What is the link between inflammation and depression?
Updated: Feb 2, 2021
Key take home points:
Inflammation is part of our bodies immune response when an injury occurs and involves the release of inflammatory markers.
Inflammation has been found to be higher in depressed people and can act as a risk factor for developing depression.
High levels of inflammatory markers can affect areas of the brain involved in feeling happy, motivated and anxious.
Doctors may be able to measure the levels of inflammatory markers to predict if a person will respond well to an anti-depressant drug.
What is inflammation?
Inflammation is a key part of our body’s immune system. Many different things can trigger inflammation, including pathogens, external injuries and exposure to chemicals or radiation [1]. When inflammation is triggered, the immune system recruits cells, proteins and tissues including the brain to mark the injury site. This causes an increased number of immune system cells in the blood. When inflammation occurs there may be several different immune cells involved. These cells release different substances, known as inflammatory markers. These markers work to increase blood flow to the injured site and make it easier for the immune cells to reach it.
How do the two link together?
There is growing evidence that inflammation can exacerbate or give rise to depression. Scientists have found that markers of inflammation are higher in people who suffer from depression compared to non-depressed people [2, 3]. However, it is important to note that depression is not an inflammatory disorder, as every patient with depression will not have inflammation.
Increased stress is often linked to low mood and depression and in mice, the more stressed the animal is, the higher the levels of inflammatory markers [4].
When inflammation occurs, and immune cells release pro-inflammatory markers these can give rise to changes within the body. These changes include a loss of appetite, sleep disturbances, loss of pleasure, cognitive impairment and suicidal thoughts [5]. In one study, cancer patients were treated with a drug to increase inflammation in their bodies. These patients suffered depression and experienced the symptoms listed above [6]. Other studies have shown that patients with higher inflammatory markers tend to be more depressed, and have often attempted suicide [7].
Markers of inflammation have been used to predict the severity of symptoms of depression. Last year, scientists studied depression in 166 twins over a period of 7 years. In this study it was found that the twin who had higher levels of inflammation was more likely to develop depression than the other twin [8].
Depression differs across each patient, and each persons struggle is different. It may be that a persons ability to cope with stressors or the sensitivity of their immune system might underlie these differences.
How does inflammation affect the brain?
The brain is very responsive to changes in the level of inflammatory markers. As discussed above, these changes can give rise to specific behaviours including fatigue, loss of pleasure and suicidal thoughts [5]. These arise through changes within the nerves in the brain.
A circuit of connecting nerves in the brain is called a neurocircuit. For neurocircuits to propagate their message through the circuit they use chemical messengers called neurotransmitters. Different neurocircuits are involved in controlling different parts of your behaviour, cognition and physical function.
In patients with increased inflammation, the neurocircuits in the brain associated with motivation, movement, arousal and anxiety are affected [9]. Changes in these behaviours are often linked to depression. Researchers have also found that increased inflammation can activate the circuits involved in feeling scared and threatened [10] and this may be why inflammation can increase suicidal thoughts in depressed patients.
Studies have also shown that inflammation can reduce the availability of monoamine neurotransmitters in the brain [9]. These include serotonin, dopamine and noradrenaline. This happens through increasing the number of pre-synaptic uptake pumps, which remove excess neurotransmitter molecules, and by reducing the levels of neurotransmitter precursors.
Can inflammation be used to predict response to antidepressants?
Differences in inflammation might explain why different people don’t respond the same to treatments. The levels of inflammatory markers may be able to predict a persons response to conventional antidepressant drugs, as well as newer drugs such as psychedelics [11].
Some researchers have found that elevated levels of inflammatory markers prior to treatment with antidepressants predicted a poor response to the drugs [12]. In one study, patients with high inflammatory markers were less likely to respond to selective serotonin reuptake inhibitor (SSRI) treatment [13]. The levels of inflammatory markers could be used in a clinical setting for doctors to predict whether a patient will respond to an anti-depressant drug.
Interestingly, the link between depression and inflammation seems strongest in people who do not respond well to current antidepressant treatments. These people are known as treatment-resistant. In these people, studies have found that there tends to be higher levels of inflammatory markers compared to patients who respond to treatments [3].
The greatest challenge is to figure out which inflammatory marker is the best at predicting a persons response to antidepressant drugs. The chosen marker also needs to be able to be easily measured by a doctor.
So what does this mean for treating depression?
Our understanding of the link between inflammation and depression is limited due to the small number of human studies. Researchers need to be able to pinpoint whether it is the innate or adaptive immune response playing a pivotal role in this inflammation.
Some data points towards the innate immune response, which involves monocytes and macrophages being recruited to the site of inflammation [14]. However, other studies report the adaptive immune system is the most active [11]. Once researchers understand which route is involved, this will help with the development of new anti-depressant drugs to target the immune system and prevent this inflammation to treat depression.
References:
1. InformedHealth.org. Cologne, Germany: Institute for Quality and Efficiency in Health Care; What is an inflammation? 2010 1 May 2020]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK279298/.
2. Haapakoski, R., et al., Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder. Brain Behav Immun, 2015. 49: p. 206-15.
3. Raison, C.L., et al., A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry, 2013. 70(1): p. 31-41.
4. Tianzhu, Z., Y. Shihai, and D. Juan, Antidepressant-like effects of cordycepin in a mice model of chronic unpredictable mild stress. Evid Based Complement Alternat Med, 2014. 2014: p. 438506.
5. Azab, M. The Brain on Fire: Depression and Inflammation. 2018 1 May 2020]; Available from: https://www.psychologytoday.com/gb/blog/neuroscience-in-everyday-life/201810/the-brain-fire-depression-and-inflammation.
6. Lotrich, F.E., et al., Depression following pegylated interferon-alpha: characteristics and vulnerability.J Psychosom Res, 2007. 63(2): p. 131-5.
7. Brundin, L., E.Y. Bryleva, and K. Thirtamara Rajamani, Role of Inflammation in Suicide: From Mechanisms to Treatment. Neuropsychopharmacology, 2017. 42(1): p. 271-283.
8. Huang, M., et al., Longitudinal association of inflammation with depressive symptoms: A 7-year cross-lagged twin difference study. Brain Behav Immun, 2019. 75: p. 200-207.
9. Miller, A.H., et al., Cytokine targets in the brain: impact on neurotransmitters and neurocircuits.Depress Anxiety, 2013. 30(4): p. 297-306.
10. Slavich, G.M., et al., Neural sensitivity to social rejection is associated with inflammatory responses to social stress. Proc Natl Acad Sci U S A, 2010. 107(33): p. 14817-22.
11. Miller, A.H. and C.L. Raison, The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol, 2016. 16(1): p. 22-34.
12. O'Brien, S.M., et al., Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J Psychiatr Res, 2007. 41(3-4): p. 326-31.
13. Rudolf Uher, M.D., Ph.D., et al., An Inflammatory Biomarker as a Differential Predictor of Outcome of Depression Treatment With Escitalopram and Nortriptyline. American Journal of Psychiatry, 2014. 171(12): p. 1278-1286.
14. Torres-Platas, S.G., et al., Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun, 2014. 42: p. 50-9.