New targets and drug candidates for depression, with rapid onset of action in 2 hours and no side effects

Depression is a common mental disorder, mainly manifested as low mood, decreased interest, slow thinking, poor diet and sleep, and can also produce pessimism and misanthropy and even suicidal tendencies
.
In addition, depression has been linked to
increased rates of cardiovascular disease, diabetes, and Alzheimer's disease.
According to the World Health Organization (WHO), depression has become the fourth most common disease in the world, and more than 350 million people worldwide suffer from depression, and it is growing rapidly
.

As early as the 50s of the last century, the monoamine hypothesis was proposed and became a classic theory of the onset of depression, which believed that the onset of depression was related to the deficiency of monoamine neurotransmitters (including serotonin, dopamine and norepinephrine), which led to the development
of a series of antidepressant drugs.

Selective serotonin reuptake inhibitors (SSRIs) are the latest generation of antidepressants that improve depressive symptoms
by selectively blocking serotonin transporters (SERTs), inhibiting the reuptake of serotonin (also known as serotonin), and increasing serotonin levels in the brain.
This is currently the first-line treatment for
depression.
But they take weeks or even longer to show efficacy
in people with depression.
In addition, these drugs have a range of potential side effects and, for many patients, do not work at
all.

On October 28, 2022, the team of Professors Zhou Qigang, Professor Zhu Dongya and Professor Li Tingyou of the State Key Laboratory of Reproductive Medicine and School of Pharmacy of Nanjing Medical University published a research paper
titled: Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN.

The study developed a compound, ZZL-7, that selectively uncouples a complex of serotonin transporter (SERT) in the dorsal nucleus region (DRN) of the middle suture with neuronal nitric oxide synthase (nNOS), and in mice, the antidepressant effect can be rapidly exerted after two hours of injection administration without any side effects
observed.

This research not only brings new insights into the classic theory of depression, the monoamine hypothesis, but also develops a fast-acting drug
candidate for depression.

The results were highly praised by the journal Science and presented as highlight
.
International peers and media also highly praised the study, believing that this is a major theoretical breakthrough
in antidepressant research in the nearly 60 years since the "monoamine hypothesis" was proposed, and the classical antidepressant fluoxetine (an SSRI drug) was discovered for 50 years.
It is also the first time that the scientific research results of Nanjing Medical University with completely independent intellectual property rights have been published
in Science journals.

Selective serotonin reuptake inhibitors (SSRIs) are thought to work in part through their effects on the 5-HT1a receptor, which binds to certain parts of the brain, such as the cortex and hippocampus, allowing cells to use serotonin (5-HT, also known as serotonin) to send signals to improve symptoms of
depression.

The dorsal nucleus region (DRN) of the middle suture is the main source of serotonin (5-HT) in the brain, where 5-HT1a receptors work differently
.
The binding of SSRIs to 5-HT1a receptors prevents cells from firing, which affects the concentration of serotonin (5-HT) downstream because the signal emitted by the DRN promotes the release
of serotonin (5-HT) in the cortex.

This also explains why antidepressants such as SSRIs take so long to work, and within a few weeks of starting SSRIs, the 5-HT1a receptor in the DRN becomes desensitized before serotonin (5-HT) signaling is more favored and patients begin to feel the relief
brought by SSRIs.

The joint research team of Professor Zhou Qigang, Professor Zhu Dongya and Professor Li Tingyou believes that the time
between medication and onset of action can be shortened by releasing serotonin (5-HT) in DRN neurons.

To do this, they looked at neuronal nitric oxide synthase (nNOS), which forms complexes with serotonin transporters (SERT) on the surface of neurons in the dorsal nucleus region of the middle suture (DRN
).
Previous studies have shown that when SERT and nNOS interact, the 5-HT1a receptor prevents cells from firing
.
Therefore, the research team believes that SERT-nNOS interaction blockers, or SNIBs, can release SERTs and reduce the inhibition of 5-HT1a receptors, resulting in faster symptom
relief in patients with depression.

The team first evaluated whether the coupling between SERT and nNOS played a role in depressive behavior, using a mouse model under long-term mild stress, and found that the higher the concentration of the SERT-nNOS complex in the dorsal nucleus region (DRN) of the middle slit, the more
depressive behavior there was.
Knocking out the nNOS gene produced the opposite result: mice that knocked out the nNOS gene showed more antidepressant behavior
under the same conditions.

To investigate how the uncoupling of the SERT-nNOS complex affects the serotonin (5-HT) pathway, the team injected a chemical directly into the dorsal nucleus region (DRN) of the middle suture to decouple the SERT-nNOS complex, and within two hours, an increase in SERT activity and an increase
in antidepressant behavior were observed.
An increase in serotonin (5-HT) in the prefrontal cortex was also found, which indicates that the uncoupling of the SERT-nNOS complex has a rapid antidepressant effect
.

Based on the above results, the research team developed a small molecule compound, ZZL-7, to specifically uncouple the SERT-nNOS complex, and after intravenous injection of ZZL-7 into a group of depressed mouse models, the depressive behavior of these mice was reversed
within two hours.
Other tests have shown that the compound has no effect on memory, cognition or aggression in mice, and does not produce abnormal brain activity
.

Comparison of the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) with SERT-nNOS interaction blockers (SNIBs).

This is in contrast to other fast-acting drugs being tested to treat depression, such as ketamine, which is still in development and works quickly but is short-lived, addictive and induces schizophrenia
.

Overall, this study brings new insights into the classic theory of depression, the monoamine hypothesis, showing that uncoupling SERT-nNOS can rapidly reverse depressive behavior in mice, opening up new avenues
for the development of mood disorder therapies.
The research team says "it should now be tested in humans.
"

As the incidence of depression continues to increase, more and more researchers have joined the ranks
of developing rapid antidepressant drugs.
In August, Axsome Therapeutics' NMDA receptor antagonist, Auvelity, received FDA approval for the treatment of major depressive disorder, with depressive symptoms relieved within a week of medication and complete relief
by week 2.
In 2019, Johnson & Johnson's nasal spray, ketamine, an isomer of ketamine, received FDA approval for the rapid treatment of acute episodes of major depression or suicidal thoughts
.
And in October, researchers at the College of Medicine of Connecticut published a paper in the journal JAMA Psychiatry [2] showing that electroconvulsive therapy (ECT) provides faster relief of major depressive disorder
than ketamine/esketamine.