Tuesday, October 27, 2009

Valdoxan: The Ideal Anti-Depressant Part 2

If you have not read my first post on agomelatine, do so now (1).

This is my usual shtick wherein I review research articles and crap all over them. The main questions I am seeking to answer through the next series of posts are:

Is agomelatine superior to SSRI anti-depressants? And,

Does it have a more tolerable side-effect profile?

Before I address those questions through the available literature, I want to bring a certain bias to everyone's attention. The bias is not mine, but rather Stuart A. Montgomery's bias.

"Who's that?"

Have you heard of the Montgomery-Asberg Depression Rating Scale (MADRS, 2)? It's that Montgomery. Here is a brief biography (3). Here is the important part: "Dr Montgomery is editor of International Clinical Psychopharmacology and editor of European Neuropsychopharmacology. He also serves on the editorial board of 18 other scientific journals." I point this out because much of the published research (including his own research) on this drug just happen to be in the two journals for which he is the editor (4, 5, 6, 7, 8, 9, 10). A siginifcant portion of these articles were published in supplement issues (i.e., pharma sponsored). He is also a "consultant" for the company (Servier) that manufactures the drug. For you lay readers, this is our much cherished "peer-review process" at work.

The Research: Part 1

The first published study demonstrating general efficacy for major depressive disorder (MDD) was in 2002 by Loo et al (10). In this study different doses of agomelatine (1, 5, and 25mg once a day) were compared to paroxetine (20mg) and placebo in people with MDD for 8 weeks.

Here are the results:
There were more patients in remission on agomelatine 25mg and on paroxetine compared to placebo. No statistical comparisons were done between the two active drugs. Here is a finding I saw quoted in almost every article I read hereafter, "25mg of agomelatine was significantly better than placebo at 2 weeks..., whereas this significant advantage for paroxetine...did not emerge until 4 weeks." I've circled the area on the graph this is in reference to:
Here are the results for severely depressed patients:
Here are the common side-effects:
Overall, both drugs were superior to placebo. Compared to severely depressed patients (i.e., HAM-D score >25), only agomelatine was superior to placebo. Patients on agomelatine 25mg responded sooner than paroxetine. Paroxetine had more side-effects when compared to agomelatine and placebo, with a significant difference for nausea. Neither drug was associated with a high incidence of sexual dysfunction.

Comment: I'm not seeing anything here that I would call a major breakthrough. The HAM-D standard deviations are pretty large (+/- 8 points or more) so there is a lot of variability in individual patient performance (common in AD clinical trials), which limits the generalizability of the study results. I wonder how both drugs would have compared to an active placebo (11). There are not too many differences in reported side-effects except for nausea. I would have expected a far worse side-effect profile for paroxetine given agomelatine's short-half life compared to paroxetine's 24hr half-life (agomelatine patients supposedly will sleep through any acute side-effects).

This study had a one-week placebo wash-out period (which they refer to as "placebo run-in"), which biases the study against placebo. The patients (including the severely depressed patients) were not actually that severely depression, "mean duration of current episode before inclusion was 4.8 months." I can't remember the last time I saw a depressed patient with an episode duration that short.

During the study, two participants committed suicide (congrats to the researchers for reporting these data!); one on paroxetine after 11 days and one on agomelatine 25mg after 10 days. There were 7 suicide attempts: 1 on agomelatine 1mg, 3 on agomelatine 5mg, 1 on agomelatine 25mg, 2 on paroxetine, and NONE on placebo (does that mean there's no risk of not treating with AD's?).

"Among these, one was an overdose with agomelatine. A patient ingested 18 capsules of 5 mg (90mg) with an unknown quantity of alcohol." This is very important: One major downfall of the tricyclic anti-depressants (TCA's) is that patients could use them to commit suicide. Doctors use to prescribe one weeks amount at a time to prevent suicides. Overdose with SSRI's is extremely difficult. A drug with hypnotic properties, when consumed with alcohol (which is commonly abused in depressed people) might suggest that this drug is contraindicated in suicidal patients; however, there was no mention of this in the article.

Part 3 coming soon.


Loo, H., Hale, A., & D'haenen, H. (2002). Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2C antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study International Clinical Psychopharmacology, 17 (5), 239-247 DOI: 10.1097/00004850-200209000-00004


Bostoniangirl said...

It seems to me that depression is a really heterogeneous condition, and that it's quite possible that agomelatine (or any other new drug) might be better for a subset of patients. Is there any way to test this hypothesis?

Neuroskeptic said...

The side-effect profile of agomelatine does look pretty benign. As you say, this could be because people sleep through the effects. But then, won't they also sleep though the benefits? I suppose not if it really works by "resetting circadian rhythms", but there is no evidence it does, at least not yet.

NeuroPsych said...


Many psychiatrists cream their pants over the idea that certain subsets of depression can be detected and treated with a specific medication.

The reality is, we are a long way from accomplishing that goal (I doubt it will ever happen).

First, our methods of diagnosis are rather pseudo-medical. The DSM is comprised of signs and symptoms. Any biological correlates (as opposed to causes) only apply to minority subsets of depression (For example, atypical depression is associated with hypocortisolism, however, only a minority of atypically depressed patients exhibit this feature).

Also, medication research is increasingly no longer driven by theory, rather marketing (SSRI development was theory driven, atypical antipsychotics for depression is market driven).

Genetics just don't seem to pan out (the SERT gene was refuted earlier this year in a study).

I think people lose sight of the fact that mental illnesses our highly complex. The medical model approach (neurochemistry/specific receptor sites) is a case of "missing the forest for the trees."

Ricky said...

Im on this drug been on it for about 8 weeks at 50mg , i really do not see it as a wonder drug , far from it , for me it has not helped with my depression not at all , and from all the information i have read up on agomelatine (valdoxan) it all says NO sexual side effects , well let me say that is not the case , i can not reach a proper erection so there is something to consider , i heard about all the hype surrounding this so called new wonder drug and could not wait to be put on these tablets , especially because of the so called NON sexual side effects and also because most of the other anti depressants did not work for me , the ones that did work had sexual side effects , so to hear this was eventually available in the UK i was like a kid in a candy store my psychiatrist put me straight on them and all i have to say is pure disappointment , they do not work better for me than any other SSRI , SNRI , TCA's etc in fact like i said before some of the other anti depressants worked a lot better for my depression , but had to stop because of the sexual side effects , now i keep pointing this side effect out because it is a very important issue when you have a partner but not many people will either talk about it or admit it but this needs to be addressed , like i said earlier too , im disappointed in its effectiveness in treating depression , im sorry but in my eyes this tablet (besides the sexual side effects) is no more better than a placebo , i will never hope for a so called wonder drug again.

Anonymous said...

Thank you for such a nice and informative post.

ProVanax - How to safely eliminate anxiety & panic attacks

Carl Farrington said...

Great article.
Ricky: Regarding lost libido. Have you tried augmenting ADs with a dopamine receptor agonist or otherwise boosting dopamine function?
I have tried venlafaxine + amineptine, but the amineptine was expensive (grey market). I will very soon be trying venlafaxine + pramipexole. I'll let you know how I get on. Venlafaxine is super, and totally works for me with panic and anxiety, but it does totally kill one's sex drive :(

Ricky said...

Hi Carl ive never tried augmenting any ADs with a dopamine receptor agonist its news to me that you could , clearly i dont know about that side of things it does seem interesting though ,
Ive just read up about amineptine which is a Tricyclic AD , im currently on a Tricyclic AD at the moment called Lofepramine , which seems to be bringing me a lot of problems so far regarding side effects (it seems you can't win) and its to early for me and any others to notice any difference in my mood maybe im again barking up the wrong tree.

It says that pramipexole can be used to counteract the problems with sexual dysfunction experienced by some users of the selective serotonin reuptake inhibitor (SSRI) antidepressants , Venlafaxine is an (SNRI) so will it help ?

I seem to of been on everthing with different success rates , it seems to me where 1 AD works for depression it also brings a lot of side effects and the ADs that dont bring nasty side effects dont seem to work , you can't really win , i too need help with anxiety and panic attacks its a living nightmare ,
I do hope you get your libido up and running again i really do know how very frustrating it is , its not a nice thing at all , well all the best and let us know how you get on.

Anonymous said...

Hi Ricky, I started on Valdoxan a month ago but have been constantly tired on it and am going to stop now, initially I felt slightly euphoric but fell back quickly. I also met an old friend and had some beers and it took me a week to recover and I also contracted a bad flu, maybe not related at all.... I feel instinctively that it is not for me. I actually started on it due to chronic tiredness and lethargy. I am at a slight crossroads in my life just now and the energy factor was a huge problem. I think I will need to look at possible dietary and exercise solutions.... Any ideas??? Ed