Is ketamine a glutamate antagonist or a spiritual kindler? Ketamine has two origin stories, each with its own understanding of how it treats depression. One came from the East, and one from the West, and after the Iron Curtain came down the two met face to face. Today, we tell that story.

Published On: 9/20/2021

Duration: 23 minutes, 27 seconds

Related Article: "Pilot Study of Ketamine vs ECT for Major Depression," The Carlat Psychiatry Report, September 2021

Transcript:

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of The Carlat Psychiatry Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

KELLIE NEWSOME: Who do you turn to when your patient doesn’t respond to antidepressants, psychotherapy, TMS, and long list of antidepressant augmenters like lithium, atypical antipsychotics, methylfolate and thyroid?

Some of you might say ECT, and some might say ketamine, and in this month’s journal we feature a landmark study – the first randomized controlled trial to compare these two giants.

And while ECT has been used in psychiatry since the 1930’s, and ketamine since the year 2000, we still don’t understand exactly how these treaments work. ECT seems to require seizures, but it also has neuroprotective effects, increasing brain derived neurotrophic factor and enhancing dopamine signaling. And ketamine, well, today we’ll focus on that one.

John Krystal published the first clinical trial of ketamine in depression. He is now chairs the department of psychiatry at Yale Medical School, and he comes from a family of notable psychiatrists who have changed how we practice today. His twin brother, Andy Krystal, helped develop the z-hypnotics, and he was responsible for many of the studies on hypnotics and depression that we covered last April. His father, the late Henry Krystal, was a psychoanalyst and holocaust survivor who helped develop our current conceptualization of PTSD and new psychotherapeutic approaches to this disorder.

DR. AIKEN: In the 1990’s, the monoamines – serotonin, dopamine, and norepinephrine – were seen as a panacea for anxiety and depression, but John Krystal wasn’t satisfied with them. He was seeing a lot of partial cures and treatment failures, and he didn’t think that simply boosting monoamines was what treated depression. That was just the initial effect of these drugs, but their antidepressant benefits came weeks later. Other research pointed to downstream effects that might better explain their actions, like changes in neurotrophic factors or glutamate transmission in the cortical-limbic pathways.

It was in these pathways between the cortex and limbic system that the symptoms of depression were thought to lie, and the monoamines were not the major players there – but glutamate was. Other glutamateric or NMDA antagonists like lamotrigine, d-cycloserine, and amantadine were showing antidepressant potential, and maybe ketamine – yes, the anesthetic agent that became a drug of abuse in the Vietnam era – could treat depression through its glutamatergic properties.

Krystal already had some experience with ketamine, as he was using it to model schizophrenia and alcohol withdrawal. I was actually a medical student at Yale when I saw  recruitment posters from his lab for a study that would model schizophrenia by giving normal subjects ketamine. I was tempted – I thought this was a great opportunity for a future psychiatrist – it would help me empathize with psychotic patients. I ran the idea by my advisor though, and he kindly shut it down. “You have no idea what ketamine could do long term, and you don’t need to be psychotic to empathize with your patients. You just need to listen and try to understand them.” I’m still grateful for that advice.

In the late 1990’s Krystal tested ketamine in depressed patients in a randomized controlled trial of 7 patients. He wasn’t expecting a treatment breakthrough; he was just looking to test a theory, but the results surprised him.

KELLIE NEWSOME: “To the amazement of our patients and ourselves, we found that ketamine produced rapid, profound, and surprisingly durable antidepressant effects that were temporally dissociated from the brief acute behavioral effects of the drug, in other words, the initial euphoria produced by ketamine was not a part of its antidepressant effect…. one third of patients with treatment-resistant symptoms achieving remission and approximately 50%−75% of patients demonstrating clinical response from a single dose.”

DR. AIKEN: In Krystal’s view, the initial euphoria that ketamine produced – the thing that made people take it to get high – was an unwanted side effect that was unrelated to the more lasting antidepressant effects it provided. Likewise, the dissociation and psychotic-like sensations it produced were also unwanted side effects. But researchers in the former Soviet Union also tested ketamine in the 1980’s, and they arrived at a very different view of its mechanism. Let’s go back to 1985 to see how things looked from the East.

The Soviet Experience

DR. AIKEN: Dr. Igor Kungurtsev wanted to help people break free from addiction. Working as a psychiatrist at the Bekhterev Psychoneurological Research Institute in Leningrad (now called St Petersburg), he saw many Russians whose lives were ruined by drink, and he had a novel idea. He had heard from his anesthesia colleagues that patients sometimes had near-death experiences after taking ketamine before surgery. The reaction was frightening, and he wondered if he could create an aversion to alcohol by pairing ketamine with a stiff drink. The patients would come to associate alcohol with dying and – he hoped – would never want to touch the bottle again.

KELLIE NEWSOME: But the experiment backfired. Instead of frightening the patients, ketamine triggered something mystical in them. They started writing poetry, painting, and reading spiritual texts for the first time. Some spoke of encounters with Jesus Christ, which was particularly puzzling since this was the Soviet Union and religious activity was suppressed by the state. Some became intrigued by nature and went frolicking in the forest.

DR. AIKEN: To better understand what was happening, Dr. Kungurtsev tried ketamine on himself, and this time he got the effect he was looking for, unfortunately. He felt his sense of self dissolve, his consciousness disappear, but it didn’t inspire poetry. It made him panic. It was very uncomfortable.

KELLIE NEWSOME: “The most unusual feeling was that I had no body, yet somehow “I” existed. The next development was indescribable. During the first stage, I seemed to exist only as a point of consciousness, but still, “I” existed. Then there was a stage where even this disembodied sense of self began to disappear, and I felt a real terror of dying.”

DR. AIKEN: He tried it again, and found that by surrendering to the experience he was able to get some of the benefits his patients were finding. He had a new sense of his place in the universe, and a deeper sense of Buddhist concepts he had previously only understood intellectually.

Later, Dr. Kungurtsev noticed that patients with Type A obsessive-compulsive personality styles felt uncomfortable with the loss of conscious control that ketamine brought, much as he did himself.

KELLIE NEWSOME: One of the qualities of successful people is that they pivot – quickly revising their strategy when things go wrong or new information suggests a change of course. And that is what Dr. Kungurtsev did. Ketamine was not going to be the aversive conditioner he was looking for, but maybe there was potential in this altered state it induced. He tried using hypnotic suggestion while patients were under the influence of ketamine, dropping hints that they should give up alcohol. That didn’t work, so he pivoted again, and developed a form of ketamine assisted psychotherapy that capitalized on the ketamine-induced transcendent state to help his patients achieve sobriety. He found similar success with anxiety and depression.

He called it “Death-Rebirth” Psychotherapy, and it was based on the idea that the ketamine experience gave patients a new sense of purpose – one that could move them beyond depression or alcoholism – and a deeper understanding of life and death. In the Western view, the out of body experiences and illusions of tunnels were psychiatric side effects, labeled dissocation. The state of self-transcedence was simply a temporary euphoria unrelated to the drug’s mechanism. But in the East, these experiences were integral to the therapy.

DR. AIKEN: Kungurtsev was joined by a colleague, Evgeny Krupitsky, and through the 1980’s they refined this technique, finding for example that the ketamine experience was enhanced if the patient listened to New Age music like Jean Michael Jarre or Kitaro while receiving the intravenous dose. He found that ketamine gave patients a new perspective on life, death, and relationships.

KELLIE NEWSOME: “Some went back to their families, they noticed problems in their relationships, or certain idiosyncrasies of their spouses and relatives which they were unaware of before treatment. Ketamine seems to increase the capacity for detached observation.”

KELLIE NEWSOME: One of Dr. Kungertsev’s strangest observations concerned his encounter with a band of soviet mystics. It’s pretty hard to summarize so I’ll just quote him directly.

“I would also like to relate some unusual anecdotes connected with our research. About one year after we began our study, a group composed of two men and one woman appeared at our hospital who were very strange looking, wore strange clothes, and had strange, shiny eyes that seemed out of focus. They called themselves “magicians”, and said that they sensed in their meditations and magic practice that in this hospital, some people were throwing other souls into the “astral plane”. They had come to see what we were doing, like “astral police”. Prior to this, we had not published the results of our work, and only a few professionals knew about it. Also, this hospital is situated in the suburbs of St. Petersburg, and is not widely known. So we described our work and showed them our hospital. They approved! They also told us that they themselves used ketamine for their underground magic practice.”

DR. AIKEN: These astral police gave the doctor textbooks of psychedelic medicine that they had smuggled into the Soviet Union, and they gave him one thing more. A mushroom plant that Dr. Kungurtsev had only read about and thought was only grown in Mexico: Psilocybin. He took the mushroom, and here is what transpired ….

KELLIE NEWSOME: “I noticed that my usual stream of thoughts (my "inner dialogue") had stopped. Sensations of the body became more precise. My awareness and mindfulness were strong and lucid. I was absolutely "here now" in every moment. I noticed that when I began to do something I was fully involved in the action forgetting all else. At the same time I felt an inner surrender from all actions. The experience was gently going deeper. I felt myself miraculously serene and in a contemplative mood. I had no desires and needs. I simply was. Bodily sensations became blissful. Periodically, waves of indescribable bliss were going through me. In this period, I saw an "as if" white light shining through ordinary reality while the feeling of individual self dissolved. Later, I called this experience "the unbearable bliss of being." In the last part of the trip, the intensity of bliss gradually decreased but I had a miraculous experience of Suchness (or Is-ness). Pure existence. The world is perfect; all happens in the proper way. There is nothing to improve, nothing to add and nothing to take off. Just to be.”

DR. AIKEN: Death-Rebirth Psychotherapy continues in Russia, though the name has been changed to the more innocuous Ketamine Assisted Psychotherapy. And the central ideal – of guiding people through a drug-induced, consciousness changing state – is now knocking on the door of the mainstream as psilocybin and MDMA assisted psychotherapy are undergoing phase III trials. And we don’t mean to imply that this is an Eastern idea – listen to our podcast from 2 weeks ago to hear how psychedelic assisted therapy got its start in 1950’s America, or Mexico or prehistorical Africa, depending on who’s counting.

KELLIE NEWSOME: Dr. Kungurtsev‘s and Krupitsky’s work on ketamine was unknown in the West. The Iron Curtain was pretty thick in those days, and didn’t start to crumble until the more open policies of Gorbachev’s perestroika and the final collapse in August 1991. A few months later, Dr. Kungerstev published the first discerptions of his work, but he did so in an obscure journal of psychedelic research, the Albert Hofmann Foundation Bulletin, and it was written in a style quite out of sync with the rigorous objectivity of a scientific paper. But Evgeny Krupitsky went further with the work, blending the Eastern and Western views of ketamine after the fall of the Soviet Union.

DR. AIKEN: In 1994, Krupitsky went on a tour of the United States, visiting psychiatry departments from New Mexico to the NIH to speak on his ketamine therapy. At the end of his visit, he met with John Krystal at Yale. Krystal was beginning his research on ketamine at the time, and the two worked out a plan to collaborate on research together on ketamine and alcohol use disorders. Dr. Krupitsky returned to Yale in 1997, where he spent a year working on research on ketamine and alcohol, and he published with Dr. Krystal on the combined effects of ketamine and nimodipine.

We asked Dr. Krystal if the Russian experience of Ketamine Assisted Therapy inspired his work on ketamine and depression, and he said that it did not. He recalls his meeting with Dr. Krupitsky this way,

KELLIE NEWSOME: “I learned what I know about, “KPT,” i.e., Ketamine Psychedelic Therapy, from him. I gleaned from Dr. Krupitsky that KPT was used to treat a variety of clinical conditions. The treatment procedure seemed to involve inducing a highly dissociated state (in this state, people may perceive the world through a perceptual tunnel) that they called a “near death state.” They employed a form of psychotherapy that created the expectation that their patients were being “reborn.” This rebirthing was believed to be an important part of the treatment.

We took a very different approach. From the outset, we were probing neural mechanisms. When we administered ketamine to patients we prepared them for what they could expect to experience during drug administration. However, we did not suggest that the subjective effects of ketamine were part of the treatment.”

DR. AIKEN: Dr. Krupitsky credits his visits to the US with helping him develop controlled, double-blind methodology to test his ideas. He has gone on to publish pivotal controlled trials of ketamine as well as naltrexone in opioid use disorders.

DR. AIKEN: These competing views of ketamine are particularly relevant as we move closer to a world where medications like psilocybin and MDMA are used to create novel experiences that – when paired with psychotherapy – can heal psychiatric disorders. So we took a deeper dive into the literature on ketamine to see what we could learn.

KELLIE NEWSOME: Carlos Zarate’s work at the NIMH adds to the story. He looked at how ketamine affects the default mode network – the part of the brain that is responsible for self-consciousness, as well as all of that negative self-talk that we call depressive rumination. Ketamine normalizes circuits in the default mode network, quieting all that depressive chatter, although the effect only lasts about 10 days. Here’s how a patient describes it, from a documentary by Vice

A 2018 study suggests that the drug’s glutamatergic actions enable these changes in the default mode network. Mindfulness meditation and behavioral activation also normalize default mode activity, and when the default mode shuts off people experience out-of body sensations of the type we hear about in near death experiences. So far, sounds like the Russians were on to something.

DR. AIKEN: But not all the evidence points in this direction. Dissociation, for example, appears to be just a side effect of ketamine - it does not predict the drug’s antidepressant effects.

DR. AIKEN: We’ve spoke today of some of the promise of ketamine. Like the psilocybin, the psychedelic we covered 2 weeks ago, ketamine may treat depression in part by bring patients into a new state of consciousness. But the human brain is complex, and all medications have the potential to do good and harm once they get in there. In the case of ketamine, those harms are exemplified by its potential to induce psychosis, and its long history as a drug of abuse. When it is taken at high doses for prolonged periods of time as it is in such cases of abuse, ketamine can has neurotoxic effects on brain cells, and can cause serious damage to the bladder.

And now for the word of the day…. Number Needed to Treat

DR. AIKEN: The Number Needed to Treat, or NNT, is the number of patients you would need to be treat in order to have specific impact on one person. In psychiatry, that impact is usually response – which is about a 50% reduction in symptoms - or remission – which is when symptoms fall to within a normal level on a standardized rating scale, even if they don’t go away 100%. You can use the number needed to treat to compare the relative efficacy of different treatments. Here are some benchmarks, and lower numbers are better here. Most treatments in psychiatry have a number needed to treat around 3-6. Of course, the all-powerful placebo effect is subtracted out of this number, and that accounts for about half of the response in psychiatry. So if the published number needed to treat suggests that 1 in 4 patients will get better from a medication, you’ll probably see much better responses in practice – more like 1 in 2 patients.

When the number needed to treat goes above 10, the treatment is pretty weak, and the FDA would need some strong convincing to approve it. At the more powerful end are stimulants in ADHD, lithium for prevention in bipolar disorder, as well as ketamine and ECT in depression – all of which have number needed to treats around 3. Next week, we’ll tell you about a genetic test that has a number needed to treat of 3, a remarkable feat for any psychiatric intervention, and particularly for a genetic test – as most of these tests barely register on the efficacy scale when it comes to making a difference in depression outcomes.

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