Extension to the Rapid Acting Antidepressant theory of Ketamine

[dopamimetic]

There has been much recent interest in the use of ketamine as a ‘rapidly acting’ antidepressant. However in this context the time-of-onset is still around 2 h, and the duration of antidepressant effect lasts about a week. These effects clearly occur long after the drug has been eliminated from the body – which is indicative of a ketamine-induced signalling cascade.61 The putative mechanisms have been reviewed in detail by Duman and co-workers4; in brief they suggest that the ketamine at low doses actually increases glutamate neurotransmission by both increased glutamate release and increased AMPA receptor expression and insertion into the synaptic plate. This causes secondary increased BDNF release, and hence activation of ERK signalling which then stimulates mammalian target of rapamycin (mTOR) – a kinase that controls protein translation – and thus via a complex signalling path, leads to increased synaptic protein expression (GluR1) and increased insertion and density of synapses – leading to increased structural connectivity between neurons, particularly in the pre-frontal cortex. (from here)

Now we have people who are 'truly' depressed in the sense of too less overall excitatory activity. They will get this para-instant effect when the ketamine wears off. But we also have others, like me, who have a somewhat disrupted glutamate system with overactivity on the one side and under activity on the other. Probably this hits mostly people who are very sensitive to stress, emotionally 'overly sensible', inattentive ADD partially.

Here actually a constant modulation of glutamate is required. I get most out of a combination of these downstream effects but while being on a low actual NMDA blockade, offering some kind of 'distance' to all this sensory input, overwhelming emotions and impulse control problems, anxiety etc. that in the end cause the depressive state.

What are the implications of this? Riluzole certainly looks promising. But will there be tolerance development to chronic low NMDA antagonism over time, eventually making things worse or not?

One thing to watch out for seems to be the increased oxidative stress many NMDA antagonists cause, which is suggested to be one of the major factors for PCP / ketamine-induced psychosis, but this could maybe be managed by inhibiting the NADPH oxidase or just taking enough of N-acetylcysteine.

 

[Cotcha Yankinov]

What would be really useful is a way to address the astrocytes that are modulating glutamate in addition to antagonizing glutamate http://www.molecularpain.com/content/pdf/1744-8069-6-50.pdf
Gabapentenoids are therapeutic vaguely in this manner as far as thrombospondin goes but don't necessarily shut down already existing glutamate very well? If there is indeed a loss of the glutamate transporter with age a transporter promoter (like there was made with serotonin) would be useful. But I think astrocytes cold be playing a big role regarding having too much glutamate, just having too many astrocytes means more glutamate. Gabapentinoids are, it seems, the only way to try to address this that is within our reach, but it could be a long time before the effects are realized (if it only stops the creation of new glutamate).

If you could shut down glutamate just with an antagonist for long enough the brain might trim some connections, though I feel like this would take years and would be more effective if done around the age of 20. But antagonism will unfortunately lead to up regulation and hyper sensitivity, even if it's up regulation of not the NMDA itself but whatever is downstream of the NMDA.

Man it would be so much easier to get some of these glutamate antagonists if we had epilepsy hahaha.

 

[dopamimetic]

Riluzole actually increases high-affinity glutamate uptake, maybe much in the same way as coluractam does with choline...!? Don't know the implications of this, because coluracetam enhances the activity of the choline system through increased uptake while riluzole soothes over-excitation ... but it could be that in the end it's all the same, if we think about tianeptine and this serotonin reuptake enhancement speculation.

At least I need to try riluzole! It has more robust evidence than memantine even to work against mental stress, depression and overexcitability, but it's so prohibitively expensive and I certainly don't have ALS (yet... another point I'm really unsure about, if and how all these glutamate-based disorders are related and one could progress into the other. ALS seems to hit only the motor neurons and leave cognition intact. But then it could be that the motor neurons are just more sensitive to over-excitation because they have much longer axons...and all that!?) Would really be interesting if e.g. Stephen Hawkins has had over-excitation problems too mentally.. and if this might be directly connected to his cognitive abilities?

The gabapentinoids might indeed make quite good drugs, my interest in them raises again ... maybe one needs just to find the right dosage? Also just read that they actually seem to potentiate the dissociative effects from NMDA antagonists which would really confirm my theory about NMDA & Ca channels- which seems to be somewhat correct in the end..

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By the way, I really speculate about temporal lobe lability being responsible for my horrid experiences to neuroleptics (which lower the seizure threshold). I've ran into brief episodes of 'mystical experiences' - synchronicity, 'the world has changed' on higher dosages of dissociatives that are also serotonergics (MXE, DXM, possibly also on a high dose of psilocybin) - there are no words for that, but it would entirely be explainable with partial temporal lobe seizures. Then I'd actually have some weird form of epilepsy and maybe should actually get onto pregabalin or valproate ... or even that strange perampanel, but I'm really wary of that because it can turn you into a psychopath, at least when you look at the side effects.