New Target Identified for Rapid Antidepressant Drugs

Summary: Ketamine’s rapid antidepressant action is due to specific synaptic effects, researchers report.

Source: Vanderbilt University

Vanderbilt researchers found that ketamine’s rapid antidepressant action is due to specific synaptic effects. This represents a new target for drug development that could fill a major gap in care for 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 examined the functional role of eEF2K, a protein involved in ketamine’s rapid antidepressant action, in neurons,” Monteggia said.

“We found that inducing similar synaptic effects independent of eEF2K resulted in rapid behavioral effects analogous to ketamine in preclinical models. This is the first study that directly examines whether the synaptic effects are producing the antidepressant behavioral activity of ketamine.”

Uncovering this pathway is a significant step toward understanding ketamine’s action in the brain and exploring whether a new class of therapeutics targeting this pathway can provide rapid antidepressant treatment.

WHY IT MATTERS

Depression, which the World Health Organization says costs $1 trillion annually in lost productivity, affects 264 million people around the world. Current pharmacological treatments for depression typically take several weeks to show efficacy and are not effective in approximately half of patients. Individuals whose depression is treatment-resistant are at far higher risk of suicide.

Monteggia and Kavalali’s goal is to find therapeutics that can overcome treatment-resistant depression and reduce depression-related loss of life.

WHAT’S NEXT?

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

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

Abstract

Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action

Highlights

Acute suppression of eEF2K elicits synaptic scaling
A similar form of synaptic scaling is rapidly elicited by retinoic acid
These two independent pathways converge at a common synaptic endpoint
Multiplicative synaptic scaling is sufficient to produce rapid antidepressant effects

Summary

Ketamine is a noncompetitive glutamatergic N-methyl-d-aspartate receptor (NMDAR) antagonist that exerts rapid antidepressant effects. Preclinical studies identify eukaryotic elongation factor 2 kinase (eEF2K) signaling as essential for the rapid antidepressant action of ketamine.

Here, we combine genetic, electrophysiological, and pharmacological strategies to investigate the role of eEF2K in synaptic function and find that acute, but not chronic, inhibition of eEF2K activity induces rapid synaptic scaling in the hippocampus.

Retinoic acid (RA) signaling also elicits a similar form of rapid synaptic scaling in the hippocampus, which we observe is independent of eEF2K functioni. The RA signaling pathway is not required for ketamine-mediated antidepressant action; however, direct activation of the retinoic acid receptor α (RARα) evokes rapid antidepressant action resembling ketamine.

Our findings show that ketamine and RARα activation independently elicit a similar form of multiplicative synaptic scaling that is causal for rapid antidepressant action.