Ketamine May Relieve Depression By Repairing Damaged Brain Circuits

https://www.npr.org/sections/health-shots/2019/04/11/712295937/ketamine-may-relieve-depression-by-repairing-damaged-brain-circuits

 

"The anesthetic ketamine can relieve depression in hours and keep it at bay for a week or more.

 

Now scientists have found hints about how ketamine works in the brain.

 

In mice, the drug appears to quickly improve the functioning of certain brain circuits involved in mood, an international team reported Thursday in the journal Science. Then, hours later, it begins to restore faulty connections between cells in these circuits.

 

The finding comes after the Food and Drug Administration in March approved Spravato, a nasal spray that is the first antidepressant based on ketamine.

 

The anesthetic version of ketamine has already been used to treat thousands of people with depression. But scientists have known relatively little about how ketamine and similar drugs affect brain circuits.

 

The study offers "a substantial breakthrough" in scientists' understanding, says Anna Beyeler, a neuroscientist at INSERM, the French equivalent of the National Institutes of Health, who wasn't involved in the research. But there are still many remaining questions, she says.

 

Previous research has found evidence that ketamine was creating new synapses, the connections between brain cells. But the new study appears to add important details about how and when these new synapses affect brain circuits, says Ronald Duman, a professor of psychiatry and neuroscience at Yale University.

 

Studying ketamine's antidepressant effects in mice presented a challenge. "There's probably no such thing as a depressed mouse," says Dr. Conor Liston, a neuroscientist and psychiatrist at Weill Cornell Medicine in New York and an author of the Science paper.

 

So Liston and a team of scientists from the U.S. and Japan gave mice a stress hormone that caused them to act depressed. For example, the animals lost interest in favorite activities like eating sugar and exploring a maze.

 

Then the team used a special laser microscope to study the animals' brains. The researchers were looking for changes to synapses.

 

"Stress is associated with a loss of synapses in this region of the brain that we think is important in depression," Liston says. And sure enough, the stressed-out mice lost a lot of synapses.

 

Next, the scientists gave the animals a dose of ketamine. And Liston says that's when they noticed something surprising. "Ketamine was actually restoring many of the exact same synapses in their exact same configuration that existed before the animal was exposed to chronic stress," he says.

 

In other words, the drug seemed to be repairing brain circuits that had been damaged by stress.

 

That finding suggested one way that ketamine could be relieving depression in people. But it didn't explain how ketamine could work so quickly.

 

Was the drug really creating all these new synapses in just a couple of hours?

 

To find out, the team used a technology that makes living brain cells glow under a microscope. "You can kind of imagine Van Gogh's Starry Night," Liston says. "The brain cells light up when they become active and become dimmer when they become inactive."

 

That allowed the team to identify brain circuits by looking for groups of brain cells that lit up together.

 

And that's when the scientists got another surprise.

 

After the mice got ketamine, it took less than six hours for the brain circuits damaged by stress to begin working better. The mice also stopped acting depressed in this time period.

 

But both of these changes took place long before the drug was able to restore many synapses.

 

"It wasn't until 12 hours after ketamine treatment that we really saw a big increase in the formation of new connections between neurons," Liston says.

 

The research suggests that ketamine triggers a two-step process that relieves depression.

 

First, the drug somehow coaxes faulty brain circuits to function better temporarily. Then it provides a longer-term fix by restoring the synaptic connections between cells in a circuit.

 

One possibility is that the synapses are restored spontaneously once the cells in a circuit begin firing in a synchronized fashion, says INSERM'S Beyeler, who wrote a commentary accompanying the study.

 

The new study suggests not only how ketamine works but also why its effects typically wear off after a few days or weeks, she says. "What we can imagine is that ketamine always has this short-term antidepressant effect, but then if the synaptic changes are not maintained, you will have relapse," Beyeler says.

 

If that's true, she says, scientists' next challenge is to find a way to maintain the brain circuits that ketamine has restored."

 

A link to the study referred to in the above article:

 

https://science.sciencemag.org/content/364/6436/eaat8078

 

"Structured Abstract

INTRODUCTION

Depression is an episodic form of mental illness, yet the circuit-level mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood. Ketamine relieves depressive symptoms rapidly, providing an opportunity to study the neurobiological substrates of transitions from depression to remission and to test whether mechanisms that induce antidepressant effects acutely are distinct from those that sustain them.

 

RATIONALE

Contrasting changes in dendritic spine density in prefrontal cortical pyramidal cells have been associated with the emergence of depression-related behaviors in chronic stress models and with ketamine’s antidepressant effects. But whether and how dendritic spine remodeling is causally involved, or whether it is merely correlated with these effects, is unclear. To answer these questions, we used two-photon imaging to study how chronic stress and ketamine affect dendritic spine remodeling and neuronal activity dynamics in the living prefrontal cortex (PFC), as well as a recently developed optogenetic tool to manipulate the survival of newly formed spines after ketamine treatment.

 

RESULTS

The induction of depression-related behavior in multiple chronic stress models was associated with targeted, branch-specific elimination of postsynaptic dendritic spines and a loss of correlated multicellular ensemble activity in PFC projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predicted motivated escape behavior. Unexpectedly, ketamine’s effects on behavior and ensemble activity preceded its effects on spine formation, indicating that spine formation was not required for inducing these effects acutely. However, individual differences in the restoration of lost spines were correlated with behavior 2 to 7 days after treatment, suggesting that spinogenesis may be important for the long-term maintenance of these effects. To test this, we used a photoactivatable probe to selectively reverse the effects of ketamine on spine formation in the PFC and found that the newly formed spines play a necessary and specific role in sustaining ketamine’s antidepressant effects on motivated escape behavior. By contrast, optically deleting a random subset of spines unrelated to ketamine treatment had no effect on behavior.

 

CONCLUSION

Prefrontal cortical spine formation sustains the remission of specific depression-related behaviors after ketamine treatment by restoring lost spines and rescuing coordinated ensemble activity in PFC microcircuits. Pharmacological and neurostimulatory interventions for enhancing and preserving the rescue of lost synapses may therefore be useful for promoting sustained remission."

 

“have found hints”

 

“In mice”

 

“appears to”

 

“scientists have known relatively little about how ketamine and similar drugs affect brain circuits”

 

“there are still many remaining questions”

 

“appears to”

 

“region of the brain we think is important”

 

“seemed to be repairing”

 

“finding suggested”

 

“could be relieving”

 

“research suggests”

 

“somehow coaxes”

 

“One possibility”

 

“study suggests”

 

“What we can imagine”

 

“if that’s true”

 

 

I.e., they don’t know jack about what this drug does.

 

 

Lol, Seltz.   So true, and applies to the majority of studies I've read.  Way more questions than answers.

I agree Selz, the same is said about almost all medicines and there may be conflicts of interest involved too.

 

But, I think it's important to present current research. I would think it even more important if I were suffering from debilitating depression.

“have found hints”

 

“In mice”

 

“appears to”

 

“scientists have known relatively little about how ketamine and similar drugs affect brain circuits”

 

“there are still many remaining questions”

 

“appears to”

 

“region of the brain we think is important”

 

“seemed to be repairing”

 

“finding suggested”

 

“could be relieving”

 

“research suggests”

 

“somehow coaxes”

 

“One possibility”

 

“study suggests”

 

“What we can imagine”

 

“if that’s true”

 

 

I.e., they don’t know jack about what this drug does.

 

Exactly. Lol (only not really funny.)

I.e., they don’t know jack about what this drug does.

 

Not only do they not know what psychoactive drugs do, they don't even know the details of what it is they are trying to "treat".

 

Many if not most doctors today will claim that benzos are "safe" 60 years after they were first introduced and they are still destroying lives. What should make us think that the next drug is any different?

And nobody knows what these possible physical effects would have on any one person clinically.  All they can do is study the drug in thousands of people and see how that might translate into the population at large.

 

I remember in the early 2000's there was an ongoing study about hormone replacement therapy in menopausal woman and the correlation with breast cancer. Half the woman took hormone replacement therapy, and half took a placebo. There were 10,000 or 20,000 women in this study. That's a HUGE clinical study. Most efficacy trials have maybe 2,000 people at most. After several years researchers saw that there might be, just maybe might be, a stronger correlation of breast cancer in women who took the HRT compared to women on the placebo. The researchers could not tell if it was just a statistical fluke or if the effect was real. They decided that, if it was real, they couldn't keep the study going, so they announced their preliminary results and stopped the study early. They recommended that women NOT take HRT unless it was absolutely necessary, and if HRT was started, as low a dose as possible for as little as time possible.

 

5 years later breast cancer rates plummeted. Because the effect was real.

 

That's how clinical studies work.

 

It doesn't really matter what the physical effects of what the drug does in the brain are. Because there are so many more physical effects that could be going on which there's no way to measure. What matters is the effect on people. And you need a large number of people to really see what any clinical effect would be.

“have found hints”

 

“In mice”

 

“appears to”

 

“scientists have known relatively little about how ketamine and similar drugs affect brain circuits”

 

“there are still many remaining questions”

 

“appears to”

 

“region of the brain we think is important”

 

“seemed to be repairing”

 

“finding suggested”

 

“could be relieving”

 

“research suggests”

 

“somehow coaxes”

 

“One possibility”

 

“study suggests”

 

“What we can imagine”

 

“if that’s true”

 

 

I.e., they don’t know jack about what this drug does.

 

omg i was just WAITING for someone to hop on the Ketamine train.... this is the same sht they spouted about LSD psilocybe cubensis and other psychedelic mushrooms cane toads DMT molecule XTC Molly mescaline san pedro cactus peyote ayahuasca and also just about every frikking drug whether psych or otherwise since the beginning of pharmacopea. i'm really tired of people jumping on the next "cure" because the initial results of the said cure induce euphoria or seem to eliminate some symptom. it's why we are all here. we all started off looking outside of ourselves and what we eat for a cure via some medicine to fix whatever was causing us pain or problems. that's how we got here. so why the hell would anyone in our position want to repeat the cycle all over again with the latest new "discovery"? and yes, i've done quite a few illicit drugs and also a bunch of the aforementioned psychedelics in my past. it was fun if you don't think too hard about the brain cells lost and all the missed work the next day. i'll pass on the special K as the club kids used to call it [glow=red,2,300]like 20 years ago[/glow] . there is NOTHING new under the sun.

Q1: What do those of you who oppose the use of medicine propose a first responder do with a despondent person when answering a 10-56A (Suicide Attempt) call?

 

Q2: If the first responder somehow prevents the despondent person from taking their own life what do you propose the despondent person do when they have tried CBT & other non-medicinal treatment options?

Q1: What do those of you who oppose the use of medicine propose a first responder do with a despondent person when answering a 10-56A (Suicide Attempt) call?

 

Q2: If the first responder somehow prevents the despondent person from taking their own life what do you propose the despondent person do when they have tried CBT & other non-medicinal treatment options?

 

What’s with the framing of your questions?  Do you think esketamine would lure the individual out of their intention to take their own life with its promise for relief?  Obviously if they were to use it, first responders would be in close enough proximity to physically prevent the individual from taking their own life.

Q1: What do those of you who oppose the use of medicine propose a first responder do with a despondent person when answering a 10-56A (Suicide Attempt) call?

 

Q2: If the first responder somehow prevents the despondent person from taking their own life what do you propose the despondent person do when they have tried CBT & other non-medicinal treatment options?

 

answer to both questions:

medicine has its place. for a short term emergency situation yes, but same goes for physical restraints. feeling suicidal is not a crime. it is a natural human experience and set of emotions. we are SUPPOSED to go thru times of intense pain and even suicidal thoughts when in crisis in our lives. taking chemicals to stop us from feeling the full spectrum of human emotion is the problem not the solution. to remove all methods of ending ones life is impractical.

 

but here's what has been proven to work, talking and crying and letting it out screaming and beating up objects and admitting to someone trustworthy the nature of the crimes commited against you and done to other sin the past, and sleeping and correct nutrition and correct breathing and getting sunlight in certain doses on a daily basis and keeping a good sleep hygeine and keeping good dental hygeine and drinking pure water and staying away from radiation and chemicals in the toxic environment and breathing pure clean air in the forest away from pollution of cities and playing with pets and hugging trusted friends or loved ones and doing things to help other people and self care and wasting time aka entertainment for the simple pleasure of it oh and exercise. walking stretching swimming running playing sports lifting weights dancing drumming playing musical instruments and listening to music. feeding ducks. watching sunrise and sunsets. bare feet on the ground and sand and ocean.

 

also, nature can teach us many things. when an animal is hurt or sick, it finds a place to hunker down where danger from outside is lessened and it is darker and quieter. it takes its time to heal. when it feels poisoned it eats grass to make itself vomit it out. it eats certain herbs and foods to help it recover. we should take this to heart and take self care very seriously. we live in "society" who gives a pill for any discomfort. and who makes violence a pastime and "entertainment". this society is not human-friendly. i am a human being and prefer to get off these man made chemical anesthetics so i can feel everything again, however intensely it may feel. i trust in nature and that with time, my body and mind will heal by doing those things i listed above that have been proven to work.

Q1: What do those of you who oppose the use of medicine propose a first responder do with a despondent person when answering a 10-56A (Suicide Attempt) call?

 

Q2: If the first responder somehow prevents the despondent person from taking their own life what do you propose the despondent person do when they have tried CBT & other non-medicinal treatment options?

 

What’s with the framing of your questions?  Do you think esketamine would lure the individual out of their intention to take their own life with its promise for relief?  Obviously if they were to use it, first responders would be in close enough proximity to physically prevent the individual from taking their own life.

 

Research & development of ketamine, esketamine and other substances may be viewed as preventative medications for suicidal/destructive tendencies and similar serious symptoms suffered by those afflicted with major depressive and related disorders.

 

Naloxone, flumazenil, physical restraints &/or force may be considered as abortive measures for acts of violence against oneself and others.

 

First responders and sufferers of major depressive and related disorders may be faced with making life sustaining/ending decisions on a regular basis.

 

Research into the causes and treatments of major depressive and related disorders is and will remain an important topic now and well into the future. 

Q1: What do those of you who oppose the use of medicine propose a first responder do with a despondent person when answering a 10-56A (Suicide Attempt) call?

 

Q2: If the first responder somehow prevents the despondent person from taking their own life what do you propose the despondent person do when they have tried CBT & other non-medicinal treatment options?

 

What’s with the framing of your questions?  Do you think esketamine would lure the individual out of their intention to take their own life with its promise for relief?  Obviously if they were to use it, first responders would be in close enough proximity to physically prevent the individual from taking their own life.

 

Research & development of ketamine, esketamine and other substances may be viewed as preventative medications for suicidal/destructive tendencies and similar serious symptoms suffered by those afflicted with major depressive and related disorders.

 

Naloxone, flumazenil, physical restraints &/or force may be considered as abortive measures for acts of violence against oneself and others.

 

First responders and sufferers of major depressive and related disorders may be faced with making life sustaining/ending decisions on a regular basis.

 

Research into the causes and treatments of major depressive and related disorders is and will remain an important topic now and well into the future. 

 

I don’t think its use is being discussed in a first responder setting.  In an acute setting it seems it has potential use but presenting it as a choice between that and suicide is a false dichotomy.

Q1: What do those of you who oppose the use of medicine propose a first responder do with a despondent person when answering a 10-56A (Suicide Attempt) call?

 

Q2: If the first responder somehow prevents the despondent person from taking their own life what do you propose the despondent person do when they have tried CBT & other non-medicinal treatment options?

 

What’s with the framing of your questions?  Do you think esketamine would lure the individual out of their intention to take their own life with its promise for relief?  Obviously if they were to use it, first responders would be in close enough proximity to physically prevent the individual from taking their own life.

 

Research & development of ketamine, esketamine and other substances may be viewed as preventative medications for suicidal/destructive tendencies and similar serious symptoms suffered by those afflicted with major depressive and related disorders.

 

Naloxone, flumazenil, physical restraints &/or force may be considered as abortive measures for acts of violence against oneself and others.

 

First responders and sufferers of major depressive and related disorders may be faced with making life sustaining/ending decisions on a regular basis.

 

Research into the causes and treatments of major depressive and related disorders is and will remain an important topic now and well into the future. 

 

I don’t think its use is being discussed in a first responder setting.  In an acute setting it seems it has potential use but presenting it as a choice between that and suicide is a false dichotomy.

 

The OP articles do not discuss the use of esketamine in a first responder setting. As noted above, research into that and other preventative medications may help prevent major depressive and similar disorders from becoming first responder incidents.

 

Major depressive and similar disorders which end in first responder actions are more common than you may realize:

 

https://en.wikipedia.org/wiki/Suicide_by_cop

 

Research into the causes and treatments of major depressive and related disorders are and will remain important topics now and well into the future. best wishes

Q1: What do those of you who oppose the use of medicine propose a first responder do with a despondent person when answering a 10-56A (Suicide Attempt) call?

 

Q2: If the first responder somehow prevents the despondent person from taking their own life what do you propose the despondent person do when they have tried CBT & other non-medicinal treatment options?

 

The OP articles do not discuss the use of esketamine in a first responder setting. As noted above, research into that and other preventative medications may help prevent major depressive and similar disorders from becoming first responder incidents.

 

Major depressive and similar disorders which end in first responder actions are more common than you may realize:

 

https://en.wikipedia.org/wiki/Suicide_by_cop

 

Research into the causes and treatments of major depressive and related disorders are and will remain important topics now and well into the future. best wishes

 

Q1:  I propose that the cop does not shoot the despondent person or give them esketamine.

 

Q2:  I propose that the cop keeps them safe until they can be seen by someone more qualified than a cop.