Ketamine

| Party drugs become a life-saving medicine |
Joe Wright has no doubt that ketamine (commonly known as “k powder”) saved his life. Wright, 34, is a middle school teacher who writes poems in front of a typewriter every day, but he has been suffering from suicide impulses for many years. When he was in high school on Staten Island, New York, he had this idea in his mind and became more intense when he was a freshman. “This is a kind of inner monologue. It doesn’t make sense to keep yourself stressed that people are alive.” He said, “It feels like you are being ambushed by your own brain.”

The summer after the second year of college, he tried to commit suicide for the first time. At that time, he swallowed a whole bottle of sleeping pills. He has been taking Prozac, Zoloft, Bupropion and other antidepressants over the years, but the idea of ​​suicide has never been completely eliminated. He used a pencil blade to cut his arms and legs, and sometimes he used a cigarette butt to burn himself.

In 2016, Wright decided to try again. This time he mixed several drugs and grinded them into powder. Just as he was preparing to pour the powder into the water, his pet dog suddenly jumped on his lap and let him wake up. In shock, he decided to change this state, find a way to save himself, and began to search for information in this regard. Occasionally, he discovered a study by Columbia University on medications for severe depression and suicidal tendencies, namely the injection of ketamine, a narcotics with decades of history, and a notorious party drug.

His first and only injection of ketamine feels like a dream: a bit strange and pleasurable. He was almost full of hope for life and became more willing to receive treatment. Within a year, he got married. Now he said that negative emotions have moved away from him and can be controlled, and the idea of ​​suicide has basically disappeared. “If they tell me in advance how much this treatment will affect me, I would never believe it. It has not been approved for the treatment of suicidal patients, which is unreasonable,” Wright said.

The reasons for not being approved are not entirely medical reasons. Over the past 30 years, pharmaceutical companies have conducted hundreds of trials of at least 10 antidepressants for the treatment of severe premenstrual syndrome (PMS), social anxiety disorder, and a variety of other diseases. One thing they have almost never done is to test these drugs on critically ill patients on the verge of suicide, with ethical considerations: doctors don’t want to provide a placebo for those who plan to commit suicide; Consider: If a patient commits suicide during a drug trial, it will affect the sales prospects of the drug.

In the United States, where suicides are endless, this risk-return calculation has changed. From 1999 to 2016, the suicide rate rose by 30%, and today it is the second leading cause of death for people aged 10 to 34, second only to traffic accidents – and the global trend is just the opposite: suicide rates are falling. The growing wealth gap, war wounds for veterans, the opioid crisis, and easy access to guns are all thought to be the cause of the rise in suicide rates in the United States, and none of these problems have been mitigated.

But the method of treating suicidal tendencies has finally been seriously explored, the core of which is ketamine, and it is vital that the pharmaceutical industry now sees a way out. The first ketamine-based drug comes from Johnson & Johnson, which may be approved as a treatment for refractory depression and approved for suicidal thoughts within two years. In the development of a quick-acting antidepressant for suicidal tendencies, Aerjian is not far behind. Such a species constitutes one of the most promising chapters in the field of scientific research in recent years.

| The medicine is so good that it is incredible |
Dennis Chaney, Dean of Mount Sinai School of Medicine in New York, has many family photos, certificates, and awards for long-term research careers. Among them, one thing hanging on the wall is different: the patent certificate for the treatment of suicidal ketamine nasal spray. In a sense, the development of this drug is also a portrayal of Charney’s career.

“If we don’t do more in-depth research, we will completely miss the antidepressant effect of ketamine.”

In the 1990s, Charney was a professor of psychiatry who directed the then associate professor John Krystal at Yale University and tried to figure out how serotonin deficiency affects the onset of depression. At the time, the study of depression was carried out around serotonin. Prozac, approved in 1987, is the first selective serotonin reuptake inhibitor (SSRI), which pioneered an era of research and development in the industry called “follow-up drugs” aimed at improving existing drugs. Instead of developing new drugs. In this narrow field, pharmaceutical companies have launched heavyweight products one after another.

Chani is a depression expert and Kristal is interested in studying schizophrenia. Curiosity leads them to the same goal: the glutamate system. The system is an excitatory neurotransmitter that helps brain cells communicate. It is considered to be crucial for the formation of learning and memory, and Kristal calls it the “high-order brain’s main information highway.” He and Chani have been using ketamine to temporarily create symptoms similar to schizophrenia in order to better understand the role of glutamate in this condition. In the mid-1990s, the two decided to conduct a single-dose ketamine test on nine patients (and eventually two people withdrawn) to see how the depression responded to the drug. The test site was selected in Connecticut. Yale University affiliated to West Haven – Connecticut Veterans Hospital.

The reputation of ketamine outside the field of anesthesiology – if any, is notorious. Street drug users sometimes take enough doses to get them into so-called “K-holes”, in which they are unable to interact with the outside world. During the day, this dose, which is purely for self-sufficiency, may be hundreds of times the dose that Chani and Kristal intend to use for the patient. Despite this, they decided to monitor patients for 72 hours, far more than two hours of ketamine impact on behavior, just to not miss any possible negative effects.

Four hours after the application, the researchers examined the patient and found an unexpected situation. Chani said: “What surprised us was that the patients began to express that they felt better, and they improved within a few hours.” This is unheard of. It is important to know that antidepressants will take several weeks or even months to work, and that the drug does not show sufficient efficacy in about one-third of patients. “We were shocked that the results of this study have not been published for several years,” said Kristal, who is now the head of the Department of Psychiatry at Yale University.

When Charney and Kristal finally published their findings in 2000, they hardly caught anyone’s attention. Perhaps because the scale of the experiment is too small and the results are too good to look like it is true; perhaps it is related to the poor reputation of ketamine as an illegal drug; or perhaps because of side effects, there is always a problem: ketamine The patient will be in a state of mental dissociation, that is, the patient feels that his consciousness and body are separated.

However, all of these factors may not be as important as the naked economic reality, and the pharmaceutical industry will not invest hundreds of millions of dollars to conduct a large-scale study on an old and cheap drug like ketamine. In 1970, ketamine was approved for marketing in the United States, and its original purpose was to use it as a safer alternative to the anesthetic phencyclidine (a more well-known name is PCP or angel powder).

Developing a drug that has long lost patent protection can rarely bring profits, even if scientists have discovered a whole new use. I don’t know why, even with all these burdens, research on ketamine has made progress. This small study, which was almost never intended to be published at the time, has now been cited more than 2,000 times.

| The brains of suicides are different |
In medicine, suicide is described as the result of a series of mental disorders and difficult situations – this tragedy may have many root causes. Diseases such as severe depression, bipolar disorder, and schizophrenia are known risk factors. Childhood trauma or abuse can also be an inducement, perhaps including genetic risk factors.

Through these facts, John Mann, a psychiatrist with a Ph.D. in neurochemistry from Australia, has made great strides. He proposed the hypothesis that if suicide has many incentives, then all brains that tend to commit suicide may have some common characteristics. Since then, he has done some of the most interesting work to explain what researchers call suicide biology. This statement itself represents a bold idea – in addition to depression or other mental illnesses, there is a potential, physiological suicide sensitivity.

In 1978, Mann moved to New York. In 1982, he began collecting the brains of suicides at Cornell University. He recruited Victoria Arango and is now a leading expert in suicide biology. At the time, the practice of studying the brain tissue of the deceased was no longer popular, and Mann wanted to restart research in this area.

They first brought the work and collected brains to the University of Pittsburgh and then to Columbia University in 1994. Now they have collected about 1,000 human brains – some from suicides and the other as contrasts – neatly placed in a freezer at about minus 80 degrees Celsius.

In the early 1990s, Mann and Arango discovered that there were subtle changes in serotonin in certain areas of the brain of suicidal depression patients. Mann remembers sitting with Arango and neurophysiologist Mark Underwood to analyze the areas of the brain affected by the defect. Underwood is Arango’s husband and her long-term research partner. They spent a lot of effort trying to uncover the secrets of the suicide’s brain, but it didn’t work very well until one day they realized that this is the same as the brain area described in a famous case study of psychiatry.

In 1848, an American railroad worker named Phineas Gage exploded early in the explosion of explosives. His skull was pierced by a shovel about 1.1 meters long. Although he survived, Gage’s character changed permanently. In a paper, the doctor wrote that Gage’s “animal habits” were revealed and he used the “most vulgar language” to speak. Modern research has shown that this shovel destroys the critical areas of the brain that are involved in suppressive function – the same areas of brain that have changed in suicidal depression.

For the Mann and Arango team, this reveals a situation where brain differences between suicidal patients and normal people are anatomically important.

“Most people will suppress suicidal tendencies. They will find a reason not to commit suicide,” said Underwood. However, due to subtle changes in certain areas of the brain, suicidal people “can’t find suicide.” Reasons.”

About eight years ago, Mann saw that ketamine research has advanced rapidly in other areas of the scientific community, and he has included this drug in his work. In one trial, his team found that ketamine therapy was more effective in reducing suicidal thoughts within 24 hours compared to control drugs. Crucially, they also found that the anti-suicidal effect of ketamine was somewhat independent of the antidepressant effect of the drug, which helped support their argument that suicidal impulses are not an inevitable by-product of depression. It was the study led by Mann’s colleague Michael Grunebom that made Joe Wright a believer in ketamine therapy.

| Reincorporated into commercial drug research and development |
In 2000, the National Institutes of Health (NIH) hired Chaney to host two studies on mood disorders and experimental drugs. For him, this is the perfect place to advance ketamine research. Here, he copied the research results of his colleagues at Yale University. In a study published in 2016, a team at the NIH found that patients received a “strong and rapid antidepressant effect” within two hours of receiving a single dose of ketamine. Responsible for this research is researcher Carlos Salat, who is currently working on NIK for ketamine and suicide. “We can’t believe this result,” said Sarat.

A study conducted in Mount Sinai in 2009 showed that suicidal thoughts in patients with refractory depression subsided significantly within 24 hours of application. In the second year, the Salat team’s research showed that the drug could exert anti-suicide effects within 40 minutes.

In the end, ketamine was reintroduced into the field of commercial drug research and development. In 2009, Johnson & Johnson dug away NIH’s outstanding ketamine researcher Husseini Manji, who was responsible for the company’s neuroscience department. At the time of excavation, Johnson & Johnson did not explicitly ask him to develop ketamine into a new drug, but after a few years in office, Manji decided to intervene in this field. This time it was a chemical close relative of ketamine, a form of nasal spray. This medicine will be allowed to be patent protected. Moreover, this nasal spray eliminates the problems that may be caused by intravenous administration. The first is that psychiatrists usually do not have the conditions to manage intravenous medications in the office.

Some doctors, mainly psychiatrists and anesthesiologists, are already taking action when the wheels of scientific research are slowly turning. Around 2012, they started the ketamine clinic. Dozens of such clinics have emerged in several major metropolitan areas in the United States. Medical insurance usually does not cover this area, but in these clinics, people can pay about $500 for this drug.

In September 2018, the American College of Ketamine Pharmacists held its first medical conference on the non-traditional use of ketamine.

“You are really dying to help you!” said Steven Mandel, who switched from an anesthesiologist to a ketamine supplier in a conference room in about 100 people in Austin. Most of these people are doctors and nurses who gather here to listen to Mandel and other early adopters about how they use the drug. When the speaker talked about some anecdotes about the effect of the drug, it was interrupted by the audience’s bursts of cheers from time to time.

| Or will sell very expensive |
There are still some issues that need to be addressed. A consensus statement published in the Journal of the American Medical Association: Psychiatry in 2017 stated that “there is a need for some guidance on the use of ketamine”. The author is particularly concerned about the lack of relevant data on the safety of long-term use of the drug in patients with mood disorders, and points out that there is a “great disagreement” in the medical community about its long-term impact.

At the moment, patients who attempt to commit suicide often leave the hospital a few days after admission, creating a risky situation: perhaps patients who have not fully recovered will return home with a bunch of antidepressants, which may even consume if they are used. A few weeks can only boost the patient’s mood.

A ketamine clinic is the solution to this dangerous situation, provided that you can afford it. For Dana Manning, a 53-year-old resident of Maine who suffers from bipolar disorder, $500 is unbearable. She said: “I want to die every day.”

“It’s like you have a shoulder load of 50 pounds, and ketamine has helped you remove 40 pounds.”

In 2013, Manning committed suicide by overdosing drugs such as alprazolam and Prozac. After that, she tried almost every drug that was approved for marketing to treat bipolar disorder, but none of them could suppress mood swings. In 2010, the depression of the depression made a comeback, so that she could hardly get up and had to resign from the work of the case specialist. Electroconvulsive therapy is the last line of defense for people with depression who do not respond to drugs, but this method does not work for her.

Eventually, her psychiatrist suggested that she try ketamine after rummaging through various medical literature. The doctor even helped her reimbursement of medical expenses from the state Medicaid program. She received four injections a week, and then moved to Pennsylvania, where more family members can take care of her.

Manning said that the first few weeks after receiving ketamine treatment was “the only time I can say that I feel normal” for 15 years. “It’s like you have a shoulder load of 50 pounds, and ketamine has helped you remove 40 pounds.”

Now Manning has returned to Maine and depression has recurred. Her current medical insurance cannot reimburse ketamine. She lives with a $1,300 disability benefit each month. “I know how to cure, but I can’t receive treatment. The word ‘frustration’ is not enough to describe this feeling,” she said.

In the eyes of scientists, ketamine is a “dirty drug” – it can affect many pathways and systems in the brain at the same time, so it is difficult to find out exactly how it works in patients who are effective after taking it. This is one reason why researchers continue to look for a better version of this drug. Of course, another reason is that the new version can be patented. If Johnson & Johnson’s ketamine enters the market, the pioneers in ketamine research and their research institutions will benefit. Three names can be found on the patent certificate of the Chani office: Krystal of Yale University, Salat of NIH, and Chaney of Mount Sinai School of Medicine, all of whom can obtain patents from the sales revenue of this drug. fee. Johnson & Johnson did not comment on the possible pricing of the drug, but there are good reasons to believe that the most significant breakthrough in the history of antidepressants since the advent of Prozac will be very expensive.

How ketamine and its close relatives, espermone, work is still the subject of debate. In essence, these drugs seem to provide a quick molecular reset button for brains that are damaged by stress and depression. Both ketamine and ketamine release glutamate. Conversely, this substance may stimulate the growth of synapses or neural connections in certain areas of the brain that may play a role in mood and ability to perceive happiness. Perhaps the drug is to stop suicide by enhancing those brain circuits, while rebuilding the necessary inhibitory functions, so that people can eliminate suicidal thoughts.

Perhaps after the opioid crisis, the biggest worry may be that the use of ketamines is too loosely controlled, which may lead to a new drug abuse crisis. This is why Wall Street analysts are eagerly awaiting the establishment of the fast-acting antidepressant rapastinel, which is still lagging behind acetamine for about a year. The researchers said that the drug, like ketamine, acts on the same target in the brain, but it works in a more subtle way, perhaps avoiding the side effects of mental dissociation and the possibility of being abused.

“Once you find something useful in the dark, you have to figure out: Can you make it better, faster, and safer?” said Amin Sergei, vice president of Air Construction. .