"New and Improved" Antidepressant - Agomelatine

[PhilRS]

Dear [altostrata],

they did not look for the discontinuation syndrome in that study. Their claim is based solely on the observation that there were no early "relapses" after replacing agomelatine with placebo. It is a shame they put in into the abstract and even in the title of their article - but hey, that's simply marketing-driven research and publication.

On the other hand, it's nice to see some researchers writing clearly that to this date there is no real evidence for any protective effect of antidepressants against relapse, since all the results of those discontinuation studies are biased by withdrawal effects. This is known for a long time to honest scientists but not covered by guidelines. As some had put it straight:

(cited there from Cornfield(11))if important alternative hypotheses are compatible with available evidence in investigations of causal relationships, the primary research question is unsettled, even if the observed association is established from a comparative randomized clinical trial.

In other words, scientifically there is no proof that antidepressants protect against depressive relapse. And the Agomelatine case is also very unclear at this point... there would be a lot to say about this study alone, some examples:

- This Servier study with the internal code CL3-041 was crucial for approval in the EU. It was not included in the first EMEA application for VALDOXAN, which subsequently failed, particlarly due to lack of long-term efficacy.
- It was only registered (and subsequently published) after it became clear that it had some positive results. The definition of "relapse" therein was somehow unusual, since it included patients that had to quit because of "lack of efficacy".
- There was another long-term trial, CL3-021, which remained unregistered and unpublished, it was included in Servier's first application. That trial lasted a few weeks longer and had negative results - placebo was numerically better than agomelatine at endpoint. It used the classic relapse definition without that strange extension and can be found by digging through the European Assessment Report.

So... Which one should we trust? Don't bother, Servier's authors did the decision for You already. Publication bias as usual.

----
And so on.There is immense misinformation out there about Agomelatine, especially on the internet and in the journals. The central points are:
- That it would be sleep-inducing without daytime drowsiness (easily falsifiable, but some beliefs about melatonine itself are very popular and used to promote Agomelatine, too).
- That it has less side-effects than other antidepressants. That already turned out to be wrong, but is hardly noticed. It's liver toxicity alone should by the way prevent any doctor from prescribing it, but in Germany and other european countries it is given out like candy at the moment.

I think I'll leave it at this, unless some of You are interested in more details about this "Life-Threatening Placebo". There will be a bigger rumble when it is withdrawn from the market - which is not so unlikely, since the safety problems that came to light during the EU approval process are hitting now a bigger patient population.

Best regards
-PhilRS.

[guitar77]

This is all just sickening. I can't imagine what the withdrawal off of a med like this might be -- never sleeping again??

I'm also curious to know the half-life time; if it's like Prozac or Valium then the withdrawals probably wouldn't hit hard until after the 1 week mark or so.

And I agree with y'all on the "long-term" reference; considering most psychs recommend a start-up time of 4 to 6 weeks just to see if your AD might work, these things are theoretically just getting started right before the study ends.

Nice.

[PhilRS]

Here is what they wrote:

However, in the present study, no separation of agomelatine from placebo occurred before 6 weeks of randomized treatment. Instead, a gradual accumulation of excess relapses over the whole observation interval was the pattern for patients switched to placebo compared with those patients continuing on treatment with agomelatine. The contrast with the abrupt appearance of relapse reported with other antidepressants is striking.23–26,28 Indeed, the previous classical pattern showed the active treatment and placebo curves separating as soon as the first month following randomization so that most of the final placebo-active treatment difference is achieved at that time.23–26,28

A skeptical observer could attribute this finding to the confounding effects of withdrawal phenomena prominent with some other antidepressants.23,29,30 All currently available antidepressant agents, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors, and atypical agents, such as venlafaxine, mirtazapine, trazodone, and duloxetine, have had case reports or warnings from their manufacturers of reactions occurring in response to either abrupt discontinuation or medication tapering.31 These discontinuation symptoms appear rapidly, typically within 3 days of stopping antidepressant medication, and what may appear to be a depressive relapse could actually be a discontinuation syndrome.31 In relapse prevention studies of escitalopram and duloxetine, the placebo group and the active treatment group separated as early as 1 month after randomization, at a time when a great number of adverse events were reported.23,25,28 Adverse events could increase the risk of a true relapse or subvert the blind and inflate the true relapse rate.

Tapering may lower the incidence of discontinuation symptoms,32 but, again, most of the final placebo-active treatment difference appears to be achieved at 6 to 8 weeks. Thus, the pharmacology of these compounds may lead to a transient depletion of key neurotransmitters, analogous to the effects of experimental monoamine depletion. For example, there is speculation concerning the possibility of a temporary deficiency of synaptic serotonin with abrupt withdrawal of an SSRI.33 This is believed to result in antidepressant discontinuation syndrome directly or indirectly via downstream effects on other neurotransmitter systems implicated in depressive disorders (eg, norepinephrine, dopamine, and γ-aminobutyric acid). With such a remodelling of neurotransmitter systems, the medication tapering would not help so much. Such depletion effects may be seen as provoking a true relapse, obviously to the disadvantage of the patient. The existence of such effects with the commonly used antidepressants is not encouraging for a field already beset by controversy.

- Since skepticism is the basic attitude of any good scientist/researcher, this means in plain text that all antidepressant withdrawal trial results are unreliable.

----
Dear [altostrata], I know the Deshauer study, and, hm well, I'm quite a specialist for antidepressant trials. Was just preparing a lengthy post - ended up with a bluescreen. If I find the time tomorrow, I would put a nice piece of information ... into which thread? What would be the best place inside paxilprogress, don't want to misuse our Agomelatine thread.

Sincerely
-PhilRS.

[PhilRS]

Found it, sorry for the last stupid question. It was late here in Finland.

[PhilRS]

Sorry that I'm late! I was in Germany, which is always very depressing.

In #33 I cited the Goodwin et al. Agomelatine relapse prevention paper.

These Servier-paid authors say that in "relapse prevention" studies the difference between antidepressant and placebo mainly stems from early relapses, ocurring in the weeks after the antidepressant was replaced by placebo. Those are caused by discontinuation symptoms, or the "relapse" is simply the misdiagnosed withdrawal misery.

And they claim that because there were not so much early relapses with Agomelatine, this new drug would be different from all the other antidepressants (competitors). But, as I mentioned already, they did not look for discontinuation symptoms in their study.

- You made some very good points in Your letter to Dr Goodwin (I do not expect him to answer, anyway.)

In the end, it is as with all the other relapse prevention trials: If the researchers do not look for withdrawal signs, they will not find them. In return they get "Level A evidence" to include in reviews and guidelines.

******

By the way, 'Dave' from The MacGuffin made some interesting remarks about VALDOXAN: Check out the parts 1, 2 and 3.

He missed out on certain points, but, more important: He took to some extent unpublished data into account (which is normally ignored by most commentators).

I'm still unsure if I leave some comments at his blog or if I translate my extensive VALDOXAN review into English. My conclusion made in December 2008 was: clearly more risks than benefits, which was confirmed in the meantime by other independent reviewers.

Sincerely
-PhilRS.

[PhilRS]

By the way, the data from the US agomelatine studies are available from the Novartis clinical trial registry, since Novartis made an unprecedented step and is putting all the results online, even for their failed or not(yet) approved drugs.

Agomelatine failed against Paxil, and was even statistically significantly (!) outperformed by placebo on the remission endpoint in one study. It did not protect against "relapses" in the long-term study, but has deleterious effects on the liver, as shown consistently by liver enzyme increases in >5% of study participants when taken over longer periods.

Now it's clear why Novartis was reluctant to send a NDA for agomelatine to the FDA, and, according to clinicaltrials.gov, they are only testing sublingual tablets with max. 1mg now, hoping for less liver damage.

It really does not look like the European VALDOXAN 25/50mg will someday become available in the US. And it seems unlikely at the moment that any agomelatine formulation could be approved, because they set up only 2 efficacy trials (with one from the EU unpublished), and the failure rate for antidepressant trials is rather high (>50%), which held true in the former trials of Valdoxan in Europe.

Sincerely,
-PhilRS.

[PhilRS]

It will not come to the US market, due to weak efficacy and potiential lethally side effects. Novartis dropped it and did not even try to submit it to the FDA.

So, for this time, you are saved ... "Amerika, Du hast es besser"

(and I was right )

BR
-PhilRS

[Lexaprotoblam]

I take it. its pretty pissweak at 25mg. but 37.5mg gives me zoloft type leathargy. As for sexual side effects, as little as 5 months on lexapro is still giviing me ongoing post ssrisd, 10 months after ive stopped. Ive taken about 4 anti d's and lexapro for some reason caused this....
anyway valdoxan has hardly any side effects at lower dose of 25mg, but it doesnt do much....i have no idea why its a wonder drug, but if it doesnt cause sexual side effects i guess it is.

[pax80]

This drug is already out there in europe, but it's an expensive melatonin pill and does nothing, doesn't even cause withdrawal.