Wednesday, April 6, 2016

#expbio ASPET Blogging: Development of Prophylactics Against Stress-induced Depression

Figure 1: Depression can be caused by many 
factors, including chronic stress. (Source)
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.”

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.
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.


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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