Ketamine's Antidepressant effects - NMDA antagonist

[OnCloud9]

Hey there,

As far as I know Ketamine blocks the receptor NMDA, which in turn increases activity of the AMPA receptor which is responsible for ketamines rapid antidepressant effects. My question is why does the AMPA receptor get over activated here?

Also would you say Ketamine administration could be used in the future for treatment resistant depression, given it's rapid antidepressant properties? Why or why not?

 

[sekio]

As far as I know Ketamine blocks the receptor NMDA, which in turn increases activity of the AMPA receptor which is responsible for ketamines rapid antidepressant effects. My question is why does the AMPA receptor get over activated here?

Here's the paper in question. Maybe also this paper, too. It's inferred, and not explained why, that AMPA activation must be happening somehow - because if you block the AMPA recptors then the antidepressant effect is not observed.

The rapid antidepressant-like effects of ketamine in both the LH paradigm and the TST were significantly blocked by subcutaneous treatment with 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)quinoxaline (NBQX), an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist. In addition, the sustained antidepressant-like effect of ketamine in the TST was partially abolished by treatment with NBQX. In conclusion, we confirmed the faster onset of the action of ketamine, compared with clinically prescribed antidepressants. Moreover, the present results suggested that direct AMPA receptor activation may play an important role in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression, although other mechanisms might be involved in the sustained action.

Also would you say Ketamine administration could be used in the future for treatment resistant depression, given it's rapid antidepressant properties? Why or why not?

Is this a trick question? It's already being used for treatment resistant depression.

 

[OnCloud9]

Here's the paper in question. Maybe also this paper, too. It's inferred, and not explained why, that AMPA activation must be happening somehow - because if you block the AMPA recptors then the antidepressant effect is not observed.





Is this a trick question? It's already being used for treatment resistant depression.

Thanks for those articles. To clarify, I meant used in practice, not just in research settings.

 

[Hammilton]

It is being used in practices around the US. Just look around. It's not cheap or FDA approved for this use so it's not covered by insurance. It is available from real physicians outside of research settings.

 

[Lightning-Nl]

I haven't read a lot about AMPA to be honest. However; it seems more likely to me that the universal downregulation of Glutamate is more likely to be responsible for Ketamines antidepressant effects.

Decreasing excitability of NMDA would lead to glutamate not being able to hyperpolarize neurons. This would make them less excitable thus leading to mood stabilization. That seems more likely to me.

 

[sekio]

Ketamine doesn't have a permanent effect at NMDAr, though, it's a temporary and transient one.

 

[ebola?]

universal downregulation of Glutamate is more likely to be responsible for Ketamines antidepressant effects.

Glutaminergic transmission is too prolific and widely distributed in the brain for this to be possible. Remember that dissociatives are specific to NMDA-type receptors, expressed mostly in the hippocampus. They exert downstream effects of varied sorts, and AMPA receptors are key and relatively directly affected.

Decreasing excitability of NMDA would lead to glutamate not being able to hyperpolarize neurons. This would make them less excitable thus leading to mood stabilization. That seems more likely to me.

For anti-depressant treatment, you don't just take K all the time; rather, after a single or a few infusions, an anti-depressant effect manifests and continues for from one week to a bit over a month, sans additional K. The underlying mechanism is not yet understood, but I have a really shaky guess...

 

[Hammilton]

I have a feeling it's related somehow to the same process that makes ECT such a powerful antidepressant. It's obviously not simple 'turning down the volume' so to speak, if it was just global glutamate receptor activity reduction (which is a short term effect, anyway) then other drugs which deep depress the activity of glutamate would have the same sort of effect. Drugs like diazepam and phenobarbital are known to have an inhibitory effect on glutaminergic activity (see pmid: 21044903, for instance) but these are ineffective treatments for depression.

What sort of doses are they administering in these trials? I haven't read a paper in full on this yet, but are these people still conscious and will they remember what goes on?

 

[sekio]

The dose regimen, if I remember right, was 0.5 mg S-ketamine or 1mg racemate/kg, in a slow IV infusion. The idea is to keep the patient concious and avoid too much psychedelia, but to still trigger a 'response' - one paper I read suggested trials were aborted if dissociative effects manifested that the pt was uncomfortable with.

 

[arctica]

I think that therapeutic dosages are anyone's guess at this point. It seems that IV ketamine is used more often in depression studies and oral ketamine is used more often in pain studies. I am taking 4 x 50 mg ketamine troches (dissolved in the mouth over a number of hours) for treatment-resistant depression and start to notice a strong antidepressant effect within 15-30 minutes of taking 50 mg orally/buccally. I don't recall much of an effect below 50 mg, but the onset is fairly rapid and the effect wears off fairly quickly. I've found it pretty easy to titrate a dose in a controlled fashion using lozenges/troches. Start low/go slow. I've noticed that I'm acquiring some amount of tolerance to it, so I would recommend starting with a lower dosage.

 

[Foreigner]

10mg IM qwk seems to do it for me.

 

[nAON]

Here's the paper in question. Maybe also this paper, too. It's inferred, and not explained why, that AMPA activation must be happening somehow - because if you block the AMPA recptors then the antidepressant effect is not observed.

Does blocking AMPA result in the psychoactive effect eliminated too? A researcher I was speaking to the other day was quite convinced that ketamines AD effect was purely as a result of its psychoactive-induced behavioural/thought changes, rather than a pharmacological one.

 

[arctica]

It is being used in practices around the US. Just look around. It's not cheap or FDA approved for this use so it's not covered by insurance. It is available from real physicians outside of research settings.

I believe Ketadvocate has a listing of U.S. doctors that prescribe ketamine for depression. In my personal experience, a single IV infusion from a company like NeuroLuminance is ~$900, and repeated every 2 weeks for a relatively short period (maybe 8 sessions, total). A 30-day supply of ketamine troches or capsules from a compounding pharmacy is costing me about ~$30/month.

 

[ebola?]

The dose regimen, if I remember right, was 0.5 mg S-ketamine or 1mg racemate/kg, in a slow IV infusion. The idea is to keep the patient concious and avoid too much psychedelia, but to still trigger a 'response' - one paper I read suggested trials were aborted if dissociative effects manifested that the pt was uncomfortable with.

Right, so if you're "tripping balls", you've overshot. It's a short acting compound, so the protraction of infusion likely limits psychoactive effects. Now anecdotally, people have had success with just above threshold dosing over an even more protracted period. All this again has been speculatively based, as far as I've been able to find.

I am taking 4 x 50 mg ketamine troches (dissolved in the mouth over a number of hours) for treatment-resistant depression and start to notice a strong antidepressant effect within 15-30 minutes of taking 50 mg orally/buccally. I don't recall much of an effect below 50 mg, but the onset is fairly rapid and the effect wears off fairly quickly. I've found it pretty easy to titrate a dose in a controlled fashion using lozenges/troches. Start low/go slow. I've noticed that I'm acquiring some amount of tolerance to it, so I would recommend starting with a lower dosage.

See, this seems atypical for NMDA-antagonist mediated anti-depression. As detailed above, while the anti-depressant effect can be rapid, the main body of therapeutic effects extend well beyond the actual dosing regimen. Usually, this precludes development of tolerance to the therapeutic effects. Maybe you're confusing the immediate effects of mild dissociation with the properly anti-depressive state K can induce (as a rough marker, the latter is almost never 'dissociative' in feel, usually the opposite, IME).
...
My speculation on the relevant mechanism:
My guess is that NMDA agtagonism results in downstream upregulation of AMPAkinergic receptors. Increased transmission via this system results in increased neuroplasticity in circuits spanning the hippocampus and PFC. But how? Not sure. Perhaps (a BIG perhaps) there is further signaling via nitric oxide leading to epigenetic changes which increase rate of synthesis of brain derived neuropathic factor. This mechanism would also suggest convergence with that of SSRIs, which also seem to depend on increased neuroplasticity localized to the hippocampus.

ebola

 

[nAON]

See, this seems atypical for NMDA-antagonist mediated anti-depression. As detailed above, while the anti-depressant effect can be rapid, the main body of therapeutic effects extend well beyond the actual dosing regimen. Usually, this precludes development of tolerance to the therapeutic effects. Maybe you're confusing the immediate effects of mild dissociation with the properly anti-depressive state K can induce (as a rough marker, the latter is almost never 'dissociative' in feel, usually the opposite, IME).
...
My speculation on the relevant mechanism:
My guess is that NMDA agtagonism results in downstream upregulation of AMPAkinergic receptors. Increased transmission via this system results in increased neuroplasticity in circuits spanning the hippocampus and PFC. But how? Not sure. Perhaps (a BIG perhaps) there is further signaling via nitric oxide leading to epigenetic changes which increase rate of synthesis of brain derived neuropathic factor. This mechanism would also suggest convergence with that of SSRIs, which also seem to depend on increased neuroplasticity localized to the hippocampus.

ebola

Wouldn't blocking NMDA transmission downregulate AMPAR via LTD?

 

[arctica]

See, this seems atypical for NMDA-antagonist mediated anti-depression. As detailed above, while the anti-depressant effect can be rapid, the main body of therapeutic effects extend well beyond the actual dosing regimen. Usually, this precludes development of tolerance to the therapeutic effects. Maybe you're confusing the immediate effects of mild dissociation with the properly anti-depressive state K can induce (as a rough marker, the latter is almost never 'dissociative' in feel, usually the opposite, IME).
ebola

Hey ebola, what would you suggest for a dosing regimen? I don't understand the distinction between a "proper" anti-depressive state and a mildly dissociated state. I understand that the theory is to do some remodeling over the medium term, which presumably leads to a durable effect, even after the ketamine is stopped. That being said, I'm not sure I agree that the short-term effects aren't helpful. It makes me feel like a competent person -- like I have the ability to change the direction that my life is going. Also, I seem to have an avoidant/traumatic response to everything right now, whether that's some random song on the radio or a tree that's changing colors or some friend that's texting me, my instant reaction is to burst into tears. The short term effects (maybe this is just "turning down the volume" in a traumatized brain) allow me to interact with my friends, enjoy music, and appreciate beauty without feeling emotionally burned and drained. While the effect is short-lived, it's a very welcome reprieve at the end of the day.

ETA: When I tried the "extended release" capsules, I didn't feel an initial buzz, probably because of the slow onset. However, it didn't seem to have as strong of an antidepressant effect. It seemed like my mood overall was sliding over the course of a week or two. I was scared that I had developed a tolerance or somehow "lost the magic," but switching back to the instant-release troches brought back the short-term antidepressant effect, and seems to contribute to feeling better in general.

Still, I would ideally want to be able to sustain the short-term effects throughout the course of the day (while still being able to function/work/drive/etc.), which is what I was hoping to get from the extended release version. I'm in search of a better ROA or dosing schedule. I feel like I'm on to something, but it definitely needs some tweaking.

 

[arctica]

I have some suspicions that the "IV infusion every 2 weeks" model is based on some sort of scientific literature "founder effect" rather than a strong understanding of what's going on in the brain. The fact of the matter is that most doctors familiar and comfortable with administering ketamine are anesthesiologists, who mostly use it IV, and the gold standard ROA for most drugs from a bioavailability standpoint is IV. However, there's a lot more personnel, monitoring, and cost overhead associated with (legal) IV administration, which means it's not practical to bring in patients for more frequent infusions. From this standpoint, it makes a lot of sense for pilot ketamine depression studies to enlist a few anesthesiologists and do some proof-of-concept studies using an ROA that isn't complicated with other factors like first-pass metabolism and in a form factor that is familiar to the doctors involved. However, I have my doubts that they happened on the perfect crystal of a ROA/dosing schedule the first time out of the gate, and most associated (depression) studies have simply mimicked the initial staggered infusion approach.

 

[ebola?]

Wouldn't blocking NMDA transmission downregulate AMPAR via LTD?

Maybe. My (highly speculative) line of reasoning is that the reduced glutaminergic activity at NMDA sites results in upregulation of other glutaminergic receptors with sufficient NMDA-antagonism over a long enough period. But you're right, in that it could just as easily be that the more immediate downregulation of AMPARs continues.

Hey ebola, what would you suggest for a dosing regimen?

For me what worked was maintaining threshold effects for 2-4 days, which was ~12 mg / hour taken intranasally, until effects at that dosage abated. Then I stopped with the k. During the treatment, I felt less depressed in that I was ever so slightly disconnected from my frustrations. But toward the end and afterward, I was...well, magically non-anhedonic, energetic, and active. I was finding value in engaging the world that was absent when I was depressed, a world more vivid and exciting. Basically, I regained my ability to be interested in things and people, crippling ennui having evaporated, looming anomie becoming less daunting. This state felt nothing like anything K induces immediately and lasted ~2 weeks. I wasn't dissociated but rather...er...associated.

This regimen was empirically derived through 1 person's (Jamshyd's) trial and error, and has been replicated by a couple of people. Clearly, this is weak evidence that the dosing schedule I chose was ideal.

 

[nAON]

Maybe. My (highly speculative) line of reasoning is that the reduced glutaminergic activity at NMDA sites results in upregulation of other glutaminergic receptors with sufficient NMDA-antagonism over a long enough period. But you're right, in that it could just as easily be that the more immediate downregulation of AMPARs continues.

It could be that ketamines antagonism results in upregulation of NMDAR, which in turn can increase nascent AMPAR LTP once antagonism is removed. Some quick googling brought this study up, however it should be noted that they used a competitive antagonist rather than a channel blocker such as ket to induce it.

 

[Reverend Random]

Here's some interesting research that shows NMDA-agonists to have anti-depressant qualities as well.

NSFW:

http://www.biologicalpsychiatryjournal.com/article/S0006-3223(13)00188-1/abstract

Background

Antidepressants, aiming at monoaminergic neurotransmission, exhibit delayed onset of action, limited efficacy, and poor compliance. Glutamatergic neurotransmission is involved in depression. However, it is unclear whether enhancement of the N-methyl-D-aspartate (NMDA) subtype glutamate receptor can be a treatment for depression.
Methods

We studied sarcosine, a glycine transporter-I inhibitor that potentiates NMDA function, in animal models and in depressed patients. We investigated its effects in forced swim test, tail suspension test, elevated plus maze test, novelty-suppressed feeding test, and chronic unpredictable stress test in rats and conducted a 6-week randomized, double-blinded, citalopram-controlled trial in 40 patients with major depressive disorder. Clinical efficacy and side effects were assessed biweekly, with the main outcomes of Hamilton Depression Rating Scale, Global Assessment of Function, and remission rate. The time course of response and dropout rates was also compared.
Results

Sarcosine decreased immobility in the forced swim test and tail suspension test, reduced the latency to feed in the novelty-suppressed feeding test, and reversed behavioral deficits caused by chronic unpredictable stress test, which are characteristics for an antidepressant. In the clinical study, sarcosine substantially improved scores of Hamilton Depression Rating Scale, Clinical Global Impression, and Global Assessment of Function more than citalopram treatment. Sarcosine-treated patients were much more likely and quicker to remit and less likely to drop out. Sarcosine was well tolerated without significant side effects.
Conclusions

Our preliminary findings suggest that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression. Establishment of glycine transporter-I inhibition as a novel treatment for depression waits for confirmation by further proof-of-principle studies.