Approximately 10 percent of the American population is affected by the major depressive disorder at a given time, and up to 20 percent will exhibit MDD symptoms during their lives.
However, despite its prevalence, the methods to treat MDD often are short for a non -insignificant portion of the population. Antidepressants, the treatment standard, do not work during 30 percent with MDD.
When it is infused with a low dose, ketamine shows remarkable efficacy as an antidepressant of rapid action, with observed effects in hours even in patients who have been resistant to other antidepressant treatments. However, Ketamine consistent infusions are needed to keep symptoms at bay, which could cause side effects, such as dissociative behaviors and the possibility of addiction, and stop treatment can cause relapse.
In a new study published in ScienceThe laboratories of Lisa Monteggia and Ege Kavalali show that it is feasible to substantially 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, directed by Zhenzhong Ma, a fantastic assistant research professor, was based on a verifiable mechanistic model that we develop that explains the rapid antidepressant action of ketamine,” Monteggia said. Monteggia has the Lee E. Limbird chair in pharmacology and is the director of the Barlow Family of Vanderbilt Brain Institute.
Previously, researchers in the field had determined that the antidepressant effect of ketamine requires the activation of a key signaling route called Erk, but only the long -term effects of ketamine, not its rapid effects, are abused when ERK is inhibited. As a rapid action antidepressant, ketamine is based on ERK -dependent synaptic plasticity to produce its rapid behavioral effects. Ma and his colleagues raised the hypothesis that they could maintain the effects of ketamine for longer periods by improving Erk’s activity.
In the recent article, Ma discovered that Ketamine antidepressant effects could be sustained up to two months using a drug called BCI, which inhibits a phosphatase protein and results in a greater ERK activity. By inhibiting phosphatase, the authors retained Erk’s activity and increased synaptic plasticity that drives the prolonged antidepressant effects of ketamine.
Although the use of BCI hinders the application of these results to the clinic, Monteggia said the results provide proof of principle that the antidepressant action of ketamine can be sustained by directing intracellular signaling. She and Kavalali, a professor of experimental therapy at William Stokes and president of the Department of Pharmacology, have worked on the project since its inception and hope that other studies that seek to identify specific molecules that improve and maintain the action of a single dose of Cetamina have worked.
Ultimately, this work will be a trampoline to improve the lives of patients with MDD by reducing treatment load.
The graduated student Natalie Guzikowski and the postdoctoral fellow Ji-Woon Kim were co-authors in the study.