Shanghai researchers have unraveled the molecular mechanism for how ketamine, an efficient anti-depressant, functions at its receptors in the human brain, paving the way for the potential development of antidepressants that act more rapidly, with fewer side effects.
In laboratory tests, the researchers discovered that a mutation in two key amino acids largely reduces ketamine's potency by blocking receptor channel activity.
They further proved that the two amino acids play an important role in stabilizing the binding of ketamine to the receptors.
Their research was published in a paper on the website of the United Kingdom-based scientific journal Nature on Wednesday.
The joint research project was undertaken by the Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, and the Shanghai Institute of Materia Medica, which are all affiliated with the Chinese Academy of Sciences.
Major depressive disorders affect 6 to 16 percent of the world's population, and can lead to suicide. Anti-depressants targeting the monoaminergic system－networks of neurons that, among other things, play a role in the regulation of emotion, memory and arousal－require prolonged treatment over weeks or months, and are ineffective in one-third of patients.
As a rapid-acting novel antidepressant, ketamine quickly reduces the core symptoms of depression, notably suicidal thoughts, within hours, and is effective in patients with treatment-resistant depression.
Ketamine can induce severe psychotomimetic side effects, such as visual and auditory distortions. It also has the potential to be abused as a recreational drug, which currently limits clinical use. However, there is increasing interest in developing fast-acting antidepressants with fewer side effects.
Scientists knew that ketamine helped mitigate depression by binding to specific receptors, which when excessively activated can result in depression, but the structural basis of the antidepressant's action on the receptors was previously unclear.
Zhu Shujia, a leading researcher on the team, said that she hopes the discovery will contribute to further research on new antidepressant drugs that target receptors more accurately.
"We should provide the public with a more in-depth understanding of depression. It is indeed a disease, and it can be cured," she said.
A peer review of the paper said "the authors describe a combined experimental and computational study of the structural basis of ketamine binding to human NMDA receptors. The topic is highly timely because of the potential for ketamine to be used clinically as an antidepressant and as such, the described results are highly relevant both for the development of ketamine variants as well as for providing insight into clinically known mutations with altered binding characteristics."
Li Yange contributed to this story.
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