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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

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Adults with a history of childhood trauma can benefit from recommended depression treatments, contrary to current theory

emotional/physical/sexual abuse before the age of 18) is known to be a risk factor for the development of major depressive disorder in adulthood

Adults with major depressive disorder who have a history of childhood trauma experience symptom improvement after pharmacotherapy, psychotherapy, or combination treatment. The results of a new study, published in The Lancet Psychiatry, suggest that contrary to current theory, these common treatments for major depressive disorder are effective for patients with childhood trauma.
emotional/physical/sexual abuse before the age of 18) is known to be a risk factor for the development of major depressive disorder in adulthood, often producing symptoms that are earlier onset, longer lasting/more frequently recurring, and with increased risk of morbidity. Previous studies have suggested that adults and adolescents with depression and childhood trauma were around 1.5 times more likely to not respond or remit after pharmacotherapy, psychotherapy, or combination treatment, than those without childhood trauma.

"This study is the largest of its kind to look at the effectiveness of depression treatments for adults with childhood trauma and is also the first to compare the effect of active treatment with control condition (waitlist, placebo, or care-as-usual) for this population. Around 46% of adults with depression have a history of childhood trauma, and for chronic depression sufferers the prevalence is even higher. It is therefore important to determine whether current treatments offered for major depressive disorder are effective for patients with childhood trauma," says Ph.D. Candidate and first author of the study, Erika Kuzminskaite.

The researchers used data from 29 clinical trials of pharmacotherapy and psychotherapy treatments for major depressive disorder in adults, covering a maximum of 6,830 patients. Of the participants, 4,268 or 62.5% reported a history of childhood trauma. Most of the clinical trials (15, 51.7%) were conducted in Europe, followed by North America (9, 31%). Depression severity measures were determined using the Beck Depression Inventory (BDI) or Hamilton Rating Scale for Depression (HRSD).

The three research questions tested were: whether childhood trauma patients were more severely depressed prior to treatment, whether there were more unfavorable outcomes following active treatments for patients with childhood trauma, and whether childhood trauma patients were less likely to benefit from active treatment than control condition.

In line with the results of previous studies, patients with childhood trauma showed greater symptom severity at the start of treatment than patients without childhood trauma, highlighting the importance of taking symptom severity into account when calculating treatment effects.

Although childhood trauma patients reported more depressive symptoms at both the start and end of the treatment, they experienced similar symptom improvement compared to patients without childhood trauma history. Treatment dropout rates were also similar for patients with and without childhood trauma. The measured treatment efficacy did not vary by childhood trauma type, depression diagnosis, assessment method of childhood trauma, study quality, year, treatment type or length.

"Finding that patients with depression and childhood trauma experience similar treatment outcome when compared to patients without trauma can give hope to people who have experienced childhood trauma. Nevertheless, residual symptoms following treatment in patients with childhood trauma warrant more clinical attention as additional interventions may still be needed. To provide further meaningful progress and improve outcomes for individuals with childhood trauma, future research is necessary to examine long-term treatment outcomes and mechanisms through which childhood trauma exerts its long-lasting effects," says Erika Kuzminskaite.

The authors acknowledge some limitations with this study, including a high variety of results among the studies included in the meta-analysis, and all cases of childhood trauma being reported retrospectively. The meta-analysis focused on symptom decline during acute treatment phase, but people with depression and childhood trauma often show post-treatment residual symptoms and are characterized by a high risk of relapse, thus they may benefit from treatment significantly less than patients without childhood trauma in the long run. The study design also did not account for differences between genders.

Writing in a linked Comment, Antoine Yrondi, University of Toulouse, France (who was not involved in the research) said, "This meta-analysis could allow to deliver a hopeful message to patients with childhood trauma that evidence-based psychotherapy and pharmacotherapy could improve depressive symptoms. However, physicians should keep in mind that childhood trauma could be associated with clinical features which may make it more difficult to reach complete symptomatic remission, and therefore, have an impact on the daily functioning."

More information: Treatment efficacy and effectiveness in adults with major depressive disorder and childhood trauma history: a systematic review and meta-analysis, The Lancet Psychiatry (2022). www.thelancet.com/journals/lan … (22)00227-9/fulltext

Link: https://medicalxpress.com/news/2022-09-adults-history-childhood-trauma-benefit.html
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What COVID Can Teach Us About Stress Management

Different coping styles tell us a lot about healthy eating

Now that COVID is somewhat behind us, we have some space to stop and reflect. We can remember the days when masks were mandatory, lockdowns were frequent, and many businesses were shutting down (except, of course, hospitals).
Some of us used the time to down-regulate our lives, taking advantage of a less hectic lifestyle. Others’ lives became even more hectic as schools closed, and daycare was a non-starter. Job insecurity became a huge issue. Supply chains were questionable. Not to mention the loss of loved ones and acquaintances.
And we had no idea when things were going to improve, at least until a vaccine became widely available. That first year was quite a challenge, and there was nowhere to go. It was a worldwide health threat.
COVID Anxiety and the Consumption of Junk Foods
A couple of studies presented in a 2022 research paper (Juad and Lunardo) looked at anxiety during 2020 in adults aged 18-35 in the United Kingdom and France. Their background research showed that this age group tended to struggle more with anxiety than older adults, showing a greater tendency to feel isolated, overwhelmed, and helpless.
This particular study decided to look at the uptick in eating junk foods (high-calorie, processed foods) and sugary drinks as a coping strategy for pandemic anxiety. Juad and Lunardo also found that there were specific coping strategies used by some individuals that did not lead to continued states of anxiety and turning to compensatory eating practices.
They discovered that feelings of helplessness caused many individuals to have a lower acceptance of the situation. Helplessness indicates a general feeling of not having the ability to find a way to cope with the situation. This is known as low self-efficacy.
Individuals who felt helpless tended to eat more junk food (often accompanied by weight gain) during the first year of the pandemic. On the other hand, those who were able to accept the situation were then able to develop positive coping strategies. As a result, they did not turn to junk food as a coping strategy.
Anxiety and Self-Efficacy
Other research has explored the connection between helplessness and feelings of low-self efficacy. Low self-efficacy can lead to ignoring or rejecting positive coping strategies that a person does not feel capable of performing. The opposite would be self-efficacy, or a person’s belief in their ability to find and use coping strategies to achieve a goal or complete a task.
These same concepts are evident when designing behavior change interventions that promote a healthy eating style compatible with maintaining a healthy weight.
What do they have in common? Both have to do with conquering the negativity that comes with stress that can leave a person stuck in an unproductive belief system. Without self-efficacy on board, it is easy to stay focused on the negative, use negative self-talk, and stay in black-and-white thinking. These patterns can lead a person to think that changing the situation is impossible.
The question is, can some interventions increase self-efficacy, and if so, how?
The Role of Stress Management
A study in 2022 (Carfora, Morandi, and Catellani) identified several techniques that had a positive effect on developing dietary self-efficacy. Self-monitoring, feedback on performance, review of behavioral goals, setting up a reward system, and social support all increased dietary self-efficacy.
The kicker was that stress management was consistently associated with self-efficacy across all analyses and came out as the strongest indicator.
This finding takes us right back to what was happening during COVID with regard to turning to unhealthy foods. Anxiety is a big part of stress. Jaud and Lunardo found a huge association between being able to handle the anxiety of an uncontrollable situation like the pandemic and the ability to make healthy food choices. That association points to the role of self-efficacy when handling the stress of the situation.
Rewriting Stress
Getting back to the question of whether self-efficacy can be increased, it would appear that stress management plays a key role. Taking it a step further, what actions can be taken to respond to stress that will lower its effect on us?
As Jaud and Lunardo indicated, the ability to accept the situation could then serve as the basis for developing coping strategies leading to the ability to maintain healthy eating during the pandemic.
Other research has supported several techniques used to reduce stress and develop coping strategies when designing healthy eating interventions. These techniques have been proven effective time and again. These strategies can be applied to the successful management of stress during challenging times, such as the pandemic, as well as using behavior change interventions in healthy eating or weight-loss programs.

psychology today