Chinese researchers say this molecule might one day deliver the ‘perfect’ drug for depression

Scientists pinpoint biological pathway used by a common antidepressant and learn how to eliminate its notorious side effects
Research could revolutionise drug treatment by neutralising hallucinations, addiction risks

Science

Dannie Peng

Published: 10:00pm, 20 Sep 2023

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In the long-standing quest to improve treatments and outcomes for hundreds of millions of people worldwide who suffer from depression, scientists in China have claimed a discovery they say has the potential to deliver the “perfect” medication.

The team, from the Interdisciplinary Research Centre on Biology and Chemistry at the Chinese Academy of Sciences, said it found a way to eliminate the drawbacks of esketamine – an approved but controversial antidepressant – by pinpointing its previously unknown working mechanism, according to a study published in Nature Neuroscience last week.

“Esketamine is the only fast-acting medication on the market that fights depression, but its fundamentals are vague. Now with our latest finding, we can make improvements and develop a better drug,” Chen Yelin, lead scientist of the study, told the South China Morning Post.

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“This is important work that provides many new insights into the mechanisms of fast-acting antidepressants. These findings are likely to have a major impact on the development of novel therapeutic agents that can elicit fast antidepressant responses without psychomimetic effects,” the paper’s reviewers said.

Esketamine, and its chemical variant ketamine – a powerful anaesthetics that has been used since the 1970s, and is also used as a recreational drug – have well-known antidepressant properties.

But esketamine – now a common prescription drug – has notorious side effects that include hallucinations and addiction.

While the rates of depression globally have been on the rise, the Covid-19 pandemic made the situation much worse. In the first year of the global health crisis, the prevalence of anxiety and depression worldwide soared 25 per cent, according to the World Health Organization (WHO).

An estimated 3.8 per cent of the world’s population – around 280 million people – suffers from depression, according to the latest data from the WHO, and more than 700,000 people die from depression-related suicide every year.

The problem is aggravated by a lack of investment in mental healthcare, a lack of trained healthcare providers, and social stigma associated with mental disorders, according to the WHO.

“It was observed that when used at a lower dose, the anaesthetics [ketamine] could help relieve this emotional disorder, and in rapid action,” said Geng Yang, co-author and a researcher from the Interdisciplinary Research Centre on Biology and Chemistry.

In the US, for instance, hundreds of clinics already provide intravenous ketamine treatments, usually six infusions over a couple of weeks for depressed patients in off-label use, as it has not officially been approved for this disease.

In 2019, the US Food and Drug Administration approved a nasal spray called Spravato, which contains esketamine, for patients with a major depressive disorder who had not responded to other treatments.

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The drug “cousins” are regarded as pharmacologically novel avenues of treatment, as their rapid and effective results outperform conventional medications, including fluoxetine, a commonly prescribed antidepressant.

Those traditional pills usually take weeks to show results, and about one-third of individuals who are classified as “treatment-resistant depression” fail to recover even at higher doses.

When esketamine was approved, some clinicians felt empowered with a new tool because, in some emergencies, a dose of esketamine might prevent a patient from being overwhelmed by suicidal thinking, Geng said.

However, those advantages come with concerns about safety, including out-of-body experiences, the risk of abuse, and mixed results.

Spravato won approval this year in China, where anaesthetics are strictly regulated over concerns about drug addiction. Huang Manli, a psychiatrist from Zhejiang province, said the spray was subject to the highest level of regulation and could only be administered by qualified doctors in hospitals.

“How ketamine and its variant work exactly at the molecular level remains unclear, which has hindered further improvements,” Geng told the Post.

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It is believed that esketamine directly targets a neuronal mechanism known as the NNMDA-type glutamate receptor, thought to be the basis of memory formation, and a primary excitatory neurotransmitter. But scientists had not been sure about the specific biological pathway that esketamine used to mediate the receptor’s antidepressant effects.

“There were at least five different hypotheses, and the academic community could not agree in the short term,” Ethan Xu, a scientist at a California-based neuroscience biotech company, said.

In 2015, when Chen Yelin returned from the United States and established his lab in Shanghai, he decided to solve the debate once and for all. “We chose a more time-consuming and expensive, but decisive methodology,” Chen said.

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His team focused on identifying target genes in genetically engineered mice, then deleting them or inactivating them to observe the results – known as “knocking out”.

Then, in 2017, they discovered that esketamine’s antidepressant activity disappeared while its hallucinogenic activity remained. That meant they had located a crucial receptor protein called GluN2A.

The researchers suspected the discovery might help them develop an innovative “perfect” therapy with the advantages of ketamine-family aesthetics, such as the instant response, but without the side effects.

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Geng said that in the past 20 years, there had been few breakthroughs in the development of depression treatments, most of which have been derivatives of fluoxetine.

Chen’s team is now urging drug development based on the newly discovered molecule with clinical trials expected to begin next year.

Still, even if all went well, it could take up to 10 years for such a treatment to become widely available, Huang said.

If you have suicidal thoughts or know someone who is experiencing them, help is available. In Hong Kong, dial +852 2896 0000 for The Samaritans or +852 2382 0000 for Suicide Prevention Services. In the US, call or text 988 or chat at 988lifeline.org for the 988 Suicide & Crisis Lifeline. For a list of other nations’ helplines, see this page.