The latest Science article from Nanjing Medical University: a new fast-acting antidepressant to overcome the shortcomings of existing drugs

According to a new study in mice, a new small molecule compound that regulates the activation of serotonergic neurons has shown rapid antidepressant effects
.
This discovery opens new avenues
for the development of a new class of therapies to treat major depressive disorder (MDD) and other hard-to-treat mood disorders.

Major depressive disorder is one of the most common mental disorders, affecting hundreds of millions of people
worldwide.
Most current antidepressants target the serotonin transporter (SERT).

However, these drugs are limited
.
Not only do they take up to 4 weeks to take effect, antidepressants against SERTs can have negative side effects, including suicide, but only a percentage of people who take these medications recover
from depression after treatment.
Meanwhile, while ketamine is already being used as an alternative, the drug's potential addiction and risk of triggering schizophrenia have raised concerns
.
Therefore, we need new, fast-acting antidepressant targets and compounds to remove these serious defects
.

In this paper, the joint research team of Professor Zhou Qigang, Professor Zhu Dongya, and Professor Li Tingyou of Nanjing Medical University discovered a new target that can develop rapid antidepressant drugs and synthesized a candidate antidepressant drug that can quickly act, which is expected to overcome the shortcomings
of existing drugs.

They came up with a solution to design a fast-acting antidepressant that works
by disrupting the interaction between SERT and neuronal nitric oxide synthase (nNOS).
The authors found that after separating the SERTs in the mouse brains from nNOS, the intercellular serotonin in the dorsal nucleus of the middle suture decreased
.
This enhances serotonin neuron activity in this region and significantly increases serotonin release
from the medial prefrontal cortex.
According to the findings, this produced a rapid antidepressant effect in a mouse model with major depressive disorder
.

Therefore, this study overcomes the defect of third-generation antidepressants relying on 5-HT self-receptor desensitization, discovers fast-acting antidepressant targets, and updates the understanding of the monoamine hypothesis that antidepressants can only work chronically—since it was first proposed in the 60s of the last century, the connotation of the monoamine hypothesis has been updated
.