Stress has been associated with Depression for a long time. The occurrence of major negative events over life, especially early life, has been shown to be strongly associated with developing Major Depressive Disorder. However, a mechanism explaining this connection has and continues to elude the scientific community. A recent review article titled From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression proposed A Social Signal Transduction Theory of Depression. Overall, this hypothesis connects stress to inflammation, and then inflammation to MDD. Detailing a mechanism provides a basis for future treatment and understanding of MDD and its development.
The overall goal of this paper was to show that stress can induce inflammation, which can then induce depression-like symptoms. First of all, what is inflammation? Inflammation is the body’s natural immune response in response to a pathogen, injury, or another external stimulus. Our body sends signals from the brain to our immune cells in order to modify protein production, transcription and translation, and create an inflammatory response. The response is the gathering of immune cells to an area and its eventual repair/disinfection. For our purposes, the stress response to major life events that are known to correlate with depression are important, like social exclusion, loss of job, loss or relationship, etc….What is supposed to happen is seen below, the brain perceives a threat, releases cortisol which prepares the body to deal with the threat by inducing that flight or fight response while at the same time depressing inflammation response. After the threat has been taken care of, the cortisol levels drop and cytokine levels rise (increased inflammation) to deal with the likely injury of said stressful event. What happens in the proposed hypothesis is that glucocorticoid resistance develops in the immune cells of the body. Like insulin resistance in Diabetes, glucocorticoid resistance leads to immune cells not responding to their signal. Effectively, this removes the suppression of inflammation from cortisol released during stressful events. This leads to elevated basal levels of inflammation markers in the body (simply meaning more overall inflammation) due to lack of suppression and can actually lead to increased levels of cortisol. This increase in cortisol has to happen so the body can still maintain the functionality of cortisol through the developing resistance. As you can see, this can turn into a snowball effect. Increased stress and cortisol lead to resistance, resistance leads to the need for higher amounts of cortisol, more resistance and it continues.
The pairing of inflammation and depression isn’t as straightforward. Because a simple, obvious mechanism of interaction isn’t easy to see, the connection must be shown through large studies and experimentation. The first body of evidence to jump out is that there are several inflammation-related disorders that co-occur with depression, including asthma, arthritis, metabolic syndrome and more. Secondly, elevated levels of inflammatory activity are seen in patients with depression. Certain cytokines present in an inflammatory response can reduce serotonin and other neurotransmitters by decreasing the availability of the precursor. The administration of certain inflammation agents into mice show the development of depression symptoms. Possibly the biggest piece of evidence for this connection is the effectiveness of anti-inflammatory agents in alleviating depression, like aspirin.
The article’s social signal transduction theory is depicted above. First, a social-environmental experience indicating a threat or adversity experience and processed in the brain. Then a brain signal goes out through the hypothalamic-pituitary-adrenal axis (2), sympathetic nervous system (3) and efferent vagus nerve (5).This leads to the production of glucocorticoids (cortisol), epinephrine, and acetylcholine respectively. Glucocorticoids and acetylcholine are anti-inflammatory, and epinephrine is pro. These effects are produced by transcription modification of immune response agents (6). Cytokines then pass through the blood-brain barrier at leaky spots (6). And then finally, cytokine stimulation of primary afferent nerve fibers to the vagus nerve relays info about mood, motor activity, motivation, and much more. This novel mechanism presents a better way of understanding depression, including its development, treatment, mechanism, and interaction with other diseases. Inflammation in the brain is a new topic that is involved in many other disorders beyond depression and further research detailing it and its effect on the brain may open the door for treatment of a variety of illnesses.
Connecting Stress, Inflammation, and Depression
