For many people, depression and anxiety impact their life on a daily basis. Pharmaceutical options often provide much-needed relief for some, but others struggle with what is often labeled ‘treatment-resistant depression’. Finding your underlying physical cause of depression or anxiety may lead you to the solutions that are right for you.
Chronically elevated inflammation causes depression and anxiety, for some people, and genetic variants impact your risk of chronic inflammation.
This article explains why inflammation causes depression and how your genetic variants in inflammatory genes may play a role in depression or anxiety. We will end with possible solutions to target specific genetic pathways of inflammation.
Depression and Anxiety: Inflammation as a root cause
Research over the past two decades clearly shows a causal link between increased inflammatory markers and depression.
Inflammation may be a root cause of depression — for some people.
Theories on depression and anxiety change over the years. Researchers think that depression, anxiety, and mood issues can have multiple causes. For a good percentage of people with mood disorders, though, addressing inflammation as an underlying factor helps to resolve depression or anxiety.[ref][ref]
Inflammation-driven depression is characterized by:[ref]
- sleep problems
- tiredness, lack of energy
- changes in appetite
While these inflammation-driven symptoms are statistically significant in research studies, they are really general and seem like they could apply to pretty much anyone with mood issues (or all of us at one time or another)…
Cause or effect? Research shows a significant increase in inflammatory cytokine levels in some depression patients. This is interesting, but it doesn’t tell us whether depression causes inflammation – or if inflammation causes depression. Or if both simply exist together.[ref]
So how can we narrow it down? You probably know where I’m headed here.
Genetics: One way to determine if inflammation is a root cause of depression is to look at the genetic variants that increase susceptibility to depression or anxiety. Sure enough, research shows a bunch of genetic risk factors for mood disorders are in inflammation-related genes.[ref] Deleting those inflammation genes causes animals to be resistant to stress-induced depression.[ref]
Other ways of determining causality: Animal models of depression let researchers experiment to determine causality. Increasing inflammatory cytokines clearly causes depression and anxiety symptoms in animals, and decreasing the inflammation takes away the symptoms.[ref] Deleting certain inflammation genes causes animals to be resistant to stress-induced depression.[ref] Additionally, human studies show drugs that decrease inflammation significantly improve depression – in some people.[ref]
Disclaimer: This article is a presentation of the research on depression, anxiety, and inflammation. It is not to be taken as medical advice. If you are under the care of a physician for a mood disorder, please talk with your provider for medical advice.
Inflammatory cytokines cause behavior changes:
Behavior changes when you are getting sick — you’re tired, irritable, and don’t want to interact with people…If you have kids, you learn to spot these signs of fighting off an illness very quickly. Even in pets, you will see that they withdraw, sleep, and avoid others when they are sick. Appetite changes and often they are hyper-vigilant as well.
Researchers call this ‘sickness behavior’, and seems as something apparent across all species of animals.
Sickness behavior makes complete sense evolutionarily when you think about it. The best way not to infect your family (herd, pack, tribe, flock, group) is to go and curl up in a corner and avoid everyone.
We have always known that illness causes behavior changes, but the connection between psychiatric illness and inflammatory response was made crystal clear in the 1980s. Interferon-alpha, an inflammatory cytokine that fights viruses, was first used in the 80s as a treatment for chronic hepatitis. Some patients reacted to the interferon-alpha with psychiatric side effects including depression, emotional instability, paranoia, agitation, and suicidal potential. These side effects occurred in patients on the highest doses of interferon-alpha, and reducing the dose took away the psychiatric problems.[ref][ref][ref]
5 common causes of increased inflammation:
While this is a huge topic, when it comes to inflammation and depression, there are a couple of key lifestyle factors that may come into play and explain why depression and anxiety are so prevalent today. The following four factors are common causes of elevated cytokines (inflammatory molecules).
#1 Gut dysbiosis and increased permeability: Your intestinal barrier keeps the microbes in your gut separate from the rest of your body. Bacteria can make you sick, but the microbes in your gut microbiome are also essential for good health. The difference between good gut microbes and getting sick is the barrier that keeps the microbes in the right place.
Lining your intestines is a mucosal barrier that keeps the gut microbes away from the epithelial cell wall. Those epithelial cells also keep out microbes by being tightly joined together. Reducing the mucosal barrier and/or loosening the tight junctions in your intestinal barrier can increase the number of microbes that your body needs to fight off.
One study on patients with major depressive disorder showed that patients have higher than average activity of the inflammatory markers for dealing with bacteria from the gut.[ref]
What can cause gut dysbiosis and increased intestinal permeability? A diet that includes a lot of junk food. (read about emulsifiers, food additives, and inflammation)
#2 Autoimmune diseases and allergies: Many autoimmune diseases including lupus, multiple sclerosis, psoriasis, and rheumatoid arthritis have links to an increase in inflammation. People with these autoimmune issues are also at an increased risk of depression. Allergies and asthma also have links to an increased risk of depression. For example, a meta-analysis calculated that the prevalence of depression in people with rheumatoid arthritis is ~39%.[ref][ref][ref][ref][ref][ref]
#3 Stress: The body undergoes a series of physical changes when stressed. Major life events such as losing a job, death of a loved one, divorce, or being locked down for a pandemic cause stress in the body. While it may be unsurprising that these events have links to depression, the physical cause of behavior changes may be due to an increase in inflammatory cytokines. For our ancestors, the stress response was often due to physical events such as an attack by a wild animal. When the stress response initiates, pro-inflammatory cytokines upregulate to enhance wound healing and improve physical recovery. So, when a boss yells at you or you become the target of negative tweets, the body’s stress response still causes an increase in pro-inflammatory cytokines, even if no physical wound exists.[ref]
#4 Omega 6: Omega 3 ratio: Another source of increased overall inflammation is consuming a higher ratio of omega 6 to omega 3 fats. Omega 6 fats are found in oils such as soybean, corn, vegetable, sunflower, and other seed oils. Our modern diet has had a huge shift in the amount of omega 6 fats we consume. It turns out that while omega 6 fats may be good in small amounts, this dietary shift to a lot of omega 6 oils causes increases overall inflammation.[ref]
Omega 3 fats are found in foods like fish and seafood. Higher amounts of omega 3 fats in the diet are usually anti-inflammatory. In our modern diet, though, we are getting a ton of omega 6 fats in fried foods, salad dressings, mayonnaise, chips, crackers, cookies, bread, etc.
#5 Obesity: Higher overall inflammation goes hand-in-hand with weight gain. Adipose tissue (fat) gives off inflammatory cytokines, increasing the overall burden of inflammation. People who are overweight and have depression also have higher inflammatory markers, on average, than normal-weight people with depression.[ref]
One study reports that severely obese people (BMI ≥ 40 kg/m2), are at a much higher risk of depression than non-obese people. It concludes: “The association between adiposity, systemic inflammation, and neuropsychiatric alterations supports the contribution of adiposity-related inflammatory processes to neuropsychiatric comorbidities in obesity.”[ref]
Why does inflammation affect the brain and mood?
Okay, so there are a number of ways that the body can have elevated inflammatory cytokines. But what does this have to do with the brain and mood?
There are a couple of ways that inflammation directly affects the brain:
Increased peripheral inflammatory cytokines directly increase the permeability of the blood-brain barrier. This allows the inflammatory cytokines to enter the brain, triggering functional changes in certain brain regions.
- Higher levels of TNF-alpha in the hippocampus and striatum have links to anxiety and depression in animal studies. TNF-alpha causes the release of glutamate in the hippocampus, causing depression behavior in animals.
- IL-1B decreases neurogenesis via the kynurenine pathway.[ref]
- Inflammation decreases the synthesis of neurotransmitters through the disruption of BH4.
- TNF-alpha and IL-1 increase the reuptake of serotonin, leaving less serotonin available.[ref]
Generally, increased inflammation shifts the body from converting tryptophan into serotonin and instead produces kynurenine, which has a neurotoxic metabolite called quinolinic acid.[ref] (We’ll come back to this in more detail below…)
Inflammatory cytokines can disrupt the production of BH4 (tetrahydrobiopterin), which is needed for the production of dopamine and serotonin.[ref]
Which inflammatory cytokines are linked to depression or anxiety?
Research shows that some people with depression have higher levels of TNFα, IL-6, IL-13, IL-18, IL-12, and IL-1RA.[ref] The “IL” stands for interleukin, which is a whole family of inflammatory molecules.
Studies also show that TNF-alpha, IL-6, and C-reactive protein have links to anxiety disorder in some people.[ref]
Studies on PTSD, which is grouped in with anxiety disorders, show that trauma elevates IL-1B, Il-6, TNF-alpha, and C-reactive protein. Generalized anxiety disorder (GAD) has links to increased levels of TNF-alpha and CRP.[ref]
In fact, to create an animal model of anxiety or depression, researchers subject the animals to mild unpredictable stress (tilting the cage, intermittent light, noise).
Brain imaging studies point to higher levels of CRP (C-reactive protein), which is a general marker of inflammation, being predictive of psychosis. Additionally, increasing IL-10, which is anti-inflammatory, is linked with greater symptom improvement in depression.[ref]
Researchers have also narrowed down that stress-induced depression is more likely to have pro-inflammatory cytokines as a cause.[ref]
Diving deeper into TNF-alpha
TNF-alpha (tumor necrosis factor alpha) is one of the body’s primary inflammatory cytokines. Its production occurs by activated immune cells, such as macrophages, mast cells, B cells, and lymphocytes. It can also be produced in other cells, such as smooth muscle cells, in response to an injury. Adipose tissue (fat tissue) also secretes TNF-alpha.[ref][ref]
When TNF-alpha elevates in depressed people, blocking TNF-alpha can ameliorate depressive symptoms. A 2008 genome-wide association study found that a TNF genetic variant increases the risk of depression.[ref]
People with rheumatoid arthritis are often given drugs to decrease TNF-alpha. The anti-TNF drugs decrease the frequency of anxiety disorder and depression in people with RA.[ref]
Researchers think that inflammation, specifically the high TNF-alpha levels, impacts the HPA axis and elevates cortisol as well. HPA axis dysfunction is strongly linked to depression. Additionally, higher TNF-alpha levels can cause increased uptake of serotonin into cells, causing depressive symptoms.[ref]
If you have ever been told ‘it’s all in your head”, that literally could be true for some people with TNF-alpha variants. A brain-imaging study found that a TNF-alpha genetic variant associated with higher TNF levels was linked to anatomical brain changes in people with major depressive disorder.[ref]
Encoded by the IL6 gene, interleukin-6 (IL-6) is another inflammatory cytokine shown to be consistently elevated in depression.
Animal studies show that inducing an elevated level of IL-6 causes depressive behavior. This can be done using stressful situations or by injecting lipopolysaccharide, an endotoxin from bacteria.[ref] Animals bred to not produce IL-6 are resistant to despair behavior usually induced by stress.[ref]
Genetic studies in humans also link higher levels of IL-6, stressful life events, and an increased risk of depression.[ref]
Interleukin-6 is one of the major cytokines released by immune cells in response to a pathogen or toxin. Chronic or acute stress can also cause the release of IL-6. In the brain, increased levels of IL-6 cause decreased neurotransmitters including serotonin. Additionally, IL-6 causes a decrease in brain-derived neurotrophic factor (BDNF) and impacts the HPA axis. All of these pathways are implicated in mood disorders.[ref]
IL-6 also impacts the amygdala’s response to socially threatening situations linking the increased immune response to greater social disconnect, fatigue, and cognitive disturbance. [ref]
Tryptophan is an essential amino acid found in many foods that contain protein.
In the body, tryptophan can go down two different pathways:
- it can be used to make serotonin and melatonin
- it can convert into kynurenine, and then into several other metabolites
Kynurenine can form quinolinic acid, which is a neurotoxin. This is part of the pathway, though, that eventually produces niacin (vitamin B3).
Tryptophan metabolism needs to balance out. The body and brain need serotonin as an important neurotransmitter. Melatonin, produced from serotonin, is an integral part of the circadian system as well as a vital anti-inflammatory molecule.
Increased inflammation causes a shift from tryptophan being used for serotonin to being used for the kynurenine pathway. This causes a double whammy – lower serotonin and higher quinolinic acid. Quinolinic acid acts on NMDA receptors and too much can kill off brain cells. Studies show that depression scores correlate to higher quinolinic acid in the blood, and postmortem studies show more cells in the brain producing quinolinic acid in suicide victims.[ref]
Hep c patients treated with interferon-alpha have depression, higher kynurenine metabolites.[ref]
Another reason tryptophan metabolism could tilt more towards kynurenine is when the body is lacking in niacin. Providing enough niacin through the diet is important here.
Genetic variants in the IDO1 gene also can skew the body towards producing kynurenine instead of serotonin. (Read more about tryptophan, kynurenine, serotonin, and genetics.)
Allergies, COVID-19, and depression and anxiety:
A study of the psychological impact of COVID-19 revealed that people with allergies, which chronically raise inflammatory cytokine levels, were more likely to have PTSD and depression after COVID-19.[ref]
Another study found that people who had systemically elevated inflammation after COVID-19 illness were at an increased risk of depression, anxiety, or PTSD.[ref]
While there is a lot of swirl and research about long-haul COVID symptoms, previous research on other viruses that remain active or reactivate (e.g. Epstein-Barr virus, cytomegalovirus) also has shown the link between infection, inflammatory cytokines, and depression.[ref]
Genetic Variants Linking Inflammation and Depression or Anxiety
Click for Member’s Quick Overview
|Gene||RS ID||Risk Allele||YOU||Notes about the Risk Allele:|
|TNF||rs1800629||A||—||Increased TNF-alpha, increased risk of suicide in depression|
|IL6||rs1800796||G||—||GG: higher IL6, increased depression|
|IL6||rs1800795||C||—||CC: increased risk of depression with stressful life events|
|IL6||rs1800797||A||—||higher IL6, increased depression risk|
|IL6R||rs4129267||C||—||CC: increased risk of anxiety, depression|
|IL1B||rs16944||G||—||GG: increased IL1B|
|IDO1||rs9657182||C||—||higher depression risk (due to interferon or inflammation)|
|KMO||rs1053230||C||—||CC: more common genotype, but higher risk of depression that T allele|
TNF gene: encodes the TNF-alpha cytokine
Check your genetic data for rs1800629 -308A/G (23andMe v4, v5; AncestryDNA):
- A/A: Higher TNF-alpha levels. [ref][ref][ref][ref], increased risk of suicide in depression[ref]
- A/G: somewhat higher TNF-alpha levels, increased risk of suicide with depression
- G/G: typical,
Members: Your genotype for rs1800629 is —.
IL6 gene: interleukin 6 (IL-6) is an inflammatory molecule that can be produced at the site of inflammation by macrophages
Check your genetic data for rs1800796 (23andMe v4, v5; AncestryDNA):
- G/G: higher IL-6; increase depression in response to interferon-alpha treatment[ref]
- C/G: typical
- C/C: typical
Members: Your genotype for rs1800796 is —.
Check your genetic data for rs1800795 (23andMe v4, v5; AncestryDNA):
- G/G: typical risk of depression
- C/G: typical risk of depression
- C/C: higher risk of depression with stressful life events[ref][ref]
Members: Your genotype for rs1800795 is —.
Check your genetic data for rs1800797 (23andMe v4, v5; AncestryDNA):
- A/A:: higher IL-6; increase depression risk (Chinese populations)[ref]
- A/G: increase depression risk (Chinese populations)[ref]
- G/G: typical
Members: Your genotype for rs1800797 is —.
IL6R gene: receptor for interleukin-6 (IL-6)
Check your genetic data for rs4129267 (23andMe v4, v5; AncestryDNA):
- C/C: increased risk of anxiety, depression[ref][ref]
- C/T: typical risk (or decreased risk when compared to C/C)
- T/T: typical risk (or decreased risk when compared to C/C)
Note that this variant is linked to rs2228145.
Members: Your genotype for rs4129267 is —.
IL1B gene: encodes the interleukin 1 beta cytokine
Check your genetic data for rs16944 (23andMe v4, v5):
- A/A: typical risk
- A/G: typical risk
- G/G: increased IL-1B, increased risk of depression with childhood maltreatment (women)[ref], earlier onset of geriatric depression[ref] more severe depression due to interpersonal stress[ref]
Members: Your genotype for rs16944 is —.
IDO1 gene: codes for the enzyme that converts tryptophan to kynurenine
Check your genetic data for rs9657182 (23andMe v5; AncestryDNA):
- C/C: more likely to have depression with IFN-alpha treatment[ref][ref]
- C/T: intermediate effect
- T/T: typical IDO1
Members: Your genotype for rs9657182 is —.
KMO gene: codes for the enzyme that converts kynurenine to 3-OH-kynurenine
Check your genetic data for rs1053230 (23andMe v4, v5; AncestryDNA):
- C/C: more common genotype, higher risk of depression[ref]
- C/T: increased 3-OH-kynurenine, decreased risk of bipolar with psychosis[ref]
- T/T: increased 3-OH-kynurenine, decreased risk of bipolar with psychosos[ref]
Members: Your genotype for rs1053230 is —.
Again, I would encourage you to talk with your health care provider about any supplements or changes – especially if you are on medications.
The lifehacks below deal with ways to suppress inflammatory cytokines, but the obvious solution is to take away the source of the inflammation, to begin with. Thus, these lifehacks may help in the immediate timeframe, but for a long-term solution, you need to figure out the source of your inflammation (e.g. obesity, stress, diet, gut dysbiosis).
You may find that multiple solutions together work best. For example, curcumin plus exercise plus an anti-inflammatory diet may be more effective than just popping a curcumin supplement.
Natural anti-inflammatory supplements:
Curcumin, a compound found in the spice turmeric, acts as an anti-inflammatory and decreases TNF-alpha and IL1B.[ref] Several good clinical trials have investigated the effect of curcumin on depression and anxiety. Overall, supplementation of curcumin is well tolerated and decreases both depression and anxiety scores.[ref]
Quercetin is another natural anti-inflammatory supplement that reduces TNF-alpha and other inflammatory cytokines. Animal studies show that quercetin is effective in reducing depression and anxiety behavior.[ref][ref] (Read more about quercetin including genetics of metabolism)
Aspirin is a COX-1 and COX-2 inhibitor, which reduces TNF-alpha, IL-6, and CRP – somewhat. Human studies on aspirin for depression have been small and inconclusive, but research does show that aspirin along with an SSRI shortened the time it took for the antidepressant to work.[ref]
Naproxen (Aleve) and ibuprofen (Advil) reduced depression scores in people who also had osteoarthritis.[ref] Studies on NSAIDs in people without an inflammatory condition show no results for depression.
Minocycline, a broad-spectrum antibiotic, easily crosses the blood-brain barrier. A recent clinical trial shows that it is effective as an adjunctive treatment along with immunomodulatory medications for treatment-resistant major depressive disorder.[ref]
Minocycline has also shown in animal studies to work on anxiety.[ref] A 2021 study showed that adding minocycline to antidepressant treatment in people with elevated C-reactive protein significantly reduced depression levels. The results showed that study participants with high IL-6 levels were much more likely to respond to minocycline.[ref]
Ketamine decreases IL-6 in depression in the prefrontal cortex and hippocampus.[ref]
Andrographolide, a component of the traditional Chinese medicine plant Andrographis, inhibits IL-6.[ref] Andrographis is readily available in health stores and online as a supplement.
In addition to responding to inflammation or stress, the body also shunts more tryptophan towards the kynurenine pathway when niacin is low.[ref] Additionally, magnesium is needed to convert quinolinic acid into niacin.
Omeprazole (Prilosec) inhibits the conversion of tryptophan to serotonin, and could thus cause increased kynurenine in addition to lower levels of serotonin. This seems to be dose-dependent, though. At higher doses, omeprazole also inhibits MAO-A, the enzyme that breaks down serotonin, and thus consequently increases brain serotonin.[ref]
Exercise – long term:
Physical activity has shown in a number of solid research studies to work as an alternative to antidepressants.[ref]
Specifically, exercise has shown to decrease depressive symptoms over a 12-week period in people who have high baseline TNF-alpha or IL-1B levels. The people in the clinical trial were previously unresponsive to SSRIs and the exercise was aerobic exercise such as treadmill or cycling. Also as an important note in this study is that depression scores continued to get better over the course of the 3-month long intervention. So this isn’t an instant cure-all, but rather something to stick with long-term.[ref]
Animal studies show that supplementing their normal diet with additional ascorbic acid (vitamin C) decreases anxiety and decreases brain levels of TNF-alpha.[ref] Foods that are high in vitamin C include orange juice, red peppers, strawberries, kiwifruit, and guava.
A healthy diet may help a lot in combatting depression. Decreasing your omega 6 to omega 3 ratio by cutting out junk food should help to reduce inflammation. Avoiding foods that you are allergic to or sensitive to can also help.
I don’t think there is a one-size-fits-all solution here. Rather, keep track of how different foods make you feel offers your best bet. In general, eating mostly fruits, vegetables, and high-quality meat is a good starting point for most people. But stressing yourself out over getting your diet perfect may backfire and increase overall stress and inflammation.
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