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Figure 1: Depression can be caused by many
factors, including chronic stress.
(Source)
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Major
depression is caused by multiple factors. In other words, there is not one gene
causing it but many genes associated with it. Some are influenced by
environmental stimuli, such as chronic stress, and the resulting stress-induced
depression is considered a subtype of the disorder. It would be great if people
could avoid stressors and the potential for this type of depression, but life
does not always allow for that. As an alternative, what if stress-induced
depression could be prevented with something similar to a vaccine, given as a prophylactic?
Dr. Christine Ann Denny, Dr. Rebecca Brachman (research fellow), and Josie
McGowan (graduate student) set out to test this hypothesis using the
fast-acting anti-depressant ketamine and the commonly prescribed
anti-depressant fluoxetine (Prozac).
For their
research, they used a model of stress-induced depression in mice. In this
paradigm, an experimental mouse is exposed to a larger aggressive mouse each
day for a specified amount of time. A divider is placed between the mice so they
cannot directly interact (i.e. fight and cause injury) but the experimental mouse
becomes stressed and shows signs of depressive-like behavior. I have previously blogged about how depressive-like behavior is tested in mice and Dr. Denny’s
lab used the same test: the forced swim test.
“In this test,
mice are placed into a deep (to them) beaker of water. The animals will try to
get out of the water and then give up and just float accepting that they cannot
escape. Administering an antidepressant prior to the test increases the
trying-to-get-out period.”
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Figure 2: K, ketamine; SD, social defeat; FST,
forced swim test; DI , dominant
interaction test,
NSF, novelty-suppressed feeding tests, EPM,
elevated plus
maze; CFC, contextual fear
conditioning, Sac, sacrifice (to collect brain
tissue for further experiments). Brachman et al., 2015.
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The experiments in
Dr. Denny’s lab started with a single dose of ketamine, given as an injection, prior to the social defeat period
(Figure 2). Following that period,
depressive-like behavior was assessed using the forced swim test. By 22 days
after ketamine injection, the socially defeated mice given ketamine showed less
depressive-like behavior than socially defeated mice not given ketamine. The
results were promising! However, scientific results are validated in several
different ways to ensure the effects are not specific only under those
experimental conditions. As a human
example, chronic stress based on personal events (such as a messy divorce) and
chronic stress on the battlefield during war are different but can both cause
stress-induced depression.
To confirm the
initial results, they used other models of stress-induced depression and
additional tests of depressive-like behavior and found similar - though not
exactly the same - results (Figure 2 shows additional tests). Unfortunately,
when they attempted the experiments using the commonly prescribed
anti-depressant fluoxetine (Prozac), the depressive-like behaviors were not
prevented. While disappointing, the results suggest there is something special
about the way ketamine works that prevents this type of depression. Knowing
this will help guide future experiments to find out how what makes ketamine
special and if that factor can be harnessed as a better treatment for
depression.
Additional
experiments in Dr. Denny’s lab will find out whether ketamine works by altering
the memory of the stressor, perhaps by making it less stressful or by improving
“forgetting” of the memory. They also will look at other targets that ketamine
affects in the brain and additional anti-depressants to see if they can prevent
depressive-like behavior after stress. Additionally, they would like to
determine if there is a critical window-of-opportunity in which to give the
anti-depressant prior to the stressor to prevent depression.
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Brachman RA, McGowan JC, Perusini JN,
Lim SC, Pham TH, Faye C, et al. Ketamine as a Prophylactic Against
Stress-Induced Depressive-Like Behavior. Biol Psychiatry. Elsevier; 2015; 1–11.
doi:10.1016/j.biopsych.2015.04.022
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