New drug could revolutionize the treatment of neurologic disorders

[Waverunner]

Some weeks ago we talked about the therapeutic effects of Ketamine. It seems, that just now, we have the perfect replacement, with the same positive outcome but much less side effects. GLYX-13 could lead into a new era of glutamatergic treatment, according to Joseph Moskal. A single dose lasted up to seven days, worked within 24 hours and it's effect was twice as good as the effect of normal anti-depressants taken over a period of four to six weeks(!). Moreover is showed significant reduction in depression symptoms in patients, who showed little to none improvement on standard drugs. GLYX-13 could also have implications in the treatment of Alzheimer's disease and other neurologic conditions.

http://www.sciencedaily.com/releases/2012/12/121207094604.htm

Dec. 6, 2012 — A first-of-its-kind antidepressant drug discovered by a Northwestern University professor and now tested on adults who have failed other antidepressant therapies has been shown to alleviate symptoms within hours, have good safety and produce positive effects that last for about seven days from a single dose.

The novel therapeutic targets brain receptors responsible for learning and memory -- a very different approach from existing antidepressants. The new drug and others like it also could be helpful in treating other neurological conditions, including schizophrenia, bipolar disorder, anxiety and Alzheimer's disease.
The results of the phase IIa clinical trial were presented today (Dec. 6) at the 51st Annual Meeting of the American College of Neuropsychopharmacology in Hollywood, Fla.
Also this week a paper reporting some of the background scientific research that provided the foundation for the clinical development of GLYX-13 was published by the journal Neuropsychopharmacology.
The compound, called GLYX-13, is the result of more than two decades of work by Joseph Moskal, research professor of biomedical engineering at Northwestern's McCormick School of Engineering and Applied Science and director of the University's Falk Center for Molecular Therapeutics.
"Our study showed that this compound is capable of eliciting a robust and rapid antidepressant effect without the typical side effects seen with other drugs that also modulate the NMDA receptor," said Moskal, who is founder and chief scientific officer of the Evanston-based biotechnology company Naurex Inc., which conducted the clinical study.
GLYX-13 works by modulating the NMDA (N-methyl-D-aspartate) receptor in the brain, as do current NMDA receptor antagonists such as ketamine, but GLYX-13 does not have their serious and limiting side effects, such as hallucinations and schizophrenia-like effects. (An antagonist is a substance that inhibits the physiological action of another.)
Moskal and his team have figured out a new way to target the NMDA receptors that maintains the positive antidepressant properties while eliminating the negative side effects.
In clinical trials administered at 12 sites across the country, a single dose of GLYX-13 resulted in significant reductions in depression symptoms among subjects who had shown little improvement with previous drugs. (Subjects had failed treatment with one or more antidepressant agents.)
The positive effects of GLYX-13 were evident within 24 hours and lasted an average of seven days. The effect size, a measure of the magnitude of the drug's antidepressant efficacy, at both these times after a single dose was nearly double the effect size seen with most other antidepressant drugs after four to six weeks of repeated dosing.
Side effects of GLYX-13 were mild to moderate and were consistent with those observed in subjects receiving a placebo.
...
"While the results we are seeing with GLYX-13 are very encouraging, I believe the most important research is yet to come," Moskal said. "We have only scratched the surface of the therapeutic potential of the glutamatergic system."
GLYX-13 currently is undergoing a phase IIb clinical trial at 20 sites across the United States. This trial is evaluating repeated doses of the drug.
The Neuropsychopharmacology paper is titled "GLYX-13, an NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects."
The research was supported by grants from the Ralph and Marian Falk Medical Research Trust, the Hope for Depression Research Foundation and the National Institutes of Health (grants MH094835, NS044421 and DA01442).
Northwestern University has exclusively licensed the intellectual property rights related to the therapeutics developed by Joseph Moskal while at the University to Naurex Inc. Northwestern also has a small equity position in Naurex.

 

[Bob]

It is very interesting research, but the problem is that the US/EU governments won't license any drugs that have any addictive potential.
The reason that we don't have any really effective anti-depressants, after so many decades of research, is that all the really effective anti-depressant experimental drugs have had addictive potential, so they've either never been licensed, or have been withdrawn after being licensed.
The only ones that get licensed are self-limiting, or are very limited in their effect, or the side effects outweigh the therapeutic effects. (So they aren't addictive.)
If an antidepressant continues to increase its therapeutic effect, as the dosage is increased, then its got addictive potential, and will not be released onto the market.
The reason Ketamine been experimented on so widely, is because it's already widely available for other therapeutic uses, but I'd be surprised if analogues of Ketamine were ever licensed solely for depression.
This drug may fail at the next stage of clinical trials, if it is shown to be addictive.

This is my understanding of the historic situation, anyway.
There's a chance that I might have it all wrong.
Ever hopeful that they will one day license properly effective anti-depressant drugs and anti-anxiety drugs.

 

[Waverunner]

You make an interesting point, Bob, but they were administering GLYX-13 at doses, which were 50 - 100 times greater than the normal dose and they still didn't get any side effects. This is no proof of course, but I don't know any addictive substance, that has the same effect at different doses.

 

[Waverunner]

The next study which points towards NMDA as culprit of depression, suicide and inflammation. It seems, that the times where serotonin was the main focus is over.

"In the future, it's likely that blood samples from suicidal and depressive patients will be screened for inflammation"

http://www.sciencedaily.com/releases/2012/12/121214091614.htm

Dec. 13, 2012 — Researchers have found the first proof that a chemical in the brain called glutamate is linked to suicidal behavior, offering new hope for efforts to prevent people from taking their own lives.

Writing in the journal Neuropsychopharmacology, Michigan State University's Lena Brundin and an international team of co-investigators present the first evidence that glutamate is more active in the brains of people who attempt suicide. Glutamate is an amino acid that sends signals between nerve cells and has long been a suspect in the search for chemical causes of depression.
"The findings are important because they show a mechanism of disease in patients," said Brundin, an associate professor of experimental psychiatry in MSU's College of Human Medicine. "There's been a lot of focus on another neurotransmitter called serotonin for about 40 years now. The conclusion from our paper is that we need to turn some of that focus to glutamate."
...
The findings explain why earlier research has pointed to inflammation in the brain as a risk factor for suicide. The body produces quinolinic acid as part of the immune response that creates inflammation.
Brundin said anti-glutamate drugs are still in development, but could soon offer a promising tool for preventing suicide. In fact, recent clinical studies have shown the anesthetic ketamine -- which inhibits glutamate signaling -- to be extremely effective in fighting depression, though its side effects prevent it from being used widely today.
In the meantime, Brundin said physicians should be aware of inflammation as a likely trigger for suicidal behavior. She is partnering with doctors in Grand Rapids, Mich., to design clinical trials using anti-inflammatory drugs.
"In the future, it's likely that blood samples from suicidal and depressive patients will be screened for inflammation," Brundin said. "It is important that primary health care physicians and psychiatrists work closely together on this."

 

[MishMash]

It's good news that they have discovered glutamate as the active agent in neurological inflammation, and depression. We get to put that serotonin nonsense in our rearview mirror. 95% of patients who took SSRIs did not do better than placebo. I'm hopeful it will actually be proven beneficial in high-quality studies.

I reckon a huge pharma corporation will come along and buy the small company that developed the drug. Pharma companies don't find drugs by themselves anymore; they buy smaller companies that have developed potential lucrative products. Seems like the company was shopping around its product at that conference.

But I think this means that Ketamine will be shoved aside (because it is unpatentable) and Ketamine does have the special ability to half Major Depression Disorder (MDD) with one treatment. I didn't see anything about treating MDD in either article. Ketamine also has the capability of reducing Complex Pain syndrome. It's a wonder drug.