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.
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.
(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.