New NMDA Receptor (Glutamate) Modulators for Depression

New NMDA Receptor (Glutamate) Modulators For Depression

"Glutamate modulating drugs are of interest for a number of diseases in addition to ALS, such as Alzheimer’s disease, Rett syndrome, dementia, dystonia, tinnitus, anxiety disorders, and affective disorders."

"Scientists and mental health researchers have long been collecting evidence to discover what causes depression. Their goal is to find a specific neurotransmitter or system that could be targeted to develop a new class of antidepressant medication that would be more effective for the masses, result in less side effects, and be considered safe. While throughout history the serotonergic system has been marketed as the “cause” of depression, it’s obvious that serotonin isn’t always the culprit.


In many cases, people are simply depressed due to poor dietary choices, inadequate exercise, unhealthy relationships, stress, and lack of quality sleep. Then there are other individuals with a genetic predisposition to depression that can live extremely healthy lifestyles, but cannot manage to shake their depression. In the event that someone has a genetically-based depression, pharmaceutical treatments are usually among the most effective options for coping.

NMDA Receptor (Glutamate) Modulators for Depression

Recently biotech firms have taken interest in the fact that glutamatergic functioning in the brain can produce an antidepressant effect. This has lead to companies developing drugs that would modulate glutamate functioning via targeting the NMDA receptor. Below is a list of all NMDA receptor antidepressants in development.

1. GLYX-13 ( Rapastinel)
This is a NMDA receptor partial agonist with selective properties. It is being developed by the company Naurex as an antidepressant augmentation strategy for individuals with treatment-resistant depression. It is not currently available in oral formulations and must be administered via intravenous injections.

Due to promising results in early phases of clinical trials, the FDA has granted it “fast track” status. In other words, if all goes according to plan and there are no major setbacks, it should get approved sooner than later. Word is that the company is also developing an oral version of this particular drug. In most recent 6-week trials, it elicited an effect size that was over double that of standard antidepressant treatments.

On March 3, 2014, the U.S. FDA granted Fast Track designation to the development of rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder.[3] As of 2015, the drug had completed phase II clinical development for this indication.[4] On January 29, 2016, Allergan (who acquired Naurex in July 2015) announced that rapastinel had received Breakthrough Therapy designation from the U.S


Not only does this drug tend to work within hours of initial dosing, it only needs to be administered once a week. The antidepressant effects last a full week (7 days) after one injection. In addition to antidepressant properties, some have suggested that it may have nootropic and neuroprotective potential based on evidence from rodent studies.

2. NRX-1074 ( Apimostinel)
This is a drug that acts very similar to GLYX-13 and is being developed by the same company Naurex. Unlike GLYX-13 though, it has not received “fast track” status (yet) from the FDA. It functions by acting as an NMDA receptor partial agonist with a selective affinity for the glycine site. It differs from GLYX-13 in that it was created in oral form, is significantly more potent, and is being researched as a standalone antidepressant option (as opposed to an adjunct).

In early studies, it has shown rapid antidepressant effects and is considered very well-tolerated in preliminary trials. Like GLYX-13, this drug works quickly and is considered an improved version of ketamine. It acts similarly, but taking it won’t result in dissociative or hallucinogenic side effects. Plus it produces a quick, highly-potent antidepressant response. During May 2014 it was in Phase II(A) clinical trials for the treatment of major depression.

Its mechanism of action and effects are similar to those of rapastinel (GLYX-13), which is under development as an adjunctive therapy for treatment-resistant depression also by Naurex; however, apimostinel is 100-fold more potent by weight and, unlike rapastinel (which must be administered via intravenous injection), is orally-active.[3] Apimostinel is intended by Naurex as an improved, follow-up drug to rapastinel.

3. Esketamine (Ketanest S)
Esketamine is derived from the drug ketamine, containing the s-stereoisomer. It is considered an anesthetic and dissociative drug and functions by acting as an NMDA receptor antagonist with non-competitive properties. In addition to acting on the NMDA receptor, it also promotes the reuptake inhibition of the neurotransmitter dopamine.

Like many other NMDA receptor modulators, it is being tested in clinical trials for the treatment of major depression. We already know that ketamine provides fast-acting depression relief. This particular drug is considered twice as potent as ketamine, and has a shorter half-life than the other “R”-stereoisomer. Current evidence suggests that Esketamine (S-ketamine) has a significant therapeutic advantage over R-ketamine.

Comparatively speaking, Esketamine provides significantly more dopamine reuptake inhibition (up to 8 times) than R-ketamine. In trials, people have reported liking the effects of Esketamine more than other formulations. Additionally those who take this form of ketamine typically have an easier time regaining normal cognitive function compared to other forms.

Another difference of Esketamine compared to R-ketamine is that it elicits a greater (3-4 times) effect on the NMDA receptor’s PCP binding site. It also has been shown to increase the metabolic processing of glucose within the frontal region of the brain, while other formulations tend to actually reduce glucose metabolism. As was already mentioned awhile back, companies are developing and testing “ketamine nasal spray” formulations using “Esketamine.”

As of August 18, 2016, it is in phase III clinical trials for treatment-resistant depression


Thoughts on NMDA Receptor Antidepressants
The development of these new medications could be groundbreaking for those who fail to get relief from modern day antidepressant options. A significant percentage of individuals (almost half) fail to get relief from existing approved antidepressant pharmaceuticals. New drugs that target the NMDA receptor in their mechanism of action may prove to be more beneficial for the masses than current drugs.

Although many are only in the investigational phases of clinical research, some have actually been granted “fast track” status due to high efficacy and low rates of adverse effects. It is clear that biotech companies have discovered that the glutamatergic system may prove to be of significant benefit in treating individuals with major depression. While it is unknown what the long-term effects of these drugs will be, existing evidence would suggest a more favorable side effect profile and potent antidepressant effect.

These treatments may prove to be extremely beneficial to those with treatment-resistant forms of depression. Not everyone is capable of biohacking their mental health with supplements or using natural cures for depression to get relief. Some individuals have a genetic predisposition to depression, and although the cause is unknown, it appears as though targeting glutamatergic functioning can provide more significant relief than existing options.

Obviously it doesn’t mean that these drugs will never be problematic. They may very well cause some sort of unwanted long-term effects and/or adverse reactions in a larger sample size. Additionally most drugs should never be regarded as being effective over the long-term due to the fact that most people eventually reach a physiological tolerance. With that said, these drugs in development are at least unique compared to other antidepressants."

 

Very cool find @Danny Boy !

More exploration into the way that NDMA receptors work is always inviting, as a reminder to others this is how Keyzilen (Auris Medical) works:

A greater understanding of these mechanisms of action is sure to answer questions on this tinnitus front!