New drug mimics benefits of ketamine for depression

Summary: NV-5138, a small molecule drug that mimics the action of ketamine, provides fast-acting antidepressant responses in rodent models of depression. The drug is currently undergoing Phase 1 testing in humans.

Source: Yale

A new small-molecule drug produced a rapid antidepressant response similar to that of ketamine when tested in mice, a new Yale-led study published April 16 in The Journal of Clinical Investigation shows.

The effects of the drug, called NV-5138, in rodent models, mimicked the rapid actions of the anesthetic ketamine, a variation of which, Esketamine, was recently approved by the FDA for use in depressed patients who do not respond to other medications. However, there still remain lingering safety concerns over the use of ketamine, as well as Esketamine, both of which have the potential to induce psychosis-like states and also have a potential for abuse.

“Recent research has raised the possibility that a new drug, such as NV-5138, could be developed that is rapid-acting but also more efficacious and safer than current formulations of ketamine,” said senior author Ron Duman, the Elizabeth Mears and House Jameson Professor of Psychiatry and professor of neuroscience.

The experimental drug does not directly stimulate neuronal activity like ketamine, but like ketamine, it spurs the growth of synapses or connections between neurons, the loss of which is associated with chronic stress and depression. The research team also showed that synaptic connectivity markers were rapidly restored in a mouse model of anhedonia, a core symptom of depression marked by an inability to experience pleasure. Mice administered a single dose of the drug also showed marked improvements in other depression-related behaviors.

This shows how NV-5138 affects dendrites
Chronic depression is marked by loss of synapses and connection between brain cells. A new study shows that the number of dendrite spines increased a day after mice were administered NV-5138, an experimental small molecule drug which mimics the effects of ketamine on depression. The image above shows spine-synapse density in the medial prefrontal cortex before (top) and after NV-5138 treatment (bottom). The image is credited to Ron Duman et al.

The drug is being developed by Navitor Pharmaceuticals Inc., which funded the study. It is currently undergoing Phase I testing in human patients.

Taro Kato, formerly of Yale and now at Sumitomo Dainippon in Japan, is lead author of the study. Yale authors have no financial interest in Navitor.

About this neuroscience research article

Media Contacts:
Bill Hathaway – Yale
Image Source:
The image is credited to Ron Duman et al.

Original Research: Open access.
“Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation”
Taro Kato, Santosh Pothula, Rong-Jian Liu, Catharine H. Duman, Rosemarie Terwilliger, George P. Vlasuk, Eddine Saiah, Seung Hahm, and Ronald S. Duman. Journal of Clinical Investigation doi:10.1172/JCI126859


Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation

Preclinical studies demonstrate that rapid acting antidepressants, including ketamine require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which activates mTORC1 signaling via binding to the upstream regulator sestrin. Here, we examined the antidepressant actions of NV-5138, a novel highly selective small molecule modulator of sestrin that penetrates the blood brain barrier. The results demonstrate that a single dose of NV-5138 produced rapid and long-lasting antidepressant effects, and rapidly reversed anhedonia caused by chronic stress exposure. The antidepressant actions of NV-5138 required BDNF release as the behavioral responses are blocked by infusion of a BDNF neutralizing antibody into the medial prefrontal cortex (mPFC) or in mice with a knock-in of a BDNF polymorphism that blocks activity dependent BDNF release. NV-5138 administration also rapidly increased synapse number and function in the mPFC, and reversed the synaptic deficits caused by chronic stress. Together, the results demonstrate that NV-5138 produced rapid synaptic and antidepressant behavioral responses via activation of the mTORC1 pathway and BDNF signaling, indicating that pharmacological modulation of sestrin is a novel approach for development of rapid acting antidepressants.

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