Drug fights hard-to-treat depression by targeting brain receptors in a new way

by Megan Fellman

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 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 , including schizophrenia, bipolar disorder, anxiety and Alzheimer's disease.

The results of the phase IIa clinical trial were presented 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 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 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.

GLYX-13 is a four-amino acid peptide that modulates one of a large family of glutamate receptors, the NMDA (N-methyl-D-aspartate) receptor, in the brain. NMDA receptors play a key role in regulating synaptic plasticity—the quality of the connection between neurons—and thus are important in regulating learning and memory functions.

GLYX-13 is administered intravenously. Moskal said Naurex also is working on an oral drug with similar properties and potential.

Moskal hopes that these positive GLYX-13 results and the research efforts of his team and colleagues will help shepherd in more research and grant support for studying the role of the glutamate-mediated processes in neuropsychiatric disorders.

"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 Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without -Like Side Effects."

More information: www.nature.com/npp/journal/vao… abs/npp2012246a.html

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Durrr
1 / 5 (2) Dec 07, 2012
D.M.T. cured my depression.
Newbeak
5 / 5 (2) Dec 07, 2012
The idiotic "War on Drugs" doesn't care that psychedelic drugs like LSD were found to have promise in mental illness in studies done in the 60's.
Torbjorn_Larsson_OM
2.5 / 5 (2) Dec 07, 2012
And the idiotic "War on "War on Drugs"" doesn't care that those studies were done with a terribly poor quality like the researchers were on LSD. (Which it is rumored some where!)

"By classifying LSD as a Schedule I substance, the Drug Enforcement Administration holds that LSD meets the following three criteria: it is deemed to have a high potential for abuse; it has no legitimate medical use in treatment; and there is a lack of accepted safety for its use under medical supervision. There are no documented deaths from chemical toxicity; most LSD deaths are a result of behavioral toxicity.[114]"

Wait until there *is* a legitimate use and demonstrated safety which can counter its high potential for abuse, before going off on an irrelevant rant without substantiated facts.
gwrede
5 / 5 (1) Dec 07, 2012
The jury is still out on LSD, but we don't need aggressive attitudes on either side. Rather, we should approach it with curiosity, prudence and diligence.

Lately, there have been a number of very interesting articles on LSD on this very site.