Ketamine and ketamines "cousin" GLYX-13 = suitable candidates for countering acute suicidality in affective disorders

http://www.sciencedaily.com/releases/2013/05/130530170052.htm

Keatmines “cousin” [GLYX-13] rapidly lifts depression without side effects:
“Human clinical studies demonstrated that ketamine can ward off major and bipolar depressive symptoms within 2 hours of administration and last for several days. Ketamine is fraught with serious side effects including excessive sleepiness, hallucinations, and substance abuse behavior.”
"Our drug, GLYX-13, is very different. It does not block the receptor ion channel, which may account for why it doesn't have the same side effects."

“Previous electrophysiological and conditioning studies had suggested that GLYX-13, unlike ketamine, enhanced memory and learning in rats, particularly in the brain's memory hub or hippocampus. GLYX-13 also produced analgesic effects.”

“GLYX-13 and ketamine produced rapid acting (1 hour) and long-lasting (24 hour) antidepressant-like effects in the rats. Fluoxetine, an SSRI that typically takes from 2-4 weeks to show efficacy in humans, did not produce a rapid antidepressant effect in this study.”

“These results are consistent with data from a recent Phase 2 clinical trial, in which a single administration of GLYX-13 produced statistically significant reductions in depression scores in patients who had failed treatment with current antidepressants. The reductions were evident within 24 hours and persisted for an average of 7 days. After a single dose of GLYX-13, the drug's antidepressant efficacy nearly doubled that seen with most conventional antidepressants after 4-6 weeks of dosing. GLYX-13 was well tolerated and it did not produce any of the schizophrenia-like effects associated with other NMDA receptor modulating agents.”

“Moskal speculates that GLYX-13 either directly binds to the glycine site on the NMDA receptor or indirectly modulates how glycine works with the receptor. Resulting activation of more NMDA and AMPA receptors leads to an increase in memory, learning -- and antidepressant effects. By contrast, ketamine only blocks the NMDA receptor, but also increases the activity of the AMPA receptor. Knowledge of these mechanisms could lead to the development of more effective antidepressants.”

This reminds me of how SSRI’s are speculated to possibly work through their effects on increasing brain derived neuro factor (BDNF) which may in turn make one hypersusceptible to new learning, in turn allowing someone in a rut to quickly learn a way out of it…

People are always suprised when I say Ketamine, horse tranquiliser, or special K as it is known in drug circles has beneficial properties. It was also shown in another study to have neuroregenerative effects:
http://www.sciencedaily.com/releases/2012/10/121004141747.htm
"In their research, Duman and others show that in a series of steps ketamine triggers release of neurotransmitter glutamate, which in turn stimulates growth of synapses. Research at Yale has shown that damage of these synaptic connections caused by chronic stress is rapidly reversed by a single dose of ketamine."

Though I've never used it, so I can't attest to this personally, but i'm all for the open study of drugs and there effects, both positive and negative.

Sapolsky on chronic stress and hippocampal damage:
 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC60045/

Chronic stress causes prolonged Cortisol release from the adrenals, which in turn feeds back to the hypothalamus and has a negative feedback on the cortisol release, as one would expect. However, there is more to this than a simple negative feedback loop. The hippocampus seems to have a negative influence upon the hypothalamic release of CRH, in turn lowering cortisol levels. Unfortunately, the sustained levels of cortisol, if an organism is chronically stressed, seem to inhibit the hippocampus through 3 possible mecahnisms described by sapolsky:
1)Temporary (reversible) retraction of hippocampal dendritic connections
2)Ihnibition of neurogenesis in the hippocampus
3)Hippocampal neurotoxicity = a loss of preexisting hippocampal neurons

This explains the loss of hippocampal volume that is common in severly depressed patients that express high cortisol levels, and might explain the permanency of various functional/mood/ learning losses as a result of depression working through permanent hippocampal damage.




The potentially good news is that anti depressants (Tianeptine - and SSRE [enhancer]) - and possibly other (SSRI's) [despite the seeming incongruity] increase BDNF, which in turn inhibits the effect of cortisol upon the hippocampus thereby preserving its integrity.
"Although the best known of these are the specific serotonin reuptake inhibitors such as Prozac, other efficacious drugs also block the reuptake of norepinephrine and/or dopamine. Nicely commensurate with the involvement of serotonin, there is some evidence that increased serotonin availability can stimulate cell proliferation in the hippocampus However, tianeptine is a distinctly atypical antidepressant (with, reputedly, only limited clinical efficacy), which increases serotonin reuptake. Thus, it decreases synaptic serotonin concentrations, rather than enhancing them."



It may well be then, that antidepressants not only help the patient now, but if they can both lower stress now, and lower the deleterious effects of stress upon the hippocampus, that the patient is less likely to have lasting permanent damage to the hippocampus, and with it permanent damage to learning and mood centres!

It is worth mentioning that a few still think some sort of neurogenesis issue in the hippocampus could lead to depression, not the other way around, but they are a minority and evidence appears scarce.

I will leave you with the great man's words himself:
"Obviously, more research is needed. It would be a boon to biological psychiatry if any antidepressants can prevent some of the neurobiological correlates of depression, in addition to alleviating the affective symptoms. But findings such as these also support the frequent uphill battle for those who study depression, or suffer from it, namely convincing others that this is a real biological disorder, rather than some sort of failure of fortitude or spirit."