Ketamine+Benzo=Noantidepressant effect? Pour quoi?

[cashmunny]

All the ketamine for depression clinics are saying that benzos or Lamictal will negate the antidepressant properties of ketamine. Now I know they use benzos with ketamine in surgical settings so the patient doesn't come out of surgery tripping balls but I can't for the life of me figure out why the ketamine for depression clinics are nixing both benzos and lamictal. The Lamictal thing is explained a bit here: http://jamanetwork.com/journals/jamapsychiatry/fullarticle/481584 although they go on to say that although perceptual abnormalities were reduced, mood elevation was increased which goes against what the clinics are recommending

But the benzo thing has me puzzled, I could only really find this case study: http://journals.sagepub.com/doi/pdf/10.1177/0004867415590631

I must say having taken ketamine with Lamictal and also benzos (not both at the same time) the clinics are right. Benzos and Lamictal attenuate the antidepressant effect of ketamine. I would just like to get a better handle on why because I really need to take both benzos and ketamine, having tried almost every other option. This isn't a DIY thing this is medically supervised so of course I''ll bring it up next time I see my pdoc but I was hoping some of the brilliant minds here could make sense of the benzo,and lamictal contraindications. Because when I try to follow the chain of events that make ketamine do it's antidepressant thing I feel like I need to get a big piece of paper and markers and make a flowchart. It's pretty damn complex.

And to throw another curveball, it looks like the therapeutic effects are not due to NMDAR inhibition by ketamine but rather the action is elsewhere.
NMDAR inhibition-independent antidepressant actions of ketamine metabolites
https://www.ncbi.nlm.nih.gov/pubmed/27144355

 

[serotonin2A]

All the ketamine for depression clinics are saying that benzos or Lamictal will negate the antidepressant properties of ketamine. Now I know they use benzos with ketamine in surgical settings so the patient doesn't come out of surgery tripping balls but I can't for the life of me figure out why the ketamine for depression clinics are nixing both benzos and lamictal. The Lamictal thing is explained a bit here: http://jamanetwork.com/journals/jamapsychiatry/fullarticle/481584 although they go on to say that although perceptual abnormalities were reduced, mood elevation was increased which goes against what the clinics are recommending

But the benzo thing has me puzzled, I could only really find this case study: http://journals.sagepub.com/doi/pdf/10.1177/0004867415590631

I must say having taken ketamine with Lamictal and also benzos (not both at the same time) the clinics are right. Benzos and Lamictal attenuate the antidepressant effect of ketamine. I would just like to get a better handle on why because I really need to take both benzos and ketamine, having tried almost every other option. This isn't a DIY thing this is medically supervised so of course I''ll bring it up next time I see my pdoc but I was hoping some of the brilliant minds here could make sense of the benzo,and lamictal contraindications. Because when I try to follow the chain of events that make ketamine do it's antidepressant thing I feel like I need to get a big piece of paper and markers and make a flowchart. It's pretty damn complex.

And to throw another curveball, it looks like the therapeutic effects are not due to NMDAR inhibition by ketamine but rather the action is elsewhere.
NMDAR inhibition-independent antidepressant actions of ketamine metabolites
https://www.ncbi.nlm.nih.gov/pubmed/27144355

It is a bit premature to conclude that "...the therapeutic effects are not due to NMDAR inhibition by ketamine but rather the action is elsewhere." Remember, the latter study is based on animal models, which can be extremely useful tools to probe antidepressant actions, but are not designed to conclusively show how drugs work in humans. It still remains possible that the antidepressant effects of ketamine are partially or entirely due to NMDA-R blockade -- indeed, there are other NMDA-R antagonists in the development pipeline that seem to be relatively efficacious antidepressants in humans.

To the extent that the antidepressant effect is due to NMDA-R blockade, the general steps are:

1. Blockade of NMDA-R-induced excitation of interneurons inhibits their firing
2. GABA release decreases
3. Disinhibition of glutamate neurons
4. Glutamate release increases
5. Glu activates AMPA receptors
6. mTOR pathway activated

BZs tend to blunt step 2. Lamictal tends to blunt step 4.

 

[cashmunny]

Thank you, that clarifies things.

Seems like the next logical step would be to synthesize (2S,6S;2R,6R)-hydroxynorketamine and do a human trial. We know it's safe since it's a metabolite (I'm assuming it's a metabolite in humans as well). You could just measure the blood levels of (2S,6S;2R,6R)HNK in ketamine responders and use that as a starting point.

Not that it's bad to trip balls every other day on Special K but things like driving, working, walking are not really possible under the influence.

Regarding step 2 from your post. I just took 40 mg of Ambien and 900 mg of gabapentin to potentiate it. I also took 100 mg of doxylamine and 150 mg of Seroquel. And I don't feel the least bit sleepy after my ketamine dose this evening. I might as well have been smoking cocaine all night. I'm just fucked for sleep tonight.

 

[d1nach]

40 mg of ambien??

 

[cashmunny]

I have a bit of a tolerance for Ambien since I take 20 mg nightly. But ketamine is like speed or something for me. No amount of sedation will make me sleep until it wears off. I was wide awake , posting on boards at 3 in the morning several hours after taking the Ambien, Seroquel, gabapentin, and doxylamine. And then bam, I was out like a light and woke up on the couch in the morning.

 

[d1nach]

Thats a sign of blacking out your lucky you didnt drive. Ambien makes me do things and not remember the nextday. For all you know you went on craigslist And said looking for lady to kick me in the balls. trust me at 40 mg ive had too many nights waking up and picking up the peices hopping I dont find out I did something with lasting consequences

 

[cashmunny]

I did actually have a bit of that. I put some bread in the oven to toast and forgot it was in there. When I woke up it was like a charcoal briquet.

 

[d1nach]

Btw i think your step 2 is wrong. Nmda antagonism blocks nmda channels at gaba interneurons. Interneurons send inhibitory signals to neurons therefore in some areas of the brain like reward centers this increases excititory signals. However in the hippocampus and mpfc there still is a inhibitory effect on excitory signaling which upregulates growth factors in those areas