Could it be possible that what we call “mental illness” is a direct consequence of the changes that occur in the body as a result of trauma and chronic stress? Could we be focusing treatment in the wrong area? Could treating, as well as preventing, the upstream aspects of chronic stress—instead of its downstream outcomes—be a more suitable and safer alternative? If so, what would these treatments look like?
Table of Contents
The Stress Response
If we are confronted by a bear, the sympathetic nervous system (SNS) is activated by the release of epinephrine, norepinephrine, and cortisol. This immediately enables us to either fight, run (flight), or freeze. Our heart rate, respiratory rate, and blood pressure increase, blood flow is redirected from non-essential areas such as the skin and gastrointestinal system and directed to the muscles, short term memory increases, and pupils dilate.
When the bear leaves, and there is no longer a threat, the cortisol is turned off through the negative feedback system and the epinephrine burns off, resulting in a return of homeostasis.
Everyday stress, whether it be external (work, financial, traumas, bad relationship, etc.) or internal (overthinking, catastrophizing, negativity), results in the same activation of the SNS. The only difference is, because the stress doesn’t go away, neither do the chemicals.
It is a fact that serotonin and cortisol help keep us alive. However, chronic, long-term secretion can lead to adverse effects that, unfortunately, do not exclude any bodily system.
Chronic Stress and Its Biological Impact
The number of Americans reporting stress is on the rise. In a 2022 survey, upwards of 87% of Americans reported being stressed for different reasons. Ever-increasing cost of living, navigating work-life balance, the state of our education and healthcare systems, tending to our own personal relationships and working with our own self-defeating thoughts are some examples of stressors Americans are facing today. Chronic stress is associated with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis, which can result in maladaptive reactions including elevated blood pressure, cardiovascular disease, stroke, low sleep quality, and stomach ulcers. It also contributes to the onset of type 2 diabetes. There isn’t an area of the body that stress does not affect.
Nervous System. Although chronic stress can upset many regions of the brain, three of the most affected areas are the hippocampus, amygdala, and prefrontal cortex. The hippocampus is responsible for learning and memories, and the amygdala’s primary function is to control emotions, such as fear, sadness, and aggression. Chronic stress and consistently elevated glucocorticoids have been found to cause dendritic shrinkage and loss of spines in both the amygdala and the hippocampus. These changes have been associated with brain atrophy, declarative memory disorders, reduction in spatial memory, weakened verbal memory, increased anxiety, PTSD-like behaviors, and social avoidance.
The prefrontal cortex (PFC) plays a central role in executive functions, including planning, judgement, decision-making, anticipation, and reasoning. Chronic stress affects this region by the debranching and shrinkage of dendrites of the PFC neurons. Further insults to the nervous system that are a direct result of chronic stress include decreasing the amount of cyclic adenosine monophosphate (cAMP) and decreasing the amount of brain-derived neurotrophic factor (BDNF). cAMP is an important intracellular second messenger molecule regulated in many physiological processes. The levels of cAMP can determine the state of function in a disease or healthy state, by mediating various biological processes including but not limited to metabolism, immune function, and gene regulation. BDNF is an important molecule involved in plastic changes related to learning and memory. It also regulates both excitatory and inhibitory synaptic transmission.7
Lastly, chronic stress has been found to alter gamma-aminobutyric acid (GABA) transmission, deplete serotonin, sustain the release of noradrenaline, increase glutamate release, and directly impacts dopaminergic neurons.
Immune System. Studies have found that stress is associated with increased susceptibility to infectious and inflammatory disease. A strong decline in innate and cellular immune responses has been noted. Additionally, chronic stress has been directly associated with growth of malignant cells and tumor expansion. Over time, chronic stress causes immune cells to become desensitized to cortisol and express fewer cortisol receptors, and there is an increased production of proinflammatory cytokines such as IL-6, IL-1 and Tumor Necrosis Factor (TNF).
Chronic inflammation can lead to a multitude of signs and symptoms, including body pain, arthralgia, myalgia, chronic fatigue, insomnia, depression, anxiety, other mood disorders, constipation, diarrhea, acid reflux, weight gain/loss, and frequent infections. Since the onset of COVID-19 affecting the world in 2020, the rates of mental health disorders, specifically anxiety and depressive disorders, have increased dramatically. According to the World Health Organization, in the first years of the pandemic, anxiety and depression increased by 25%. Other than the social isolation the pandemic caused, another possible impact of COVID-19 that could cause, or worsen, “mental illness,” is inflammation.
According to one study, after a COVID-19 respiratory infection, 20-70% of patients who presented with post virus symptoms such as anosmia, cognitive and attention deficits, brain fog, fatigue, new-onset anxiety, depression, psychosis, seizures, and suicidal behavior, continue to have these symptoms even months after the illness resolved. The researchers note that traditional medications used to treat depression and anxiety today, such as selective serotonin reuptake inhibitors (SSRIs), do not typically help this subset of patients. Why is this?
According to the National Institutes of Health, this is result of overactive immune cells releasing high levels of inflammatory substances, the immune system making autoantibodies that attack a person’s own organs and tissues, and the virus becoming active again.
Endocrine System. Other hormones are also directly affected by chronic stress. Gonadotropins, follicle stimulating hormone (FSH), and luteinizing hormone (LH), are suppressed, growth hormone (GH) secretion decreases, thyroid function is downregulated, prolactin is affected, insulin availability decreases, leptin decreases, and ghrelin increases (which results in increased hunger, leading to obesity). It is well-researched that changes in hormone homeostasis can directly affect our mood.
Gastrointestinal (GI) System. Chronic stress has also been found to cause GI inflammation, as well as affect the absorption process, motility, intestinal permeability (i.e. leaky gut), mucus and stomach acid secretion, and function of ion channels. Neuroscientists have noted the bi-directional link between gut physiology and brain function; the linkage between gut functions and emotional and cognitive processes is provided through afferent and efferent neural projection pathways, bi-directional neuroendocrine signaling, immune activation and signaling from gut to brain, altered intestinal permeability, modulation of enteric sensory-motor reflexes, and entero-endocrine signaling. It is the gut microbiota, which communicate to the brain through the vagus nerve, that directly influence all of these pathways.
The gut microbiome is the largest microecosystem in the human body. It is interdependent with the host and maintains normal physiological processes in a dynamic equilibrium state. Any imbalance may result in neurodegenerative diseases, cardiovascular disease, metabolic disease, and gastrointestinal diseases. Chronic stress affects the microbiota in the gut, and dysfunction in the microbiome has been associated with stress-related disorders such as anxiety and depression.
With all of the pathological changes that occur throughout our bodies as a result of chronic stress coupled with the dramatic increase in reported stress, it is no wonder the incidence of multiple chronic illnesses continues to rise, to include diabetes, autoimmune disorders, cardiovascular disease, and “mental illness.” The widespread inflammation that occurs as a result does not omit any bodily system. Could subtle changes in inflammatory, hormonal, and cortisol markers be a measurable sign of these ramifications?
Potential diagnostic biomarkers of chronic stress include cortisol, ACTH, BDNF, catecholamines, glucose, HbA1c, triglycerides, cholesterol, prolactin, oxytocin, dehydroepiandrosterone sulfate (DHEA-S), CRP, and interleukin-6 and -8.
What Can We Do?
Although more research is needed in this area, there have already been quite a few studies on possible solutions to the chronic stress dilemma. Most of them are non-pharmacologic. Eating healthy, learning time management, setting realistic goals and boundaries, getting more sleep, exercising, learning and practicing mindfulness, building stress reduction skills, and diaphragmatic breathing are some of many non-pharmacologic methods that have been researched as potential interventions to reduce the adverse effects of chronic stress.
With regard to pharmacologic therapies, there have been few studies performed. Those have focused on the widespread inflammation caused by chronic stress. Some studies have found that patients with depression and anxiety are helped by anti-inflammatory medications, anti-inflammatory diets, and nutritional supplements that have been designed to curtail inflammation.
With the ever-increasing demands of today’s society, resulting in chronic stress, subsequently leading to chronic illnesses, including “mental illness,” it is of utter urgency that treatment begin, not end, with stress prevention and management, as well as the treatment of the biological ramifications of chronic stress.
Mad in America hosts blogs by a diverse group of writers. These posts are designed to serve as a public forum for a discussion—broadly speaking—of psychiatry and its treatments. The opinions expressed are the writers’ own.
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