Ketamine may not be a perfect cure, but it can be used as a tool to reveal the biological causes of depression.
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Editor’s note: Ketamine is the main component of the so-called “K powder”. Ketamine was first used as an anesthetic, and later, due to its hallucinogenic effect, it was used as a “drug” until the scientific community discovered it recently. It has antidepressant effect, and it is regarded as “righteous”. Traditional antidepressants are usually slow to work and are not useful for everyone. New research provides evidence that ketamine may be a safe, fast and effective treatment for major depression. The United States and the European Union have approved nasal sprays containing ketamine for depression patients whose other therapies fail to work. But ketamine also has shortcomings. Although it has a quick effect, the effect lasts for a short time. Some experts regard ketamine as a tool to reveal the biological causes of depression, and maybe one day, it can really cure depression. This article is translated from Medium, author Lauren Tanabe, the original title is Ketamine Is Revealing a New Understanding of Depression and the Brain, I hope that You are inspired.
“Some people say that ketamine makes them feel like cotton candy.”
At the first consultation, the therapist explained to me through the computer screen. I myself asked a few people how ketamine feels, and the answer I get is slightly different each time. But the general consensus is that it makes me feel floating, I may see something, I may feel relaxed or upset. And my biggest fear is that there will be panic attacks during the experience. “For this, we can also give you some treatments,” the therapist assured me.
My history of depression has been nearly 20 years. I don’t remember what it feels like not to be depressed. Faced with anything, I can’t help but think about the worst possible outcome. I decided to find a new treatment.
Citalopram (Celexa), Lexapro, Amitriptyline (Elavil), Cymbalta (Cymbalta), I have tried all these drugs before, but none of them succeeded in eliminating depression in my brain . As I grew older, my depression caused anxiety and panic. Becoming a mother makes it all to the extremelimit. However, the doctor continued to prescribe these same drugs. “These are useless,” I protested. “We have to keep trying different methods,” they will answer.
Almost all antidepressants conform to the monoamine hypothesis about depression that emerged in the 1950s. The hypothesis suggests that depression is caused by low levels of chemical messengers in the brain called monoamine neurotransmitters, including serotonin, dopamine, and norepinephrine. The idea is simple: increase the levels of these neurotransmitters in the brain and reverse depression.
The prescription drugs prescribed for this purpose are divided into several categories, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and Older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). They all affect one or more monoamine neurotransmitters. However, these antidepressants are usually slow to work, and it may take several weeks to several months to reduce the symptoms of depression.
The problem is that these drugs are only effective for about half of people.
A review published in the journal Neuron in 2019 believes that in the past few decades, due to narrow attention to these neurotransmitters and their role in depression As a result, scientists missed the opportunity to identify other neurobiological causes of depression, and therefore missed potential new treatments. According to the author, in addition to monoamine neurotransmitters, “there have long been clues” that some changes in the brain are related to depression. For example, the increase in BDNF may be caused by signal transduction outside the monoamine pathway. In fact, although antidepressants can increase this growth factor, it may be more of a subtle change than the dramatic change needed to relieve depression.
So it’s not surprising that typical antidepressants don’t work for many people. The STAR*D trial is one of the most widely cited and largest studies on the efficacy of common antidepressants. The trial showed that more than half of patients treated with several different antidepressants still have symptoms. “A large percentage of them have relapsed. Obviously, these antidepressants are not as effective as we thought,” said Robert McClure, associate professor of psychiatry and psychiatrist at North Carolina School of Medicine. Dr. (Robert McClure, MD) said.
When these drugs were approved by the U.S. Food and Drug Administration (FDA), they were based on data showing efficacy, he said, “But when these studies are repeated in a more scientific way, rather than when pharmaceutical companies try to When performed in the context of FDA-approved treatments, we found that these treatments were not as effective as thought.”
1. Beyond the “monoamine hypothesis”
In addition to traditional monoamine neurotransmitter drugs, medications for depression include ketamine and psychedelics. Strictly speaking, ketamine is not a psychedelic, but an anesthetic, although it can cause hallucinations and mental liberation. According to Carlene MacMillan (MD), a doctor of medicine, a psychiatrist, the CEO and co-founder of Brooklyn Minds, the way they affect the brain may also overlap.
Drugs such as ketamine can quickly trigger neuroplasticity, which is the reconstruction and strengthening of connections between neurons, and the way the brain reorganizes itself. They also suppress the default mode network (DMN) of the brain, which is thought to be involved in introspection and distraction. When this connection calms down, “the preconscious, emotional, and primitive parts of the brain will take center stage in the experience,” Macmillan said. “It is in this space that we see new connections and changes in perspective.”
Michael Pollan’s “How to Change Your Mind” describes another way of understanding psychedelics. He compared his brain to a snow mountain covered with traces of a sleigh. In this analogy, the sled is thought. Over time, certain ski trails become very deep, making it difficult to take other routes. These deep grooves represent the nerve pathways that pass the most, and these pathways happen to pass through the DMN. The effect of psychedelic drugs is like a layer of fresh snow, erasing previous traces. This allows people to travel in new directions and create new paths in the brain.
The therapist in my clinic also used the metaphor of “Xinxue” when describing the effects of ketamine. This drug can create new neural connections in the brain and create different ways of thinking. “Try not to approach it with fear, but approach it with curiosity,” she explained.
2. Ketamine-a game changer
Ketamine is not a new medicine. It was produced in the 1960s and quickly became popular as an anesthetic during the Vietnam War. The full name of ketamine is 2-o-chlorophenyl-2-methylaminocyclohexanone, which is a derivative of phenylcyclohexidine (PCP). Because its physical shape is usually white powder, and the first letter of the English name is K, it is commonly called K powder. It is generally used as an anesthetic in clinical medicine. In the past few decades, its label has undergone a transformation from anesthetics to drugs and then to antidepressants. “You can use ketamine in surgery, which is basically achieved by shutting down the cerebral cortex,” McClure explained.
But until decades later, scienceThe family only began to consider whether this drug might also be an effective antidepressant. Unlike drugs that target monoamines, ketamine acts through a different type of neurotransmitter glutamate. Specific proteins recognized on neurons and affected by glutamate include N-methyl-d-aspartate (NMDA) receptors. Drugs such as ketamine can inactivate the NMDA receptor and seem to improve the stress response in rodents. Then, researchers at Yale University discovered that ketamine can relieve people’s major symptoms of depression. In 2006, it was discovered that ketamine had the same effect on patients who had tried (but unsuccessfully) more than 6 antidepressants. It can also effectively suppress suicidal thoughts.
“Ketamine is a huge game changer,” McClure said. “There have been no new drugs for depression for many, many years.”
Ketamine also works faster. McClure said: “Anyone who has taken oral antidepressants knows that it takes six weeks to work. If you use ketamine, people can experience improvement in symptoms within 24-48 hours.” /p>
But because ketamine is not a new drug, it cannot be patented and it is difficult to make money. So pharmaceutical companies are competing to develop other drugs that mimic the blocking effect of ketamine on NMDA receptors. In 2019, esketamine nasal spray (Spravato for short) was approved by the FDA.
Macmillan said: “For patients receiving ketamine [intravenous] injection, the effective rate is generally between 50-80%.” Compared with traditional antidepressants, Spravato is also more effective. After one month of treatment, the general response rate of esketamine is 53-69%.
McClure pointed out that there is no large-scale positive comparison test yet, so it is difficult to say which one is better. Intravenous ketamine is easier to tailor for patients, but because intravenous ketamine is still considered “experimental”, nasal sprays are more likely to be covered by insurance.
3. Ketamine is not a cure, but a tool
Some experts regard ketamine as a tool that can reveal the biological causes of depression and may one day cure depression. “Ketamine provides us with an unprecedented opportunity to study the brain’s rapid transition from severe depression to mood improvement within a few hours,” said Chadi Abdallah, MD, a psychiatrist and medical officer at Baylor College of Medicine. Associate Professor of Psychiatry in the Department of Behavioral Sciences and Chairperson of Military Post-Traumatic Stress Syndrome Neuropsychiatry.
The effect of ketamine on the brain is still being studied. But most scientists believe that this is related to glutamate, which is the most abundant neurotransmitter in the brain, and is also related to the strengthening of connections between neurons in depression-related areas. Macmillan likes to putThink of ketamine as fertilizing the garden. He said: “Ketamine can quickly increase the activity of the neurotransmitter glutamate in the frontal area of the brain, which is inactive during depression. This leads to the formation of new connections between neurons in this area.” /p>
The loss of synapses caused by depression may disrupt certain brain networks that ketamine can restore, at least temporarily.
Vanderbilt University (Vanderbilt University) Professor of Pharmacology, Vanderbilt Brain Institute (Vanderbilt Brain Institute) Director Dr. Lisa Monteggia (Lisa Monteggia) and her laboratory are carefully mapping ketamine and NMDA The condition when the receptor binds and blocks its activity. According to Montegia, the location of these receptors can significantly affect signal transmission between neurons because they are located at the synapses that communicate. “This is why you are triggering the effects of these antidepressants. You are in the right place to influence rapid neurotransmission changes.”
Her laboratory discovered that when ketamine inhibits the activity of these receptors, a series of events occur, including a new, unconventional type of signal, passing through another glutamate receptor called AMPA Produced on the synapse. This effect is called enhancement. “This enhancement is the antidepressant effect.”
But ketamine will not solve the problem. Instead, it is a window. “We are revealing depression, not solving depression,” Montegia said when explaining the antidepressant effect. Unfortunately, the antidepressant effects of ketamine on the brain are temporary. The new connection is short-lived, and symptoms will recur in about 10-14 days.
Montegia emphasized that the causes of depression are multifaceted, involving a variety of genetic, environmental factors, and brain circuit errors. “It’s hard to believe that ketamine can enter and repair all these different circuits, but it may be able to cover it to some extent because you trigger the enhancement just mentioned.”
It is a challenge to figure out how to maintain these new synaptic connections.
The clue may come from other areas of depression research. Abdullah said: “It is believed that the abnormally high inflammation in depression first leads to the loss of brain connections, and then to the elimination of ketamine-induced connections.” He and his colleagues recently published a study and found that Giving patients rapamycin (an anti-inflammatory drug) before intravenous ketamine can prolong the antidepressant effect.
Rapamycin may protect new connections by reducing inflammation, but it also has other possible explanations. For example, it will increase autophagy, “cells use this process to remove toxic substances and dead elements from tissues,” Abdullah said. In other words, it helps to remove garbage in neurons and also helps to preserve new synapses.
It’s still time to judge whether this strategy or other measures can retain the effects of ketamineToo early. McClure believes that research on inflammation and the microbiome may inspire depression and treatment. He said that at the University of North Carolina, they are very interested in biomarkers, which make a patient’s characteristics measurable, such as specific protein levels, and can also be used to explore other possible ways in which ketamine can work. If you can find reliable biomarkers, you can understand who is more likely to respond to specific treatments, such as ketamine. “I think psychiatrists really want to have predictors, whether it is clinical features or biomarkers, we can use them to predict who will respond to which treatment.”
Most ketamine studies examine the situation after one infusion of ketamine, but the clinical protocol requires at least one month of infusion, one infusion of ketamine every two weeks, and then ketamine maintenance treatment at longer intervals. After starting a series of treatments, the time between these intensive treatments largely depends on the patient’s response. McClure said that some studies have found that continuous ketamine treatment is necessary for sustained remission. He said: “This is not surprising, because we know that in order to prevent recurrence, continuous antidepressant treatment is necessary for patients with recurrent major depression.”
But neurobiology is only part of the puzzle. Patients with depression may benefit from ketamine treatment at the same time or subsequent psychotherapy. Experienced people can help people understand this process and apply the newly acquired insights to their lives. Macmillan said: “After using ketamine, psychotherapy can use this window (enhancing neuroplasticity) to stimulate thinking changes.” Although reducing depression symptoms is the hope of many people, McClure warns. Change, even a good change, will bring pressure.
4. What’s next?
Like other drugs, ketamine can have a miraculous effect on some people, but it is useless for others (about 30% of people will not respond). And some people, like me, are somewhere in between. After 8 treatments, I cannot say that I am no longer depressed, but both my husband and the therapist said that they have noticed that my condition has improved, although I still have some doubts.
Ketamine really gave me a new experience. I once saw singularities in space in my mind, saw the rotating mandala, felt the collapse of time, and felt the sensation of the boundary of my body disappearing. I felt a connection that transcended myself. I felt ecstatic. A deep and wide abyss of grief frightened me. Throughout the process, I always felt that I was about to be inspired.
But ketamine is not the end. Scientists like Montegia are busy mapping molecular pathways and the synaptic effects of many treatments, including psychedelics, transcranial magnetic stimulation and electroconvulsive therapy. Both Macmillan and McClure said that these treatments are also effective for many people, but the key is to find the right provider.
For Montegia, synaptic enhancement is a key factor. The more drugs or treatments scientists can find to evoke it, the more potential treatment options. When ketamine doesn’t work for people, Montegia said: “Maybe they have some kind of abnormal synapses in this pathway. Maybe they may produce another drug that triggers this enhancement through “another way”. Response. For many different reasons, the brain may not respond, so we must recognize this complexity. If we can see progress in treating these people, it will be a real benefit.”
I don’t know if my brain will reconnect, or if new synapses will degenerate over time. I know that I will never forget the changes ketamine brought to me. In Noonday Demon, Dr. Andrew Solomon, a professor of clinical psychology at Columbia University Medical Center, wrote: “In depression, you don’t think that you are wearing a gray veil. Observe the world through the haze of bad emotions. You just think that the veil of happiness has been taken away, and now you see it really.”
What I want to say is that if depression makes you think that everything you see is real, then ketamine will allow you to see everything possible, even for a short while.
Translator: Jane