Friday, December 21, 2012

Ketamine-Like Anti-Depressant Works Within Hours

Ketamine has been shown in at least a dozen studies by now to alleviate the symptoms of treatment-resistant depression within hours, and with a couple of follow-up treatments, the person can remain free of disabling depression for weeks or months.

The only downside to this is that Ketamine is a powerful drug that can cause hallucinations, hypertension, memory deficits, and other cognitive impairment in some users (as well as analgesia, anesthesia). So researchers have been trying to come up with a chemically similar analogue that removes the side effects - seems they may have done it.

It appears that this chemical also has powerful impact on pro-social behavior in some autistic individuals [see Moskal JR, Burgdorf J, Kroes RA, Brudzynski SM, Panksepp J. (2012, Oct). A novel NMDA receptor glycine-site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism. Neurosci Biobehav Rev. 2011 Oct;35(9):1982-8. doi: 10.1016/j.neubiorev.2011.06.006].

The original abstract for the paper is below - the article is behind a paywall.

New Anti-Depressant Works Within Hours 
Orion Jones on December 16, 2012, 1:30 PM

What's the Latest Development?

Researchers at Northwestern University are testing a new drug that can relieve the symptoms of depression within hours. Called GLYX-13, the new formula is similar to Ketamine, a strong sedative used in veterinary medicine and after-parties of a certain flavor. While both drugs target NMDA receptors, quickly removing symptoms of depression, GLYX-13 is hallucination-free. "Those who received the drug reported that their symptoms got better within two hours, with no significant side effects. The drug also performed significantly better than the placebo."

What's the Big Idea?

In the study, GLYX-13 or a placebo was given to 116 patients with depression that did not respond to other kinds of treatment. Scientists reckon that the new drug works by boosting either the strength or number of connections between neurons, although it is not yet clear why this improves symptoms. "Gerard Sanacora at Yale School of Medicine thinks that people with depression may experience a slump in activity in the frontal cortex of the brain, and that the drug might reverse this." Northwestern scientists want to help the drug to market by 2016.
Here is the abstract, hosted by Nature.

GLYX-13, an NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects

Jeffrey Burgdorf, Xiao-lei Zhang, Katherine L Nicholson, Robert L Balster, J David Leander, Patric K Stanton, Amanda L Gross, Roger A Kroes and Joseph R Moskal


Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDA receptor glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/ kainate receptor activation as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 hr) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of ‘metaplasticity’ by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.

Full Citation:
Burgdorf, J, Zhang, X, Nicholson, KL, Balster, RL, Leander, JD, Stanton, PK, Gross, AL, Kroes, RA, and Moskal, JR. (2012, Dec 3). GLYX-13, an NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects. Neuropsychopharmacology, doi:10.1038/npp.2012.246
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