Are Ketamine Metabolites Antidepressants? The Story of Hydroxynorketamines

[@tristafrog]

I’m currently writing my senior undergrad thesis on this exact topic. So cool to see others out here making content about it!!! Keep it up dude!!

[@hippos_rock3855]

Very interesting! I’m glad I discovered this channel, I’ll have to watch all of your other videos. Neuropharmacology of dissociatives is my favorite topic :)

[@Neuropharmacist]

Thanks! I hope you'll find some interesting stuff in my other vids as well :) I'll try to keep updating content related to dissociatives in the future.

[@heatsingh2205]

@@Neuropharmacist i find your thoughts very informative and evidence based ,we have very less research in terms of psychoactive drugs in treatment of mental disorders here in india i hope i can share your research with the indian psychatric community keep posting more . in fact i am following few more channels like yours .

[@Neuropharmacist]

@@heatsingh2205 Thanks!

[@darrenemerick9148]

Ketamine's neuropsychiatric effects are mediated by glial cells. Glia are more abundant than neurons and are involved in both immunomodulation and neuroplasticity. The time course of the improvements (1 to 7 days) would support this hypothesis, beyond the direct receptor effects.

[@Neuropharmacist]

It is likely glial cells are involved in ketamine's effects, but I'm not sure how the time course of the improvement supports glial involvement.

[@darrenemerick9148]

@@Neuropharmacist The time course suggests a transcription dependant cytokine/neurotrophin modulation, not unlike glucocorticoid effects which take 24 - 72 hours.

[@maenad1231]

I always feel smarter than I actually am after watching one of your videos

[@Neuropharmacist]

Thanks! And don't worry, most of the time I feel extremely stupid as well.

[@zzink]

Thanks for the video. What do you think about this 2018 journal publication that showed that ketamine antidepressant effects were almost entirely blocked by pre administration of naltrexone? It would potentially provide an explanation for the rapid AD effects by ketamine or more specifically an active mu-opioid metabolite with a better understood mechanism of action. But it does raise the question if opioids are an appropriate treatment as they come with a whole range of risks involved and would be frowned upon for non physical pain related usage. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism 10.1176/appi.ajp.2018.18020138

[@zzink]

HNK does somewhat bear structural resemblance to phencyclidine analogue 3-HO-PCP, another NDMA antagonist which is known to have mu-opioid activity with reasonably high binding affinity.

[@zzink]

Unraveling the opioid actions of S-ketamine and R-ketamine: comment on Bonaventura et al. 10.1038/s41380-021-01167-1 This paper also mentions the separation between the rapid action (within an hour or so) AD effects and the semi long term (following weeks/month) are likely not the same mechanism which has created a layer of confusion when discussing ketamine AD activity.

[@Neuropharmacist]

It's an interesting study, but I'm not ready to make any real conclusions based on 12 subjects. The effects of naltrexone may be complicated when examining it beyond receptor pharmacology. E.g. I'm pretty sure benzodiazepines could block ketamine's antidepressant effects.

[@Neuropharmacist]

@@zzink Sounds interesting, I'd have to read that. In my opinion, both rapid and sustained effects stem from the same principal mechanism, which I've outlined in the ENCORE-D hypothesis pharmrev.aspetjournals.org/content/72/2/439

[@elliemae4887]

Is it possible to see, live, how this affects the brain in a PET scan? Would a PET scan show what neurotransmitters are affected?

[@hippos_rock3855]

My understanding of using PET scans is that you can radio-label a drug (Like HNK with a carbon-14 atom or something to that extent) and then see where it’s going in the brain. So you could see some effects of the drug within the brain but you would not know exactly what neurotransmitters are affected with a PET scan (I may be wrong though, this is just what I remember!)

[@Neuropharmacist]

@@hippos_rock3855 That's right. You can also PET image metabolic processes with appropriate tracers. With MR spectroscopy you can get a glimpse of neurotransmitter change, but the spatial and temporal resolution is horrible.

[@heatsingh2205]

@@Neuropharmacist is there any company working on increasing the spatial and temporal resolution ?

[@Neuropharmacist]

@@heatsingh2205 I'd guess so, but I don't have a good understanding of the method and its limits in terms of physics and chemistry.

[@lucacantoni794]

Thanks for the video! I knew that mTOR was involved in the long-lasting effects of ketamine. I find it hard to explain the long antidepressant effects just through NMDAs, I think they can explain the immediate relief from depression, just like N2O does.. Or you think it is also possible that the 1h (or so) effect of ketamine on NMDA can modulate thoughts so much to give the person such a long relief from depression, just through the sensations they experience during the "trip" such as a normal psychdelic? Just speculating of course but I would like to hear something from you!

[@Neuropharmacist]

I do believe that 1 hour of pharmacological activation could be enough to plant the seed of neurobiological change, as brain imaging studies also show rapid changes in network connectivity. I've hypothesized that the subsequent night of sleep could be important in consolidating this change, since ketamine's effects become most prominent 24 hours after the treatment (i.e. after a night of sleep), and because ketamine may increase deep slow wave sleep, that has been suggested to play a role in synaptic homeostasis.

[@lucacantoni794]

@@Neuropharmacist very interesting answer! Thank you very much!

[@Neith93]

thanks for the vid

[@Neuropharmacist]

Thanks for watching!