea pigs! Then when the poor results come in.... to much money being made better burn those results..... disgusting!

[elisa]

Well, I tried the regular over the counter Melatonin for a day or two and felt sick. After discontinuing it, I felt better.

It really doesn't say how long the trial lasted. It just mentions results of discontinuation symptoms, one week after stopping both.

[roy100]

This new AD has been aproved for market in Europe, finallly after been rejected once.

Probably next year in the USA ,after the FDA aproves it.

According to them very little side effects.

Will see, .!

[LCrawford67]

I merged these two threads, as they're the same topic. Interesting to see that after three years and at one rejection, it's being put out there.

I wonder what further "evaluating" they've done since this thread started.

[altostrata]

Thanks for combining the info, LC.

[LCrawford67]

Originally Posted by altostrata

Thanks for combining the info, LC.

You're welcome!

[TryingtoGetWell]

I've also been noticing a lot of airings recently of an Abilify TV commercial that says "if your antidepressant alone isn't doing enough" or something to that effect.

I've been concerned that may be because a lot of people are going into poop out (or have ripped through all the other options and doctors are hoping for a new "magic bullet").

It's been on my mind that doctors will be turning to anything new when they've run out of bunnies to pull out of their hats... Here we go again, I think.

[Songbird]

What is weird is that agomelatine is a serotonin antagonist, so if we are all depressed and anxious from low serotonin, as some would have us believe, then you would expect this drug to have the opposite affect to paroxetine. It shows that they don't really understand how serotonin and other neurotransmitters work. I think they just make something and then try it out to see what it does.

[WendyHasReturned]

oh goodie another one created. the latest moron to create this kind of drug should bend over and shove it up his whazoo.

[altostrata]

(Mods, could you retitle this "New and Improved" Antidepressant -- Agomelatine ? That way it could be found in search. Thanks.)

Looks like phama is gearing up for marketing this one -- several papers have been published recently.

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/1...t=AbstractPlus

J Psychopharmacol. 2008 Sep;22(7 Suppl):9-12.

Innovation translates into antidepressant effectiveness.
Goodwin G.

University Department of Psychiatry, Warneford Hospital, Headington, Oxford, UK. guy.goodwin@psych.ox.ac.uk.

Abstract Unipolar depression is a major cause of disability in developed societies. There is significant unmet need because existing treatments are neither as effective nor as free of adverse effects as we would hope. Agomelatine is a new antidepressant with a novel profile of pharmacological action. Its efficacy in major depression has been reported in short-term placebo-controlled trials and in direct head-to-head comparison with existing products. The pooling of data from the agomelatine short-term studies allows analysis of sub-groups within the study populations. There is a trend for a larger effect size to be seen with more severely ill patients as a consequence of placebo responses falling. Efficacy is also reported in the maintenance of effect seen after clinical response in a recently completed relapse prevention study, analysed initially after 6 months. What is unusual, certainly compared with the selective serotonin reuptake inhibitors (SSRIs) and venlafaxine, is the clear absence of an excess of early relapses soon after agomelatine withdrawal. This parallels the absence of an immediate withdrawal effect seen in the pattern of subjective symptoms in another study. It underlines the distinct and novel pharmacological properties of the product, and has evident clinical advantages for the patient. Agomelatine is well tolerated in other respects; only occasional dizziness emerges at significant rates higher than with placebo in the controlled data.

[altostrata]

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/1...t=AbstractPlus

J Psychopharmacol. 2008 Sep;22(7 Suppl):19-23.

Treating each and every depressed patient.

Kennedy Sh.

University Health Network, University of Toronto, Toronto, Ontario, Canada. sidney.kennedy@uhn.on.ca.

Abstract Major depressive disorder (MDD) is a prevalent condition with substantial heterogeneity in terms of clinical symptom profiles, overlapping syndromes and degree of severity. The challenge for any new antidepressant is to demonstrate efficacy across the spectrum of patient subpopulations with a diagnosis of MDD. The anxious depressed patient historically has a lower rate of response to traditional antidepressants and high pretreatment anxiety symptoms have also been shown to increase the risk of recurrence. In addition, severity based on standard antidepressant rating scale scores influences treatment outcomes. Some antidepressants display greater placebo separation at higher levels of severity while others fail to separate from placebo in more severe populations. Gender differences in antidepressant response have also been reported in several studies. In particular, women appear to experience a greater side-effect burden with current antidepressants. This is also important in treating late-life depression, where elderly patients are more prone to experiencing side effects and drug interactions. Despite the improved tolerability with SSRIs and other novel antidepressants, restoration of healthy sleep patterns has frequently been lacking. Finally, antidepressant efficacy must include demonstrated relapse prevention during placebo-controlled drug discontinuation trials. As a novel antidepressant with melatonin receptor agonist and 5HT(2C) antagonist properties, agomelatine has demonstrated efficacy in randomized placebo-controlled trials. Additional analyses support the benefits of agomelatine in anxious depression, increasing efficacy with greater baseline severity, including severe late-life depression. Agomelatine has also demonstrated favourable tolerability and efficacy in separate analyses of women and men and displays successful relapse prevention at doses 25 and 50 mg. Both subjective and polysomnographic measures of sleep support increased sleep efficiency and decreased awakenings during agomelatine treatment. Combining these efficacy data with favourable effects on sexual function, CNS and GI systems, there are grounds to endorse the view that agomelatine is a well-tolerated and efficacious antidepressant for a diverse range of depressed populations.

[altostrata]

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/1...t=AbstractPlus

J Psychopharmacol. 2008 Sep;22(7 Suppl):13-8.

Addressing circadian rhythm disturbances in depressed patients.

Lam R.

Division of Clinical Neuroscience, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. r.lam@ubc.ca.

Abstract Desynchronisation of normal circadian rhythms, including the sleep-wake rhythm, is common in major depressive disorder (MDD). The association between sleep disturbances and depression has long been recognised. Disturbed sleep is a diagnostic criterion for MDD, and insomnia commonly precedes the onset of symptomatic mood disorders. Disruptions of the sleep-wake cycle (sleep architecture and timing) are residual symptoms that may prevent the attainment of high-quality remission and delay recovery from MDD. Therefore, early recognition and treatment of sleep disturbances may be important for the treatment and prevention of recurrent depression. Evidence suggests that melatonergic (MT(1) and MT(2)) and the 5-HT(2C) serotonergic receptor subtypes are important modulators of circadian rhythmicity. Agomelatine is the first melatonergic antidepressant; an agonist of melatonin MT(1) and MT(2) receptors, with additional antagonist properties at the 5-HT(2C) receptors. Agomelatine combines antidepressant efficacy including quality and efficiency of sleep, with a more favourable side-effect profile than current antidepressant treatments, including neutral effects on sexual function, bodyweight and the absence of discontinuation symptoms. These positive features provide a novel approach to the treatment of depression and the attainment of high-quality remission in MDD.

[TryingtoGetWell]

Originally Posted by altostrata

...Abstract Unipolar depression is a major cause of disability in developed societies. There is significant unmet need because existing treatments are neither as effective nor as free of adverse effects as we would hope...

I find these two sentences extremely telling.

Very often I get on my "soapbox" about how our society has gotten horribly off-course and no longer meets human needs in too many ways. But the idea of having people a pill because our society needs a major overhaul is insane to me.

And very significant to me that they openly say that existing treatments lack effectiveness and have more adverse effects than they want. So why do doctors still say what we go through isn't from the meds???????

Wow.

[Samalabear]

New and improved -- yeah, that's what they said about Prozac and then Zoloft and then Paxil was safer and better than both of those -- so my doc said. Right! Believe me, there are days when I would like a magic bullet to get rid of the anxiety, depression and sleep problems I've still been left with. But I know better. There is no such thing as a magic bullet. It's time to stop ****ing with the brain. Playing God, indeed.

[PhilRS]

Hi there,

I've just come over from our german ADFD site, which is a project similar to paxilprogress for central europe - to check what You have about Agomelatine here on our big sister site. I was doing some private research on that drug since I found out that a med school friend of mine was an investigator in an agomelatine study in Berlin, and she reported "strange" behaviour of the manufacturer's employees there (first I got it wrong, I have still to correct statements in that thread over there). Over the past months, I attempted something that turned out to be the most extensive review on Agomelatine in the web, including the negative data, it is in our wiki and, unfortunately, written in German.

I don't have the time&energy to translate it, but at a glance - I have reason to believe that Agomelatine is a big scam. The approval in the EU had scandalous circumstances, but that's left for future articles by bloggers or investigative journalists.

For the moment only some remarks about the withdrawal study mentioned above.

So, according to the manufacturer's marketing releases and bogus journal supplements, Agomelatine has no risk for withdrawal symptoms. This claim is based on that single study and also cited by EMEA regulators. But has any of them understood the thing at all?

The study was enrolling 335 patients, 167 to AGO 25mg/d and 168 to PAR 20mg/d for 12 weeks. 88 AGO patients and 104 PAR patients achieved remission after 12 weeks and were randomized to withdrawal ("Paroxetine was given at the minimum effective dose and therefore abrupt discontinuation was considered justified"). Here it becomes strange: "27 patients discontinued agomelatine on to placebo, 61 patients continued agomelatine" where we would expect a chance distribution of 44:44. For PAR the ratio was 43:61. The authors blame this on an external firm who did the randomization.

Assessments used the DESS. Patients who discontinued PAR experienced significantly more DESS symptoms than those continuing on PAR (7.3±7.1 vs. 3.5±4.1, P<0.001), no surprise I guess. Those on AGO did better, it seems: 3.0±4.2 DESS points for those discontinuing and 4.4±5.7 for the continuing, a moment please - yes, a decrease. That's by the way exactly what was mentioned by elisa 3 years ago for melatonin

I tried the regular over the counter Melatonin for a day or two and felt sick. After discontinuing it, I felt better.

Spurious, of course, since in this study here P was 0.250. How would it have been with equal randomization (I'm no statistician, sorry)?

But wait, what did it say - all patients had 3 or more DESS points anyway. 4 pts or more make a discontinuation syndrom according to the original DESS authors (Rosenbaum et al 1998*) and 3 points are enough for the diagnosis according to Tint et al 2008*. What do the manufacturer's authors make out of it? "For example, it is not unusual to obtain endorsement of three or four symptoms on the 43-item list even when no discontinuation has taken place. This casts doubt on the validity of the definition of a discontinuation syndrome characterized by a minimum of four symptoms on the DESS as proposed by Rosenbaum et al." Let's take the result we need and explain away the rest by dismissing our outcome measure? A shame for a scientific paper.

May be it would have been a better idea to examine the original DESS and subsequent publications. Those clearly measure the increase in DESS points during withdrawal, to avoid this recall bias. This means You have to do a baseline assessment, which Servier's paid doctors did not do, or at least they did not report it. In other words, this whole study here was biased by design and could not have any useful results. But it put a number of patients on PAXIL withdrawal.

In the end, this adds up to the pile of bad studies and scam publications I have read on Agomelatine, which is probably a problem drug, if You look at liver toxicity for example. But sure we will go through all the well-known steps of an unfolding scandal after the approval I suppose.

Best wishes in any case,
Sincerely
-PhilRS.

*correct cited sources upon request/-PhilRS.