Is Depression a Disease—or a Symptom of Inflammation?
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Is Depression a Disease—or a Symptom of Inflammation?

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The idea that depression and other mental health conditions are caused by an imbalance of chemicals (particularly serotonin and norepinephrine) in the brain is so deeply ingrained in our collective psyche that it seems almost sacrilegious to question it. 

A depressed person
Depression and inflammation are linked. Find out how. iStock.com/AntonioGuillem

Of course, Big Pharma has played a role in perpetuating this idea. Antidepressant drugs, which are based on the chemical imbalance theory, represent a $10 billion dollar market in the U.S. alone. According to the CDC, 11 percent of Americans over 12 years old take antidepressants, and they are the second-most prescribed medications (after cholesterol-lowering drugs). Doctors wrote a staggering 254 million prescriptions for antidepressants in 2010. (1)

Research suggests that depression may be primarily caused by inflammation. Check out this article to find out more about the depression–inflammation connection. #healthylifestyle #chriskresser #wellness

Yet as popular as this theory has become, it is riddled with problems. For example: 

  • Reducing levels of norepinephrine, serotonin, and dopamine does not produce depression in humans, even though it appears to do so in animals.
  • Although some depressed patients have low levels of serotonin and norepinephrine, the majority do not. Several studies indicate that only 25 percent of depressed patients have low levels of these neurotransmitters.
  • Some depressed patients have abnormally high levels of serotonin and norepinephrine, and some patients with no history of depression have low levels of them. (2)

What if depression isn’t caused by a “chemical imbalance” after all? More specifically, what if depression itself is not a disease, but a symptom of an underlying problem? 

That is exactly what the most recent research on depression is telling us. A new theory called the “Immune Cytokine Model of Depression” holds that depression is not a disease itself, but instead a “multifaceted sign of chronic immune system activation.” (3)

To put it plainly: depression may be a symptom of chronic inflammation.

The Connection between Depression and Inflammation

A large body of research now suggests that depression is associated with a low-grade, chronic inflammatory response and is accompanied by increased oxidative stress. 

In an excellent review paper by Berk et al, the authors presented several lines of evidence supporting the connection between depression and inflammation: (4)

  • Depression is often present in acute, inflammatory illnesses. (5)
  • Higher levels of inflammation increase the risk of developing depression. (6)
  • Administering endotoxins that provoke inflammation to healthy people triggers classic depressive symptoms. (7)
  • One-quarter of patients who take interferon, a medication used to treat hepatitis C that causes significant inflammation, develop major depression. (8)
  • Remission of clinical depression is often associated with a normalization of inflammatory markers. (9)

During an inflammatory reaction, chemicals called “cytokines” are produced. These include tumor necrosis factor (TNF)α, interleukin (IL)-1, interferon (IFN)ɣ, and interleukin (IL)-10, among others. Researchers discovered in the early 1980s that inflammatory cytokines produce a wide variety of psychiatric and neurological symptoms which perfectly mirror the defining characteristics of depression. (10)

Interestingly enough, antidepressants (particularly SSRIs) have been shown to reduce the production of pro-inflammatory cytokines like TNF-α, IL-1, interferon IFN-ɣ and increase the production of anti-inflammatory cytokines like IL-10. (11, 12) They also change the gene expression of some immune cells that are involved in inflammatory processes. This suggests that SSRIs are anti-inflammatory, which would explain their mechanism of action if inflammation is a primary driver of depression.

The research on this topic is robust, and the connection between depression and inflammation is now well-established. But if depression is primarily caused by inflammation, the obvious question that arises is, “What is causing the inflammation?”

Nine Common Causes of Inflammation and Depression

If you’ve been following my blog for any length of time, you know that inflammation is at the root of nearly all modern disease, including diabetes, Alzheimer’s, cardiovascular disease, autoimmune disease, allergies, asthma, and arthritis. So perhaps it shouldn’t come as much of a surprise that depression is also caused by inflammation

The downside of this connection is that our modern diet and lifestyle are full of factors that provoke inflammation—and thus cause disease. The upside is that if we address these factors and reduce inflammation, we can prevent and even reverse the chronic, inflammatory diseases that have become such a fixture of industrial civilization.

According to the authors of the Berk et al review paper I referenced above, the following are the most common causes of inflammation that are associated with depression. 

1. Diet

There are several problems with the modern diet. It is high in foods that provoke inflammation, such as refined flour, excess sugar, oxidized (rancid) fats, trans fats, and a wide range of chemicals and preservatives. And it is low in foods that reduce inflammation, like long-chain omega-3 fats, fermented foods, and fermentable fiber. Numerous studies have associated the Western diet with major depressive disorder. (13)

2. Obesity

One of the most harmful consequences of the modern diet has been the dramatic increase in obesity. Obesity is an inflammatory state. Studies have shown higher levels of inflammatory cytokines in obese people, and weight loss is associated with a decrease in those cytokines. (14) Obesity is closely linked with depression, and while that relationship is likely multi-factorial and complex, inflammation appears to play a significant role. (15)

3. Gut Health

Disruptions in the gut microbiome and leaky gut (i.e. intestinal permeability) have both been shown to contribute to inflammation and correlate with depression. For example, a leaky gut permits endotoxins called lipopolysaccharide (LPS) to escape the gut and enter the bloodstream, where they provoke the release of inflammatory cytokines such as TNF-α, IL-1 and COX-2. (16) And numerous studies have linked unfavorable changes to the bacteria inhabiting our gut with major depressive disorder. (17

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4. Stress

Stress may be one of the most obvious causes of depression, but the link between stress and inflammation is less well-known. Research has shown that psychosocial stress stimulates the pro-inflammatory cytokine network, including increases in TNF-α and IL-1. (18) These increases in inflammatory cytokines are in turn closely related to depressive symptoms, as described above. 

5. Lack of Physical Activity

There’s a huge amount of evidence indicating that exercise is an effective treatment for depression—in many cases as effective or more so than antidepressant drugs. It has also been shown to prevent depression in healthy people with no pre-existing symptoms. (19) Interestingly enough, while exercise initially produces the same inflammatory cytokines that are associated with depression, that is quickly followed by induction of anti-inflammatory substances. (20) This is known as a hormetic effect, where an initial stressor provokes a compensatory response in the body that has positive, long-term consequences. 

6. Sleep Deprivation

Chronic sleep loss has been shown to increase inflammatory markers even in people that are otherwise healthy. (21) And although temporary sleep deprivation has been used to therapeutically improve depression, chronic sleep loss is a well-known contributing factor to developing depression in the first place. (22

7. Chronic Infection

Chronic infections produce ongoing inflammation, so it’s no surprise to see that depression is associated with Toxoplasma gondii, West Nile virus, Clostridium difficile, and other pathogens. (23, 24, 25

8. Dental Caries and Periodontal Disease

Dental caries and periodontal disease are another source of chronic inflammation, and thus a potential cause of depression. According to one large study of over 80,000 adults, researchers found that people with depression were more likely to have tooth loss even after controlling for several demographic and health factors. (26

9. Vitamin D Deficiency

Low levels of vitamin D are common in Western populations, and there is growing evidence linking vitamin D deficiency to depression. Vitamin D modulates immune responses to infection, including reducing inflammatory markers like TNF-α and IL-1 that are associated with depression. (27) Supplementation with vitamin D to normalize serum 25D levels has been shown to to reduce inflammatory markers in some, but not all cases. (28)

The Biggest Problem with the Chemical Imbalance Theory

The early 1980s discovery that inflammatory cytokines produce all of the characteristic signs and symptoms of depression should have made a big splash. For the first time ever, scientists had discovered a class of molecules that were tightly and consistently associated with depression, and, when administered to healthy volunteers, produced all of the symptoms necessary for the diagnosis of depression. 

Unfortunately, the “chemical imbalance” theory continues to be the dominant paradigm for understanding depression nearly 30 years after this profound discovery, despite the weak correlation between serotonin, norepinephrine, and dopamine and depressive symptoms. There are probably several reasons for this—and you’d be correct if you guessed that some of them are financial—but I’ll leave that discussion for another time.

The significance of this finding is huge—both for patients and clinicians. It shifts our focus from viewing depression as being a disease caused by a chemical imbalance, which often requires medication to correct, to being a symptom of a deeper, underlying problem. It also leads to entirely new avenues of treatment—many of them more effective and safer than antidepressant drugs.

Understanding the physical roots of depression can have a profound effect on people who are suffering from it. Although the stigma surrounding depression has decreased in recent years, many who are depressed still carry the burden of thinking that there’s something wrong with them, and the depression they experience is “their fault.” When my patients with depression learn that theres an underlying physiological cause of their symptoms, they often feel a tremendous sense of relief and empowerment. Whats more, when we address this underlying cause, their mood improves dramatically and they quickly realize that the self-judgment and shame they felt about being depressed was misplaced and unwarranted.  

I don’t mean to suggest that emotional and psychological factors don’t play an important role in depression. In many cases they do, and I’ve written on that topic before. However, the assumption in mainstream medicine that depression is exclusively caused by those factors is obviously not true, and too often these other potential underlying causes go unexplored. The doctor prescribes an antidepressant, the patient takes it, and thats the end of the discussion.

What to Do If You’re Suffering from Depression

With this in mind, what can you do if you’re suffering from depression? Follow these two steps:

1. Adopt an Anti-Inflammatory Diet and Lifestyle

This means eating a nutrient-dense, whole foods diet, getting enough sleep, managing stress, engaging in appropriate (not too little or too much) physical activity, and nourishing your gut. For more on how to do this, see my book, The Paleo Cure.

2. Investigate Other Underlying Causes of Inflammation

On your own or with the help of a good Functional Medicine practitioner, explore other possible causes of inflammation that could be contributing to depression. These include gut issues (SIBO, leaky gut, dysbiosis, infections, etc.), chronic infections (viral, bacterial, fungal), low vitamin D levels, dental caries and periodontal disease, exposure to heavy metals and mold or other biotoxins, obstructive sleep apnea, and more.

Now I’d like to hear from you. Were you aware of the link between depression and inflammation? If not, how has learning about it changed your view of depression? Have you experienced an improvement in depressive symptoms after implementing an anti-inflammatory diet and lifestyle? Let me know in the comments section.

369 Comments

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  1. I was reading some articles about this magic truffles and shrooms before engaging my self for the first time. Like this one from https://www.trufflemagic.com/blog/magic-mushrooms-illness-and-anxiety/ .They say that it has a very potent effect on the brain and hallucination. Unlike marijuana does it have any medical use? In one article that I’ve read magic truffles or shrooms compaired to synthetic drugs are very alarming. Also magic mushroom are use on reducing the symptoms of depression, obsessive-compulsive disorder and anxiety. It can also help people to quit smoking and alcohol addiction.

    • It’s interesting to note that a known halucinogen, ketamine, is now being investigated to break therapy resistence in Prof Schoevers research group in Groningen, The Nls. For those who don’t want to part from their AD meds.

  2. Hi All, I just want to ask if anyone ever tried using medical cannabis as an alternative meds? I have read many articles about medical marijuana and how it can help you in terms of chronic pain, bone injuries, eating disorder/anorexia, anxiety disorders and panic attacks, inflammation, even cancer and a lot more. Like this article about a marijuana strain from:http://www.ilovegrowingmarijuana.com/alaska/ . Cbd and thc are also new to me and I don’t even smoke. If this is true I cant find any solid conclusive evidence that speaks to its efficacy. Any personal experience or testimonial would be highly appreciated. Thanks

  3. We have great experience with Solaray’s Special Formula Turmeric and Pharma Nord’s SelenoPrecise. Both are great anti-inflammatory tools. Will help with anything from oxidative stress, arthritis and a number of inflammation-related issues, including overuse injuries and even hypothyroidism (SelenoPrecise).

  4. The difference between depression and inflammation or fatigue is condition of adrenals and levels of cortisol. Depressed patients suffer enlarged adrenals that over-produce cortisol and cause weight gain. Inflamed patients with fatigue suffer shriveled adrenals that produce little or no cortisol. Inflamed, fatigued patients lose weight easily and exhibit signs of all hormoen deficicency: thyroid underfunction, pituitary dysfunction, adrenal deficiency, sleep and metabolism hormone imbalance. Anyone who measures just one set of hormones without blood-testing or ultra-sound testing for all hormones is a charlatan. Should not be treating inflamed, fatigued patients at all. Psychiatry has no place in treating Chronic Fatigue Syndrome.

  5. Another perspective from someone who is daily helping people with depression is that depression is when you turn your anger inward towards yourself. At the same time you cover that with tears. So the task with someone who is depressive is to get to the anger and find healthy ways of expressing it.

    • It’s a little scary you’re helping so many people with depression. Not only is the idea that depression is anger inward ARCHAIC (in use by EARLY psychoanalysts or ones today with little experience) and created by Freud, there has been no convincing evidence for it. As someone who is healing (quite successfully) from depression, you really need experience and properly taught before dealing with depressed people. The last thing anyone, especially depressed people, need is a focus on “expending emotions”. A way, way more healthy, realistic and working approach is to know and understand how thoughts and emotions work in tandem. For anyone dealing with *mental* depression, this article will somewhat apply to you, but you’re much better off looking into Dr. David D Burns work and Martin Seligman. For those with the more physical “depression”, this article will be more applicable to you, and I would suggest also looking at your calorie count and making sure that not only are you eating foods healthy for YOUR body, but also ENOUGH.

  6. My 8-year old daughter recently started having daily stomach aches and a little depression. I believe they are connected and are related to inflammation, as she comes from a long line of inflammatory diseases (including depression and other auto-immune disorders). However, she eats gluten free and breakfast and lunch and paleo at dinner. Takes omega 3, probiotics and vitamins 5-6 days/wk and does not eat a lot of sugar. So I am wondering where to go from here. Obviously breakfast and lunch could be improved, maybe a stronger probiotic, but what else can I do?

  7. Thank you for this!! I first noticed my health was deteriorating iat Christmas 2015, I had already eliminated dairy & gluten in June 2015, I got ill in Africa in 2014 and on returning home my doctor asked why I needed to repeat blood tests and said “I wish I cod close weight like you” I was skeletal, I hadnt eaten in 9 days, ot took me 3days to travel from the Sahara to sebuta the spanish territory where I ended up in hospotal with dehydration, kidney issies and goodness knows what, I was given 9 different drips!! My gut has bee
    n bad since that but I kept eating and dealing with more regular stomach cramps, bloating, I was already diagnosed with IBS years previously by a professor.
    So in Dec I was getting more and more ill, I started working at a school where I would pick up every cough and cold feom the children, I felt like I had no immunity and I was constantly feeling ran down, up until then I was eating well and at a healthy weight. The more the IBS symptoms happened the kore I started eliminating food to find the cause or trigger, but with zero help from the gp I continued to cut foods, my doc tested for allergies and didnt believe Iin IBS and offered me antidepressants. I have worked out most days since I was 15, then 28, I didnt want meds I wanted to find the reasons why! I saw another doc who advised me to take buscapan… she didnt listen or understand why I wanted to eliminate foods that affected me rather than mask the symptoms. I went back to the second gp who by now I had lost a lot of weight.. he said because now I had anxiety towards food and had eliminated a whole range of stuff that he will only presfribe antidepressants to surpress my anxiety to allow me to eat more. I saw a CBT therapist, who worked with the GP who then started telling me at each session I needed antidepressants. . I bought a book on gut health and learnt that you are able to test gut bacteria by the american gut. (Im still waiting for the results) I decided to try on my own, I started eating better and forcing myself to go for a bike ride, a bit scary cause I was so underweight, ive now gone private for a full GI test to find the imbalances and issues caused in my gut and will work with a private nutritionist to work out a protocol of supplements, pre/pro biotics, but I have had to go through deep dark depression and suicidal thoughts due to the lack of support! Private healthcare will cost over £1000 (uk) but at least I will learn where and what the inflamation is

    • I can relate Kayleigh! Long ago, I came back from Puerto Vallarta, Mexico with intestinal cramping and pains. This was back in 1989. I had no idea I had a parasite in the colon..this created the IBS and candida overgrowth…plus eventually a bacterial overgrowth.
      I have struggled most of my life with anxiety and depression all due to not being breast fed and given numerous broad spectrum antibiotics and never told to take probiotics.
      You have a bacterial overgrowth, so I hope that you can get this diagnosed by a Gastroenterologist first, then you need to take antibiotics to kill off the bad bacteria, then you need to implement the good guys (bacteria) back into the digestive tract. Otherwise, you’ll end up with heartburn or barrett’s esophagus from bad bacteria relocating from the colon into the small intestines. You will need a Functional/Integrative Medicine MD that specializes in Gastroenterology that can help to get back onto the road of life.
      Unfortunately, for me, I have mold that spread from the digestive tract into my tissues, because the candida and bacterial overgrowth weren’t treated properly and timely, so I am suffering with mold in my arms, legs, back, kidneys, liver, bladder. It loves fats and metals…it has been quite a journey for me. Please get help right away….I wish that someone could have helped me along the way long ago. Can’t go back!
      Good Luck to you…you have quite a support network here.

      • Ann, So sorry re what you have been through. Just wanted to mention that I breast fed my older son for 6 mos., but he has struggled w/ depression for years. (I do agree that breast feeding is important for many reasons). He wasn’t on antibiotics very often as a child, but I did know to put him on probiotics during & after antibiotics. My point is that depression is complex & not necessarily caused by what we may think. Best anti-depressive results for everyone in my family have been by adopting an Ancestral (Paleo) diet and exercise. C. Kresser has also written more recently about the most common micronutrient…deficiencies Including magnesium) that can contribute to depression. My favorite new book is ‘Paleo Principles’ (late 2017) by Sarah Ballantyne, PhD. It is the most comprehensive Paleo book written that also provides the Science that supports the paleo diet & lifestyle. (It isn’t a book about depression, though it is addressed under mental health: 1-2 grams daily of omega 3’s help depression in multiple studies. Also, low levels of the following are linked to depression: Vitamin D, B6, B9, B12, Zinc, & certain amino acids. These can all be corrected. Of course, many studies show exercise helps. Dr. Ballantyne states exercising outdoors w/ exposure to sunlight may be more beneficial to mental health than exercising indoors. (Brisk 20 min. walk outside w/ increased light exposure, 5 days per week). Yes, you can definitely move forward!

    • Well done love n you keep going, no doubt you will get much better as you heal your gut. Including bone broth in your diet everyday will help with the gut healing, from clean grassfed or free range animals of course, cheap and wonderful. I use a pressure cooker to make mine and double or triple cook the bones replacing and saving the broth after the first cook and i get a very “jelly” broth from it and enough to last a week.
      God bless you!