Valdoxan: The Ideal Anti-Depressant Part 3

You can read my previous posts on this drug here (1, 2).

The Research: Part 2

The second study published on the efficacy of agomelatine was by Kennedy and Emsley (2006, 3).

This was a 6-week, double-blind, randomized, placebo-controlled study involving 212 patients. Dosage ranged from 25-50mg/day (dose adjustment at week 2 for poor responders). No other active comparator (e.g., paroxetine) was used in this study. Similar to the previous study (Loo et al, 2002), the efficacy of agomelatine on a severely depressed subpopulation was examine too.

Surprise, surprise, agomelatine was shown to be superior to placebo (HAM-D total score 14.1 +/- 7.7 versus 16.5+/- 7.4). Plot twist: "The proportion of patients who were in remission by the end of the acute treatment period was not statistically different between the two treatment groups." Of course, that could be due to the short duration (6-weeks) of the study.

Remember this quote from the previous study I reviewed: "25mg of agomelatine was significantly better than placebo at 2 weeks..., whereas this significant advantage for paroxetine...did not emerge until 4 weeks." Here is the survival analysis for this study:
The difference did not occur until week 4, the same as paroxetine in the previous study. So this study failed to replicate the result of the first study.

Common side-effects reported include: "dizziness, nasopharyngitis and influenza were more common in the agomelatine group that placebo." Again, no sexual side-effects were reported (sorry, no fancy chart to show).

Part 3:

The third published study was by Olie and Kasper (2005, 4). This study is similar in design as the study mentioned-above. At the end of 6-weeks, there was a superior response for agomelatine compared to placebo (3.44 point difference).

Here is the survival analysis curve for time to first response:
Here, you can see a difference was noted at week 2 (replicating the original result), but then they merge at week 4 (difference was still significant) and then separate again thereafter. What is interesting about placebo temporarily merging with the active drug at week four, is that there was a dose adjustment from 25mg to 50mg for poor responders at week 2. Probably not the robust result they were looking for, but a reaction non-the-less.
Reported side-effects are similar to the previous studies:
Comment: Both of these study are extremely short (6-weeks). 2/3 of depressed patients usually do not respond to their first anti-depressant. Moreover, while response rates (50% reduction in symptoms) are usually robust, remissions rates a paltry (usually 1/5-1/3 remission). No long-term information can be gathered from these two short-term studies. There is long-term data, but it's unpublished.

Side-effect do appear mild. However, many SSRI antidepressant trials show mild side-effects. It's not until the drug is widely prescribe do common side-effects become evident.

All three studies were biased against placebo (i.e., 1 week placebo wash-out period).

Keep in mind that these are published studies of positive trials. There are negative trials that are simply not published (I'm shocked!).

The European Medicines Agency, the parallel to the FDA, initially rejected the drug in 2006 (5).
Here is what they said:
In case you cannot read the image, it says, "The major concern of the CHMP was that the effectiveness of Valdoxan/Thymanax had not been sufficiently shown. The long-term study (the unpublished data I mentioned) did not show that the medicine was effective. The short-term studies shown that the medicine has an effect, but the extent of this did not allow the Committee to draw a firm conclusion on the medicine's effectiveness."

The drug was finally approved in 2008 (6). In their report they list all the submitted trials.

Some highlights:

-In study CL3-22, which included a fluoxetine comparator. This study, which was a short-term with a long-term (1 year) extension found that both agomelatine and fluoxetine were not statistically superior to placebo. (oops!).

-In study CL3-23 agomelatine and paroxetine were not statistically superior to placebo over the short-and-long term. (whoops!).

-CL3-24, the results were identical to CL3-33. (strike three, you're out!).

-Study CL3-21 was a relapse prevention study against placebo. At the end of the trial, agomelatine had a relapse rate of 26% versus 24% for the placebo group (strike four! wait that's not right). They did a post-hoc analysis (i.e., statistical masturbation) and found that only for severely depressed patients there was a statistical difference. The proper thing to do at this point is to run a NEW study to test that intriguing hypothesis since the analysis was done after the fact. (It didn't happen, obviously).

-Efficacy in the elderly was not demonstrated

-Because of concerns over liver toxicity, liver monitoring is required. (do they require that for SSRI's)

Versus other Antidepressants

Much of the hoopla around this drug has been it's supposed superiority against fluoxetine (Prozac). If you head over to the official website, they tout the findings of a recent study (7). But is it really superior? The data submitted to the EMEA showed agomelatine to be equal to SSRI's (2 paroxetine studies, 2 fluoxetine studies, & 2 venlafaxine studies). With the exception of one study where superiority to sertraline (submitted later) was shown. Here's is what the EMEA had to say about the matter:
"magnitude appears less than the active comparators."So that's 2 studies out of 8 that showed a superior effect. There are many studies in the literature that show one antidepressant being superior to another (8). However, results like theses are the exception, not the rule.

The Hype

Based on my review of the data, I'm not seeing much in the way of a wonderful new addition to the anti-depressant family. Aside from liver toxicity, side-effect profile does seem favorable, which is certainly an advantage compared to SSRI's. However, efficacy does not appear any greater than currently available treatments (maybe less effective overall). Just like SSRI's, there are a number of negative trials, so the effect is certainly not consistent.

Furthermore, during my review, I found 6 review articles (see my first post), which rehash the same 3 primary studies over and over again. What's worse, these 6 articles were published within a 3 year period and all in the journals for which Montgomery is the editor. They also read like the democratic party's "talking points" on health care reform, meaning, they all stay on message. That message being "need for better antidepressants" "safety and tolerability" "unique mechanism of action." This strikes me as familiar to the recent trend in second generation antipsychotic articles (9, 10, 11). What I truly enjoyed, though, is the SSRI bashing that was going on in these studies. Last Psychiatrist discussed quite well last year (12, 13).

My Final Verdict

Slightly better side-effect profile, actual clinical efficacy is uncertain.



KENNEDY, S., & EMSLEY, R. (2006). Placebo-controlled trial of agomelatine in the treatment of major depressive disorder European Neuropsychopharmacology, 16 (2), 93-100 DOI: 10.1016/j.euroneuro.2005.09.002

Pierre Olié, J., & Kasper, S. (2007). Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder The International Journal of Neuropsychopharmacology, 10 (05) DOI: 10.1017/S1461145707007766

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

Valdoxan: The Ideal Anti-Depressant Part 1

Have you heard the news? Not only is there a novel anti-depressant with a "unique" mechanism of action on the horizon, it is also more effective than Prozac and with none of the side-effects! (1) What is this new wonder drug? Is it truly the ideal anti-depressant? (2) The new drug is agomelatine (Valdoxan, 3). The questions that should be asked are, does it really live up to the hype? Or is the hype just a marketing ploy?

Pharmacology

First, the boring stuff.

Agomelatine is a potent agonist of melatonin receptors MT1 and MT2 (same as Rozerem). Moreover, it is an antagonist (i.e., blocker) of the serotonin 5HT-2c receptor. Agomelatine is metabolised by the liver and excreted mainly in urine. The drug's half-life (i.e., time it takes to eliminate half of the compound) is 2.3 hours.

The drug is theorized to work in two ways. First, its actions at the MT1 and MT2 receptors are supposed to help "reset" circadian rhythms and improve sleep architecture. That seems simple enough, as melatonin is freely bought at any drug store; however, whether people with depression have a true circadian rhythm disorder (e.g., delayed sleep phase syndrome) or if their insomnia (or hypersomnia) is connected to another biological mechanism (hyper-or-hypo-cortisolism) is a matter of debate (My bias is with the latter theory).

The second mechanism is antagonism of the 5HT-2c receptor. This particular serotonin receptor is a post-synaptic receptor that is mainly found in the choroid plexus (4), cerebral cortex (5), globus pallidus (6), substantia nigra (7), and spinal cord (8). Drugs that affect the 5HT-2c receptor represent a subclass of anti-depressant known as norepinephrine/dopamine disinhibitors (NDDI).

According to psychopharmacology god Stephen Stahl, "Serotonin action at 5HT-2c receptors inhibits both NE and DA release...Drugs that block 5HT-2c receptors have the opposite action and thus disinhibit both NE and DA release." Keep in mind that is has only been demonstrated in rats. It is much harder to prove in humans. Stahl also notes that, "...this action is generally activating and may be why many patients, even from the first dose, detect an energizing and fatigue-reducing effect."

Did anyone pick-up on the drug's paradoxical mechanism of action? It is both a sedative-hypnotic and activating-energizing. I'm not sure how that works out when the drug is supposed to be taken at night (Any patient testimonials?). Also, as Neuroskeptic pointed out to me, "it is also very rapidly metabolised so if you take it at night there's probably none left by the next day..." With a half-life of 2.3 hours, most (but not all of the drug) will have been excreted by the time you wake-up in the morning and almost completely gone by next dosing time.

All anti-depressants have pretty lengthy half-lives (minus paroxetine), and a steady-state blood level is required for the drug to have a consistent effect. Usually it is the rapid shift in blood levels that contribute to side-effect severity (hence paroxetine's problems). With such a short half-life, can this drug truly be more effective? Is our current paradigm of how previous anti-depressants work just plain wrong?

Sleep and Depression

Now, more boring stuff.

Will this drug's action at the MT1 and MT2 receptors contribute to its overall efficacy? I have not been able to find any published studies utilizing polysomnography to measure its effects. Why is it important to test this drug with a polysomnograph? Here are some of the sleep findings in pateints with depression:

Depression is associated with a relative increase in central cholinergic activity compared with monoaminergic activity (i.e., serotonin); cholinergic systems reduce short-wave sleep (SWS) and increase REM sleep.

Initial insomnia is inversely proportional to age: the young do not fall asleep easily and complain of initial insomnia; older adults have trouble with sleep maintenance and complain of early morning awakening.

REM sleep abnormalities may persist after successful treatment of depression; short REM latency and SWS deficits can be familial and are found in relatives of depressed patients who do not have depression. Also, depressed individuals have increased sleep fragmentation; their sleep is unstable.

You might think it wise to discover if the drug actually benefits depressed people by resolving at least some of these problems. We'll see if any of the research addresses these issues.

Another MT1 and MT2 agonist drug on the market, Rozerem (ramelteon) is not very effective. According to the medical letter: "Ramelteon (Rozerem), a melatonin receptor agonist, is not a controlled substance and apparently has no potential for abuse, but its hypnotic effect is not impressive. In clinical trials, it produced small, statistically significant improvements in sleep latency, but had little effect on sleep maintenance." The two drugs have similar melotonin properties and half-lives (2.3 hours versus 2.6 hours) Also, it should be noted that depression associated insomnia is distinct from primary insomnia (i.e., psychophysiological insomnia). Typically, people who have insomnia that is a manifestation of a primary psychiatric illness tend not to respond well to the hypnotic class of drugs. As mentioned-above, the drug is somehow both sedating and activating. It's hard to tell how that will affect sleep quality as well.

In the real world, it is unlikely this property (i.e., MT1 & MT2 agonism) will have a clinically meaningful effect.

Part 2.

"White House advisers say Fox News is not news"

News flash: If this is you're leading news story (CNN, 1), (MSNBC, 2), it's not a news organization either.

Six Biggest Myths about Psychology that Everyone Believes

This is by Angela Peterson (No idea who she is). She requested a plug. So here it is (1).

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