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There is a certain irony here:

"Ugh, tricyclics! Low selectivity for the serotonin transporter over the noradrenaline transporter, and what's with all the antagonism at histamine, alpha and 5HT2A receptors? Dirty stuff! Thankfully this is the 90's, and we have Selective Serotonin Reuptake Inhibitors!"

"...eh, maybe you do need a bit of a noradrenaline boost on top. Thankfully this is 2000, and we have SNRI's!"

"...and maybe it would be nice to have some histamine/5HT2-antagonism-mediated anti-anxiety action, too. It's 2010, try some Seroquel or Mirtazapine on top of your antidepressant!"

"...and we do want some alpha1-adrenergic receptor antagonism to normalize the HPA axis! And some FIASMA / BDNF would be nice. R&D, get started! It's 2018!"

"...or just have a tricyclic."

:lol::P

I would not be surprised if they try to market anticholinergics as new groundbreaking anxiolytics in a few years from now... <_<

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9 hours ago, Velvet Elvis said:

The problem with TCAs was that there was a real fatal overdose risk.  That meant anyone at risk of suicide could not be prescribed them unless they were inpatient.

This is true. I believe it's because they inhibit sodium channels which has something to do with interfering with cardiovascular function.

8 hours ago, maxor said:

That's true, but I can easily off myself with Paracetamol & a bottle of booze if I have to: 

http://a.co/8JP4AcV

I don't need tricyclics to do it...

TCAs have a mechanism of action by which they more readily cause death in overdose than that of acetaminophen combined with booze. In a TCA OD, your heart could stop beating, which, obviously, if this isn't caught within a critical window, one could die. With acetaminophen and booze, one would basically be waiting for liver failure, which is an agonizing death, but the window of opportunity to rescue one from an OD from acetaminophen is much larger than that of TCAs. Otherwise, if one didn't consume enough of one or both to shut down their liver, one might come out on the other end of the experience with a fucked up liver.

I'm not condemning the use of TCAs though. Although I've taken a number of TCAs without good experiences, some bad experiences, the one good experience is with desipramine, which is what I take now (with sertraline) and I love it. I just don't think they are good first line medications, and also aren't good choice medicines for certain patients, like suicidal patients, as @Velvet Elvis pointed out. The same would go for the MAOIs.

 

Sort of related to the topic of the pharmaceutical industry's "reinventions..."

The next antidepressant we're looking at coming out is apparently ansofaxine, which acts as a prodrug to desvenlafaxine, but what's "unique" about ansofaxine is that it's more potent of a DRI than anything, but it still looks like it's pretty week at doing that, and who knows how much clinical effect that will have in relevance to the effect that the desvenlafaxine it produces will have. I mean, I'd be okay with another SNRI, but can we please get away from making more products based off venlafaxine/desvenlafaxine? Please?

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13 hours ago, mikl_pls said:

Sort of related to the topic of the pharmaceutical industry's "reinventions..."

The next antidepressant we're looking at coming out is apparently ansofaxine, which acts as a prodrug to desvenlafaxine, but what's "unique" about ansofaxine is that it's more potent of a DRI than anything, but it still looks like it's pretty week at doing that, and who knows how much clinical effect that will have in relevance to the effect that the desvenlafaxine it produces will have. I mean, I'd be okay with another SNRI, but can we please get away from making more products based off venlafaxine/desvenlafaxine? Please?

Interesting ratios, but the affinities are weak, indeed. Would need to take a high dosage for any clinical effect.

A potent selective SNDRI with some 5HT-"modulation" (agonist, inverse agonist, antagonist) and moderate H1-antagonism would be very interesting. Hope they come up with something like that in the future..

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1 hour ago, maxor said:

A potent selective SNDRI with some 5HT-"modulation" (agonist, inverse agonist, antagonist) and moderate H1-antagonism would be very interesting. Hope they come up with something like that in the future..

Why do you think an antidepressant needs H1 antagonism? I'm just curious.

As for SNDRIs in general, there have been plenty of others that have been developed and put through clinical trials.

Amitifadine was an SNDRI that was undergoing trials for MDD but failed to show superior efficacy to placebo, but supposedly it was due to being underdosed. It's now being developed for alcoholism and smoking withdrawal. The Ki for the SERT, NET, and DAT, respectively, are 99 nM, 262 nM, and 213 nM, and the IC50 for SRI, NRI, and DRI, respectively, are 12 nM, 23 nM, and 96 nM.

Centanafadine is an SNDRI for the treatment of ADHD that inhibits the reuptake of NE, DA, and 5-HT with a ratio of 1:6:14, respectively. In 2017, Otsuka acquired the rights to it, and as of this year (2018), Otsuka's pipeline indicates that it's in Phase III clinical trials. So perhaps this may be used off-label as an antidepressant?

Dasotraline is an SNDRI that is no longer under the development for the treatment for MDD but still under investigation for the treatment of ADHD and eating disorders (I believe binge eating?). It is a stereoisomer of desmethylsertraline (an active metabolite of sertraline, and an SNDRI similarly). It acts as a potent inhibitor of the DAT (IC50 = 3 nM) and NET (IC50 = 4 nM) and a weaker inhibitor of the SERT (IC50 = 15 nM). Perhaps it, too, could be used off-label for depression?

Tesofensine is an SNDRI that was being developed for treatment of Alzheimer's and Parkinson's disease, but didn't quite make it, but is now instead being investigated for treatment of obesity due to weight loss and appetite loss being some of the side effects. If this goes through, I highly doubt most insurance companies will pay for it since it would be marketed as a "weight loss" drug, and insurance companies don't like to cover those at all, unfortunately...

Desmethylsertraline, as aforementioned, is an active metabolite of sertraline, and it just so happens to be an SNDRI.

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21 hours ago, mikl_pls said:

Why do you think an antidepressant needs H1 antagonism? I'm just curious.

Severe depression most often comes with sleep problems (insomnia and problems getting to sleep because of too much rumination), low appetite / weight loss and agitation. Psychosomatic ailments are mostly "digestive problems".

Thus some moderate sedation is useful in alleviating those symptoms. (for example through 5HT2 and H1 antagonism or some form of GABA-mechanism, but there are certainly other mechanisms too). Too much sedation is of course counterproductive...

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23 hours ago, mikl_pls said:

As for SNDRIs in general, there have been plenty of others that have been developed and put through clinical trials.

Amitifadine was an SNDRI that was undergoing trials for MDD but failed to show superior efficacy to placebo, but supposedly it was due to being underdosed. It's now being developed for alcoholism and smoking withdrawal. The Ki for the SERT, NET, and DAT, respectively, are 99 nM, 262 nM, and 213 nM, and the IC50 for SRI, NRI, and DRI, respectively, are 12 nM, 23 nM, and 96 nM.

Centanafadine is an SNDRI for the treatment of ADHD that inhibits the reuptake of NE, DA, and 5-HT with a ratio of 1:6:14, respectively. In 2017, Otsuka acquired the rights to it, and as of this year (2018), Otsuka's pipeline indicates that it's in Phase III clinical trials. So perhaps this may be used off-label as an antidepressant?

Dasotraline is an SNDRI that is no longer under the development for the treatment for MDD but still under investigation for the treatment of ADHD and eating disorders (I believe binge eating?). It is a stereoisomer of desmethylsertraline (an active metabolite of sertraline, and an SNDRI similarly). It acts as a potent inhibitor of the DAT (IC50 = 3 nM) and NET (IC50 = 4 nM) and a weaker inhibitor of the SERT (IC50 = 15 nM). Perhaps it, too, could be used off-label for depression?

Tesofensine is an SNDRI that was being developed for treatment of Alzheimer's and Parkinson's disease, but didn't quite make it, but is now instead being investigated for treatment of obesity due to weight loss and appetite loss being some of the side effects. If this goes through, I highly doubt most insurance companies will pay for it since it would be marketed as a "weight loss" drug, and insurance companies don't like to cover those at all, unfortunately...

Desmethylsertraline, as aforementioned, is an active metabolite of sertraline, and it just so happens to be an SNDRI.

Yeahh, I've been researching SNDRIs for the last 6 hours ^^

Many interesting molecules, but also many failures. Seems like a lot of trial and error.

https://en.wikipedia.org/wiki/DOV-102,677

https://en.wikipedia.org/wiki/DOV-216,303

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4 hours ago, maxor said:

Severe depression most often comes with sleep problems (insomnia and problems getting to sleep because of too much rumination), low appetite / weight loss and agitation. Psychosomatic ailments are mostly "digestive problems".

Thus some moderate sedation is useful in alleviating those symptoms. (for example through 5HT2 and H1 antagonism or some form of GABA-mechanism, but there are certainly other mechanisms too). Too much sedation is of course counterproductive...

That's true for agitated patients, but for patients who suffer from psychomotor retardation, hypersomnia, hyperphagia, weight gain, etc.--atypical depression patients... Agents that cause stimulation and anorexia are typically useful to them, like fluoxetine and sertraline. Sure they're SSRIs, but they work for some. The initial start-up agitation usually goes away within weeks for patients with anxiety and can be mitigated with low and slow titration. For them, H1 antagonism might not be the best answer, though some 5-HT2 antagonism would likely still be helpful.

I read an article at some point that said that there wasn't going to be any antidepressants to come out any time within the next ten years or something like that, because all the pharmaceutical companies are fleeing from trying to develop antidepressants because it's far to costly and difficult to develop a successful drug. Instead, they're all circling around orphan drugs because that's where the big money is at... Pharmaceutical companies and their money, I swear... T__T

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14 hours ago, mikl_pls said:

That's true for agitated patients, but for patients who suffer from psychomotor retardation, hypersomnia, hyperphagia, weight gain, etc.--atypical depression patients... Agents that cause stimulation and anorexia are typically useful to them, like fluoxetine and sertraline. Sure they're SSRIs, but they work for some.

For them, H1 antagonism might not be the best answer, though some 5-HT2 antagonism would likely still be helpful.

Yes, but there is a certain dogma among psychiatrists to push SSRIs on everybody... for different types of depression there are different fitting antidepressant-classes, but many doctors try the "one size fits all" route...

If someone suffers from psychomotor retardation, hypersomnia, weight gain, then Sertraline, Duloxetine or Bupropion might indeed be the fitting med. But pushing the same med on someone with converse symptoms might be fatal.

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