New York, April
12, 2019 • 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.

NIH-supported
study sheds light on the neural mechanisms underlying remission of depression

“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, M.D., 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.

About Ketamine

“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.”