Stress linked to chronic inflammation can cause depression. Explore this connection and ways to improve your quality of life both on and off the job.

If you’re stressed and/or have been diagnosed with depression — a fairly familiar occurrence among veterinary practitioners — you may also have chronic inflammation and don’t even know it. The incidence of chronic inflammation increases with age, and there are a wide range of common causes. They include genetic factors,¹ exposure to xenobiotics such as plastics and pesticides,² an unhealthy microbiome,³ the American diet,⁴ metabolic disease,⁵ obesity,⁶ chronic conditions such as heart disease,⁷ an imbalance of Phase I and Phase II enzymes in the liver,⁸ poor early-life nutrition⁹ and vitamin D deficiency⁹ — but they also include stress⁹ and depression.¹¹

The relationship between stress, inflammation and depression

Psychosocial stress increases inflammatory cytokines, including interleukin-6 (IL6), interferon gamma, and tumor necrosis factor alpha (TNFα). Affected people also show lower levels of beneficial interleukin-10 (IL10) than those without stress and anxiety.¹²

Chronic stress leads to an imbalance between the sympathetic and parasympathetic systems, marked by increased stimulation of the sympathetic system and decreased vagal tone. An increase in stress hormones influences the immune system to create a pro-inflammatory state, while decreased vagal tone leads to a pro-inflammatory state in the gut. The end result is generalized inflammation, platelet activation, loss of heart rate variability, and endothelial dysfunction. These symptoms are not only seen in people with cardiovascular disease, but also in most of those who have been diagnosed with major depressive disorders.¹¹

Core features of major depression include an increased reactivity to negative information, a less positive reaction to rewards, a lowered ability to control thoughts, and an extreme focus on physical symptoms. Pain or fatigue can cause major emotional distress to the point where the patient has difficulty functioning in daily life activities. Increased inflammation makes these signs worse.¹³

Chronic inflammation is a major factor in six of the ten leading causes of death in the United States, as well as in depression (the second most common mental illness in the U.S.).^11,14 In fact, there is evidence that while inflammation can cause depression, depression also causes inflammation. Increased inflammation makes depression worse, and high levels of inflammatory markers are associated with depression that is more resistant to antidepressant therapy.¹⁵

C-reactive protein (CRP) is a test for the general level of inflammation in the body, and is easily available as an addition to any blood panel. Inflammation increases with stress, and we all know that many stressful incidents occur in a veterinary practice. Incidence of chronic inflammation increases as we get older, yet CRP is not routinely included in annual blood tests – not even for seniors.

Genetic tests are available for other markers of chronic inflammation, including genes for inflammatory cytokines, especially interleukin-1 beta (IL-1β), IL-6, IL-10, monocyte chemoattractant protein-1, TNFα, CRP and phospholipase A2. Moreover, increased blood cytokines mRNA expression (especially of IL-1β) identifies patients that are less likely to respond to conventional antidepressants.¹

Phase I and II liver enzymes

With long-standing inflammation, prolonged exposure to xenobiotics, persistent toxicants that are hard to eliminate — or a Phase I/Phase II liver enzyme imbalance³⁴ — merely adding antioxidant foods and supplements might not be enough. Toxicants that are not directly eliminated through the kidneys are processed through Phase I and Phase II liver enzymes, and when the level of toxicants exceeds the capacity of the liver to process them, detoxification is necessary to eliminate them.

Phase I enzymes primarily consist of the cytochrome P450 group (CYP450), along with a few others. The role of Phase I enzymes is to take a fat-soluble substance and make it more chemically reactive, by oxidation/reduction and/or hydrolysis reactions. Because the products of Phase I actions are highly reactive, they are also highly inflammatory, but in a healthy balanced liver they immediately react with Phase II enzymes.

Phase II enzymes conjugate those molecules with hydrophilic cofactors. This results in water-soluble molecules that can be excreted through the kidneys. Phase II enzymes include UDP-glucuronosyl transferases, glutathione S-transferases, amino acid transferases, N-acetyl transferases, and N- and O- methyltransferases. The cofactors used for conjugation include glucuronic acid, sulfate, glutathione, various amino acids, an acetyl group and a methyl group.³⁵

There are a number of ways that Phase I/Phase II imbalances can interfere with the elimination of inflammatory substances. When there is a low level of both enzymes, the liver processes waste products and toxins more slowly, and those toxic substances build up in the body. Initially, they are stored in body fat, but when fat depots are full, they remain in interstitial spaces, where they interact with cells and cause inflammation. The same effect occurs with a low level of Phase I enzymes alone, since Phase I treatment is required for Phase II reactions to occur.

When the imbalance is reversed, so that you see an excess of Phase I reactions, or lower than normal Phase II enzyme activity, a buildup of inflammatory highly-reactive electrophilic molecules occurs. This can result in local liver inflammation, or system-wide inflammation, when they are released into the bloodstream.

If there are not enough cofactors to allow full conjugation of all the inflammatory products of Phase I, the result is the same. In addition, Phase I enzyme activity can easily be increased, especially with high exposure to toxic substances. It is more difficult to increase Phase II, so the result again is an imbalance, with excess Phase I activity with respect to Phase II activity.³⁶

A determination of Phase I/Phase II imbalances could help with cases of chronic inflammation that do not yield to dietary, herbal or nutraceutical intervention.³⁷ Two labs that offer tests to determine Phase I/Phase II imbalance are Genova Diagnostics in Asheville, NC, and The Great Plains Laboratory in Lenexa, KS.

For optimal elimination of toxic substances, a number of principles must be followed. To safely increase this elimination, the level of substances normally processed by the liver must be decreased. This frees up more Phase I/Phase II enzymes to process toxins. It also allows toxic substances to be released from fat storage, as total blood concentration decreases.

A high amount of naturally-produced waste products will decrease the level of toxic products that can be processed. Those products will be stored elsewhere in the body — first in the fat and later, when fat depots are filled, in interstitial spaces. They are generally inflammatory, contributing to the inflammatory cascade and causing chronic inflammation.

The best way to remove inflammatory products is to decrease the amount of normal waste products present. A fast eliminates most by-products of digestion, and is part of the detoxification process.

In addition, enough conjugates must be available for Phase II enzymes to work at full capacity. The body must stay hydrated to flush the end products away as quickly as possible. Essential nutrients must be maintained so that organs and muscle are not degraded while the process is going on. Additional nutrients must be added to support microbiome health throughout the process, and to provide antioxidant capabilities. A proper detoxification protocol accomplishes all of this.

Treating depression and inflammation

• • Physicians are starting to use NSAIDs in addition to conventional drugs to treat depression, especially celecoxib and aspirin. They often get better results than with drugs alone.^14,16,17,18 Most studies have used NSAIDs for acute depression, not chronic depression, but it is logical that anti-inflammatory agents should also be useful for chronic depression. It’s likely it would take longer to see effects in cases of long-standing depression.
  • Some antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), decrease inflammation. They decrease pro-inflammatory cytokines, including TNFα, interferon (IFN) γ and IL-1, and increase anti-inflammatory cytokines such as IL-10.^19,20
  • A natural way to accomplish the same effect is to change to an anti-inflammatory diet. Diets high in fruits and vegetables decrease CRP levels, and normalize factors that affect endothelial health, including soluble intercellular adhesion molecule 1, soluble vascular adhesion molecule 1, and E-selectin molecules.21 Metabolic disease, associated with the typical American diet, predicts a poor response to standard treatment for those with depression ²²
  • Immune cells and gut microbiota influence the brain,²³ and fiber favorably influences the gut microbiome.²⁴ Beta-glucans, which promote normal immune function, are plentiful in whole grain foods.²⁵ Consumption of whole grains decreases the risk of inflammatory disease.²⁶
  • Certain herbs, vitamins and supplements also have anti-inflammatory actions^27,28 and are not associated with the types of side effects seen with long-term NSAID use. However, one must be careful using these supplements, since a number of them have hermetic (biphasic) effects, where a low dose can cause one effect and a high dose may cause the opposite.^8,29
  • Avoiding dietary substances such as glutamate both reduces inflammation and improves depression.30 Induced sweating, both from exercise and from saunas, can increase excretion of phthalate plasticizers.³¹ Exercise has beneficial effects in general, and can help decrease liver inflammation.³²
  • The microbiome also plays a part in chronic inflammation. There are multiple links between gut organisms, diet and depression. Early life trauma, the effects of various drugs, especially antibiotics, as well as nutritional factors affect the microbiome. In turn, a change in gut flora composition has been shown to affect depression, positively or negatively, depending on the change. Including prebiotics can help: inulin selectively stimulates colonic bifidobacteria, which play a part in maintaining a proper balance of microbiome species.³³

Detoxification and medical fasting

Detoxification is a recognized procedure in reversing chronic disease.³⁸ It is a modified form of fasting, with added nutritional products that support Phase I/Phase II enzyme activity in the liver. In Europe, this procedure is known as “medical fasting”, an established therapeutic approach supported within clinical departments of integrative medicine.³⁸ Research demonstrates its association with deceleration or prevention of chronic inflammatory diseases.³⁹ Medical fasting reduces or prevents the generation of cytokines that promote oxidative stress.⁴⁰ It decreases free radical generation by mitochondria, decreases oxidative damage to mitochondrial DNA,⁴¹ and increases autophagy.⁴² Most importantly, it eliminates persistent toxicants.⁴³ Fasting can also help depression. Its efficacy on improving mood is well established.⁴⁴ Symptoms of depression usually start improving on Day 2 of the fast, with an enhancement in alertness and mood, and a sense of tranquility.⁴⁵

It is important for fasting to be done properly. There must be enough nutritional support to reduce inflammation from Phase I processes, decrease the chances of over-activating the Phase I process, and to supply enough cofactors for Phase II conjugation to proceed as thoroughly as possible. The detoxification process can be modulated using foods and nutraceuticals.

Fasting also has a dark side. It can decrease the immune system’s performance and cause atrophy in various organs.⁴⁶ It causes changes in blood glucose regulation, plasma growth hormone (GH), insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein-3 (IGFBP-3).⁴⁷ There is a need for some protein and healthy fats during fasting⁴⁸ to support the body’s daily metabolic processes, so that muscle and organ tissue will not be destroyed in order to provide the required nutrients. When fasting is excessively prolonged and suddenly ended, re-feeding syndrome has been reported,⁴⁹ which can result in illness or death. Intracellular phosphate, magnesium and potassium may be low, though serum measurements of the three electrolytes are normal. With a reversal of metabolism from fat-based to carbohydrate-based, electrolytes are needed but not available, resulting in hypokalemia, hypophosphatemia and hypomagnesemia. Death from heart failure can occur. Unexplained deaths have been reported in obese individuals who were fasting.⁵⁰

The best way to avoid these unpleasant effects when detoxing is to use a supplement with nutraceuticals that support Phase II conjugation, decrease the inflammatory effects of Phase I activity without stopping the wanted chemical effects, and supply necessary components to avoid tissue and organ destruction. In addition, rather than abruptly starting and stopping the fast itself, a more gradual introduction to the fast and resumption of a normal diet will avoid reactions similar to re-feeding syndrome.

Two products are available that will do this: Ultra-Clear from Metagenics in CA, and Mediclear from Thorne Research in SC. These products are accompanied by guides for their use and the proper beginning and end of the detoxification process. This approach is superior to some popular fasting methods, including the water fast. When properly conducted, a fast can decrease or eliminate toxicants that are causing inflammation and depression. With severe depression, fasting should not be done without medical supervision and appropriate supplementation. It is safer if the only object is to reduce potential chronic inflammation without any overt signs of disease, but the healthiest way is still a fast with the addition of proper products to avoid protein degradation in the body, support Phase II conjugation, decrease inflammation, and maintain proper electrolyte balance.

For more information, see Dr. Scanlan’s blog at longerhealthierlife.net.

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