Major depression is a common and sometimes fatal disorder that is a leading cause of disability worldwide. The prevalence of depression in chronically ill patients can be as high as 40% or more. However, depression often goes unrecognised in physically ill patients and thus this value may not be an accurate representation of reality. Recent studies have shown a link between chronic immune responses and the development/presence of major depression.

The Immune system’s link to the brain

The immune, neural and psychological systems all interact with one another. One of the major communication pathways between the brain and the immune system is the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system. This pathway mediates our immune response to psychological factors such as stress, anxiety and other emotions. This bidirectional relationship between the brain and the immune system has led to the question about the role of the immune system in neuropathological processes.

Our immune system acts as the sensory organ when our body is confronted with pathogens. The immune system alerts the brain, and the rest of the body, to the presence of these pathogens by generating an immune response. The cells responsible for our immunity (T cells, B cells and mast cells) release cytokines in response to activation. Cytokines, such as interleukins and interferons, are peptides (proteins) that orchestrate the immune response. They are released both in the periphery as well as the brain during immune stimulation, and can affect neural, neuroendocrine, and behavioural functions.

In addition to standard physiological responses that we’re all probably used to such as fever, activation of the HPA axis also produces some behavioural changes. At one point or another, most of us would have had experiences that are referred to as ‘sickness behaviour’. This behaviour is exhibited by physically ill people and can present as depressed mood, anorexia, weight loss, sleepiness and altered sleep patterns, fatigue and retardation of motor activity, reduced interest in the physical and social environment, and impaired cognitive abilities. This behavioural response is considered to be an adaptive response to aid the recovery process, rather than being caused by the illness itself. This is essentially why we don’t go out and stay in bed when we’re ill — thus speeding up our recovery!

So, how do cytokines affect our behaviour and how do they act?

They affect levels of important neurotransmitters

There are a couple of proposed mechanisms for this, so I’ll talk about the more widely explored ones. One of the main ways in which cytokines affect behaviour is modulating neurotransmitter activity. Neurotransmitters, such as serotonin, dopamine and acetylcholine are what permit neurons in our nervous system to communicate with one another. The levels of these neurotransmitters that need to be maintained for normal functioning are specific, and the balance delicate. Thus, when cytokines interfere with the normal functioning of certain neurotransmitters, we see behavioural alterations. For example, serotonin, which is a neurotransmitter critically involved in the pathophysiology of depression, is affected by the presence of cytokines.

Synthesis of serotonin is largely dependent on the availability of its precursor, Tryptophan (an amino acid). Cytokines activate another enzyme (IDO) that converts tryptophan into something else (quinolinic acid). This reduces the availability of tryptophan, thus reducing serotonin synthesis. The activation of the IDO pathway and production of its byproducts have additional consequences on the brain — the byproducts have been implicated in several psychiatric (e.g anxiety) and neurodegenerative disorders (e.g Parkinson’s). In addition, the byproducts affect the production of reactive oxygen species (ROS) and the metabolism of monoamine oxidase (MAO) — which have also been linked to depression.

In addition to this, cytokines also activate another pathway that reduces the production of dopamine and results in the production of neopterin instead — again having important behavioural consequences, for dopamine is our reward signal and important for positivity. Dopamine is what makes you feel good when you eat chocolate, drink beer, go out with friends and so much else!

Prolonged HPA axis hyperactivity

First, what is the HPA axis? It is a major neuroendocrine system that regulates our response to factors such as stress, and regulates many body processes, including digestion, the immune system, mood and emotions. Hyperactivity of the HPA axis has also be associated with depression.

There is bidirectional communication between the HPA axis and the immune system. Cytokines activate the HPA axis and thus lead to the release of cortisol, the stress hormone, which ordinarily suppresses the immune response. Cortisol also inhibits its own release and thus the body is able to maintain a stable immune response through a tightly regulated feedback inhibition system. This regulation mechanism seems to be dysfunctional in depressive disorders and is thought to occur because of cytokine mediated receptor resistance to cortisol, thus impairing feedback inhibition. This essentially means that cytokines make cortisol unable to act on the receptors that would inhibit its release. Long story short — the HPA axis is hyperactive because of cytokines, leading to a chronic stress response because cytokines impair the body’s ability to regulate it — thus leading to depressive symptoms.

During chronic infections and other chronic medical conditions associated with intense immune activation, the sickness behaviour syndrome can develop into a depressive episode.

Studies have found that certain cancer and hepatitis c therapies, which often involve the use of cytokines, have been associated with the development of flu-like depressive symptoms. The causal role of the cytokines has been established by the fact that the depressive symptoms appear almost immediately after cytokine administration and disappear shortly after cytokine treatment is terminated.

Using lipopolysachharide (LPS) administration (the major cell-wall component of some bacteria), one can activate the immune response and induce a fever in individuals. It is a very safe way to study the immune response because it doesn’t induce any physical sickness. A blind study found that LPS administration led to the development of depressive symptoms when compared to controls (that were injected with saline). Positive correlations were found between cytokine secretion and LPS-induced depressed mood and anxiety. This essentially means that the depressive symptoms were associated with the immune response and not physical illness (because there wasn’t any!).

The use of antidepressants

Antidepressant medication has been used successfully in treating depressive symptoms associated with medical illness. The use of antidepressants before the administration of cytokine therapy prevented the development of depression in a significant number of patients. The manner in which antidepressants do this is poorly understood, however, there are a few of proposed mechanisms that are outside the purview of this article. Briefly however, they are thought to change neurotransmitter levels, restore negative feedback of the HPA axis and inhibit cytokine-induced IDO activation.

Finally, why do some people develop depression while others don’t?

Again, this is poorly understood and our knowledge is rather limited. Depression can be considered a genetic disorder and the genetics of the immune system in relation to depression has also been studied. Certain changes in the cytokines themselves (because of genes) may make an individual more vulnerable to developing depression.

Are we sure that cytokines play a causal role in the pathogenesis of depression?

Currently, even though there is substantial evidence in support of the cytokine hypothesis of depression, the exact role of cytokines in depressive symptoms hasn’t been understood yet. The question whether cytokines are causally involved in depression so far remains to be solved. It is also important to understand that depression isn’t one single type of disorder, it is extremely heterogenous. This implies that the cause and manifestation of the illness could both be different for different individuals and shouldn’t be studied as one.

References:

Raison, C. L., Capuron, L., & Miller, A. H. (2006). Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends in Immunology, 27(1), 24–31. https://doi.org/10.1016/j.it.2005.11.006

Schiepers, O. J. G., Wichers, M. C., & Maes, M. (2005). Cytokines and major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 29(2), 201–217. https://doi.org/10.1016/j.pnpbp.2004.11.003

Yirmiya, R. (2000). Depression in medical illness: the role of the immune system. The Western Journal of Medicine, 173(5), 333–6. https://doi.org/10.1136/ewjm.173.5.333