New drug development target could fill major depression treatment gap

The idea

Vanderbilt researchers found that ketamine’s rapid antidepressant action is due to specific synaptic effects. This represents a new target for the development of drugs that could fill a major gap in the care of depression.

The research was led by Lisa Monteggia, professor of pharmacology and director of the Vanderbilt Brain Institute, Ege Kavalali, professor and acting chair of the department of pharmacology and William Stokes professor of experimental therapeutics, and first author Kanzo Suzuki, research instructor in pharmacology.

We investigated the functional role of eEF2K, a protein involved in the rapid antidepressant action of ketamine, in neurons. We found that induction of similar synaptic effects independent of eEF2K resulted in rapid ketamine-like behavioral effects in preclinical models. This is the first study to directly examine whether synaptic effects produce the antidepressant behavioral activity of ketamine. “

Lisa Monteggia, Professor of Pharmacology and Director of the Vanderbilt Brain Institute

Finding this pathway is an important step in understanding how ketamine works in the brain and exploring whether a new class of therapies targeting this pathway can provide rapid antidepressant treatment.

Why is this important

Depression, which according to the World Health Organization costs $ 1,000 billion a year in lost productivity, affects 264 million people worldwide. Current pharmacological treatments for depression generally take several weeks to show their effectiveness and are not effective in about half of patients. People whose depression is resistant to treatment are at much greater risk of suicide.

Monteggia and Kavalali’s goal is to find therapies that can overcome treatment-resistant depression and reduce the loss of life associated with depression.

And after

Kavalali, Monteggia and their labs plan to probe further for these specific synaptic effects required for rapid antidepressant activity. In particular, they aim to link synaptic changes to behavioral phenotypes by systematically tracing the impact of these changes on neural circuits.

Go further

The article “Convergence of distinct signaling paths on synaptic scaling to trigger rapid antidepressant action” was published in the journal Cell reports November 2.


This research was funded by the National Institutes of Health and the Brain and Behavior Research Foundation.


Journal reference:

Suzuki, K., et al. (2021) Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action. Cell reports.

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