“I Feel Depressed! So, What’s in the Relief Pipeline?” Let’s Chat GLYX-13

Feel Depressed

“Hmmm, I’ve been thinkin’. When it comes to how to deal with depression, what if the target of my antidepressant isn’t where the action is? I mean, I still feel depressed, so that must mean the remedy isn’t taking care of biz.”

And I’m thinkin’ you have a valid point (‘course, assuming you’re participating in therapy). Not only that, I believe you’re well within your rights to feel – well – cheated.

Okay, let’s say you’re taking a selective serotonin reuptake inhibitor (SSRI: Prozac, Lexapro, Zoloft, Celexa, etc.); or perhaps a serotonin norepinephrine reuptake inhibitor (SNRI: Effexor, Pristiq, Cymbalta). News flash! Research tells us 30-40% of adults are unresponsive to them.

So maybe the supposition in the opening statement is spot-on. Impacting the reuptake of serotonin and norepinephrine – even dopamine, for our bupropion (Wellbutrin) users – isn’t really where it’s at when it comes to a reasonably fast-acting depression knock-out punch. Don’t know about you; however, if such is the case, I’m hoping other targets are being identified, and interventions being devised to influence them.

Even though their appearance on pharmacy shelves may be a significant amount of time away, I believe it’s important to bring you news regarding what’s in the depression and anxiety medicinal relief pipeline. That said, I have an update I’m thinking you’ll find interesting – and hopeful.

In December of last year I posted an article on a revolutionary antidepressant in development currently known as GLYX-13. I came upon some updated information on it not long ago, and I knew I had to bring it to you.

What you’re about to read is grounded in a study funded by the National Institute of Mental Health (NIMH), published this past April in the journal Neuropsychopharmacology.

So we know the neurotransmitters serotonin, norepinephrine, and dopamine have been the traditional targets of antidepressants. Well, it seems as though the neurotransmitter glutamate is getting tons of attention these days, specifically its NMDA (N-methyl-D-aspartate) receptors.

How ’bout a bit of history? Some 40 years ago, researchers figured out NMDA receptors were players in learning and memory. In the 1980s, drugs were developed that blocked these receptors with the hope of preventing strokes. Unfortunately, the result was an increase in cardiovascular disease. So for the brain-trust of biotech and pharmaceutical companies, that would be that for NMDA receptors.

However, in the early 2000s it was discovered that the anesthetic drug ketamine – a glutamate receptor antagonist (blocks or dampens action) – put the kibosh on unipolar and bipolar depressive symptoms within two hours of administration. And the effect lasted several days! ‘Course, very intense side effects formed a major practicality barrier.

Oh, almost forgot to mention – the senior author of our study is Joseph Moskal, PhD. Dr. Moskal is a research professor of biomedical engineering at Northwestern University’s School of Engineering and Applied Science. He’s also the director of their Falk Center for Molecular Therapeutics. And go figure, Moskal discovered GLYX-13. And, yes, he also happens to be the founder and Chief Scientific Officer of Naurex, the neuropharmaceutical company developing it.

As he considers the history of ketamine, Moskal reflects, “Ketamine lit the field back up.” And he goes on to point out GLYX-13 doesn’t share ketamine’s side effects profile likely because of different blocking action on the NMDA receptor.

So let’s take a look at Moskal’s study. He and his team incorporated several behavioral and molecular experiments, using rats. Tested were four compounds: GLYX-13, an inactive version of GLYX-13 with rearranged amino acids, ketamine, and the antidepressant fluoxetine (Prozac).

Here’s what went down. GLYX-13 and ketamine generated antidepressant-like effects within one hour, lasting 24 hours. Fluoxetine failed to produce a fast-acting antidepressant effect. And the “rearranged” version of GLYX-13 generated no impact at all. It’s important to note, GLYX-13 produced no ketamine-like side effects.

Well, then, exactly what makes GLYX-13 effective? Moskal and team speculate it all goes down in the brain’s hippocampus. Without going into all of the biochemical yada, yada, GLYX-13 (and ketamine) promotes long-lasting signal transmission in neurons. For the record, it’s called long-term potentiation/synaptic plasticity, and it’s a must for learning and memory. So it’s all about enhanced communication between neurons.

The very good news here is the study results are consistent with data from GLYX-13s Phase 2 clinical trial. Behold! A single dose of GLYX-13 produced statistically significant reductions in depression scores in patients who had failed treatment with current antidepressants. But there’s more! These reductions were observable within 24 hours and lasted for an average of seven days. Even more! GLYX-13s antidepressant effect was some 200% greater than that seen with most existing antidepressants after four to six week’s use.

Finally, GLYX-13 was well tolerated and didn’t produce even one schizophrenia-like side-effect, often seen with other NMDA receptor modulating agents.

So what’s next in the GLYX-13 saga? Phase 2 trials continue, in which Moskal and his Naurex team are searching for optimal dosing in humans. They also want to determine if GLYX-13 impacts other receptor subtypes, and determine if it will work on other disorders, such as schizophrenia, autism, and attention deficient-hyperactivity disorder (ADHD).

Check this out from Dr. Moskal…

One could call NMDA modulators such as GLYX-13 ‘comeback kids.’ A toolkit that I developed in 1983 is now setting the stage in 2013 for the development of possible new therapeutics that may provide individuals suffering from depression with a valuable new treatment option.

After many moons, if Job 1 in your neck of the woods is how to deal with depression, having GLYX-13 in the pipeline may be a life-changing reality. Yes, I realize it may be several years away from our mouths and bellies; however, it’s super important to keep our eyes and ears on the future.

And if you continue to shout, “I feel depressed!,” doesn’t knowing someone (actually many) out there is working their tail off to bring you relief provide a measure of comfort? I sure hope so.

UPDATE!!! GLYX-13 now has a name: Rapastinel. So development is chugging along.

“More Chipur articles!,” you say? Just a click away

  • Megan June 16, 2013, 2:18 am

    Ketamine? “Special K”, right? That’s crazy. I have never been able to shake my depression. My psychiatrist won’t allow me to suggest new medications because he thinks he knows what’s right for me. I hear about the new antidepressants and I wonder how well they work. When I first started on Zoloft, it really boosted my spirit. Unfortunately, it didn’t take much for the depression to start up again. I truly believe if I had access to a truly good antidepressant that many of my anxiety symptoms would go away. I know this because of my early experience with Zoloft. I’ve even tried to get back on Zoloft but the monkey in his office in his Cosby sweaters won’t let me speak for myself. /sigh It’s so frustrating! When did he reach that point where he doesn’t have to listen to clients? There are so many frustrating things coming out of psychiatry and psychology. I am mainly speaking of the ineptness of doctors and their hubris which leads them to dismiss a patient and their suffering as minimal. There’s a great lack of empathy.

    • chipur June 16, 2013, 9:16 pm

      Yes, ma’am, Megan – “Special K.” isn’t that something? I mean, there are all sorts of pieces of hope out there. And I really do believe researchers are hot after them. Now, I have no doubt many of them are in it to help folks who are having a tough time of it. But I’m sure some are in it for the loot. And you know what? So be it, if efficacious depression/anxiety remedies come of it.

      A pet pieve of mine is psychiatrists – any medical doc – who won’t consider her/his patient’s opinion. You know, i have several therapy clients who do quite a bit of research and take their findings and request(s) to their psychiatrist – and very often walk away with a requested prescription. Okay, yeah, your psychiatrist may have thoughts as to “what’s right” for you; however, who would know better? I mean, to just cut you off is so disrespectful.

      Thanks for sharing, Megan. Always appreciated.


    • Renee June 19, 2013, 3:04 am

      I’m sorry you’ve had bad experiences with psychiatrists. I don’t think you’re alone there. Of course there are some excellent, caring doctors as well but I think they can be hard to find. This doesn’t replace a regular psychiatrist/therapist, but I recommend checking clinicaltrials.gov to see if there may be a clinical trial with Ketamine or a Ketamine-like drug in your area. They’re actually being conducted all across the country. Of course what they’re looking for varies so it’s not guaranteed you qualify, but it definitely doesn’t hurt to send an email or call and see.

      If you search Ketamine the GLYX-13 ones should come up too. There is also an existing pill called Riluzole used for ALS (I know, weird) that has shown some efficacy in depression. I don’t know much about it but it’s supposed to be sort of chemically similar to Ketamine and there are current trials with it as well. Personally I would contact the study coordinator of the one that appeals to you even if you don’t find one listed in your specific city – I found a GLYX-13 trial 2 miles away that way and start this week. Hang in there.

      • Megan June 19, 2013, 9:29 am

        Thanks, Renee! It still is creepy to me that they’re using something similar to Ketamine. All I can think about is taking the drug and everything being trippy. From what I read, it doesn’t have the hallucinogenic effects but I’m still scared to give it a try because of the image I get in my mind concerning Ketamine and anything related to it. I live in the sticks so there are no programs near me. It’s the thought that counts!

      • chipur June 19, 2013, 10:30 am

        Sure appreciate the response to Megan, Renee. Great information!!!

  • Eric July 30, 2013, 5:53 pm

    I’ve been hearing about an antidepressant that is expected to get FDA approval in October. It’s called Brintellix (vortioxetine) and seems to have a unique mechanism of action. In other words, not another SSRI/SNRI. Yay! Bill, have you heard anything about it?

    • chipur July 30, 2013, 10:30 pm

      Thanks for the visit and contribution, Eric. Vortioxetine is a treatment for major depressive and generalized anxiety disorders. It’s a serotonin transporter blocker (a serotonin transporter removes serotonin from the synaptic cleft back into the synaptic boutons – putting the kibosh on the effects of serotonin and at the same time allowing its reuse by the presynaptic neuron). It also influences several serotonin receptors. Hey, let’s see what happens, as it will no doubt help some. Am I doing cartwheels over it? Um, no. More info? http://en.wikipedia.org/wiki/Vortioxetine

  • Eric July 31, 2013, 6:32 pm

    Hey Bill- Have you heard about vortioxetine (aka Brintellix)? Sounds like a new mechanism of action. In other words, not another SSRI/SNRI. It’s set for FDA approval in October. Fingers crossed we’ll see it soon. So tired of the ssri/tricyclic/natural remedy merry go round..

    • chipur December 19, 2013, 1:07 pm

      Boy, Eric, you caught me sleepin’. I’m sorry I didn’t reply upon your posting. My reply to a question on the Chipur Facebook page…
      (Brintellix) was FDA approved for the treatment of adult Major
      Depressive Disorder two months ago. It may also be efficacious in the
      treatment of Generalized Anxiety
      Disorder. It’s being referred to as a “serontonin modulator and
      stimulator.” This, as opposed to the trendy reuptake inhibitors. Other
      serotonin modulators: nefazodone (Serzone), trazodone (Desyrel).
      Vortioxetine’s primary actions: serotonin transporter blocker, which
      inhibits the termination of serotonin action – and – 5-HT1A receptor
      high-efficacy partial agonist/near-full agonist. This piece is about
      neuromodulation. It aids in preventing serotonin-deficient states and
      minimizes receptor overstimulation in the presence of an excess of
      neurotransmitter. This action is also desirable beause it’s often
      efficacious and diminishes liability for producing side effects or
      toxicity. Important is the fact that there are tons of 5-HT1A receptors
      in the midbrain and the limbic system – key in the mood/anxiety
      disorders. Issues with 5-HT1A receptor-mediated response has been
      reported in those with problematic depression, which suggests a
      desensitization of these receptors is involved in the mood/anxiety
      disorders. Blah, blah, blah, right? Bottom-line: Trial results look
      pretty decent, but I’m not jumping up and down. Like any other
      antidepressant, it will work for some – not for others. Nothing
      earth-shaking here IMHO.

  • citygirl December 19, 2013, 11:42 am

    According to those administering the study in which I am participating, an open label study for glyx-13 is expected to begin in early 2014 and is planned to run until FDA approval.

    • chipur December 19, 2013, 1:02 pm

      Thanks for the update, citygirl. Is it working for you? Side effects? I’d appreciate it if you’d share…

  • Daryn February 7, 2015, 1:43 pm

    Great article from a “whats new” standpoint. As a veteran depression-symptom sufferer I love to hear positive news regarding new treatment. Ketamine’s antidepressant qualities was written about as far back as 2000 based on my research. So why has it taken so long to bring ketamine research to where it is today?
    Looking around on the National Institute of Mental Health website the answer is quite apparent. Current funding is dismal relative to the US budget. It seems that leaders in the government, medical institutions, and corporate world can’t seem to get together and agree that the 30 to 40 thousand self inflicted deaths each year combined with the one million suicide attempts (in the US alone) are worth the critical funding needed to provide treatment.
    When adding to the equation the heinous crimes of mass shootings one finds the human anguish to be monumental and yet it doesn’t seem to be important enough for us to get serious about developing an effective plan for treatment research.
    The US budgets only a few tenths of a percent annually for mental health research. The director of the NIMH Tom Insel said in a recent article that their annual funding has actually dropped since 2003 when factoring in inflation.
    In my view the priorities of our country’s leaders is warped but then I think it has been for some time. Hopefully humanity will wake soon.
    Thanks again for the article Bill.

    • Chipur February 7, 2015, 3:46 pm

      Hey Daryn!

      Glad you stopped-on-by and commented. We’re in the midst of very frustrating, life-taking, circumstances.

      As you say – “It seems that leaders in the government, medical institutions, and corporate world can’t seem to get together and agree that the 30 to 40 thousand self inflicted deaths each year combined with the one million suicide attempts (in the US alone) are worth the critical funding needed to provide treatment.”

      Stigma – and denial – strike once again!

      On the optimistic side of the fence, there’s the information in this article http://www.latimes.com/science/sciencenow/la-sci-sn-mental-illness-research-20140722-story.html#page=1

      Thanks for your passion, Daryn. One of these days a collective passion may just drive results…