A Little History: The Beginnings of Ketamine the Depression Dragon Slayer

The Legend of Ketamine the Depression Dragon SLAYER

Doesn’t that sound exciting…?  Conjures up images of kings, knights, dragons…and princesses. Ketamine the Depression Dragon SLAYER … the knight in shining armor, equipped with world-class weaponry … vanquishing the enemy.

But this is no fairy tale. This is the real deal. The story of a tool…a drug…that slipped in quietly to center stage as a mild-mannered anesthesia medicine.  A drug so boring it literally put people to sleep.

Then somebody noticed it was leaving relaxed, productive, happy people in its wake…

Have you wondered where this remarkable treatment came from? Did it… for instance, start out as a medicine, or was it a club drug? 

Ketamine: The 21st Century “Miracle”

Have a seat and get comfortable while I tell you the story of this 21st century hero who’s Ketamine the Depression Dragon Slayer… and subjugator of a host of other mood disorders. It all started in an early 1960’s laboratory, where a team of researchers were working on a new compound…

PCP for Anesthesia??

A certain anesthesia drug — Sernyl — had been developed a decade earlier but had so many extreme side effects like delirium, agitation, and hallucinations that it was quickly taken off the market in ’65. No doctor wanted to deal with a drug like that.

But, like some drugs do, it snuck onto the streets and was manufactured illegally. And it was highly addictive. The generic name for it was phencyclidine; its street name was PCP or angel dust.

Meanwhile back at the lab, even before Sernyl was pulled, Dr. Calvin Lee Stevens was working at Wayne State University to develop similar compounds and better anesthesia agents for Parke-Davis, the oldest and largest pharmaceutical company in the U.S. at the time. (Parke-Davis has its own interesting story, but we’ll save that story for a different blog.)

In 1962, Dr. Stevens developed ketamine hydrochloride, an effective and safe short-acting anesthesia drug with much milder side effects, and far less risk of addiction.

When it was first tested on humans, they asked for volunteers at Jackson Prison. 

Unbelievable, right? 

And the first study subjects reported a “floating feeling” and, in some cases, numbness in their arms and legs.

Ketamine Approved by FDA

So … now the story gets juicy.  One of the scientists who developed it ran away with it to Belgium to have it patented without the knowledge of Parke-Davis. And the battle began! Lawsuits, patent wars, big money . . . and intellectual property were at stake.

In 1970, ketamine hydrochloride was approved by the FDA under the name Ketalar as a short-acting anesthetic for children, adults and the elderly.

The Pentagon wasted no time ensuring it was available to the war zone. And it was quickly put to use to treat wounded soldiers during Vietnam, with widespread success.

It’s not hard to fathom that for anesthesia, a floating sensation and absence of feeling in the body could be a good thing. Neat. The blood pressure doesn’t drop. You don’t lose the airway. And you can work fast — really fast. Especially in the case of big trauma … or setting a broken arm. So those characteristics weren’t really negative, but actually positive.

And, by the way, as neuroscientists and doctors were considering this floating feeling and the inability to feel limbs … one of the key researchers, Edward Domino, MD, was scratching his head about how to characterize this medicine. What to call it, really. His wife Toni came up with the term dissociative anesthetic and he kind of liked that idea. (I love this story–so real.) He used the term with his colleagues and it stuck. Today, ketamine is considered everywhere as a dissociative anesthetic.

A new term for a new type of drug.

Ketamine is so safe, and so effective, that it’s been included on the World Health Organization’s List of Essential Medicines. That list is used by the Red Cross when stocking medications for disaster responses, emergency settings, and in war zones. 

Ok, ok, so ketamine is safe for anesthesia. But how did it come to be used as a treatment for depression?

Who Can Vanquish the Depression Dragon?

For a long time, the idea was that if we could just give the brain a chance to make the stuff it knows how to make, and if we could help make sure that stuff hangs around long enough to get to where it’s supposed to go, then everything could function as it should — and mood and behavior and thinking would be restored to function as they should.

But that’s pretty simplistic and it just doesn’t happen that way.  That’s one of the reasons so many different antidepressants were developed.  We kept trying to find different neurotransmitters that might be the key to treating certain kinds of depression and certain types of anxiety , thinking that we could hit on the thing that would work. For most people.

But, the fact is, we needed something different.

Something that worked more effectively in more parts of the brain to do more than just keep serotonin hanging around. It’s easy to do that. Anybody who’s ever taken an SRI (new term that’s replaced SSRI) and had it work knows that.

But for the 70% who’ve had one fail, or who’ve had one after another after another fail . . . well, those millions of people realize that it’s just not so simple.

We needed something that would activate things like the AMPA receptor, stimulate growth of BDNF, “fertilize” new growth of synapse branches, move G proteins off the lipid rafts faster.

We needed solutions that truly rebuilt the communication system in the brain.

And ketamine began to appear – surprisingly – like a possible solution…

In 2000, (remember this is 36 years after ketamine was developed and widely used as an anesthesia) a randomized, double-blind study with only 7 subjects was conducted as a “proof of concept” to study ketamine –  and its effect on Major Depressive Disorder. These patients were given a small dose of ketamine IV spread out over 40 minutes.

Then, their depression symptoms were assessed based on a couple of tools used in psychiatry and neuroscience research: the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI).

The results for this first time study?  Within 4 hours, ketamine produced rapid and robust positive results that lasted up to 72 hours.

When you compare that to the 4-12 week and even 16 week wait time patients have always endured to experience results from the traditional antidepressants that focus on increasing the levels of neurotransmitters, these results were pretty spectacular.

And there’s more.

Those side effects that produce the floating feeling subsided within about 2 hours and before the antidepressant effects took effect. This is important, and we’ll get back to that in a minute.

Ketamine Vanquishes the Depression Dragon

This was the first clinical study to show that drugs – like ketamine – that act on glutamate.. a neurotransmitter that excites reactions in your brain’s chemistry lab… just might be effective for treating major depressive disorder.

Now, a weakness of this study, besides the small number of participants, was the fact that there was no follow-up assessment of the subjects beyond the three days after the infusion. So, it was impossible to know the duration of ketamine’s antidepressant effect.

As a result, in 2006, another study was conducted to measure just that. In this one, the participants were assessed at 110 minutes after the infusion, and continually up until 7 days.

It turns out 71% of these participants reported a positive response (measured by that same tool, HDRS) after one day.  And even more thrilling, 29% achieved full remission.

Plus, 35% of the participants maintained that positive response still on day 7.

That was when the study ended. But many more studies have followed and dozens are going on today. Different doses, different protocols, different lengths of time, and in different disorders like PTSD, OCD, phobias, bipolar disorder. The more researchers learn about ketamine, the more they want to learn.

Ketamine the Depression Dragon Slayer

At the time of the first human trial for ketamine as treatment for depression, the only known action of ketamine was in its direct impact on glutamate, the more “exciting” of the neurotransmitters.

However, in recent years much more about ketamine’s extraordinary action in the brain has been discovered. To date, there are four known actions ketamine takes in the cells in the brain that rejuvenate the synaptic connections, and restore wellbeing.

There’s Just No Other Like Ketamine the Depression Dragon Slayer

But the best guess of any of us is that more will be found. There are other drugs being studied to treat depression that work much like ketamine does. In fact, one of them, esketamine, is in Stage III trials toward FDA approval.

They all wannabe like ketamine but they don’t wannado what ketamine does during an infusion. They don’t want to create the feeling of dissociation.

The Amazing Handiwork of a Masterful Restoration Expert

However, there’s a point to consider. The “floating sensation” and whatever goes with it is an important aspect of the treatment.  And here’s why.

Because when you’re experiencing those moments of “dissociation,” ketamine is actively working in your brain cells to rebuild and restore function. Notice in the research that they said the side effects had stopped before the antidepressant benefits began.

That strange feeling is what you experience when ketamine is “fixing” your brain.

We have medications to treat any aspect of the infusion experience that might become overwhelming for you. But, when you receive ketamine treatment, know that this particular sensation is part of the restorative process. It’s where the transformation begins. Embrace it…relax…and allow it to take its course.

Because those sensations are a sign that your restoration is coming.

Be hopeful. We are. We so appreciate the work of Parke-Davis, the neuroscientists, the anesthesiologists, and researchers who have brought all the information public about ketamine’s track record in treating psychiatric mood disorders.  And, we also appreciate the research and the medical professionals who continue to explore ketamine more deeply, and all who will participate in this adventure in the future.

Ketamine’s not going anywhere. One by one, those who were skeptical and who held ketamine therapy at arm’s length are crossing over to join us in watching the daily transformation this incredible drug provides.

Like anything else, ketamine’s not perfect. But it’s the most exciting treatment that’s come along in psychiatry in our lifetime. At Innovative Psychiatry, we consistently see 80% of patients who’ve been failed by other treatments get better.

If you’ve suffered from psychiatric mood disorders that have not responded to treatment, call us. Let’s find out if you’re a candidate for ketamine treatment. While it’s not for everyone, it may be just what you need to really live again.

Let’s find your best self together,

Lori Calabrese, M.D.