Ask Scicurious: Agomelatine

Sci feels really famous today! That’s because someone actually emailed her to ask her a question!!!! This makes her feel very knowledgeable and wise, even though she had no idea what the person was asking and had to look it up. Anyway, here goes nothing, your very first Ask Scicurious!

t’s me, Juniper. I hope I’m not bothering you.
I would like to please pester you with some questions. In your opinion, is agomelatine as good as it sounds? What about for patients who once responded to NDRIs but no longer do? (Does that last question even make any sense?)
I thought you might be a good person to ask because of your dopamine obsession. 🙂 I found this because I was researching antidepressants to ask my doctor about. It was particularly interesting to me because bupropion is particularly interesting to me. I am always more than willing to read and try to understand PubMed articles, but I don’t have access to the ones about agomelatine. Besides, I really want to know what you personally think.
Just so you know, I’m only asking you out of curiosity. I wouldn’t ever ask anyone but my doctor for medical advice, and you can’t even get this drug in the States anyway. Also: I totally understand if you are way too busy to address my silly questions.
P.S. Objectively, 10 Things I Hate About You is a really bad film. I only think it’s cute because I’m old and nostalgic and I was a teenager in the ’90s.

Hi Juniper!
Fret not. There are no stupid questions or stupid answers. There are only stupid people, and I know from experience you are not one of them. And I know you’re not going to take it as medical advice, I just put that warning on comments and stuff so people don’t take what I tell them as the FSM’s honest trooth when they go to the doctor. You never know.
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(Sci wishes she had FSM powers, but she’s not so lucky)
I have to say I had not heard of agomelatine until just now. So I did a little bit of digging. That is one cool drug (but then, I think cocaine is wicked cool, so take that with a grain of salt…). I had no idea they were marketing melatonin agonists for antidepressants, but I’m also REALLY interested that it’s a 5-HT2C antagonist as WELL! Funky. I blame the double ring structure with the carboxyl hanging off the carbon chain. Never trust those.
So I take it you are dealing with someone who was once a buproprion responder and now isn’t? Or do you want this as compared to buproprion? Buproprion (Welbutrin) is a DAT/NET inhibitor, classic stimulant actually, though not very potent, which is its saving grace. Also an excellent antidepressant for those with atypical depression. Here’s what I can tell you:
Melatonin is a circadian controlling hormone. Right now, there is a small portion of the psychiatric world that is beginning to think that some problems with diseases like depression, drug abuse, anxiety, etc, stem from issues with circadian rhythm control (for some insight into the drug abuse work, you can check out the hypocretin/orexin literature). So the idea is that if you sleep better (with normal rhythm), and have a well-controlled sleep schedule, some issues with depression may be resolved. This isn’t a foolish idea, though it does beg the question of whether the classic sleep disturbances involved in depression are a cause of the disease or a symptom. Still, it’s symptoms that you want to cure, as psychiatric problems are symptoms, not necessarily an underlying cause. And melatonin may have some positive influence on libido (though I don’t know of any real studies that substantiate that), which sounds a lot better to most people than the reduced libido that goes along with the SSRIs.
The 5-HT2C inhibition is what REALLY geeks me out. 5-HT2C is an inhibitory 5-HT receptor, though keep in mind that it’s where the 5-HT receptor is PLACED that determines whether the final result really is inhibitory, if you’re inhibiting an inhibitory circuit, the result will be activation, etc. Interestingly, it’s thought (Adell and Artigas, PDF) that the 5-HT2C receptor mediates most of the inhibitory influence of 5-HT on the mesolimbic dopamine (DA) system. This means that stimulation of the 5-HT2C results in decreases in mesolimbic dopamine, and DA as we all know is associated with hedonic properties of things like psyschostimulants.
So if you were to INHIBIT 5-HT2C…well, it depends on what lit you look at. 5-HT2C agonists can potentiate the rewarding properties of psychostimulant drugs (that’s a PDF, too) in some areas (reduces rewarding effects in others), and may increase dopamine cell firing on their own (via inhibition of 5-HT2C receptors controlling dopamine cell firing in the ventral tegmental area, which contains the DA neurons firing toward the nucleus accumbens, your classic reward and reinforcement area). Off the top of my head, I can think of a few studies showing that 5-HT2C antagonists can help with depressive symptoms (fluoxetine is thought to have 5-HT2C actions), and the dopamine mechanism would be the obvious one to me, though 5-HT2C could also mediate melatonin release directly and enhance that mechanism. Keep in mind, though, that 5-HT2C receptors are located in LOTS more areas in the brain, especially the prefrontal cortex, so I’m only naming the first mechanism that comes off the top of my head.
So what do I THINK…hmmm…Well, if someone is tolerant to buproprion, this is a different mechanism, so it might be effective when buproprion is not. However, keep in mind that it’s only about as effective in studies as Prozac or Celexa, and those are only effective 60% of the time. So it’s not an assurance that it will work at all, and some patients respond very differently from others. So I’d keep that in mind. And it seems pretty new, so I’d want to see how it catches on in Europe first. But I don’t think it’s a bad idea for a new antidepressant target. I’d worry a little about possible side effects of high melatonin, and I don’t know what those might be.
I hope that helps answer some questions!

PS: I KNOW it's bad, but do NOT mock Heath Ledger. Sigh…he was so cute in that movie…I need to keep my 90's nostalgia.
10 things i hate about you.jpg

9 Responses

  1. Hmm.. all this anti-depressant neurotransmitter stuff got beyond me a few years ago- when I look at diagrams of the different types of receptors inhibited or facilitated by different psychoactive drugs, I almost go nuts! as a long-term depressed person I am intrigued by the way brains can be fixed by one agent and not another; also how one drug like fluoxetine can work for years, and then gradually lose it’s good effects, along with it’s nasty side effects as well- how can the rest of the brain work properly when part of the system has apparently habituated to a substance that is needed? Weird stuff- brains are far too complicated to be likened to computers! I have been on an antidepressant roundabout for about 6 years now- I cannot find anything post-Prozac that keeps me OK. I sometimes get a slight perk up for a few weeks or months when started on a high dose of something new, like citalopram, but never get back to the feeling of “normality” I had most of the time on fluoxetine. I had experienced several hours per day of feeling quite perky on the old tricyclics, but the neurological disturbances and frightful constipation eventually forced a neurologist to tell me I should get off them (I needed no encouragement, having had strange episodes of my head suddenly bashing itself to the ground forwards, sideways or backwards, being unable to sit up in bed and uncontrollable nystagmus where people said my eyes boinged sideways continually as I fell towards that side! I never lost consciousness but felt I didn’t own my body!) I must look into bupropion and this new thing that acts on melatonin as I am very much governed by the light part of the day- if it is dark in the morning I get very morose and winters are hell. I even react badly to the start of daylight saving, where suddenly it is dark in the mornings at the same clock time it used to be light! So your investigations on behalf of Juniper have got me a little fired up- thanks for this!

  2. If anyone is curious about how people do on Agomelatine, there’s a google group about people sharing their experience:
    Many are from USA, so clearly some of them found a way to import it from Europe.

  3. Again, Sci, thanks for this post. You rock.

    Many are from USA, so clearly some of them found a way to import it from Europe.

    Apparently, a now-banished troll completely unacquainted with me and therefore unqualified to do so nevertheless used this post as an opportunity to impugn my intelligence. If I weren’t depressed, this would be hilarious. As it is, I’m now irritated and hurt enough to respond with humorless sensitivity to even the unrelated comment above:
    Obviously, any motivated American can find a way to obtain pharmaceuticals not yet approved by the FDA but approved for European markets. Obviously, people all over the world find ways to illicitly or illegally obtain all sorts of drugs. I wrote what I did because I have little interest in taking antidepressants not readily prescribable to me by an American physician. I was writing from the perspective of someone who probably must stick to choosing from antidepressants reviewed and approved by the FDA. That’s all. The next time I write a letter to a Seed blogger for public consumption, I won’t write so carelessly.
    P.S. Dr. Dumbfuck Troll Who Doesn’t Even Motherfucking Know Me: there wasn’t a single thing in Sci’s response to me that I didn’t have more than enough intellectual ability to understand, you reprehensible criminal douchehound. In the spirit of science, I even double-checked. So go fuck yourself.

  4. PS: I KNOW it’s bad, but do NOT mock Heath Ledger. Sigh…he was so cute in that movie…I need to keep my 90’s nostalgia.

    It’s ok. I have no memory whatever of that movie, and I spent the 1990s completely sober.

  5. M: I’m fairly sure (well, 100% sure), that Juniper didn’t mean you. She meant someone who has since been moved to spam for comments that lacked a certain amount of scientific basis and which implied that she was incapable of understanding my writing. Not you. Sorry, those comments got moved to spam and I guess that’s why you figured it was you.

  6. M, my comment wasn’t addressed to you at all. It is addressed to someone who did deserve every inch of my reaction. Scicurious is right.

  7. @Juniper & Scicurious
    Oh. Well, glad to know it wasn’t the most severe reply in the history of the Internet. 😛 Beside the fact that the other comment has been deleted, another factor was that Juniper comment starts by quoting me: “Many are from USA, so clearly some of them found a way to import it from Europe.”
    I guess it was a mistake then?
    Btw, Good post Scicurious. I wish more available drugs would offer strong 5-HT2c antagonism and it would be great to have at least one that is very selective. 5-HT2c is a cool antidepressant mechanism of action which also geek me out. Prozac is now considered by many [citation needed](Dr.Stalh is of those ‘many’) a NDDI (Norepinephrine & Dopamine disinhibitor) rather than a SSRI since it’s now thought that the antidepressant effect of Fluoxetine is more attributable to its 5-HT2c antagonism than its less than average SRI. Ironic that what is considered by most (erroneously) to be the prototypal rock star SSRI wouldn’t be one by today standard. Isolated 5-HT2c antagonism for many people, especially those who can’t live with some of the SSRI/SNRI/TCA/MAOI side effects, would be great but it doesn’t seems currently possible to get that NDDI isolated enough: Beside Fluoxetine and Agomelatine, Ziprasidone and Trazodone are also interesting. In low enough dose, Ziprasidone offers strong 5-HT2c antagonism without much significant dopamine antagonism and SRI. Trazodone has as much 5-HT2c antagonism than Agomelatine (which btw, is about 30% weaker than Fluoxetine), but one of its metabolite is mCPP which is a 5-HT2c agonist. Nefazodone isn’t available in some countries because of liver toxicity case reports and has stronger SRI than Trazodone anyway. Mirtazepine, while antagonizing 5-HT2c, touch so much receptors that is about as much selective as a hydrogen bomb. Agomelatine has a pretty short half-life and can’t be taken in daytime being also MT1/MT2 agonistic.
    “Ask Scicurious”? Okay.. well .. Scicurious, would you please develop the perfect 5-HT2c antagonist? That would be great, KTHXBYE! 😉
    I didn’t read it yet, but for anyone interested in NDDI and especially Agomelatine (or TIK-301, LY156735) there’s this 2007 paper from the great Dr.Stall SM: Novel mechanism of antidepressant action: norepinephrine and dopamine disinhibition (NDDI) plus melatonergic agonism. @

  8. There’s actually quite a buzz about this drug, most of the reviews i have seen are positive. At the same time i have read reviews of people thinking of doubling the dosage as they don’t feel any effect !!

  9. I came across this site through a Google search about agomelatine and am a layman so didn’t understand a damn thing that you all argued about. But I have to say that Scicurious sounds hot. The way she writes is very seductive. God I love blogs.

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