Researchers extend ketamine antidepressants to two months

Researchers extend ketamine antidepressants to two months

Approximately 10 percent of the U.S. population is affected by major depressive disorder at some point, and up to 20 percent will experience MDD symptoms during their lifetime.

Despite its prevalence, methods to treat MDD often fail to cover a non-significant portion of the population. Antidepressants—the standard of care not for 30 percent with MDD.

When infused at low doses, ketamine shows remarkable effectiveness as a rapid-acting antidepressant, with effects also observed in patients resistant to other antidepressant treatments. However, consistent infusions of ketamine are required to keep symptoms at bay, which can lead to side effects such as dissociative behavior and the possibility of addiction, and stopping treatment can lead to relapses.

In a new study published inScienceLisa Monteggia and Ege Kavalali's laboratories show that it is feasible to significantly extend the effectiveness 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 fantastic research professor, was based on a testable mechanistic model we developed that accounts for the rapid antidepressant effects of ketamine. “

Lisa Monteggia

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 found that ketamine's antidepressants require activation of a key signaling pathway called ERK, but only ketamine's long-term effects—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 behavioral effects. MA and colleagues hypothesized that they could maintain ketamine's effects for longer periods of time by improving ERK activity.

In recent work, MA found that ketamine's antidepressant effects could be maintained for up to two months through the use of a drug called BCI, which inhibits a protein phosphatase and leads to increased ERK activity. By inhibiting phosphatase, the authors maintained ERK activity and increased synaptic plasticity, which drives ketamine's longer antidepressant effects.

Although the use of BCI complicates the application of these results to the clinic, Monteggia said the results provide proof of principle that ketamine's antidepressant effects can be maintained 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 to encourage other studies that seek to identify specific molecules that enhance and sustain the effects of a single dose of ketamine.

Ultimately, this work will be one Steppingstone to improve the lives of MDD patients by reducing the burden of treatment.

Doctoral student Natalie Guzikowski and postdoctoral researcher Ji-woon Kim were co-authors on the study.

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