Category: Esketamine

Esketamine Nasal Spray from Lori Calabrese, MD | The Ketamine Blog

We provide these articles about esketamine nasal spray, known by the brand name Spravato, to inform… and explain the similarities and differences between esketamine and ketamine, the compound esketamine was derived from.

Racemic Ketamine and Its Twin Molecules

As a compound made of two mirror-image molecules, racemic ketamine performs with extraordinary and robust antidepressant strength. We call those mirror-image molecules enantiomers. So, the word “racemic” simply means a compound made of right-handed and left-handed molecules.

You probably notice that identical twins look not so much exactly the same, but rather, they look like mirror images of each other. This phenomenon occurs all through nature. And you see it on the cell level, too.

The fact that these molecules are mirror images of each other doesn’t mean they’re identical. They’re similar…and have similar properties. Sometimes you see this with identical twins. For instance, one twin shows empathy, compassion, and introversion, while the other fills a room with laughter and friendliness.

In the same way, these molecules act differently also, with one showing stronger properties of one kind and the other showing stronger properties of another. It’s the synergy between the two that creates the characteristics of the full racemic compound.

The ketamine compound dynamically illustrates this. Each enantiomer behaves in some ways like the other, and behaves differently from the other in other ways.

We recognize the left enantiomer molecule s-ketamine…”s” being an abbreviation for the latin term for “left.” We recognize the right one r-ketamine, which is much easier to remember, right? So, with this in mind, they created a name that uses the “s” or the “r” phonetically. So these enantiomers enjoy the nicknames of esketamine and arketamine. Clever-ish…maybe?

Creating a NEW Medicine with an Old Molecule

Researchers hoped that by separating the left mirror-image molecule from the right-side one, they could produce an antidepressant with fewer side effects and less addiction risk. They knew they needed an entirely new compound. Because they needed the financial benefits of a patent to pay for the extensive research and testing that would be required to receive FDA approval.

It turned out that their new medicine required the aide of a newly initiated anti-depressant to perform as an antidepressant effectively. But with that antidepressant added, it showed some promising ability for erasing suicidal thinking and lifting depression.

Unfortunately, life in the laboratory behaves a lot like life everywhere else. It can be unpredictable. During the trials required for FDA approved, esketamine performed like a champ in some trials, and failed rather miserably in others.

At a time when the suicide rate rises higher and higher, psychiatrists need medicines that erase suicidal thinking. As a result, the FDA approved this new medicine along with its specially designed spray in March 2019. They took precautions, however.

They imposed safeguards. One such safeguard required that doses be restricted to administration in the office under medical supervision. Another one required that the doctor hold the patient for observation in the office for 2 hours after each dose, in case of side effects.

A Ketamine-Derived Medicine Covered by Insurance?

Janssen, a company owned by Johnson&Johnson which developed this medicine, promises that esketamine nasal spray will be covered by insurance. So, we’re waiting to hear what the coverage will be.

Will Spravato replace IV ketamine treatment? Probably not.

While esketamine may not be as effective as ketamine and is more expensive to administer. Does it have a place in treatment of depression and suicidal thinking? We certainly hope so. The fact that insurance companies plan to provide coverage for it will hopefully make it available to patients who find IV ketamine treatment is out of reach financially.

Because of the way the media promoted Spravato (esketamine), most people think that ketamine nasal spray was approved by the FDA. Esketamine isn’t ketamine, but it IS derived from ketamine. It performs with some of ketamine’s traits, but not others.

At Innovative Psychiatry, we embrace treatments that may help. And we hope esketamine will help some who haven’t been helped by traditional antidepressants or anxiety medicines. As you read these articles about esketamine nasal spray, remember this is a new medication and we’ll know more as we use it to treat the conditions it’s been developed to relieve.

Ketamine KRIYA Conference 2018

KRIYA!!

The most phenomenal ketamine conference to date!

Last weekend I attended and presented at the ketamine KRIYA Conference 2018 in San Francisco. This conference emerged as the most dynamic gathering of front-line ketamine practitioners I’ve ever experienced.

And what an event!

The ketamine KRIYA Conference 2018 was extraordinarily different than any other research or clinical conference I’ve attended. It’s clear that the realm of ketamine treatment for psychiatric disorders is growing wider and deeper.

There was a true spirit of inquiry, extraordinarily open collaboration, and presentations of risks, failures, and triumphs. Sheer transparency. Openly exposed vulnerabilities. A clear admission of the limitations of what we know. The latest information about clinical uses of ketamine in psychiatry.

The insider news.

What happened when Raquel put all of it — and all of us — together?

Palpable energy instantly exploded!

During the presentations — which were riveting. As we met for coffee. Chatted on the beautiful conference grounds, sprawled out over the steps, snugged down into comfy couches, talked over creative and inventive lunches, inhaled coffee (for some of us, all throughout the day!) — there was the sense that we needed to learn from each other as fast as we could. So … we shared Ubers and Lyfts and dinner tabs.

We came from all over the country … and from as far away as Russia.

We’re serious about this.

And what a weekend! We learned so much from each speaker and each other. We talked about our data, our practices, our experiences, what we’ve learned. What we still don’t know.

Soooo many different backgrounds, so many different approaches providing patient care, so much desire to reduce suffering in our patients.

Founded by Raquel Bennett, Ph.D., KRIYA is the Ketamine Research Institute and it is devoted to understanding the use of therapeutic ketamine in psychiatry and psychotherapy.

I must give a shout out to Raquel Bennett.

In such a few short years, she single-handedly founded, organized and grew KRIYA, an organization devoted to helping people heal and live fuller lives through safe, legal, and effective ketamine treatment. She is originator of the first international ketamine conference — KRIYA’s first conference, in 2015 — on the therapeutic use of ketamine.

Raquel has earned our respect, appreciation, and applause for the enormously hard work of bringing together experts who work with therapeutic ketamine in very different ways, using different routes, for different therapeutic purposes, in all aspects of psychiatry and psychotherapy, as well as in chronic pain and hospice.

Ketamine is a visionary medicine.

But Raquel Bennett, Ph.D, is a visionary.

Fantastic speakers, wonderful food, and gorgeous (read: non-hotel) settings gave all of us opportunities to pick the brain of someone nearby. We shared, we ate, we discussed, we listened. And at the end, we kept talking until they put away the chairs, and turned out the lights … until we each left for the airport. And then checked in and kept going.

Meet me in Terminal 2. I’m at Starbucks. Find us in the International Terminal. We’re sitting in the food court.

Until one by one, each had to break away to catch a plane.

… You haven’t seen anything til you’ve seen the excitement that comes from connection.

Many thanks to Raquel and her incredibly talented, organized and generous team for making this all possible.

Raquel Bennet, Psy.D.

Though our backgrounds are different, and our methods varied, it was clear that we share the same passion: to help reduce suffering from psychiatric symptoms and physical pain.

Next, let me say, I can’t possibly share it all with you here — there were 30 different speakers over 2 days, fascinating and varied discussion panels, and a lively sharing of experiences and ideas that kept us on our toes till the wee hours.

This conference was thrilling.

Thrilling.

I attended KRIYA last year. But there has been so much growth, so much more research, so many new frontiers since then … that this gathering really can’t compare.

These 30 speakers ran the full gamut of experience with using therapeutic ketamine in psychiatry — different practice settings, different studies, varied doses, varied routes of administration, varied preparation. Varied goals.

This was no room for small or closed minds.

We ALL learned and grew during those two days.

Raquel Bennett opened to set the stage for this smorgasbord of ideas.

She said, “We are witnessing the birth of a new field.” She spoke about how ketamine was developed for anesthesiology and has served that field well. But the therapeutic use of ketamine has birthed a new field of ketamine in psychiatry.

And she emphasized that the two are as different as apples and toast.

One way they’re different is in the goals of treatment. For anesthesiologists, ketamine has been used for managing consciousness or sedation and addressing physical pain. In psychiatry, the goal of treatment is all about treating psychiatric symptoms and managing psychiatric distress.

The second difference is in training and areas of expertise, diagnostic skills, and managing emergencies, and she described the differences between anesthesiologists and psychiatrists. Anesthesiologists are best at managing surgical emergencies, interventional pain procedures and life support. But psychiatrists are experts in diagnosing psychiatric conditions and managing psychiatrist emergencies.

The third difference is in the type of patient who presents for treatment. In psychiatry, our patients need a lot of contact, a high degree of emotional safety, and a great deal of emotional support and reassurance. Things we’re deeply attuned to by our psychiatric training.

She also talked about the differences in routes of administration as well as the dose used for each type of patient to reach the individual goals of sedation vs. relief of psychiatric symptoms.

Add to that the amount of preparation required in each field. An anesthesiologist can walk into the surgical area, say hello to his patient, and tell him to count backwards from 12.

However, psychiatrists and psychologists offering ketamine treatment invest in substantial and detailed preparation of the patient before beginning ketamine treatment — to prepare for the treatment itself, the treatment experience, and how to metabolize or make sense of the treatment experience.

And the preparation involves not only a thorough history of symptoms, treatment course, previous medication and treatment failures, but also a thorough developmental and social history.

Our education and training centers on entering into an ongoing therapeutic relationship with our patients and the critical understanding and provision of a safe, therapeutic frame to do the deep work we do.

These two fields are two different animals.

Dr. Bennet encouraged everyone to learn from everyone else, in effect, to “cross pollinate” these fields and help each other to improve in clinical practice.

Then she described the use of ketamine in psychotherapy as a “lubricant” for psychotherapeutic work.

Several of the speakers described this method in their practices. This is called ketamine-assisted psychotherapy, or ketamine-facilitated psychotherapy.

And she went a step further, to describe the use of therapeutic ketamine in psychotherapy as a tool for deep spiritual exploration. This is where the goal of treatment is not symptom relief per se, but personal growth, self-knowledge, or transcendent exploration.

All in all, she encouraged matching the treatment to the individual patient, recognizing our responsibility to learn more about varied strategies and to share our findings within our field.

Speakers were diverse and fascinating. If you’ve been keeping up with progress in the field of psychiatric ketamine treatment, some of these names are sure to jump out at you:

Will Van Derveer, M.D., Wesley Rylan, M.D., Scott Shannon, M.D., Michael Stanger, M.D., Jeffrey Becker, M.D., Jason Wallach, Ph.D., Dan Engle, M.D., Lori Calabrese, M.D., John Krystal, M.D., Phil Wolfson, M.D., Jeff Guss, M.D., Elias Dakwar, M.D., George Greer, M.D., Evgeny Krupitsky, M.D., Patrick Sullivan, D.O., and Jennifer Winegarden, D.O.

And we had some lively and fascinating panelists, including Gary Bravo, M.D., Alison McInnes, M.D., Steven Levine, M.D., Steve Best, M.D., Veronica Gold, M.F.T., Greg Wells, Ph.D., Bob Grant, M.D., Genesee Herzberg, Psy.D., Jessica Katzman, Psy.D., Jennifer Dore, M.D., Julie Megler, P.N.P., Steven Levine, M.D., Steve Best, M.D., Sandhya Prashad, M.D., Steve Mandel, M.D., and me.

Oh yes, I mentioned I also presented my own data, and am excited to tell you more about that…

But… that will have to wait for another day … Without question, our fledgling new psychiatric field has turned a corner.

Ketamine KRIYA Conference 2018.

We’ll never forget this one. We can only hope they keep getting better…if that’s possible.

As exciting as this wealth of information may be, if you’re suffering from depression, bipolar depression, PTSD, OCD, social anxiety, substance use disorders…and even suicidal thinking, don’t wait. Call us.

Thankfully, if your symptoms are mild, there are a host of antidepressants and other medicines and treatments that can hopefully help you.

Ketamine is at its best for those who are severely suffering.

If you’re deeply affected by severe symptoms of depression and anxiety, we can help. Call and arrange an appointment.

Ketamine isn’t for everyone. Of course not. It doesn’t help everyone. But even among those who aren’t helped initially… sometimes there are those who get a delayed response and in a few months reach remission quite by surprise.

And even though we can’t promise everyone they’ll reach remission, the truth is that a very large percentage do.

As we’ve said before, ketamine is the most rapid and effective treatment for depression that we’ve seen in our lifetime … and really … ever.

We’re constantly learning ways to help more people benefit and get better. And chances are…you’ll experience the most remarkable transformation you could have imagined.

Our Results

At Innovative Psychiatry, we see people with these symptoms and disorders get better every week with ketamine treatment. Our results are extraordinary, and our remission rate is very high. Call for an appointment and let’s talk.

Ketamine works in some different areas of the brain in different ways than traditional medicines you might have tried that didn’t work for you. Your life really can improve dramatically.

Find out what this remarkable treatment can do for you.

November 12, 2018
So You Want to Buy Esketamine Nasal Spray… Really??
Is It the Hype…? Or Is There Something about Esketamine You Really Want…?

Ok, you’ve been wishing for a remedy for your distress with this mood disorder. I get it. Something that will do more than take the edge off, but instead will really help you feel good again. You’ve heard about ketamine treatment, but having to go to an office and undergo IVs 6 times sounds just a bit daunting..? Then you heard about esketamine nasal spray, and that it’s close to receiving FDA approval. And it’s a nasal spray! How easy is that??

What’s more, you’ve looked on the internet and its cost will probably be a great deal less than a series of IV ketamine infusions in a doctor’s office because you should be able to administer it yourself..? What a perfect alternative! …or is it?

So your excitement is building that hope is around the corner…within a few short months…or maybe even weeks…?

But wait…

Take a breath…ok? Of course, it’s possible…but…

Just a couple weeks ago, Janssen (a company under Johnson & Johnson’s umbrella) announced that things haven’t been going all that well with their testing.

Well, they didn’t exactly say it like that.

You know that it takes a ginormous amount of testing to get FDA approval on a drug. And all that testing costs lots of money.

When a pharma company pours years of resources into R&D (research and development), they hope the compound they’ve made will do what it’s designed to do, what it’s supposed to do. But they’re taking the risk it may not.

And they have lots of investors to please.

It’s a bit early to make judgments about esketamine nasal spray. Janssen has had some good trial results, but some weren’t that convincing at all.

Back in May, they made an announcement that even though they’d had both promising and disappointing results with esketamine nasal spray, they weren’t discouraged about its potential. They were determined to continue the trials.

Of course, investors want to see a return on their investment. Insignificant or conflicting results won’t butter their bread, if you know what I mean.

Then, after announcing September 4, 2018, that they were applying for a New Drug Application (NDA) for esketamine, a few weeks later they announced that esketamine failed yet another study in their Phase III trials.

They said esketamine nasal spray had failed to meet its primary end point in this study…to lower the depression scale for these subjects significantly from the level they were at the beginning by 4 weeks after the esketamine doses began.

Frustrating for Janssen.

So much money, so much work, in laboratories across the globe.

So, let’s take a closer look at Janssen’s quest for FDA approval of esketamine.

It’s easy to understand that even as they made the announcement that esketamine had failed this study, they continued to point out all the tests it has passed. Reminding investors that a disappointment is no reason to throw the baby out with the bath water. (At least, they hope that won’t happen.)

When they filed the NDA on September 4, it was based on 5 Phase III studies of esketamine in treating people with treatment-resistant depression: 3 short term studies, one “withdrawal maintenance of effect” study, and one long-term study.

The long term study was aimed at establishing the safety of esketamine use up to 52 weeks, and it found that esketamine is generally well tolerated. Not that surprising, since ketamine is well-tolerated in controlled, small doses.

HUGE Disappointment for Janssen

But this most recent study, where results were announced September 21, 2018, showed esketamine nasal spray failed to meet a primary end point. It did not have a statistically significant positive effect in reducing depression symptoms in the subjects. Janssen is quick to say however, that even though the response didn’t meet the goal it was intended to meet… the numbers still support the use of esketamine combined with an antidepressant.

Really…?? How is that?

You get the feeling Janssen tries to do damage control in each of its press releases…. Pay attention to the good stuff…and minimize the bad. (There seems to be a lot of that going around.)

Still, look at this: The trial investigated esketamine plus an antidepressant at two different doses, 84mg and 56mg. The plan was to test both doses.

However, the larger dose didn’t shake out better than placebo! So obviously there was no point in testing the lower dose.

What a blow for Janssen.

I’ve not made it a secret that I’m skeptical of esketamine nasal spray. But, I’ll concede for now that the jury is still out as psychiatrists and researchers evaluate all of the results coming in from all of the clinical trials.

We’ve got a medicine with IV ketamine treatment that works — and more and more basic science, translational, and clinical research supports this. But look at all the cards stacked against esketamine.

And…if the goal is to have a nasal spray form that’s more affordable, comfortable, and accessible to more people, that’s understandable. We get it. (Even if that nasal spray form would make it easy to hide, easy to share, and easy to abuse. Those risks are formidable risks that need to be addressed.)

But why use just esketamine when ketamine works so well?

You know why.

Because of money. Ketamine can’t be patented after 50 years of use. Esketamine can be, if they can just get it to work…even half as well.

To take this a step further let’s look at the problem that happened in May.

May 2018 Press Release More of the Same

So in May, Janssen made another announcement. That it had just completed 2 studies in its Phase III trials. In one of the two studies, they announced that in a group of subjects 65 or older, esketamine nasal spray had failed to show statistically significant findings. (Yep, just like it did in this most recent study.)

So…wait…Does that mean 2 out of 5 studies failed to show any significant advantage over a placebo…?

Now let’s be clear.

In all of these studies, Janssen is investigating esketamine nasal spray in conjunction with an antidepressant in comparison to an “active” placebo compound delivered by nasal spray along with an antidepressant.

So, even with esketamine bolstered by an antidepressant like Lexapro, Cymbalta, Zoloft, or Effexor… esketamine showed no statistically significant beneficial response in patients with treatment-resistant depression. Even at the highest dose they tested.

Reasons Why Esketamine May Fall Far Short of IV Ketamine Treatment

1. It’s NOT ketamine! Esketamine is only the left-facing form of ketamine . Ketamine consists of right- and left- facing forms and esketamine is the left-facing. So with esketamine, some of the beneficial aspects of having both available may be missing. We’d love to think esketamine is the important one, and that maybe it does all the work, right? But…maybe not.

2. Traditional SRIs and SNRIs have not helped a full third of people suffering psychiatric disorders…so why would adding these partially effective medications help esketamine do a better job??

3. It’s a nasal spray, for goodness’ sake. Let’s talk about that.

Problems with Esketamine Nasal Spray

We’ve talked before about the differences in various routes of administration with ketamine.

A huge factor is bioavailability. You know, the amount of medicine that actually reaches your brain to treat it. Everything else is digested, or somehow altered, or bound by proteins, or otherwise eliminated by your body … which does you no good at all.

We give ketamine by IV, so it can go straight into the blood stream and straight to your brain where it’s needed to treat the problem. Virtually 100% of the ketamine we infuse into your blood stream goes exactly where it’s needed. And because the brain’s structures and systems are so very delicate, we want to be very precise about how much reaches it and how fast.

With a precise infusion pump and IV access, we can control those factors exactly. There are no obstacles that prevent ketamine from reaching the systems in the brain in the amount we want, at the rate we want. And we can slow it, and we can stop it at any time.

But what is it about a nasal spray?

In the case of a nasal spray, there are all sorts of variables.

It has to be absorbed through mucous membranes to find its way into your bloodstream.

So picture this:
- It has to emit a spray that’s a perfectly suspended and evenly concentrated mist to saturate your mucous membranes—that are hopefully healthy enough and not bogged down by inflammation from allergies or a cold to absorb it properly. (It wouldn’t be a good thing if some days you can’t absorb your medication because you’ve got a cold.)
- When you spray it into your nostril, it has to be aimed just right…high enough that it won’t drip right back out your nose and straight enough that it will be absorbed before it runs down the back of your throat and into your stomach to be digested — where it’s bioavailability will drop even further.
- It has to be sprayed so carefully that none is wasted in the air and gently enough that it isn’t sneezed right back out.
Then add to all this, that once sprayed, there are only a few seconds for absorption to bring change to the critical and delicate brain systems…the ones vital to you getting better.

With IV ketamine, there are at least 40 minutes that ketamine is being continuously infused into the blood stream reaching the brain at a precise dose and rate. 40 minutes vs. a few seconds!

Esketamine nasal spray has been in the news all this year…and last year too.

Anytime Janssen has an announcement to make about esketamine we want to hear it.

Even if it’s disappointing. Not meeting a primary endpoint on its large major Phase III trial for approval? HUGELY disappointing. Shocking, really.

So, while we wait, we’re so thankful we do have ketamine treatment. It doesn’t work perfectly and it doesn’t work for everyone. But when it does, it can save lives by stopping suicidal thinking in 4 hours or less. It can bring relief and remission to those who suffer the most with severe depression, bipolar disorder, social anxiety, PTSD, OCD, substance abuse disorders… It works fast.

And extremely well, better than anything we’ve ever seen.

At Innovative Psychiatry we see so many patients who get better every day. Not just 50% better, but completely better. We see them achieve remission, and they go on to enjoy life as the best they’ve ever been.

They’re creative again, motivated, full of initiative …and hope. With lives that have meaning. And they’re glad to be alive.

So if you’ve invested your hope in esketamine nasal spray, don’t let disappointing news stories push you to give up.

There’s still all kinds of hope available that we’ve never had before. It just isn’t in esketamine nasal spray.

At least not yet.

But ketamine is still going full steam ahead helping many patients who thought they were treatment-resistant turn around… heal… and be restored.

To enjoy their lives fully.

If you suffer from treatment-resistant depression, and the problems that often go along with it, call us.

We’re all about helping you reconnect with the best you you can be.

To the restoring of your best self,

Lori Calabrese, M.D.
October 15, 2018
Ketamine Wannabe Drugs … of the Future

Ever have somebody copy you? You know, try to be like you? Imitate what you do, where you go? try to get what you have? They wannabe like you. Well, maybe not just exactly like you — kind of like you and better than you all at the same time.

It’s happening with ketamine.

We’ve been talking for awhile now about the breakthrough of low dose IV ketamine. In fact, everybody’s been talking about ketamine for treatment-resistant mood disorders. We’ve expounded on its effectiveness in relieving suicidal thinking, treatment-resistant depression, and other psychiatric disorders. Did you catch the discussion about which route is most effective and why we use it? Check it out here.

You should know about all the ways it’s changing the horizon for psychiatric treatment. Like how it stops suicidal thinking within hours, rather than weeks. And how people who have lived with depression and despondency for years — no matter what medication they were taking — can feel depression just lift within hours. Maybe you’ve been there yourself, or you know someone who has.

But there’s more to talk about.

The discovery of ketamine’s therapeutic effects on depression has opened doors to more revelations of the chemical sort. Mechanisms of action. Delivery systems. Ways of leveraging the funding of pharmaceutical companies to develop more versions of ketamine, maybe with the same or similar benefits, but without any side effects …

Think of it like this:

Ketamine wannabes want to “be like” ketamine and wannado like ketamine — except better, without side effects, for longer.

But it turns out that’s easier said than done.

Since ketamine is no longer under patent, it’s unlikely that a pharmaceutical company would be interested in investing the necessary funds to conduct extensive trials and research about its effectiveness to treat mood disorders at this stage … at least on ketamine specifically.

Or that a company would shell out time and money to study long-term response and remission rates, or long-term safety, for a well-known generic like ketamine — even if it is being used in a new way in new settings to treat new conditions. There just wouldn’t be the return on investment in the long term.

However, by making changes in the molecules and targets that provide the therapeutic results for ketamine, new versions of the drug in the form of ketamine wannabe compounds that specifically target mood disorders are being designed and developed, and are in the race for FDA approval.

Ketamine Wannabe Drugs

So grab your chemistry lab goggles, and let’s explore some of these molecular discoveries among ketamine-wannabe molecules.

Ketamine is a racemic compound — it has two parts that are mirror images of each other joined together like Siamese twins. If we split it right down the middle where the mirror images join — presto! — we have two “new” drugs. One faces right and the other faces left. We call the left-facing one “S” or in the world of pharmaceuticals, “es–” as in esketamine. So it turns out in this case that changing the structure of ketamine slightly could give us the same benefit, hopefully fewer side effects, and easier use. In other cases, molecules like ketamine are coming down the pike that act on similar targets or in similar ways to help with depression without some of the potential side effects of ketamine.

They both wannabe and don’t wannabe like ketamine. They wannado better.

Esketamine

Esketamine has been approved in Europe for a decade and a half – specifically for anesthesia – and Janssen Pharmaceuticals has acquired a patent to utilize it in the US as an intranasal spray for treatment-resistant depression.

The Food and Drug Administration has awarded “breakthrough” status to esketamine to zoom its advancement through to approval with less interference from various obstacles and the usual red tape that slows everything down.

They plan to specify it for use it in a clinical setting (as opposed to at home) for the sake of controlling the dosage, as well as to prevent sale on the street.

Rapastinel

Another pharmaceutical company – Allergan in Dublin, Ireland – has designed a peptide in this same “ketamine-like” category. You may know that a peptide is a chain of amino acids bonded together in a specific way, and this one looks pretty effective as an adjunctive treatment in depression. It has characteristics like being fast-acting and long-lasting and it’s given as an IV infusion, like ketamine.

Ketamine’s action with NMDA receptors is to block ion channel activity. Here’s where rapastinel is different. It binds to the glycine site on the receptor and regulates or modulates it by changing the shape of that site. Pretty cool. The result is that rapastinel reportedly has a minimum of dissociative or out-of-body side effects that are sometimes experienced with IV ketamine infusions.

Rapastinel is in Phase III trials in the US as an adjunctive treatment for major depressive disorder, and more trials are expected in Europe and Japan. Soon, it’ll be ready for FDA approval for use in the clinical setting to treat depression.

AV-101

Still another pharmaceutical company in San Francisco is working to create a small molecule drug that possesses all the good traits of ketamine without its potential dissociative side effects: VistaGen Therapeutics.

This molecule is one that’s back on the scene from over 30 years ago. At that time, it couldn’t cross the blood-brain barrier to do its work. And consequently, couldn’t impact the depressive symptoms a person was experiencing.

But now, the molecule (which is considered to be a “pro-drug”) has been revamped and this current version does cross the blood brain barrier, And when it does, it’s metabolized from a pro-drug into an active drug that modulates a certain glycine binding site at the NMDA receptor — unlike ketamine and different from rapastinel.

So while ketamine completely blocks certain NMDA receptor ion channels, AV-101 just sort of regulates the receptor gently…which seems to result in gentler side effects.

A New Frontier – Ketamine and Ketamine Wannabe Drugs

There are plenty more versions of modified “ketamine wannabe” molecules in the wings, developing to hopefully even replace ketamine at some point. Hoping to improve on ketamine’s action. Aspiring to lesser side effects. Working towards easier administration. We’ll just have to see how that goes.

And one day this miraculous breakthrough medication – ketamine – may become obsolete like so many cornerstone discoveries of the past.

But right now, boy are these exciting times! We’re on the threshold of a brave new world in psychiatry. A world where people who’ve suffered without relief for years, even decades, can finally experience relief and build a fulfilling life.

One last thought…

All of the companies working with these small molecule drugs are investing in priceless research that’s opening more doors and windows of understanding –. which will, in turn, only increase the benefits for people who just haven’t responded to or tolerated anything else.

For example, we know that ketamine, rapastinel, and AV-101 all work at the NMDA receptor site. So it’s been assumed that that action is the key to their effectiveness. However, when researchers blocked the AMPA receptor, none of these drugs worked. I’ll say it again. None.

Which revealed that the AMPA receptor needs to be activated for the drugs to deliver their fast antidepressant, anti-suicidal results.

And this revelation may lead to more breakthroughs for more who suffer … through ketamine wannabe drugs.

We’re on this. We stay up at night. We watch closely to glean all we can from the research that’s exploding, so we can continue to provide the most up-to-date, cutting edge, fresh discoveries that neuroscience offers.

And…we’ll be here to help you find your best self.

So call us, and let’s find the right innovative solution for you.

To the emerging of your best self,

Lori Calabrese, M.D.

April 12, 2017