Friday, December 15, 2006

Could Agomelatine be the Ideal Antidepressant?

The above title is from a journal article (Pandi-Perumal et al., 2006). I’ve not been able to track down the actual article yet, but even asking if something could be “the ideal antidepressant” in a journal article title is patently ridiculous. If a medication caused remission of symptoms in 100% of patients with minimal side effects, it would be ideal. But maybe we've finally cured depression -- perhaps agomelatine really does magically cure depression. Let’s take a look...

The data: I found one study from which I could estimate the treatment estimate based on the abstract (Kennedy and Emsley, 2006). Here’s what the abstract said, in part: “The efficacy and safety of flexible dosing with the antidepressant agomelatine (25-50 mg/day) was evaluated in a 6-week, double-blind, randomized, placebo-controlled study involving 212 patients who met Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria for major depressive disorder-current major depressive episode. Patients receiving agomelatine (25 mg and 50 mg/day) had a significantly lower mean Hamilton Rating Scale for Depression (HAM-D) score at endpoint compared with those who received placebo (14.1 +/- 7.7 vs. 16.5 +/- 7.4, p = 0.026)” Based on these means and standard deviations, I come up with an effect size of .31, which is considered small. A small effect does not make for “the ideal antidepressant.”

Duplicate Publication Watch: Read the abstracts from these two articles (Montgomery, 2006 and Kennedy and Emsley, 2006). I reproduced a segment from the Kennedy/Emsley abstract above and here’s a piece from Montgomery’s writing below:

“In a recent placebo-controlled study, 212 MDD patients were randomly assigned double-blind to receive placebo or agomelatine 25 and 50 mg/day. There was a significant advantage for agomelatine after 6 weeks according to scores on the Hamilton Depression Rating Scale (HAM-D) (P = 0.026) and the Clinical Global Impression Severity (P = 0.017), with an improved response rate (P = 0.03).”

Look familiar?

More hype: Montgomery’s abstract closes with: “Agomelatine may fill the gap in the current therapeutic armamentarium by combining efficacy with a favorable tolerability profile and additional clinical benefits.

I have not seen the tolerability-related data, but I see not one shred of data to support “additional clinical benefits," unless he's referring to potential improvement in sleep. But if we're thinking of clinical benefits in the manner of better reduction of patient symptoms, there is simply no data to support that assertion. The "gap in the current therapeutic armamentarium" is that current treatments are not much more effective than placebo (as demonstrated by agomelatine), and they have notable side effects. When SSRIs and atypical antipsychotics emerged, they were considered to be much safer and better tolerated treatments than their predecessors and we now know that is not the case. Does this new “ideal” drug have a better safety profile? We had better wait and see before jumping on yet another bandwagon for a treatment that is overly hyped.

By the way, I tried to find more clinical trial data on this drug from the Novartis website, but their clinical trial register was not functional at the time.


Anonymous said... had a chance to read this 'patently ridiculous' journal article yet?

What is the remission rate for non-pharmacological and COMBO theray for depression? Would you rather call such treatments as 'ideal' treatment? Did the authors 'allude' agomelatine as an ideal antidepressant or you 'assume from the title' it without reading or justifying your claim? Was it written by industry funded experts?

With your clinical experience, do you actually think a remission of 100% is possible without any adverse side effects for any kind of therapy for depression?

I would appreciate your follow-up postings on this topic that would generate serious discussions.

CL Psych said...

No, I've not read the article. From the abstract alone, I made a calculation of the effect size of treatment versus placebo. The effect was small. The title of the article asked "Could agomelatine be the ideal antidepressant?"

I did not call the article "patently ridiculous" -- I said that the tile was "patently ridiculous" and I stand by that assertion given that the drug was not much better than a placebo.

I don't know of the funding source of the authors; I've not looked into it.

Of course a 100% remission rate is not possible. Neither is a treatment without any side effects. This is my point -- there is no such thing as an "ideal" treatment (including psychotherapy), so titles of articles should not be asking if the "ideal" antidepressant has been found, especially when the treatment is not much better than a placebo.

I hope that I addressed your concerns. Please feel free to post further comments on the study if you'd like.

Anonymous said...

Dear Bloggers:

The discussions here are somewhat misleading. I personally think there is nothing wrong with the title at all! I think the authors chose an eye catching title that would make the perspective audience to make them read the paper carefully. There is nothing more to it, I suppose. If any such controversial titles happen to appear in ‘Science’ or ‘Nature’, such discussion would not arise. Am I right?

Have you heard of the 'characteristics of an ideal hypnotic’? Is there any 'ideal hypnotic' actually exist in the market? Then why would most if not all scientific papers that discuss on the pharmacotherapy for insomnia highlight the characteristics of an idea hypnotic. Wouldn’t that be wrong? Also, we should remember that the drugs that are being discussed in any such articles are NOT ideal hypnotic. No author would make any such claim.

Similarly, when it comes to this paper; you should think along this line, and disregard any negative or wrong interpretation of the connotation made by the authors. We wouldn't know the exact reason why such title was chosen over others by the authors if we actually didn't read the entire article and their interpretation of the subject. Perhaps the title could be very appropriate for the discussions and claims made by the authors.

I went one step further and ran a quick ‘Pubmed’ and ‘Google’ search. All I can say, the authors are qualified and well established researchers in their own right. Considering their academic and research background of the authors, I am sure, they know what they are talking about!

In fact, from my personal opinion; the alluded title here was a question posed by the authors to the audience of this paper and cannot be considered as a statement.

Anonymous said...

could someone tell how this drug work?

CL Psych said...

OK, I'll track down the article and then I'll let you know what I think about the title. I was certainly not expecting that the title of the article would become such a huge bone of contention, but I suppose that half the fun of having a blog is the surprise at what gathers comments and what does not.

Anonymous said...

I've been following the research on agomelatine closely. It's a promising drug. It does not work for everyone ... indeed the rate of response may be no better than previous antidepressants. However it does have some specific benefits and a good side effect profile. It has a particular benefit on sleep and circadian rhythms which are disturbed in depression. It may be beneficial in sleep disorders and circadian rhythm disorders as well.

Agomelatine has a good side effect profile. It seems to have few or no side effects relating to sexual function which is a problem with many current antidepressants.

It also has a good anxiolytic effect.

Ideal antidepressant? Well, that's a big claim. If it doesn't work for a particular patient it's not ideal for him or her, obviously. But a good case could be made that if agomelatine works for someone it could be their ideal antidepressant due to it's low side effects and ancillary benefits.

Keep in mind that with each new antidepressant, a certain percent of formerly treatment-resistant patients now can be treated. This is less the case with "me-too" drugs. A new SSRI would not help all that many patients (but might help a few). However agomelatine is not a "me-too" drug. Its mode of action -- a combination of melatonin agonist and 5-HT2 antagonist -- is unique. It may be a real help for some patients.

It did not get approved on the first round in Europe for reasons unknown - perhaps a need for more evidence of efficacy - and is being resubmitted. It's now in phase III in the US from what I hear.

It looks like a good attempt at a truly innovative drug. The ultimate outcome is not yet known, but such attempts should be encouraged.

(I have no financial interest in this drug.)


CL Psych said...

Hi Jim,

I am in the process of tracking down more research on agomelatine. You are correct that at least it's not yet another SSRI. From the data I've seen, efficacy seems modest, but I can't say that for certain until I've read a bit more.

We'll see what happens regarding the safety profile. When SSRI's and atypical antipsychotics were new, the word was that their safety/side effect profiles were a big improvement, and we know that did not turn out to be true.
Agomelatine's initial safety data look good, but I'm not ready to jump on the safety bandwagon for it quite yet.

More to come. Thanks for your comment.

Anonymous said...

REALLY late on the bus with this:

"The efficacy and safety of flexible dosing with the antidepressant agomelatine (25-50 mg/day) was evaluated in a 6-week, double-blind, randomized, placebo-controlled study involving 212 patients who met Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria for major depressive disorder-current major depressive episode. Patients receiving agomelatine (25 mg and 50 mg/day) had a significantly lower mean Hamilton Rating Scale for Depression (HAM-D) score at endpoint compared with those who received placebo (14.1 +/- 7.7 vs. 16.5 +/- 7.4, p = 0.026)”"

Six weeks is barely over 1 month - how is that enough time to determine long-term use? Not only that, I think 212 patients are pretty meager.

I don't know how old the clinical trials was, but I'm curious to know the drop-off rate and how many relapsed a year later.

Anonymous said...

I am enrolled in agomelatine trial, needless to say this drug has turned my life around. Because of agomelatine I no longer have major depression. Before agomelatine I was treated with SSRI's. Agomelatine is far better than SSRI's and has no side effects.

Anonymous said...

Would you please be so kind to let us know more of your experience with agomelatine if you have been enrolled in a trial?Thank you very much.

Anonymous said...

Currently am using agomelatine since it available here in Ukraine where I am from. It works very well for me and my bad sleep habits too. I was very depressed before and am no longer after 2 month using Melitor which is good drug. My English poor sorry, had my friend from USA help translate my message and post this for me.

Anonymous said...

I've had a severe case of free-running delayed sleep phase syndrome for most of my life (I am 27 now), which has resulted in OCD and depression. I have taken Effexor in the past which helps with all of this, but I have never been able to tolerate it's sexual side effects. The idea that there is a drug now that is supposed to work as an antidepressant without these side effects, and that works directly to correct circadian rhythm disorders sounds completely ideal to me. I really wish I could have this now in the USA because it would completely change my life to have a working treatment for my condition.