Depression: Goodbye Serotonin, Hello Stress and Inflammation
New research on depression focuses on the immune system.
Inflammation plays a key role in the pathology of stress-related diseases.
Inflammation can contribute to the development and severity of depression.
Conventional mechanisms linking stress and disease have focused on the HPA axis and the sympathetic nervous system.
Accumulating evidence indicates that stress is a common risk factor for more than 75 percent of physical and mental diseases, increasing the morbidity and mortality of these diseases. Psychiatric disorders such as depression are the most common stress-related disease.
In the past, medical experts believed that depression was essentially a brain illness due to a deficit of serotonin that led to treating depression with drugs that increased the concentrations of serotonin in the brain. Depression may be much more complex than that.
New research shows that stress can induce inflammatory changes in the brain and the peripheral immune system. This results in the production of inflammation-enhancing cytokines that travel to the brain’s reward center and largely deactivate it, leading to anhedonia, or loss of interest and pleasure. Anhedonia is a prominent symptom of depression.
Stress, Inflammation, and Depression
For a long time, inflammation was considered an essential response to tissue injury or microbial invasion. Increasingly, it is viewed as being precipitated by stress and a significant contributor to psychiatric disorders, including depression. People with depression often have higher levels of inflammatory cytokines in their blood. Many studies have demonstrated that treating inflammation can improve depression.
Stressful events activate the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, which trigger the “fight or flight” response that floods the body with catecholamines, glucocorticoids, and other stress-related substances, which, in turn, activates certain cells of the immune system to produce cytokines.
Cytokines are a broad category of small proteins, such as interferon, interleukin, and others. There are pro-inflammatory cytokines, which promote inflammation, and anti-inflammatory cytokines, which fight inflammation. We are learning now that certain pro-inflammatory cytokines are involved in anxiety, chronic pain, and, by blocking the function of the brain’s reward center, the development of depression. The reward system comes to associate diverse stimuli (substances, situations, events, or activities) with a positive or desirable outcome (i.e., feeling good and happy). When it is down, a person finds no pleasure in anything. The depressed person isolates and feels sad.
Dr. Steve Cole, professor of medicine, psychiatry, and behavioral science at the UCLA School of Medicine, has pioneered research on the signal transduction pathways that give rise to psychological and social states in the context of gene regulation. Signal transduction pathways relay information from outside the cell, through the cell membrane into the interior of the cell, where it can then start a chain reaction that ultimately leads to turning on or turning off genes inside the nucleus.
In a recent paper, Cole reported on his study of Black mothers in racially segregated neighborhoods on the South Side of Chicago. The overwhelming feeling that a majority of the subjects expressed was one of “being trapped.” These women suffered increased mental distress in the form of posttraumatic stress disorder (PTSD), depressive symptoms, and glucocorticoid receptor gene regulation. Feeling trapped, living in a violent environment was associated with greater cortisol output from the HPA axis and consequent negative feedback inhibition of the glucocorticoid receptor (GR) mRNA levels.
Writing on the subject of biological determinants of discrimination, Cole found that discrimination was associated with alterations of brain networks related to emotion, cognition, and self-perception, and structural and functional changes in the gut microbiome. This study contributes toward our understanding of how social inequalities become a whole-body experience and how a common expression like “racism makes me sick to my stomach” actually makes scientific sense.
Intestinal bacteria, the microbiome, produce metabolites such as bile acids, choline, and short-chain fatty acids (SCFAs) that are essential for host health as well as myriad neuroactive compounds such as serotonin, dopamine, and other brain chemicals that regulate mood. Therefore, it is not surprising that psychiatric and neurological illnesses, including multiple sclerosis, autism, schizophrenia, and depression, are often present simultaneously with gastrointestinal disease. Recent research expands our understanding of how the microbiome communicates with the enteric nervous system (“The Thoughtful Bowel”), the immune system, and, by way of the vagus nerve, the brain.
There is now considerable evidence that loneliness is a risk factor for poor psychological and physical health. Loneliness typically refers to the feelings of distress and dysphoria resulting from a discrepancy between a person’s desired and achieved levels of social relations. Scientists from the University of California, San Diego, La Jolla, found that loneliness was associated with a lack of diversity in the gut microbiome and, consequently, reduced resistance and resilience to stress-related disruptions, leading to downstream physiological effects, such as systemic inflammation and depression.
It follows that many factors such as stress and inflammation, in addition to “a chemical imbalance,” read “serotonin deficit” as promulgated by Big Pharma, are responsible for the development of depression and other mental and physical diseases.
Depending on a person’s microbiome, certain antidepressants may benefit some people but not others. No doubt, assessing an individual’s microbiome before commencing treatment will be an important lab test in the future.
Moreover, nonpharmacological treatments for major depression such as exercise may be mediated by anti-inflammatory actions. Omega-3 fatty acids have been identified as potential treatments for major depressive disorder–related inflammations.
Enhancing good gut microbes—whether with probiotics or by adding yogurt or other fermented foods to the diet—may be an answer to intractable depression, the kind conventional treatments can’t touch.
Steve Cole has written much on the subject of self-regulation. He holds, and I totally agree with him, that we are architects of our own lives more than we realize. Our subjective experience carries more power than our objective situation. If we feel good about ourselves, not only will our health improve but so will our relationships. There are many ways in which we can raise our self-esteem and become more optimistic.
Treatment approaches that target inflammation and the gut microbiome in conjunction with SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors) may be more effective than SSRIs or SNRIs alone.
Thomas R. Verny, M.D., the author of eight books, including The Embodied Mind, has taught at Harvard University, University of Toronto, York University, and St. Mary’s University of Minnesota. His podcast, Pushing Boundaries, may be viewed on Youtube or listened to on Spotify and many other platforms.