Depression: Good-bye Serotonin, Hello Stress and Inflammation

Introduction

Accumulating evidence indicates that stress is a common risk factor for over 75% 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 which 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 which 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 flood 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, in 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 in 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 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 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 a myriad of 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 with the brain. Therefore, it is not surprising that psychiatric and neurological illnesses, including multiple sclerosis, autism, schizophrenia and depression, are often present simultaneously with gastrointestinal disease.

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 University of California, San Diego, La Jolla, found that loneliness was associated with 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 development of depression and other mental and physical diseases.

Stress Busting

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, non-pharmacological 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 MDD-related inflammations.

Enhancing good gut microbes – whether with probiotics, or by adding yogurt or other fermented foods to the diet – may be the 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 (serotonin reuptake inhibitors) and SNRI’s (serotonin–norepinephrine reuptake inhibitors) may be more effective than SSRIs or SNRI’s alone.

Key Takeaways

 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.

 Now research focuses on how alterations in the HPA axis and the sympathetic nervous system affect the immune system.

 Cytokines and other substances secreted by cells of the immune system dial down the brain’s reward center producing anhedonia, a principal feature of depression.

 Healthy, diverse gut microflora may buffer the negative effects of chronic stress.

References

Boyle, C. C., Cole, S. W., Irwin, M. R., Eisenberger, N. I., & Bower, J. E. (2023). The role of inflammation in acute psychosocial stress-induced modulation of reward processing in healthy female adults. Brain, Behavior, & Immunity-Health, 100588.

Dong, T. S., Gee, G. C., Cole, Steve, ... & Gupta, A. (2022). How Discrimination Gets Under the Skin: Biological Determinants of Discrimination Associated with Dysregulation of the Brain-Gut Microbiome System and Psychological Symptoms. Biological Psychiatry.

Kim, I. B., Lee, J. H., & Park, S. C. (2022). The relationship between stress,

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