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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.

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, 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.

Reference: Psychology Today

18 replies
  1. Bahar aghamiri
    Bahar aghamiri says:

    Many people in our society do not know the impact of biological issues on mental health. It was a very useful article

  2. Hannaneh Ghalandari
    Hannaneh Ghalandari says:

    Professor, in my opinion, if depression is not taken seriously and nothing is done to treat it, it will create destructive and irreparable effects in a person’s life, and it will even affect the lives of those around that person, because depression causes a person to become discouraged about his life and even his loved ones.

  3. Sara ebadi
    Sara ebadi says:

    Sara ebadi
    In fact, if anxiety is not treated, it can cause various mental disorders and disrupt a person’s life, apart from mental disorders, it will also have many effects on the body.

  4. Zeynb nami
    Zeynb nami says:

    The article was very informative. Depression may occur due to decreased levels of serotonin (a neurotransmitter) in the brain. Also, stress and inflammation may also cause depression. Therefore, by reducing stress and inflammation and increasing serotonin levels, you can help improve your mental and emotional state.

  5. Armina Armansharif
    Armina Armansharif says:

    Indeed, stress is the cause of many diseases and as discussed in this article, the treatment of stress is different for different people. Omega-3 works wonders for depression because I have seen the effect of taking Omega-3 in one of my friends who was suffering from depression.

  6. fatemeh sarhadi
    fatemeh sarhadi says:

    Depression is associated with feelings of loss, anger and sadness, which disrupts a person’s daily activities.

  7. fatemeh sarhadi
    fatemeh sarhadi says:

    When a stressor creates a sense of anxiety in a person, it may eventually lead to more negative feelings or despair in the person. Even if this stressor is temporary, it will still have the aforementioned effects.

  8. fatemeh sarhadi
    fatemeh sarhadi says:

    Stress is actually the body’s response to physical or emotional needs. Emotional stress can contribute to depression or be one of its symptoms

  9. fatemeh sarhadi
    fatemeh sarhadi says:

    Stress and anxiety do not always have a behavioral reaction, but sometimes appear as physical problems, each of which can be a sign of severe stress and anxiety. Some of these physical symptoms are:
    Fast heartbeat, fast breathing.

  10. fatemeh sarhadi
    fatemeh sarhadi says:

    Stress affects our ability to do our work effectively and our work relationships with others and can have serious effects on our future career, general health and relationships. Long-term stress can also cause burnout, cardiovascular disease, stroke, depression, high blood pressure, and a weakened immune system.

  11. fatemeh sarhadi
    fatemeh sarhadi says:

    Depression is a mood state that includes listlessness and avoidance of activity or apathy and reluctance and can affect a person’s thoughts, behavior, feelings, and happiness and well-being.

  12. zahra kakavand
    zahra kakavand says:

    Stress plays a key role in the formation of mental, psychophysical and social disorders. If a person has a disorder of reduced tolerance and ability to stress, injuries and social pressure will have a much greater impact on him than people who have more tolerance, and he will face confusion and psychological and personal deviations.
    Social stress in psychology has an important effect and role in explaining the causes and even the triggers of individual and social dissatisfaction (reporter and 2015).
    In today’s society, there are various individual and social pressures and stresses that cause individual and social tensions. Economic occupational tensions and pressures, tensions from the dominant system, individual and family tensions, tensions caused by educational-control systems, gender pressure tensions, etc., stresses in society and the lower and traditional classes of society. With stress in high social classes with age, ethnicity, gender, education, it is different and can be investigated.
    Stress is related to depression, isolation, psychosomatic diseases, obsessive compulsive disorder on the one hand, and social violence, addiction and social injuries on the other hand.
    According to psycho-neuroscience, stress affects the frontal lobe of the brain and the release of dolphorin and pain tolerance.

  13. Shirin farrokh
    Shirin farrokh says:

    The state of social life today, which is more and more towards the individuality of people, has made more people vulnerable to the feeling of loneliness, and this adds to the need to pay more attention to this lesser-known mental state.

  14. Hasti Razzazchian
    Hasti Razzazchian says:

    I think stress is an inevitable factor in such a busy and modern life style.

    There are so many ways to mitigate the negative risks of stress as some of them have been mentioned in the article but I believe each person needs to find the way that suits them the best depends of life style.
    We always need to remember life is going on and with having such a good information available in many articles like this, ensure to have a good work life balance and always seek the ways to reduce the stress level in life

  15. Mohadeseh khan mirzaie
    Mohadeseh khan mirzaie says:

    In my opinion, depression is a common problem in today’s world, and its direct effect on the immune system causes the spread of diseases such as cancer and autoimmune diseases, and even affects the brain.
    And in my opinion, the statistics of these diseases in those who participated in the war are people with stressful jobs. And those who have had severe accidents are more.
    Exercising, meditating, and taking therapy courses can reduce it

  16. Maryam farajkhah
    Maryam farajkhah says:

    Hi professor the content was quite comprehensive but l wish they would know that depression is a silent death and they should definitely seek treatment now if necessary with medication or counseling the relatives of depressed people should also take more care of their loved ones

  17. mahnaz nouruzi
    mahnaz nouruzi says:

    Hi dear profess
    Recently, I read an article about the treatment of depression with traditional medicine and herbs I will quote a part of it that was interesting and related to this article
    Nature-based treatments
    Being in nature reduces tension and increases pleasant feelings. Looking at a scene of natural beauty, people describe their feelings with words such as peace, beauty, joy, hope, and vitality. Connecting with nature not only makes people feel better emotionally, but also lowers blood pressure, heart rate, muscle tension, and the production of stress hormones, all of which are signals of stress and fear.

    So when you’re treating depression and anxiety with traditional medicine or other natural methods, find a park or green space and go for a walk or get outside and work in your garden.
    good luck


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