I think everyone has a grasp of the concept that stress exacerbates depression, and chronic stress can increase the negative effect. Researchers have found that elevated cortisone levels are often found in depressed patients. For clarity, I want to state upfront that this post is not about the type of acute stress that leads to Post Traumatic Stress Disorder.
Currently, Selective Serotonin Re-uptake Inhibitors (SSRIs) are the most common treatment for depression. We know they work for severe depression, but the exact mechanisms are still being studied. Scicurious is a blogger with a PhD in Physiology who often writes about the physiology of the brain. One of her topics is the physiology of depression. Here is a list of some of the articles she has written on the topic:
- Depression Post 1: Etiology and Symptoms
- Depression Post 2: Current Available Therapies
- Depression Post 3: Studying Depression in the Lab
- Depression Post 4: The Serotonin System
- Depression Post 5: The Serotonin Theory of Depression (and why it’s probably wrong)
- Depression Post 6: The Genetics of Depression
- The neurogenesis theory of depression.
This is a great series to bring you up to date on what is known about the physiology of depression.
This week, on her Scientific American blog, she talks about some recent research involving the interactions of corticosterone induced stress in mice and the effects of the SSRI fluoxetine (Prozac) on the physical and neurological responses of mice.
The study is:
David, D., Samuels, B., Rainer, Q., Wang, J., Marsteller, D., Mendez, I., Drew, M., Craig, D., Guiard, B., & Guilloux, J. (2009). Neurogenesis-Dependent and -Independent Effects of Fluoxetine in an Animal Model of Anxiety/Depression Neuron, 62 (4), 479-493 DOI: 10.1016/j.neuron.2009.04.017. (The link opens the abstract and there is a pdf of the entire paper available for download.
In order to stimulate depressive symptoms in the mice, David et al. treated the mice with corticosterone in their drinking water.from Scicurious’ article:
The animals became more anxious, spending less time in the
center of an open area (mice prefer the dark and an open arena is a measure of anxiety), and eating less food in novel environments (another measure called novelty suppressed feeding). The mice also showed reductions in neurogenesis in the hippocampus, and a rough coat state and decreased grooming, all signs of a mouse not taking care of itself. Interestingly, though, they couldn’t get effects in other antidepressant tests like the forced swim test or tail suspension test. The reason for this might be because corticosterone increases locomotor activity, and if the animals had higher locomotor activity, it would mess up some of those measures.
They then used fluoxetine or imipramine (an older tricyclic anti-depressant) along with the corticosterone. The fluoxetine improved the performance of the mice in such standard tests as grooming, forced swimming, time in the open, and novelty feeding, among others. (details of these are available in the original paper).
Along with the performance effects:
Corticosterone alone decreased neurogenesis in the hippocampus, like we have come to expect (lots of studies show that stress reduces the birth of new neurons). But when you added an antidepressant on top of that, you didn’t just get recovery. No, instead you got AUGMENTATION. The animals had much higher neurogenesis than expected.
So what was causing these effects? How is fluoxetine producing its effects on behavior and how could corticosterone be augmenting them? David et al first looked at the role of the hippocampus. When they used X irradiation to get rid of the hippocampus in the corticosterone treated mice, they saw that some of the behavioral effects, like the novelty suppressed feeding effects, were blocked, showing that these effects were hippocampus-dependent, when the hippocampus isn’t there, fluoxetine can’t have its effect. But other behavioral effects of fluoxetine, like the open field effects, were NOT blocked when the hippocampus was gone. These effects appear to be independent of the hippocampus, but do depend on the present of corticosterone and fluoxetine. So where are they coming from?
To take this to the next level, David et al. looked at the genes involved.
the authors looked at gene expression of various genes in different brain areas. They found that three genes, beta arrestin 1, 2, and Gi alpha 1, were changed in an area of the brain called the hypothalamus, both in response to the corticosterone alone and in the response to the combination of corticosterone and fluoxetine….
The hypothalamus is one of key players in the hypothalamic-pituitary axis, which controls the stress reponse and the secretion of corticosterone. Beta arrestin 1 and 2 and Gi alpha 1 are all genes that are involved in the control of G protein coupled receptors, and would help control how the hypothalamus responds to stress or antidepressants.
To look at this further, David et al took a bunch of beta arrestin 2 knockout mice, who had no gene for beta arrestin 2. They found that these mice had no reaction to the effects of the antidepressant fluoxetine, which suggests that this protein is necessary for antidepressant response.
While this is very interesting in mice as an animal model, it is still uncertain how this might translate into improved treatment for severely depressed humans. Recent studies have also shown that SSRIs are more effective in treating cases of severe depression than they are in treating milder cases. It is possible that measurements of cortisol may improve the selection of patients who would favourably react to medication.
Of course, all of this still leaves the exact mechanism of action of SSRIs a mystery.