3 ms·

Reminder that the FDA seems to fast track the wrong drug: They gave "breakthrough designation" ( https://en.wikipedia.org/wiki/Breakthrough_therapy https://en.

Reminder that the FDA seems to fast track the wrong drug: They gave "breakthrough designation" ( https://en.wikipedia.org/wiki/Breakthrough_therapy https://en.wikipedia.org/wiki/Breakthrough_therapy ) to Esketamine under pressure from Johnson & Johnson: https://en.wikipedia.org/wiki/Esketamine#Depression https://en.wikipedia.org/wiki/Esketamine#Depression Although Arketamine seems like it has a lot more responsibility for the antidepressant effect of racemic ketamine: https://en.wikipedia.org/wiki/Arketamine#Novel_antidepressant https://en.wikipedia.org/wiki/Arketamine#Novel_antidepressan... https://en.wikipedia.org/wiki/Hydroxynorketamine https://en.wikipedia.org/wiki/Hydroxynorketamine https://www.ncbi.nlm.nih.gov/pubmed/24316345 https://www.ncbi.nlm.nih.gov/pubmed/24316345 (2013) http://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2014.12.1.72 http://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2014.... (2014) https://www.ncbi.nlm.nih.gov/pubmed/26327690 https://www.ncbi.nlm.nih.gov/pubmed/26327690 (2015) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910398/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910398/ (2016) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487269/#__sec4title https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487269/#__sec4... (2017) That isn't to say Esketamine doesn't have an antidepressant effect. In light of the fact that Esketamine makes you Trip Balls(tm) while Arketamine doesn't, I like to think of it this way: You can likely get an antidepressant effect out of Esketamine in the same way that you can get an antidepressant effect out of psychdelics like LSD-25 & Psilocin. However, like those, it could possibly also make depression worse, and unlike Arketamine doesn't seem to represent anything awfully novel. It however also makes me suspect that like with other racemic drugs like Amphetamine, a shifted ratio preparation might make for a better drug overall than isolating the stereoisomers. For example, Adderall contains 75% dexamphetamine, 25% levoamphetamine, in the form of various amphetamine salts (wheras racemic amphetamine contains 50% of each, typically as a single salt.). [Semi-related: I still don't comprehend why pharmaceutical companies have yet to create a combination preparation of Lisdexamfetamine with something like Lislevoamfetamine, - which I haven't seen synthesized but I don't see anything speaking against it -, in a ratio akin to the one seen in Adderall. The rational behind that ratio seems sound, albeit I'd perhaps go for an 80/20 split instead of a 75/25 split...]

ShabbosGoy 9y ago
> You can likely get an antidepressant effect out of Esketamine in the same way that you can get an antidepressant effect out of psychdelics like LSD-25 & Psilocin. LSD-25 and Psilocin simply amplify your emotional state at a given time, because they act on 5HT receptors. That’s not what an anti-depressant does. In fact, anti-depressants help one regulate emotions correctly. In that sense, Esketamine is truly novel for being a rapid anti-depressant, because it acts as a NMDA antagonist.
- sigotirandolas 9y ago
  Psychedelics are not simply dumb emotional amplifiers as you characterize them, they can radically alter your mood (for the better or the worse) pretty radically from your initial mood. They can generate or amplify one small insight into a wonderful state of mind, or they can generate or amplify an absurd fear to the point that you lose all sense of hope and reality.
  - ShabbosGoy 9y ago
    Correct, but that happens to you every day on a minor level. You just don’t notice it because there are filters in your brain. Psychedelics remove those filters. It comes down to inhibitory control. People suffering from depression lack inhibitory control of negative thoughts and emotions, which leads to a feedback loop of thinking more negative thoughts and feeling more negative emotions.
  - opportune 9y ago
    They also tend to cause permanent personality changes (increasing "openness to experience")
aaavl2821 9y ago
I think the answers to your questions are unfortunately not scientific but business related Fast track designation must be requested by the company developing the drug. J&j is developing esketamine; I don't know of any companies developing arketamine I think a big reason j&j decided to develop esketamine vs ketamine is because ketamine is an old approved generic drug (i.e. Cheap). they chose it over arketamine probably for all the pharmacologic and therapeutic reasons cited in the second to last paper you link to. Last December they released phase 2 data that looked pretty good though there were dissociate side effects The new data on arketamine are interesting but I view them with a grain of salt. There's only so much you can conclude about depression biology and structure activity relationship from animal models. Plus the mechanism of action of ketamine is so complex and poorly understood that by trying to be too precise with our receptor targeting we risk losing desired traits. We don't really know that AMPA is a better target than NMDAR; and we don't know the right ratio, and we don't know whether there are other important receptors beyond these

ShabbosGoy 9y ago

> You can likely get an antidepressant effect out of Esketamine in the same way that you can get an antidepressant effect out of psychdelics like LSD-25 & Psilocin. LSD-25 and Psilocin simply amplify your emotional state at a given time, because they act on 5HT receptors. That’s not what an anti-depressant does. In fact, anti-depressants help one regulate emotions correctly. In that sense, Esketamine is truly novel for being a rapid anti-depressant, because it acts as a NMDA antagonist.

sigotirandolas 9y ago
Psychedelics are not simply dumb emotional amplifiers as you characterize them, they can radically alter your mood (for the better or the worse) pretty radically from your initial mood. They can generate or amplify one small insight into a wonderful state of mind, or they can generate or amplify an absurd fear to the point that you lose all sense of hope and reality.
- ShabbosGoy 9y ago
  Correct, but that happens to you every day on a minor level. You just don’t notice it because there are filters in your brain. Psychedelics remove those filters. It comes down to inhibitory control. People suffering from depression lack inhibitory control of negative thoughts and emotions, which leads to a feedback loop of thinking more negative thoughts and feeling more negative emotions.
- opportune 9y ago
  They also tend to cause permanent personality changes (increasing "openness to experience")

aaavl2821 9y ago

I think the answers to your questions are unfortunately not scientific but business related Fast track designation must be requested by the company developing the drug. J&j is developing esketamine; I don't know of any companies developing arketamine I think a big reason j&j decided to develop esketamine vs ketamine is because ketamine is an old approved generic drug (i.e. Cheap). they chose it over arketamine probably for all the pharmacologic and therapeutic reasons cited in the second to last paper you link to. Last December they released phase 2 data that looked pretty good though there were dissociate side effects The new data on arketamine are interesting but I view them with a grain of salt. There's only so much you can conclude about depression biology and structure activity relationship from animal models. Plus the mechanism of action of ketamine is so complex and poorly understood that by trying to be too precise with our receptor targeting we risk losing desired traits. We don't really know that AMPA is a better target than NMDAR; and we don't know the right ratio, and we don't know whether there are other important receptors beyond these