Ketamine reverses neural changes underlying depression-related behaviors in mice
Study sheds light on the neural mechanisms underlying remission of depression
April 11, 2019
Science Daily/NIH/National Institute of Mental Health
Researchers have identified ketamine-induced brain-related changes that are responsible for maintaining the remission of behaviors related to depression in mice -- findings that may help researchers develop interventions that promote lasting remission of depression in humans. The study, funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health, appears in the journal Science.
Major depression is one of the most common mental disorders in the United States, with approximately 17.3 million adults experienced a major depressive episode in 2017. However, many of the neural changes underlying the transitions between active depression, remission, and depression re-occurrence remain unknown. Ketamine, a fast-acting antidepressant which relieves depressive symptoms in hours instead of weeks or longer, provides an opportunity for researchers to investigate the short- and long-term biological changes underlying these transitions.
"Ketamine is a potentially transformative treatment for depression, but one of the major challenges associated with this drug is sustaining recovery after the initial treatment," said study author Conor Liston, M.D., Ph.D., of Weill Cornell Medicine, New York City.
To understand mechanisms underlying the transition from active depression to remission in humans, the researchers examined behaviors related to depression in mice. Researchers took high-resolution images of dendritic spines in the prefrontal cortex of mice before and after they experienced a stressor. Dendritic spines are protrusions in the part of neurons that receive communication input from other neurons. The researchers found that mice displaying behaviors related to depression had increased elimination of, and decreased formation of, dendritic spines in their prefrontal cortex compared with mice not exposed to a stressor. This finding replicates prior studies linking the emergence of behaviors related to depression in mice with dendritic spine loss.
In addition to the effects on dendritic spines, stress reduced the functional connectivity and simultaneous activity of neurons in the prefrontal cortex of mice. This reduction in connectivity and activity was associated with behaviors related to depression in response to stressors. Liston's group then found that ketamine treatment rapidly restored functional connectivity and ensemble activity of neurons and eliminated behaviors related to depression. Twenty-four hours after receiving a single dose of ketamine, mice exposed to stress showed a reversal of behaviors related to depression and an increase in dendritic spine formation when compared to stressed mice that had not received ketamine. These new dendritic spines were functional, creating working connections with other neurons.
The researchers found that while behavioral changes and changes in neural activity in mice happened quickly (three hours after ketamine treatment), dendritic spine formation happened more slowly (12-24 after hours after ketamine treatment). While further research is needed, the authors suggest these findings might indicate that dendritic spine regrowth may be a consequence of ketamine-induced rescue of prefrontal cortex circuit activity.
Although dendritic spines were not found to underly the fast-acting effects of ketamine on behaviors related to depression in mice, they were found to play an important role in maintaining the remission of those behaviors. Using a new technology developed by Haruo Kasai, Ph.D., and Haruhiko Bito, Ph.D., collaborators at the University of Tokyo, the researchers found that selectively deleting these newly formed dendritic spines led to the re-emergence of behaviors related to depression.
"Our results suggest that interventions aimed at enhancing synapse formation and prolonging their survival could be useful for maintaining the antidepressant effects of ketamine in the days and weeks after treatment," said Dr. Liston.
"Ketamine is the first new anti-depressant medication with a novel mechanism of action since the 1980s. Its ability to rapidly decrease suicidal thoughts is already a fundamental breakthrough," said Janine Simmons, M.D., Ph.D., chief of the NIMH Social and Affective Neuroscience Program. "Additional insights into ketamine's longer-term effects on brain circuits could guide future advances in the management of mood disorders."
https://www.sciencedaily.com/releases/2019/04/190411145105.htm
Study answers why ketamine helps depression, offers target for safer therapy
June 21, 2017
Science Daily/UT Southwestern Medical Center
UT Southwestern Medical Center scientists have identified a key protein that helps trigger ketamine's rapid antidepressant effects in the brain, a crucial step to developing alternative treatments to the controversial drug being dispensed in a growing number of clinics across the country.
Ketamine is drawing intense interest in the psychiatric field after multiple studies have demonstrated it can quickly stabilize severely depressed patients. But ketamine -- sometimes illicitly used for its psychedelic properties -- could also impede memory and other brain functions, spurring scientists to identify new drugs that would safely replicate its antidepressant response without the unwanted side effects.
A new study from the Peter O'Donnell Jr. Brain Institute has jumpstarted this effort in earnest by answering a question vital to guiding future research: What proteins in the brain does ketamine target to achieve its effects?
"Now that we have a target in place, we can study the pathway and develop drugs that safely induce the antidepressant effect," said Dr. Lisa Monteggia, Professor of Neuroscience at UT Southwestern's O'Donnell Brain Institute.
The study published in Nature shows that ketamine blocks a protein responsible for a range of normal brain functions. The blocking of the N-methyl-D-aspartate (NMDA) receptor creates the initial antidepressant reaction, and a metabolite of ketamine is responsible for extending the duration of the effect.
The blocking of the receptor also induces many of ketamine's hallucinogenic responses. The drug -- used for decades as an anesthetic -- can distort the senses and impair coordination.
But if taken with proper medical care, ketamine may help severely depressed or suicidal patients in need of a quick, effective treatment, Dr. Monteggia said.
Studies have shown ketamine can stabilize patients within a couple of hours, compared to other antidepressants that often take a few weeks to produce a response -- if a response is induced at all.
"Patients are demanding ketamine, and they are willing to take the risk of potential side effects just to feel better," Dr. Monteggia said. "This demand is overriding all the questions we still have about ketamine. How often can you have an infusion? How long can it last? There are a lot of aspects regarding how ketamine acts that are still unclear."
Dr. Monteggia's lab continues to answer these questions as UT Southwestern conducts two clinical trials with ketamine, including an effort to administer the drug through a nasal spray as opposed to intravenous infusions.
The results of these trials will have major implications for the millions of depressed patients seeking help, in particular those who have yet to find a medication that works.
A major national study UT Southwestern led more than a decade ago (STAR*D) yielded insight into the prevalence of the problem: Up to a third of depressed patients don't improve upon taking their first medication, and about 40 percent of people who start taking antidepressants stop taking them within three months.
Ketamine, due to the potential side effects, is mainly being explored as a treatment only after other antidepressants have failed. But for patients on the brink of giving up, waiting weeks to months to find the right therapy may not be an option.
"Ketamine opens the door to understanding how to achieve rapid action and to stabilize people quickly. Because the (NMDA) receptor that is the target of ketamine is not involved in how other classical serotonin-based antidepressants work, our study opens up a new avenue of drug discovery," said Dr. Monteggia, who holds the Ginny and John Eulich Professorship in Autism Spectrum Disorders.
https://www.sciencedaily.com/releases/2017/06/170621165928.htm