Roughly 10 per cent of the U.S. Population is afflicted with major depressive disorder at any given time, and up to 20 per cent will exhibit MDD symptoms over their lifetimes.

Yet despite its prevalence, methods to treat MDD often fall short for a not-insignificant portion of the population. Antidepressants—the standard of treatment—don't work for 30 per cent with MDD.

When infused at a low dose, ketamine shows remarkable efficacy as a rapidly acting antidepressant, with effects observed within hours even in patients WHO have been resistant to other antidepressant treatments. However, consistent infusions of ketamine are needed to maintain symptoms at bay, which could result in side effects such as dissociative behaviours and the possibility of addiction, and stopping treatment can lead to relapse.

In a new study published in Science, Lisa Monteggia's and Ege Kavalali's labs demonstrate that it is feasible to substantially extend the efficacy of a single dose of ketamine from its current duration of up to a week to a longer period of up to two months.

"The premise of this study, led by Zhenzhong Ma, a talented research assistant professor, was based on a testable mechanistic model that we developed, which accounts for ketamine's rapid antidepressant action," Monteggia said. Monteggia holds the Lee E. Limbird Chair in Pharmacology and is the Barlow Family Director of the Vanderbilt Brain Institute.

Previously, researchers in the field had determined that ketamine's antidepressant effect requires activation of a key signaling pathway called ERK, but only ketamine's long-term effects—not its rapid effects—are abolished when ERK is inhibited. As a fast-acting antidepressant, ketamine relies on ERK-dependent synaptic plasticity to produce its rapid behavioural effects. Ma and colleagues hypothesised that they could maintain ketamine's effects for longer periods by enhancing ERK activity.

In the recent paper, Ma discovered that ketamine's antidepressant effects could be sustained for up to two months by using a drug called BCI, which inhibits a protein phosphatase and results in increased ERK activity. By inhibiting the phosphatase, the authors retained ERK's activity and augmented the synaptic plasticity that drives ketamine's prolonged antidepressant effects.

Although the use of BCI makes the application of these results to the clinic challenging, Monteggia said that the findings provide a proof of principle that ketamine's antidepressant action can be sustained by targeting intracellular signaling. She and Kavalali, the William Stokes Professor of Experimental Therapeutics and chair of the Department of Pharmacology, have worked on the project since its inception and hope that it fosters further studies to identify specific molecules that will enhance and sustain the action of a single dose of ketamine.

Ultimately, this work will serve as a stepping stone toward improving the lives of patients with MDD by reducing the treatment burden.

Graduate student Natalie Guzikowski and postdoctoral fellow Ji-Woon Kim were coauthors on the study.