New mechanism is expected to set a “milestone” in human antidepressants

On September 14, Nature Neuroscience published the research results of Chen Youlin’s research group, a researcher at the Interdisciplinary Research Center of Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, on new antidepressant drugs. The study, which took six years and more than two years of submission, discovered the mechanism of action of the antidepressant esketamine. According to the relevant targets and mechanisms of action, it is expected to develop “perfect drugs” with rapid antidepressants and lower side effects.

Therefore, the study was evaluated by the reviewers as a particularly thorough and excellent study. This work has important theoretical and practical guiding significance, and may have a major impact on human beings in the fight against depression and become a “landmark event”.

Depression treatment dilemma

According to WHO, depression affects more than 300 million people worldwide. Before the new crown epidemic, more than 50 million people in our country suffered from depression. Post-pandemic surveys found that about 100 million people were affected by depression.

People have realized that depression is not simply “bad mood”, it is actually a brain disease. Depression not only affects people’s normal work and life, but also leads to suicide in severe cases. “Depression has caused great distress to people, but there is still a lack of effective treatment drugs,” Chen told China Science News.

Chen Coconut Forest. Photo courtesy of interviewee

At present, the treatment of depression is mainly based on psychiatric drugs represented by Prozac. These drugs achieve antidepressant effects by increasing levels of monoamine neurotransmitters such as serotonin and norepinephrine in the brain. These drugs are slow to take effect, usually taken for more than 3 weeks to determine whether they are working, and if they do not work, the dose is increased for further attempts.

“One third of patients do not respond no matter how much they increase the dose or try other antidepressants, which is very troublesome and the cost of trial and error is high.” Chen Yulin said, “These drugs usually take more than half a year, and stopping the drugs abruptly will produce a withdrawal reaction.” Some patients do not have a long onset and may disappear in a month or two, which may become an additional burden. More importantly, these drugs do not relieve suicidal tendencies, and suicidal patients cannot take this drug. ”

All these problems pose a huge challenge to people in the fight against depression.

“Strong and bad” ketamine

In April this year, the National Medical Products Administration approved a rapid antidepressant drug Spravato (esketamine) nasal spray for marketing. This is the first antidepressant drug with a new mechanism of action approved in China, which can quickly relieve the symptoms of patients with acute suicidal ideation or behavior.

“In fact, this drug[ketamine]has been used in the medical system as an anesthetic and analgesic for decades.” Su Tonghui, a joint author of the paper, said that ketamine is composed of two chiral symmetric molecules of left-handed and right-handed in a ratio of 1:1, of which esketamine is a component (dextroketamine).

In 2004, scientists accidentally discovered that esketamine has a rapid antidepressant effect, which can relieve depressive symptoms within two or three hours, and is also effective in patients with treatment-resistant depression, and can also relieve suicidal tendencies.

In 2019, esketamine was approved for marketing in the United States. Although the drug has excellent rapid antidepressant activity, it has hallucinogenic effects, can cause a “feeling of separation between the mind and the body”, and also has a certain degree of addiction. This has led to the drug being classified as a controlled drug and must be used under the supervision of a doctor in a designated clinic. Patients usually stay in the hospital for two or three hours and wait for the hallucinations to disappear before leaving, which causes great medication inconvenience.

“Esketamine is a new mechanism of drug action, but it is not clear what this mechanism is.” Lu Yi, a co-author of the paper, said, “Because it was accidentally found to have antidepressant effects, and people did not know its mechanism of action, the drug has not been optimized, and the side effects are very obvious.” ”

Chen Coconut Grove team. Photo courtesy of interviewee

Take a hard road

How to further develop rapid antidepressants with weaker side effects based on the mechanism of esketamine has become the focus of attention in this field. But two key questions have been plaguing the development of such drugs: first, the target of esketamine’s action is unknown, and second, whether the side effects of esketamine are related to the mechanism of antidepressant activity, and can the two be separated?

Before esketamine was marketed in the United States, academic research on its mechanism of action had begun. In 2005, there were published papers discussing the rapid antidepressant activity of ketamine. Because of his long-term research on glutamate receptors, these papers immediately attracted the attention of Chen Yulin, who initially had the idea of “figuring out its mechanism”.

In 2015, when Chen Youlin went to the Interdisciplinary Research Center of Biology and Chemistry of the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences to build her laboratory, the academic research on the antidepressant activity mechanism of ketamine was controversial. NMDA-type glutamate receptors are thought to be direct targets for the antidepressant effects of esketamine. In particular, the GluN2B subtype NMDA receptor is widely recognized as a direct target of esketamine. However, several selective inhibitors targeting GluN2B have not yielded satisfactory results in clinical development. Therefore, it has been reported that the mechanism of action of esketamine is not related to NMDA receptors at all, and some people even believe that the active ingredient that really works is not esketamine itself.

“The target and drug mechanism of action are the criteria for drug development, and the original discovery from 0 to 1 in the field of drug development mainly comes from the confirmation of the mechanism and target.” Chen said, “One reason for the divergent theories is that previous mechanism studies were mainly based on pharmacological methods, and it was difficult to exclude the ‘off-target effect’ of drugs, and the research on the target itself was also limited.” Although the genetic method has a longer research period, it can draw clear conclusions without worrying about the off-target effects that the drug may bring. ”

Based on these ideas, Chen Yulin’s team began to use genetic means to analyze esketamine, and explore the antidepressant activity of drugs by knocking out potential targets in experimental mice. This requires a series of work such as identifying targets, breeding transgenic mice, and testing antidepressant activity. Obviously, this is a “dumb method” that is expensive, time-consuming, and requires a lot of effort.

The choice of “no shortcuts” research scheme made Chen Yulin’s team pay great hardships, and even the team repeatedly hit a wall in the initial experiment. It was not until later that all the experiments were done that it was found that the predictions made according to the mainstream theory in the early stage were almost “completely wrong”.

To this end, Chen Yulin has spent more than 8 years. His 3 students also devoted their time to follow for 8 years.

This made Chen Yulin quite emotional: “When doing research, there are many details that must be ‘cut’ clearly, and sometimes it is not enough to read the literature, because if your findings are consistent with the mainstream view, it means that your research has not made a breakthrough…”

High-level papers are just “by-products”

In the past 8 years of intensive work, researchers have not only clearly explained the antidepressant targets and mechanism of action of esketamine, published a theoretical article in the “top journal” in the field of neuroscience, but also adopted a “two-pronged” research method to simultaneously develop new drugs according to the theory when clarifying the theoretical work.

In 2017, Chen found that ketamine’s antidepressant activity disappeared, but its hallucinogenic activity remained, after knocking out a potential target in mice.

“I was like, oops! That’s interesting. Six or seven years later, Chen recalled that the situation was still difficult to hide the excitement in his tone, “because if the antidepressant activity and hallucinogenic activity cannot be separated, it means that we cannot remove the side effects, and we can never develop better drugs.” ”

“This discovery convinced us that this direction is right, and the rest is a matter of details, just figure it out.” The paper is jointly written by Fu Chaoying.

“Professor Yuan Junying has always hoped that our research will not only publish papers, but also make practical contributions to the industry.” Chen added, “Although it was still far from publishing a paper at that time, it was enough to guide the development of drugs. ”

With the theoretical mechanism mastered, anyone can carry out new drug development. However, the initiative of the Interdisciplinary Research Center of Biology and Chemistry of the Chinese Academy of Sciences to “guide practice with theory, practice and contradict theory” has allowed them to take the lead in the research and development of new drugs for depression for at least 6 years.

At present, the center has obtained “small molecule” compounds with rapid antidepressant effects and no side effects, and has confirmed the effect in model animals.

“The development of related drugs is expected to enter the clinical trial stage next year.” Chen said, “Let’s look forward to the official launch of a new antidepressant drug that benefits hundreds of millions of people. (Source: Zhang Shuanghu, China Science News)

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