Depression caused by inflammation and oxidation. Not a serotonin imbalance

Depression itself is not a disease, but a symptom of an underlying problem. A new theory called the “Immune Cytokine Model of Depression” holds that depression is a “multifaceted sign of chronic immune system activation,” inflammation. Depression may be a symptom of chronic inflammation. And 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—not a serotonin imbalance.

Researchers discovered in the early 1980s that inflammatory cytokines produce a wide variety of psychiatric and neurological symptoms that perfectly mirror the defining characteristics of depression. Cytokines have been shown to access the brain and interact with virtually every mechanism known to be involved in depression[1] including neurotransmitter metabolism, neuroendocrine function, and neural plasticity.

This is now supported by increasing lines of scientific evidence[2] including:

  • Depression is often present in acute, inflammatory illnesses.
  • Higher levels of inflammation increase the risk of developing depression.
  • Administering endotoxins that provoke inflammation in healthy people triggers classic depressive symptoms.
  • One-quarter of patients who take interferon, a medication used to treat hepatitis C that causes significant inflammation, develop major depression.
  • Up to 50% of patients who received the cytokine IFN-alpha therapy to help treat cancer or infectious diseases developed “clinically significant depression.”[3]
  • An experiment involving the administration of a Salmonella typhi vaccine to healthy individuals produced symptoms of fatigue, mental confusion, psychomotor slowing and a depressed mood.[4] These symptoms correlated with the increase in cytokine concentrations.
  • Remission of clinical depression is often associated with a normalization of inflammatory markers.
  • There is now a large body of literature regarding laboratory animals demonstrating that cytokines … can lead to a host of behavioural changes overlapping with those found in depression. These behavioral changes include decreased activity, cognitive dysfunction and altered sleep.[5]
  • All the activities associated with reducing the prevalence of depression and depression symptoms are anti-inflammatory. These include increased sunlight and time spent outside, exercise and physical activity, relaxation and meditation techniques, healthy eating as well as administering anti-inflammatory nutritionals.

There is further support from large epidemiological studies. A number of longitudinal studies have now shown that inflammation in early adulthood predicts depression at a later stage in life. In a large longitudinal study, the risk for depression and psychotic experiences in adolescence was almost two-fold higher in individuals with the highest compared to the lowest levels of inflammation as indicated by interleukin-6 (IL-6) levels in childhood. Children who were in the top third of IL-6 levels at the age of 9 years were 55% more likely to be diagnosed with depression at the age of 18 than those with the lowest childhood levels of IL-6. Children in the highest level of IL-6 levels at the age of 9 were also 81% more likely to report psychotic experiences at the age of 18.[6] A study of more than 73,000 men and women showed increasing inflammation levels were associated with increasing risk for psychological distress and depression. Increasing inflammation (CRP) levels were also associated with increasing risk for hospitalization with depression.[7]

In support of the inflammation depression link, recent studies have found a significant link between the dietary inflammatory index (DII) and risk of depression. In an Australian study of 6,438 middle-aged women, those with the most anti-inflammatory diet had an approximately 26% lower risk of developing depression compared with women with the most pro-inflammatory diet.[8] Similarly, a study in the UK examined the DII and recurrent depressive symptoms over five years in 3,178 middle-aged men and 1,068 women. Researchers found that for each increment of 1 level of DII score (increased inflammation), odds of depression increased by 66% in women, whereas in men the risk increased by only 12%.[9] In a study of 15,093 university graduates in Spain, those on the highest DII (strongly pro-inflammatory diet) had a 47% risk of depression compared with those in the bottom, with a significant dose-response relationship, which means as the diet became more inflammatory it increased the risk of depression. Further analysis also showed the association between DII (the inflammatory diet) and depression was stronger among participants older than 55 years, with an increased risk of 270% and those with cardiometabolic comorbidities (high blood pressure, diabetes, etc.) had an 80% increased risk of depression.[10] In a study of 43,685 women (aged 50–77) without depression at baseline, the risk of developing depression was 41% higher if they were on the highest compared to the lowest Dietary Inflammatory Index diet.[11]

Oxidative stress is closely related to the inflammatory pathway in particular. Pro-inflammatory cytokines are produced in reaction to oxidative stress and oxidative stress in turn amplifies the inflammatory response. High cortisol levels have been associated with increased levels of oxidative damage.[12] Depression has been associated with increased oxidative stress and increased severity of depression is associated with increased systemic oxidatively generated DNA and RNA damage.[13] Severe depression is associated with increased systemic oxidatively generated RNA damage, which may be an additional factor underlying the somatic morbidity and neurodegenerative features associated with depression. In a meta-analysis, 1,308 subjects depressed persons had increased oxidative stress and decreased anti-oxidant defences (as measured by 8-OHdG and F2-isoprostanes).[14] The results indicate that depression is associated with increased oxidative damage to DNA and lipids. The brain is particularly vulnerable to oxidative damage due to its high oxygen consumption and low antioxidant defences. Sustained oxidative brain damage during a depressive episode may make a sufferer prone to developing another depressive episode. Therefore, it has been hypothesized that exposure to oxidative stress could be an explanatory mechanism in the remitting and chronic course of depressive disorders.[15] There is also evidence from post-mortem studies suggesting that in depression oxidative stress is increased[16] and antioxidants are decreased[17] in the brain.

A study of 37 patients with bipolar disorder showed that bipolar disorder is associated with increased oxidatively generated damage to nucleosides, which could be contributing to the increased risk of medical disorders, shortened life expectancy, and the progressive course of illness observed in bipolar disorder.[18] Another study showed increased oxidative stress as indicated by increased nitric oxide (NO) and lipid peroxidation, measured by thiobarbituric acidic reactive substance (TBARS) assay in patients with bipolar disorder.[19]

There is evidence suggesting that antioxidants are decreased in depression, illustrated by lower antioxidant levels,[20] including carotenoids,[21] and antioxidant enzymes.[22] There is some evidence to suggest that antidepressants have antioxidant properties and may act through reducing pro-inflammatory cytokines and ROS production and improving levels of antioxidants such as superoxide dismutase.[23]


[1] Miller et al. 2009.

[2] Berk et al. 2011.

[3] Miller 2009.

[4] Brydon et al. 2008.

[5] Dantzer et al. 2008.

[6] JAMA Psychiatry 13, 2014.

[7] Wium-Anderson et al. 2013.

[8] Nitin Shivappa et al. 2016 British Journal of Nutrition.

[9] Akbaraly et al. Clinical Psychological Science 2016.

[10] Sanchez-Villegas A et al. British Journal of Nutrition 2015.

[11] Lucas et al. 2014.

[12] Joergensen et al. 2011.

[13] Jorgensen et al. 2013; Pandya et al. 2013.

[14] Black et al. 2014; Palta et al. 2014.

[15] Moylan et al. 2013.

[16] Wange et al. 2009; Michel et al. 2012.

[17] Gawryluk et al. 2011.

[18] Munkholm et al. 2015.

[19] Andreazza et al. 2008.

[20] Palta et al. 2014.

[21] Milaneschi et al. 2012.

[22] Sarandol et al. 2007.

[23] Khanzode et al. 2003; Lee et al. 2013.