Drug that acts on brain's dorsal raphe nucleus could rapidly treat depression

Selective serotonin reuptake inhibitors, or SSRIs, can take weeks or even longer to show efficacy in depressed patients. They also come with a list of potential side effects and, in many patients, fail to work at all. Now, scientists have developed a compound that they believe could circumvent these issues—with promising initial results in mice.

In the results of a study published Oct. 28 in Science, researchers from Nanjing Medical University in China described how they designed a compound that breaks apart a complex between an enzyme called neuronal nitric oxide synthase, or nNOS, and SERT, a protein that moves the neurotransmitter serotonin into and out of cells. In mice, decoupling nNOS and SERT resulted in an antidepressant effect around two hours after administration, without any deleterious side effects.

SSRIs are believed to work in part through their effects on the 5-HT1a receptor. In some parts of the brain, like the cortex and the hippocampus, binding to this receptor makes the serotonin available to cells so they can use it for signaling.

But in the dorsal raphe nucleus (DRN), the main source of serotonin in the brain, the 5-HT1a receptor works differently. Binding to the receptor prevents the cells from firing. This affects concentrations of serotonin downstream, as signals from the DRN promote serotonin release in the cortex.

This is one explanation for why antidepressants take so long to work. Within a few weeks after starting SSRI treatment, the 5-HT1a receptors in the DRN become desensitized. This tips the balance in favor of greater serotonin signaling—and patients start feeling relief from SSRIs.  

The Nanjing Medical University team believed they could reduce the time between administration and effect by releasing serotonin from neurons in the DRN. To do this, they looked to nNOS, which forms a complex with SERT at the surface of DRN neurons. Previous studies had shown that when SERT and nNOS interact, the 5-HT1a receptor prevents the cells from firing. The researchers hypothesized that a SERT-nNOS interaction blocker, or SNIB, would release SERT and reduce inhibition by the receptor, more quickly relieving patients’ symptoms.

The scientists started by assessing whether the coupling between SERT and nNOS played a role in depressive behaviors, as had been postulated in the past by other researchers. Using mice that had been exposed to chronic mild stress, a standard rodent model of depression, they found that higher concentrations of SERT-nNOS complexes in the DRN were associated with more depressive behaviors. Knocking out the gene for nNOS had the opposite results: Under the same conditions, the knockout mice displayed more antidepressant behaviors than their counterparts.

To see how dissolving the complex would impact serotonin circuitry, the researchers injected a chemical to break SERT and nNOS apart directly into the DRN. Within two hours, they saw increased SERT activity as well as an increase in antidepressant behavior. They also found increased serotonin in the prefrontal cortex, suggesting that ameliorating the complex had a fast-acting antidepressant effect.

Armed with these results, the researchers developed a small molecule to break apart SERT and nNOS. They administered it intravenously into a group of depressed mice. Just as they had seen in earlier experiments, their depressive behaviors were reversed within two hours of administration. Additional tests showed that the compound had no impact on memory, cognition or aggression, nor did it produce abnormal brain activity. This comes in contrast to other fast-acting drugs being tested for treatment of depression, such as ketamine, which can induce schizophrenia-like side effects.

“In sum, we show here that dissociating SERT-nNOS can rapidly reverse the depressive behaviors caused by [chronic mild stress] in mice, opening a new avenue for developing therapeutics for mood disorders, which should now be tested in humans,” the researchers wrote.

The researchers join a growing list of scientists pursuing fast-acting antidepressants. In August, Axsome Therapeutics’ NMDA receptor antagonist Auvelity won FDA approval for use in major depressive disorder. Axsome’s studies found that patients’ depressive symptoms were alleviated within one week of taking the drug, with full remission by Week 2. Johnson & Johnson’s nasal spray Spravato, or esketamine—a ketamine derivative—was approved by the FDA in 2019 for rapid treating acute episodes of severe depression or suicidal ideation.