<p>What are the mechanisms by which ketamine reduces the symptoms of depression and anxiety? E.g. <a href="https://clinicaltrials.gov/ct2/show/NCT00088699" rel="nofollow noreferrer">https://clinicaltrials.gov/ct2/show/NCT00088699</a>.</p>

CC BY-SA 3.0
2016-06-24T13:08:30.077Z
Does ketamine do that? If yes, could you add sources to that claim? I've never heard of NMDA antagonists having antidepressant properties. Of course, if you give it in anesthetic dosages it will knock you out - no depression, but no consciousness either - and that's probably not what you are after here.
AliceD
CC BY-SA 3.0
2016-06-24T14:12:11.303Z
E.g. https://clinicaltrials.gov/ct2/show/NCT00088699. It would be nice if the OP could give some background info in his question.
huh
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2016-06-24T14:16:05.663Z
@huh now that's interesting!
AliceD
CC BY-SA 3.0
2016-06-24T19:17:55.963Z
"the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors)." [(Zanos et al., 2016)](http://www.nature.com/nature/journal/v533/n7604/abs/nature17998.html)
mrt
CC BY-SA 3.0
2016-06-25T03:42:46.267Z
This might be related? http://slatestarcodex.com/2016/06/07/ketamine-research-in-a-new-light/
Seanny123
CC BY-SA 3.0
2016-06-25T20:58:16.547Z
If there's a clinical trial, there must be some mechanistic pre-clinical data available. Happy to upvote this question, once it''s edited with appropriate links as mentioned in the comments.
AliceD
CC BY-SA 4.0
2021-10-15T15:30:46.013Z
@AliceD "If there's a clinical trial, there must be some mechanistic pre-clinical data available" - eh, not necessarily. We don't really know how antidepressants in general work. We certainly know low-level mechanisms: receptor affinities and cellular effects. Ketamine is of course principally an NMDA receptor antagonist, though it has lots of other effects, too. At the systems level, though, it's mostly still a puzzle and though everyone has their pet theory they can show evidence for, they often conflict.
Bryan Krause
CC BY-SA 4.0
2021-10-15T16:16:19.157Z
@BryanKrause phase I trials are preceded by animal model experiments where at least some of the mechanistic actions are investigated, no?
AliceD
CC BY-SA 4.0
2021-10-15T16:33:06.850Z
@AliceD Sometimes, but not always. For depression, the mechanisms of depression aren't known, either, so it's not really possible to design a trial testing those in animal models. Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000). Antidepressant effects of ketamine in depressed patients. Biological psychiatry, 47(4), 351-354. is probably the place to start, and they do talk about some preclinical work, but it's a bit of a stretch to say the mechanism of ketamine is depression is known.
Bryan Krause
CC BY-SA 4.0
2021-10-15T16:35:57.713Z
The evidence could be summarized as "some, but not all, animal models of depression involve glutamate and NMDARs, and some, but not all, animal models of depression show improvement with NMDAR antagonists, and some, but not all, antidepressants used in humans cause NMDAR changes in rodents. We don't know how animal models of depression relate to human depression, but depression sucks and ketamine is pretty safe used as an anesthetic so let's give it a shot".
Bryan Krause
CC BY-SA 4.0
2021-10-15T20:32:40.010Z
@BryanKrause something along those lines would have helped to improve this question by adding some background.
AliceD
<neuroscience><emotion><abnormal-psychology><psychopharmacology>
Mechanism of ketamine in treatment of depression and anxiety?
BitShrink
# Mechanism of ketamine in treatment of depression and anxiety?

(Asked by: username_0 on 2016-06-24)

What are the mechanisms by which ketamine reduces the symptoms of depression and anxiety? E.g. <https://clinicaltrials.gov/ct2/show/NCT00088699>.

**Tags:** neuroscience, emotion, abnormal-psychology, psychopharmacology

> **Comments:**
> **username_1**: Does ketamine do that? If yes, could you add sources to that claim? I've never heard of NMDA antagonists having antidepressant properties. Of course, if you give it in anesthetic dosages it will knock you out - no depression, but no consciousness either - and that's probably not what you are after here.  
> **username_2**: E.g. https://clinicaltrials.gov/ct2/show/NCT00088699. It would be nice if the OP could give some background info in his question.  
> **username_1**: @username_2 now that's interesting!  
> **username_3**: "the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors)." [(Zanos et al., 2016)](http://www.nature.com/nature/journal/v533/n7604/abs/nature17998.html)  
> **username_4**: This might be related? http://slatestarcodex.com/2016/06/07/ketamine-research-in-a-new-light/  
> **username_1**: If there's a clinical trial, there must be some mechanistic pre-clinical data available. Happy to upvote this question, once it''s edited with appropriate links as mentioned in the comments.  
> **username_5**: @username_1 "If there's a clinical trial, there must be some mechanistic pre-clinical data available" - eh, not necessarily. We don't really know how antidepressants in general work. We certainly know low-level mechanisms: receptor affinities and cellular effects. Ketamine is of course principally an NMDA receptor antagonist, though it has lots of other effects, too. At the systems level, though, it's mostly still a puzzle and though everyone has their pet theory they can show evidence for, they often conflict.  
> **username_1**: @BryanKrause phase I trials are preceded by animal model experiments where at least some of the mechanistic actions are investigated, no?  
> **username_5**: @username_1 Sometimes, but not always. For depression, the mechanisms of depression aren't known, either, so it's not really possible to design a trial testing those in animal models. Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000). Antidepressant effects of ketamine in depressed patients. Biological psychiatry, 47(4), 351-354. is probably the place to start, and they do talk about some preclinical work, but it's a bit of a stretch to say the mechanism of ketamine is depression is known.  
> **username_5**: The evidence could be summarized as "some, but not all, animal models of depression involve glutamate and NMDARs, and some, but not all, animal models of depression show improvement with NMDAR antagonists, and some, but not all, antidepressants used in humans cause NMDAR changes in rodents. We don't know how animal models of depression relate to human depression, but depression sucks and ketamine is pretty safe used as an anesthetic so let's give it a shot".  
> **username_1**: @BryanKrause something along those lines would have helped to improve this question by adding some background.  

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## 0 answers

