Summary: Ketamine is a fast-acting antidepressant that can relieve symptoms of major depressive disorder (MDD) within hours, including in cases that have not responded to conventional treatments. Its clinical benefit after a single low-dose infusion, however, typically wanes within about a week, and repeated dosing raises concerns such as dissociation and potential for misuse. New research shows that boosting a specific intracellular signaling pathway can extend ketamine’s effects from days to months, offering a promising strategy to sustain rapid antidepressant relief while reducing the need for frequent dosing.
Key Facts:
- Rapid relief: Low-dose ketamine produces antidepressant effects within hours, even in treatment-resistant patients.
- Extended duration: Experimental augmentation of ERK signaling extended ketamine’s behavioral benefits to as long as two months in preclinical studies.
- Mechanism-focused approach: Targeting intracellular signaling—specifically ERK activation via inhibition of a phosphatase—can augment the synaptic plasticity that underpins ketamine’s sustained antidepressant action.
Source: Vanderbilt University
Prevalence and clinical gap: Major depressive disorder affects roughly 10 percent of the U.S. population at any given time, and up to 20 percent of people may experience MDD during their lifetime. Although standard antidepressant medications help many patients, about 30 percent of individuals with MDD do not respond adequately to available treatments, leaving an urgent need for alternative therapies that work quickly and last longer.
Ketamine, when given at low doses, stands out because it can produce rapid improvement in depressive symptoms within hours, including for people who have not benefited from other antidepressants. The challenge is that the antidepressant benefit from a single ketamine infusion is transient. Patients often require repeated administrations to maintain remission, which increases exposure to side effects such as dissociation and raises concerns about longer-term safety and dependence. Stopping frequent ketamine treatment can also lead to relapse.
In a study published in Science, researchers in the laboratories of Lisa Monteggia and Ege Kavalali investigated whether ketamine’s relatively short duration of effect could be prolonged by targeting downstream intracellular signaling that drives synaptic plasticity. Their work, led by Zhenzhong Ma, tested the idea that transiently enhancing ERK (extracellular signal–regulated kinase) activity could sustain the synaptic changes and behavioral improvements produced by a single ketamine dose.
Previous work had already shown that ERK signaling is required for ketamine’s longer-term antidepressant actions, although not for its immediate effects. Building on that mechanistic insight, the team used a small molecule known as BCI to inhibit a dual-specificity phosphatase (DUSP6), a regulatory enzyme that normally reduces ERK activity. By blocking this phosphatase, BCI transiently increased ERK signaling and thereby augmented synaptic potentiation at hippocampal CA3–CA1 synapses—a synaptic substrate thought to underlie antidepressant responses.
The key finding was that transient inhibition of DUSP6 extended the behavioral antidepressant-like effects of a single ketamine administration for up to two months in preclinical models. The researchers also showed that deleting TrkB (tropomyosin receptor kinase B) specifically in excitatory neurons abolished the synaptic and behavioral effects produced by DUSP6 inhibition, linking ERK augmentation to TrkB-dependent synaptic plasticity.
While the compound used in these experiments (BCI) and the approach tested present challenges for immediate clinical translation, the results offer a clear proof of principle: selectively boosting intracellular pathways that sustain synaptic plasticity can markedly prolong the antidepressant effects of ketamine. This mechanistic strategy points toward the possibility of developing safer, longer-lasting interventions that amplify the therapeutic benefits of a single ketamine dose without requiring frequent redosing.
Monteggia, who holds the Lee E. Limbird Chair in Pharmacology and directs the Vanderbilt Brain Institute, and Kavalali, the William Stokes Professor of Experimental Therapeutics and chair of the Department of Pharmacology, emphasize that these findings should stimulate follow-up studies to identify clinically viable molecules that safely target the same intracellular mechanisms. Their work aims to reduce the treatment burden for people with MDD by minimizing the need for repeated ketamine exposures while preserving rapid symptom relief.
About this psychopharmacology and depression research news
Author: Marissa Shapiro
Source: Vanderbilt University
Contact: Marissa Shapiro – Vanderbilt University
Image: The image is credited to Neuroscience News
Original Research: Closed access. “Enhanced ERK activity extends ketamine’s antidepressant effects by augmenting synaptic plasticity” by Lisa Monteggia et al., Science. DOI: 10.1126/science.abb6748
Abstract (summary):
Repeated ketamine treatment to maintain rapid antidepressant effects can lead to cumulative side effects, creating a clinical need for strategies that prolong the benefits of a single dose. Ketamine promotes synaptic potentiation at CA3–CA1 synapses, and this form of synaptic plasticity is proposed to be a key substrate for its antidepressant action. The study found that transiently increasing ERK activity by pharmacologically inhibiting DUSP6 augmented ketamine-induced synaptic potentiation and extended antidepressant-like behavioral effects for up to two months. Conditional deletion of TrkB in excitatory neurons abolished the synaptic and behavioral enhancements produced by DUSP6 inhibition, supporting a model in which selectively targeting downstream intracellular signaling sustains ketamine’s rapid antidepressant effects.