Depression’s Link to Inflammation Gains Strength
October 09, 2016
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By Dr. Mercola
Depression is increasingly recognized as a problem rooted in chronic inflammation. While other factors may also be involved, inflammation can have a profound impact on your mental health.
The study of these connections is known as psychoneuroimmunology, i.e., the impact of inflammation on behavior. As noted in one 2012 study in the journal Neuropsychopharmacology:1
Cytokines in your blood, or inflammatory messengers such as CRP, interleukin-1 (IL-1), interleukin-6 (IL-6), and TNF-alpha are all predictive of3 and correlate4 to depression.
For example, in melancholic depression, bipolar disorder and postpartum depression, white blood cells called monocytes express pro-inflammatory genes that provoke secretion of cytokines.5 At the same time, cortisol sensitivity goes down, and cortisol is a stress hormone that buffers against inflammation.
Together, these inflammatory agents transfer information to your nervous system, typically by stimulating your vagus nerve, which connects your gut and brain.6
During inflammatory states, brain cells called microglia are activated. When this happens, an enzyme called indoleamine 2 3-dioxygenase (IDO) directs tryptophan away from the production of serotonin and melatonin, instructing it instead to produce an NMDA (an amino acid derivative) agonist called quinolinic acid, which can trigger anxiety and agitation.7
After taking an anti-inflammatory drug, there were significant changes in their brains’ neuro-chemical circuitry. Importantly, pathways known to be involved in alleviating depression were favorably altered.
Interestingly, work by Carmine Pariante, a professor of biological psychiatry, shows that people who have overactive immune systems are less likely to respond to anti-depressants.
He also found that emotional trauma may alter your immune system and “prime” it in such a way that it predisposes you to depression. BBC quotes Pariante, saying:
The problem with this approach is that you’d simply be switching from one form of drug to another, and virtually all drugs have side effects. Sometimes terminal, as the 60,000 who died from the anti-inflammatory Vioxx.
Fortunately, you don’t need drugs to combat inflammation. One of the most effective ways to quell inflammation is to eat a ketogenic diet, high in healthy fats and low in net carbs (total carbs minus fiber).
In fact, one of the most remarkable effects of nutritional ketosis is that your C-reactive protein (CRP) level (an inflammatory marker) virtually disappears. It can really drive your inflammation levels about as low as they can go.
This remained true even when other anti-inflammatory dietary and lifestyle strategies such as exercise, body weight and smoking were taken into account. I use macadamia nuts and pecans nearly every day as part of my diet plan, about 2 ounces of each, as they really help safely keep my calorie level high.
My favorite nuts, macadamia and pecans, provide the highest amount of healthy fat while being on the lower end in terms of carbs and protein. Raw macadamia nuts also contain high amounts of vitamin B1, magnesium and manganese. Moreover, about 60 percent of the fatty acid in macadamia is the monounsaturated fat oleic acid. This is about the level found in olives, which are well known for their health benefits. This little tidbit is a fact few people make note of when discussing the benefits of macadamias.
Pecans also boast more than 19 different vitamins and minerals that studies suggest can help you lower LDL cholesterol and promote healthy arteries, and are in the top 15 foods known for their antioxidant activity, according to the U.S. Department of Agriculture (USDA).
One of those antioxidants is vitamin E, which may convey neurological protection and keeps blood lipids from oxidizing in your body. Beta-carotenes, lutein and zeaxanthin in pecans also help rid your body of harmful free radicals, protecting it from inflammation. One ounce of macadamia nuts has only 4 grams of carbs, but over half of those are non-digestible fiber so it provides an ultra-low 2 grams of sugar per ounce of nuts.
Furthermore, the marine-based DHA and eicosapentaenoic acid (EPA) are actually structural elements needed by every cell in your body; part of their biological effects include anti-inflammatory activity and communication within the cell and between cells. With this in mind, it’s important to avoid making the mistake of thinking you can get all the omega-3 you need from plant sources.
You simply cannot afford to get this wrong, especially if you’re struggling with depression or other inflammation-based conditions. To learn more about the differences between plant- and animal-based omega-3 fats, please see my previous article, “How Good Fats Prevent Heart Disease.” Good sources of animal-based DHA and EPA include fatty, cold-water fish like wild Alaskan salmon, sardines, herring, fish roe and krill oil.
Daily supplementation with 50 micrograms (mcg) — equivalent to 2,000 International Units (IUs) — of vitamin D for nine months increased blood concentrations of anti-inflammatory interleukin-10 (IL-10) by 43 percent, while simultaneously preventing an increase in the pro-inflammatory cytokine TNF-alpha in patients diagnosed with congestive heart failure (CHF).
Vitamin D deficiency has also been linked to depression specifically. In one previous study, seniors with the lowest levels of vitamin D were found to be 11 times more prone to be depressed than those who had normal levels.
In addition to its anti-inflammatory and immune-boosting properties, vitamin D receptors appear in a wide variety of brain tissue, and researchers believe optimal vitamin D levels may enhance important chemicals in your brain and protect brain cells by increasing the effectiveness of glial cells that help nurse damaged neurons back to health.
To learn more about how to optimize your vitamin D level through sensible sun exposure, please see my interview with Dr. Michael F. Holick, who is a well-recognized expert on vitamin D. A vitamin D3 supplement can also be used, but you'll need to monitor your levels regularly. To reap maximum benefit, you need a vitamin D level of at least 40 to 60 nanograms per milliliter (ng/ml).
If you give your body a false signal with oral vitamin D, there is potential that you will disrupt some important physiological cycles. I personally have not swallowed vitamin D in seven years, but moved to Florida to get high quality sun exposure.
Also, UVB is not the only wavelength in sunlight. You really need all the frequencies to effectively treat depression. For example, daily exposure to sunlight outdoors without glasses or contacts (ideally grounded to the earth) for several minutes within an hour of sunrise is a powerful stimulus to normalize your circadian rhythm. Avoiding all blue light from artificial sources is another factor. When these are done you typically sleep better, which is a profoundly important factor for depression.
Raw organic nuts are a great source of healthy fats, but I wouldn’t recommend hitching your hopes on nuts alone. You also need to ditch the processed foods (which are chockfull of inflammatory ingredients) and switch to real foods, as that’s where you’ll find important antioxidants and nutrients that help combat inflammation. I would strongly encourage you to consider a ketogenic diet — the anti-inflammatory capacity of which is truly profound.
Also be sure to address your gut health, as impaired gut flora is also frequently involved in depression. One of the easiest ways to help reseed your gut with beneficial bacteria is to eat traditionally fermented and cultured foods such as kefir, natto, kimchi and fermented vegetables, most of which are also easy and inexpensive to make from scratch at home.
Depression is increasingly recognized as a problem rooted in chronic inflammation. While other factors may also be involved, inflammation can have a profound impact on your mental health.
The study of these connections is known as psychoneuroimmunology, i.e., the impact of inflammation on behavior. As noted in one 2012 study in the journal Neuropsychopharmacology:1
“Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms.
Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation …
Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence.”
Inflammation and Depression
In this model, depression is the result of your body’s attempts to protect itself from an inflammatory response, and involves hormones and neurotransmitters. Depressive symptoms most strongly associated with chronic inflammation include flat mood, slowed thinking, avoidance, alterations in perception and metabolic changes.2Cytokines in your blood, or inflammatory messengers such as CRP, interleukin-1 (IL-1), interleukin-6 (IL-6), and TNF-alpha are all predictive of3 and correlate4 to depression.
For example, in melancholic depression, bipolar disorder and postpartum depression, white blood cells called monocytes express pro-inflammatory genes that provoke secretion of cytokines.5 At the same time, cortisol sensitivity goes down, and cortisol is a stress hormone that buffers against inflammation.
Together, these inflammatory agents transfer information to your nervous system, typically by stimulating your vagus nerve, which connects your gut and brain.6
During inflammatory states, brain cells called microglia are activated. When this happens, an enzyme called indoleamine 2 3-dioxygenase (IDO) directs tryptophan away from the production of serotonin and melatonin, instructing it instead to produce an NMDA (an amino acid derivative) agonist called quinolinic acid, which can trigger anxiety and agitation.7
Errant Immune System May Alter Your Mood
Recent research again highlights the inflammatory underpinnings of depression. As reported by BBC:8“The focus is on an errant immune system causing inflammation in the body and altering mood … [Professor Ed Bullmore, head of psychiatry at the University of Cambridge and an employee of GlaxoSmithKline] said: ‘Depression and inflammation often go hand in hand …
[I]f you have flu, the immune system reacts to that, you become inflamed and very often people find that their mood changes too. Their [behavior] changes, they may become less sociable, more sleepy, more withdrawn.
They may begin to have some of the negative ways of thinking that are characteristic of depression and all of that follows an infection’ …
Inflammation is part of the immune system's response to danger … If it is too high, it causes damage. And for some reason, about one-third of depressed patients have consistently high levels of inflammation.”When patients diagnosed with rheumatoid arthritis were treated with anti-inflammatory drugs targeting specific parts of the immune system, they also reported an improvement in mood. This was what raised the curiosity of professor Iain McInnes, a consultant rheumatologist. He told the BBC:
"When we give these therapies we see a fairly rapid increase in a sense of well-being, mood state improving quite remarkably often disproportionately given the amount of inflammation we can see in their joints and their skin."
Anti-Inflammatories Boost Mood
McInnes’ team performed brain scans on patients with rheumatoid arthritis, before and after giving them an immune targeted drug. The brain scans seemed to confirm and validate the patients’ feedback.After taking an anti-inflammatory drug, there were significant changes in their brains’ neuro-chemical circuitry. Importantly, pathways known to be involved in alleviating depression were favorably altered.
Interestingly, work by Carmine Pariante, a professor of biological psychiatry, shows that people who have overactive immune systems are less likely to respond to anti-depressants.
He also found that emotional trauma may alter your immune system and “prime” it in such a way that it predisposes you to depression. BBC quotes Pariante, saying:
"We think the immune system is the key mechanism by which early life events produce this long-term effect.
We have some data showing adult individuals who have a history of early life trauma, even if they have never been depressed, have an activated immune system so they are in a state of risk."
Arthritis Drug Being Tested on Depressed Patients
The arthritis drug sirukumab is currently being tested on depressed patients. GlaxoSmithKline and others are also working on developing anti-inflammatory drugs targeting depression.The problem with this approach is that you’d simply be switching from one form of drug to another, and virtually all drugs have side effects. Sometimes terminal, as the 60,000 who died from the anti-inflammatory Vioxx.
Fortunately, you don’t need drugs to combat inflammation. One of the most effective ways to quell inflammation is to eat a ketogenic diet, high in healthy fats and low in net carbs (total carbs minus fiber).
In fact, one of the most remarkable effects of nutritional ketosis is that your C-reactive protein (CRP) level (an inflammatory marker) virtually disappears. It can really drive your inflammation levels about as low as they can go.
Snacking on Nuts Decreases Inflammation
Raw nuts are a great source of healthy fat, and eating 1 ounce (about a handful) of nuts five times per week can reduce inflammation according to recent research.9,10,11 As reported by Reuters:12“Past research has linked eating nuts to lower rates of heart disease and diabetes, but the exact reason was unknown, senior study author Dr. Ying Bao, an assistant professor of medicine at Harvard Medical School in Boston, told Reuters Health.
‘We hypothesized that nuts may exert these health benefits by reducing inflammation,’ Bao said …”By looking at data from two long-term studies — the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) — in which participants documented what they ate and provided blood samples that were analyzed for inflammatory biomarkers, the researchers found that people who ate nuts at least five times a week had 20 percent lower CRP levels and 16 percent lower IL-6 than those who rarely or never ate nuts.
This remained true even when other anti-inflammatory dietary and lifestyle strategies such as exercise, body weight and smoking were taken into account. I use macadamia nuts and pecans nearly every day as part of my diet plan, about 2 ounces of each, as they really help safely keep my calorie level high.
Other Health Benefits Linked to Regular Nut Consumption
Other research has linked regular nut consumption to:- Weight loss13
- Lower systolic blood pressure
- Fewer risk factors for metabolic syndrome14 and a lower risk for diabetes
- Improved cardiovascular health
- Reduced mortality risk and increased longevity. In one study, people who ate a small handful (1 ounce or 28 grams) of nuts seven times per week or more were 20 percent less likely to die for any reason, compared to those who avoided nuts. Eating nuts at least 5 times per week was associated with a 29 percent drop in mortality risk from heart disease and an 11 percent drop in mortality risk from cancer specifically15,16,17,18
Top Picks: Macadamias and Pecans
Most nuts’ nutritional makeup closely resembles what I consider to be an ideal ratio of the basic building blocks, with fat making up the greatest amount of your daily calories, followed by a moderate amount of high quality protein and a low amount of non-vegetable carbs (see my Food Pyramid for Optimal Health). That said, some nuts have more ideal ratios than others.My favorite nuts, macadamia and pecans, provide the highest amount of healthy fat while being on the lower end in terms of carbs and protein. Raw macadamia nuts also contain high amounts of vitamin B1, magnesium and manganese. Moreover, about 60 percent of the fatty acid in macadamia is the monounsaturated fat oleic acid. This is about the level found in olives, which are well known for their health benefits. This little tidbit is a fact few people make note of when discussing the benefits of macadamias.
Pecans also boast more than 19 different vitamins and minerals that studies suggest can help you lower LDL cholesterol and promote healthy arteries, and are in the top 15 foods known for their antioxidant activity, according to the U.S. Department of Agriculture (USDA).
One of those antioxidants is vitamin E, which may convey neurological protection and keeps blood lipids from oxidizing in your body. Beta-carotenes, lutein and zeaxanthin in pecans also help rid your body of harmful free radicals, protecting it from inflammation. One ounce of macadamia nuts has only 4 grams of carbs, but over half of those are non-digestible fiber so it provides an ultra-low 2 grams of sugar per ounce of nuts.
The Importance of Animal-Based Omega-3 DHA
Animal-based omega-319 is a potent, all-natural anti-inflammatory. While many nuts contain plant-based omega-3 (with the exception of pecans, which are very low in omega-3 and omega-6), your body cannot efficiently convert the alpha-linolenic acid (ALA) found in plants to the docosahexaenoic acid (DHA) found in marine animals such as fatty fish and krill. DHA is particularly important for brain health, as more than 90 percent of the omega-3 fat found in your brain tissue is DHA.20Furthermore, the marine-based DHA and eicosapentaenoic acid (EPA) are actually structural elements needed by every cell in your body; part of their biological effects include anti-inflammatory activity and communication within the cell and between cells. With this in mind, it’s important to avoid making the mistake of thinking you can get all the omega-3 you need from plant sources.
You simply cannot afford to get this wrong, especially if you’re struggling with depression or other inflammation-based conditions. To learn more about the differences between plant- and animal-based omega-3 fats, please see my previous article, “How Good Fats Prevent Heart Disease.” Good sources of animal-based DHA and EPA include fatty, cold-water fish like wild Alaskan salmon, sardines, herring, fish roe and krill oil.
Vitamin D — Another Important Anti-Inflammatory
Vitamin D, which is best obtained from regular, sensible sun exposure, also inhibits inflammation. It produces over 200 anti-microbial peptides and up-regulates a large number of genes, including one that boosts your ability to fight infections and chronic inflammation. In one placebo-controlled study, high-dose vitamin D supplementation boosted anti-inflammatory molecules, showing promise as an anti-inflammatory “medicine” for people with heart failure.21Daily supplementation with 50 micrograms (mcg) — equivalent to 2,000 International Units (IUs) — of vitamin D for nine months increased blood concentrations of anti-inflammatory interleukin-10 (IL-10) by 43 percent, while simultaneously preventing an increase in the pro-inflammatory cytokine TNF-alpha in patients diagnosed with congestive heart failure (CHF).
Vitamin D deficiency has also been linked to depression specifically. In one previous study, seniors with the lowest levels of vitamin D were found to be 11 times more prone to be depressed than those who had normal levels.
In addition to its anti-inflammatory and immune-boosting properties, vitamin D receptors appear in a wide variety of brain tissue, and researchers believe optimal vitamin D levels may enhance important chemicals in your brain and protect brain cells by increasing the effectiveness of glial cells that help nurse damaged neurons back to health.
To learn more about how to optimize your vitamin D level through sensible sun exposure, please see my interview with Dr. Michael F. Holick, who is a well-recognized expert on vitamin D. A vitamin D3 supplement can also be used, but you'll need to monitor your levels regularly. To reap maximum benefit, you need a vitamin D level of at least 40 to 60 nanograms per milliliter (ng/ml).
Optimal Sun Exposure
Please remember that there are inherent dangers in using vitamin D3 as an oral supplement. It is a hormone, not a vitamin, and has profoundly important physiologic actions. Ultimately, we were designed to get nearly all of our vitamin D from appropriate solar exposure and, as such, vitamin D is a marker for UV light exposure, which also has a wide ranging host of metabolic benefits.If you give your body a false signal with oral vitamin D, there is potential that you will disrupt some important physiological cycles. I personally have not swallowed vitamin D in seven years, but moved to Florida to get high quality sun exposure.
Also, UVB is not the only wavelength in sunlight. You really need all the frequencies to effectively treat depression. For example, daily exposure to sunlight outdoors without glasses or contacts (ideally grounded to the earth) for several minutes within an hour of sunrise is a powerful stimulus to normalize your circadian rhythm. Avoiding all blue light from artificial sources is another factor. When these are done you typically sleep better, which is a profoundly important factor for depression.
Regain Your Mental Health by Quelling Inflammation
If you suffer from depression, it may be well worth your effort to take steps to reduce the level of inflammation in your body. No drugs are necessary for this. In fact, your best strategy is to address your diet, and make sure to get enough animal-based omega-3 and vitamin D.Raw organic nuts are a great source of healthy fats, but I wouldn’t recommend hitching your hopes on nuts alone. You also need to ditch the processed foods (which are chockfull of inflammatory ingredients) and switch to real foods, as that’s where you’ll find important antioxidants and nutrients that help combat inflammation. I would strongly encourage you to consider a ketogenic diet — the anti-inflammatory capacity of which is truly profound.
Also be sure to address your gut health, as impaired gut flora is also frequently involved in depression. One of the easiest ways to help reseed your gut with beneficial bacteria is to eat traditionally fermented and cultured foods such as kefir, natto, kimchi and fermented vegetables, most of which are also easy and inexpensive to make from scratch at home.
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