Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants

[plumbus-nine]

Background
The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that “classic” serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period.

The cellular mechanisms underlying ketamine and serotonergic psychedelics (SPs) may converge at glutamatergic synapses. The mechanism of action of SPs primarily begins with 5-hydroxytryptamine receptor 2A (5-HT2A) receptor agonism and activation (although 5-hydroxytryptamine receptor 1A [5-HT1A] agonism is also present) that, in turn, leads to glutamate release and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) potentiation, with subsequent stimulation of tropomyosin-related kinase B (TrkB), the primary target of brain-derived neurotrophic factor (BDNF), and an upstream activator of mechanistic target of rapamycin complex 1 (mTORC1). In contrast, ketamine selectively blocks a subset of N-methyl-D-aspartate receptors (NMDARs) localized to gamma aminobutyric acid (GABA)ergic interneurons, though the mechanisms underlying this action are not fully elucidated. This causes disinhibition of their glutamatergic (pyramidal) target neurons, triggering a surge in extracellular glutamate and correspondingly elevated non-cell autonomous glutamatergic synaptic transmission coupled with AMPA potentiation. Ketamine may also induce rapid BDNF translation in brain areas, in part through reduced phosphorylation and activation of eukaryotic elongation factor (eEF2). Growing evidence suggests that the (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] metabolite acts independently of ketamine at presynaptic sites to promote glutamate signaling. As with SPs, the enhanced neural activity triggers BDNF release and is followed by transient activation of the mTOR pathway and increased expression of diverse proteins acting at glutamatergic synapses, along with functional strengthening of glutamatergic synapses. GPCR, G protein-coupled receptor; mGluR, metabotropic glutamate receptor; PSD95, post-synaptic density protein 95.

Methods
This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed.

Results
Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies—such as engagement of the downstream glutamatergic pathway—the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research.

Conclusions
Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.

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I've speculated for longer that the visuals from dissociatives [which I never really got btw] might be at least partially due to endogenous activation of the 5ht2a pathway. Anybody able to conclude if this makes that more or less plausible, and other implications?
Noteworthy that one of the authors (Dr Zarate) is listed as a co-inventor for a patent for the use of K in MDD (so responsible for these over-charging clinics I guess).

 

[Skorpio]

There is kind of some controversy about the hydroxynorketamine theory. Zarate is a proponent of it, and the lab of Monteggia rejects it. There are some spicy letters in journals between the two going back and forth on each others data.

I do not think this is evidence for dissos activating the 5ht2a pathway in a way conducive to psychadelia. If I had to throw my hat into the ring I would say that the mgluR part of the ht2a-mgluR heterodimer has a contribution to the neurogenesis effects of psychs.