Nobody likes a copycat.
They’re boring. Tired from the get-go. Out to ride on somebody else’s coat tails. They want to steal some of the glory.
Is esketamine just a ketamine wannabe copycat drug?
You may have heard some things about it. Like it’s a nasal spray. Esketamine intranasal. It’s supposed to be an easier form of ketamine … a spray instead of an IV infusion. Small enough to slip into your pocket … dangerous enough to share or slip into somebody’s drink.
Maybe you’ve wondered how to find it. Or if it works like ketamine…? …or if it’s better? Drugs like esketamine are ketamine copycats …. wannabe’s ….. that are similar to ketamine but different, too. They’re in the works, up and coming and eagerly awaited — and you should know how they operate and their relationship to ketamine for depression.
So let’s get it out on the table about esketamine, and it’s counterpart arketamine, and answer some of those questions.
As you may already know, IV ketamine treatment for depression and other psychiatric mood disorders has been enjoying a groundswell of recognition and application across the US and around the world. More and more physicians are reading the literature, the clinical studies, talking to other physicians, and referring patients for this treatment — people who haven’t benefitted from traditional SRIs and SNRIs (serotonin and serotonin-norepinephrine reuptake inhibitor) antidepressants, and many of the other antidepressants and mood stabilizers on the market.
Skeptics Wait for the Copycats
So … ketamine was FDA-approved for use as in anesthesia for adults, adolescents, and children more than 50 years ago. And no pharmaceutical company will pay for the studies required to get this medication for anesthesia to be FDA-approved for a new indication — treatment of depression — because it can’t be patented again.
Typically, it’s the big drug companies that fund all those whoppin’ huge human trials needed for FDA approval of a new drug for a specific indication. They hope that if their drug is patented and then approved for a specific indication, the profits would not only reimburse the costs of trials, but rake in billions more.
They’re not interested in ketamine because the patent expired.
They’ll never spend the millions it takes to get it approved for depression or other psychiatric disorders because it went generic.
What big drug companies can do, and are doing, is making a very small change in the structure of generic ketamine that they can patent. And by patenting it, they can own it for years, fund studies, push for FDA approval for different indications or conditions … like depression … or suicidal thinking … and enjoy the profits that pour in.
It’s business. Drug companies aren’t Mother Teresa. Let’s just be honest.
So … how are the drugs they’re patenting and seeking FDA approval for related to ketamine, which is already available? How do they compare?
Esketamine Wants to be Better than Ketamine
Sometimes drug companies develop a “new” drug similar to an established drug by splitting it in half.
They can do this easily with ketamine because it’s racemic. That means it’s made of 2 mirror image molecules attached to each other. Sort of like Siamese twins.
If you were to split ketamine right down the middle, you’d have two “new” molecules that are mirror images.
The one that’s facing left is the S molecule of the original one, S-ketamine or esketamine, and the one facing right is R-ketamine or arketamine.
(OK … scientists aren’t creatives. Phonetic spelling is just fine.)
Interestingly enough, these two molecules behave differently from each other. What’s more, they both behave differently from original racemic ketamine compound.
This is pretty surprising because most people figure that mirror image molecules are identical in what they are and do … just maybe half as strong as the compound they come from.
Well, when joined together, esketamine and arketamine bring the balance to ketamine that makes it work so remarkably well. But unlike Siamese twins, when ketamine is separated in half, there are different sets of characteristics in each half.
And here’s where it gets interesting.
Mirror Image Twins – Completely Different Characteristics
Now, we know that ketamine is described as possessing rapid, robust antidepressant effects consistently in 75-80% of cases with treatment-resistant depression. Suicidal thoughts can evaporate. PTSD symptoms, anxiety, OCD, and even phobias relent.
When you slice the ketamine molecule in half, because it’s racemic, you get two molecules that are mirror images of each other. So how do they behave in comparison to ketamine?
- Arketamine is the phonetic name of “R” ketamine – the half (called the “enantiomer”) of the original racemic ketamine molecule that faces Right. Standing alone it is its own molecule, and presents its own strengths and weaknesses.
Arketamine is far less potent as an NMDA receptor antagonist than either ketamine. It possesses 4-5 times less affinity for the NMDA receptor — that means its binding or sticking power to the NMDA receptor is 4-5 times weaker. But this is surprising: its binding there is even 4-5 times weaker than its sister, esketamine. So, arketamine is very weak compared to esketamine as an anesthetic, analgesic, or sedative hypnotic drug.
But arketamine appears to be FAR more potent than esketamine as a rapid acting antidepressant.
It could be because it’s an AMPA receptor agonist. That means it’s an initiator or activator of the AMPA receptor. It’s less potent as a NMDA receptor antagonist, but shows stronger and longer-lasting rapid antidepressant actions than esketamine, so seems like more of an obvious choice for treating depression if a drug company wanted to develop and patent a ketamine mirror image molecule for depression. (We wonder why nobody is doing this.)
But again, ketamine has already mastered that job.
Arketamine is also considered more relaxing for the patient, less dissociative, and probably less likely to encourage abuse.
- Esketamine, on the other hand, is the phonetic name of “S” ketamine and is the half of the racemic ketamine compound that faces Left. Now, esketamine is a true-blue NMDA blocker. And … it’s 8 times more powerful as a dopamine reuptake inhibitor than its sister, arketamine.
Esketamine is far more potent as a NMDA receptor antagonist, and as such provides more benefit for pain relief, reward sensations … and a higher likelihood for abuse, but less benefit as an antidepressant.
Wait. How could that be?
FDA Approval Doesn’t Mean It’s the BEST
When a study was conducted to explore this, it turned out that ketamine’s antidepressant power isn’t caused just by its inhibiting of the NMDA receptor — or even mostly by inhibiting it — but it acts in a number of ways including a super-important very cool way — by activating and sustaining a different glutamate receptor, the AMPA receptor, through a metabolite called hydroxynorketamine.
This was a laboratory study, and although more studies are needed to verify this finding in humans, this is huge.
Because it seems like when you read about ketamine, and esketamine, you just hear about the NMDA receptor all the time. (Sometimes it’s called NMDAR so they don’t have to write out “receptor.”) As though it’s the new key to treating depression. The one new hot receptor that holds the key to the treatment of depression.
It’s so much more complicated than that.
Compared to ketamine, every other NMDA receptor antagonist drug that has been tested so far to treat depression and suicidal ideation has produced only modest results. They’ve kind of failed. They don’t work.
But researchers and the company making esketamine are betting that this one does.
Although esketamine is the weaker mirror image molecule for treating depression, it showed a 67% response rate when it was first studied as an IV infusion. It showed promise in FDA Phase II trials, and it’s the one now in FDA Phase III trials. It does other things, too, besides antagonizing the NMDA receptor … for instance, it increases glucose metabolism in the frontal cortex of the brain. Some think this action contributes to the tendency for esketamine to produce dissociative or hallucinogenic activity.
Of course, stronger hallucinogenic effects increases the likelihood of abuse.
We’re especially worried about this with a nasal spray.
Breakthrough Therapy Designation
In November of 2013 and again in August of 2016, esketamine received Breakthrough Therapy Designation by the FDA. For treatment-resistant depression the first time, and for treatment of major depressive disorder and imminent risk of suicide the second time. This status is given to a drug that’s urgently needed to treat a serious or life-threatening disease or condition and the drug has shown evidence for providing substantial improvement over existing treatments.
It helps expedite and remove delays and obstacles in the FDA approval process.
As I’ve mentioned before, lifting depression and suicidal thoughts are things that ketamine has already mastered. Everyone in the field and in the trenches knows this.
So back to the wannabes…
Currently, esketamine is in Phase III trials toward gaining FDA approval in the US, and 6 specific studies using intranasal esketamine are being conducted here … More than 30 have been launched in the US in the past couple of years and in Argentina, Austria, Belgium, Brazil, Canada, Czech Republic, France, Lithuania, Poland, Turkey, and the UK. The world is on fire with this. And the urgency is evident. Some studies center around using esketamine in intranasal form in conjunction with an SRI or SNRI. Interesting … but maybe not what you’d be looking for if those haven’t worked for you or you’ve had intolerable side effects.
Why the Focus on Esketamine…?
So back to the point. In spite of esketamine’s breakthrough status with the FDA, in spite of the fact that it comes from ketamine, it doesn’t seem to possess the characteristics that make ketamine so effective as an antidepressant. Hmmmm. A recent paper in the journal Nature demonstrated that the NMDA receptor is, in fact, not the target for its antidepressant effects, but rather AMPA.
Esketamine doesn’t have much impact on AMPA receptors.
As you can see, the studies (and the controversies) go on. There’s huge interest in ketamine, ketamine-like drugs, glutamate and AMPA receptors, and the way up and coming antidepressants work — and different opinions about this — around the world. Neuroscientists pore over the data, set up new preclinical and clinical studies, check and double-check each other’s findings around the world. Drug companies hope their own candidate for FDA approval will come out on top.
So Why Arketamine and Esketamine: Ketamine Wannabe Copycat Drugs?
Since ketamine already has all the features we want, and esketamine seems to have far weaker antidepressant benefits, why don’t we stick with what we KNOW works great?
Well, let’s be honest. Because of money. FDA approval means that insurance companies will probably pay for esketamine to be used in depression, and that makes it available to people who don’t live near a ketamine clinic or who cannot afford ketamine infusions that aren’t covered by insurance. And convenience — no needles, no IVs. And I predict that the pharmaceutical company that’s promoting FDA approval for esketamine will market it as superior, safer, and readily available.
But is it superior? That hasn’t been tested yet in a head-to-head study.
It’s half the molecule…it drips, it runs down your nose or down your throat if it’s not aimed right…it’s not as reliable…it’s not as bioavailable…it still has the same side effects…and it may not work as well.
Cheap Ways to Make Billion$
Janssen is doing the same thing with ketamine.
Tiny Adjustments = Recycling
So drug companies recycle: they split old molecules, or try to invent a new delivery system….you know…they make something extended release, controlled release, change the release mechanism, turn it into a patch, or into a nasal spray.
Ultimately they want to make their drug available, bring it to more people, offer something effective and safe and well-tested and versatile. These are all good things. With esketamine … get it FDA-approved as a nasal spray. Small enough to slip into your purse like a lipstick. Well-known enough to have patients clamoring for it after they see it advertised on TV.
Risk, addiction, and rape could be just around the corner … with a spray.
Combined as ketamine, esketamine and arketamine together are a powerful weapon team against treatment-resistant depression, suicidal thinking and intention, and chronic – as well as emergent – pain. Physicians administer it — in carefully controlled, supervised, and safe settings in hospitals, clinics and offices. Separated … well … now you know some of the positives and the pitfalls.
A New Era
This is the era of ketamine look-alike drugs, because ketamine has changed the world of psychiatric mood disorder treatment for the better. In the coming years, we’ll see more drugs approved that work off the basic premise that makes ketamine so life-changing.
We’re excited about that — we’re all over it, because we want to see people get well.
And so we carefully evaluate the ketamine wannabes and copycats. And we ask … are they better? Safer? More effective? Longer lasting? More convenient? Riskier? Addictive? More dangerous?
At Innovative Psychiatry, Ketamine is Changing Lives
And in our practice, we’re so pleased to report consistent 80% responses in cases of treatment-resistant depression and other psychiatric mood disorders.
If you still suffer after years of unsuccessful treatments, don’t wait. Innovative Psychiatry is all about finding a novel treatment, appropriate for you, that can make you feel truly better. More like you felt before depression ever knocked on your door the first time.
We’re here to treat you if you’ve suffered without relief for years.
When we first meet, I’m going to want to know about the best you’ve ever been. So we can both learn what it was like when you were your best self. And it will be our goal to help you reach that point again.
To the recovery of your best self,
Lori Calabrese, M.D.