▎WuXi AppTec Content Team Editor
October 10 is World Mental Health Day launched by the World Psychiatric Association to raise awareness of the importance and urgency of mental health across the community. According to the World Health Organization (WHO), nearly 1 billion people around the world suffer from mental health problems, of which depressive disorders (including depression) have become the second most prevalent disease in the world, with more than 300 million people affected troubled. However, compared with the prevalence of the problem, people’s attention and awareness of mental health are still lacking.
Recently, the WuXi AppTec content team conducted a mental health cognition survey on nearly 1,500 students from more than 260 universities and research institutions in China. According to the survey results, most college students agree with the importance of mental health (74% of the participants believe that mental health is as important as physical health), but only 14% of the participants said that they are “very aware of the importance of mental health.” Effective interventions and treatments”, up to 26.5% of the participants did not know much about it. And the effective intervention and treatment methods for mental health problems are also the most concerned topics for college students who participated in the survey.
For the college community, it is true that mental health issues cannot be ignored. According to a paper in The Lancet, major depression is increasing rapidly among young people around the world, especially among women. According to a 2019 survey of doctoral students by the journal Nature, more than one-third of respondents said they had sought help for depression or anxiety.
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The number of people suffering from mental health problems such as depression continues to increase, while antidepressant research has long been hindered. Traditional antidepressant drugs mainly include monoamines and serotonin. On the one hand, the improvement of symptoms is relatively slow; on the other hand, it is only effective for some patients with depression, and more patients cannot be effectively treated.
Fortunately, a turning point has emerged. A number of studies in recent years have brought our understanding of the mechanism of action of depression and related drugs a big step forward, and based on this, a number of potential emerging treatments and intervention strategies have emerged. In this article, we’ll describe several emerging breakthroughs that promise to change the status quo.
If you want to learn more about the academic and industry cutting-edge developments in the field of depression and other mental illnesses, the following forum is worth paying attention to. At 10:00 am on October 15th, WuXi AppTec will hold a special session on R&D in the field of mental illness in the series of forums “Let Science Lead”. At that time, more than a dozen industry leaders, including academic leaders, innovative pharmaceutical companies “R&D leaders”, and industry investors, will gather in the cloud to jointly analyze the current urgent medical needs and gain insight into cutting-edge scientific hotspots and treatments. innovation trends. This forum is open to the global audience for free. The full agenda and guest list are attached at the end of the article. Welcome to register to watch!
Diet, Exercise Intervention
Compared to antidepressant drugs, daily intervention strategies tend to be more direct and direct to more readers. In a study this year, a research team from the Institute of Biomedical Research in Girona, Spain found that, as a common amino acid ingested through the diet, higher blood levels of proline were associated with depression. Symptoms are more severe. The level of proline in blood depends on dietary proline intake on the one hand, and is also affected by intestinal flora on the other hand. Therefore, this study provides new ideas for developing new treatments or interventions based on diet and gut microbiota.
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In addition to diet, the impact of exercise on depressive symptoms cannot be ignored. This year, a review in the journal JAMA Psychiatry summarizes the preventive effects of exercise on depression. The recommended amount of physical activity (equivalent to 2.5 hours of brisk walking per week) reduces the risk of depression by 25% compared to inactivity; even half the amount of physical activity reduces the risk18 %.
The study also pointed out that the mechanism by which exercise helps prevent depression is uncertain, but is likely the result of a combination of factors: including short-term neuroendocrine changes, immune responses, and long-term adaptation (including changes in the neural structure of the brain). In addition, there may also be some social psychological and behavioral factors.
One of the inescapable topics of emerging antidepressant treatments is hallucinogen-based research. In recent years, the potential of hallucinogens in the treatment of depression has received attention, but due to their hallucinogenic and addictive properties, the scientific community is trying to decouple the antidepressant effect from the hallucinogenicity and design a hallucinogenic effective safe therapy.
In 2019, Spravato (esketamine) nasal spray, a drug approved by the US FDA for the treatment of severe depression with a new mechanism of action, is based on this principle. Its main ingredient, esketamine (the S-santiomer of ketamine), is hallucinogenic, so doctors need to be extra careful when using this drug clinically. On the other hand, the target of esketamine was not clear at the time, becauseAt the time of approval for marketing, its mechanism of action was unclear.
In 2021, a research team from the Chinese Academy of Brain Sciences unveiled a high-resolution structure of the S-spironomer of ketamine bound to NMDA receptors on human neurons. Cryo-electron microscopy revealed two key amino acid residues on NMDA receptors that bind to ketamine. When these two residues were mutated, the control effect of ketamine on glutamate-gated ion channels decreased. In this way, the communication of signals between neurons changes. This breakthrough lays the structural foundation for the design of new, safer antidepressant therapies targeting the NMDA receptor.
And another Science paper, led by the iHuman Institute of ShanghaiTech University and the Center for Excellence and Innovation in Molecular and Cellular Science of the Chinese Academy of Sciences, is based on the effect of hallucinogens and receptors A new class of antidepressant molecules with no hallucinogenic effect was designed. The known hallucinogens all produce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2aR), but the mechanism of action is still unclear. The research team designed a new 5-HT2aR receptor agonist by modifying existing drugs, and screened out a molecule that has antidepressant effects comparable to hallucinogens but does not exhibit hallucinogenic effects.
Deep Brain Stimulation
Another type of technology with great potential is deep brain stimulation. The technology is already approved to treat movement disorders such as epilepsy, obsessive-compulsive disorder and Parkinson’s disease, and in the treatment of depression, deep brain stimulation targets two key brain regions.
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One is an area close to the front of the brain: cingulate gyrus of the corpus callosum. This brain region is associated with negative emotions associated with depression. Previous clinical trials have not gone well, but the research team is trying to re-explore the feasibility of this idea through a more precise implantation procedure. In a small trial of 8 participants, a study published in Translational Psychiatry reduces depressive symptoms were observed one week after surgery. Currently, the research team is testing more patients.
Another stimulation site for deep brain stimulation is Ventral Capsule/Ventral Striatum (VC/VS). In a study published in Nature Medicine, one patient had sustained symptom relief for more than a year after surgery, showing potential for further applications.
Inflammation and Depression
Last year, a study by the USTC team in the journal Neuron explained how infection as early as before birth increases the risk of depression in adolescents through inflammation. Once inflammation occurs at a critical time in young brain development, although inflammation can be recovered, the brain’s immune cells, microglia, are chronically affected and their ability to adapt to stress is weakened, resulting in promotes the occurrence of depression. This mechanism is also expected to bring about a new means of diagnosing and treating depression.
 Jordi Mayneris-Perxachs et al., (2022) Microbiota alterations in proline metabolism impact depression. Cell Metabolism. Doi: https://doi.org/10.1016/j .cmet.2022.04.001
 Pearce M, Garcia L, Abbas A, et al. Association Between Physical Activity and Risk of Depression: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2022;79(6 ): 550–559. doi: 10.1001/jamapsychiatry.2022.0609
 Huang L U, Xi Y, Peng Y, et al. A visual circuit related to habenula underlies the antidepressive effects of light therapy[J]. Neuron, 2019, 102(1) : 128-142.e8.
 Dongmei Cao et al., Structure-based discovery of nonhallucinogenic psychedelic analogs. Science (2022). DOI: 10.1126/science.abl8615