Depression from an immunological perspective

Symptoms of depression. Source: OCD-UK

Major depressive disorders (MDD, more commonly known as simply “depression”) is a psychological disorder characterized by prolonged low mood and/or loss of interest in activities. It is also accompanied by many other symptoms such as low self-esteem, altered sleep cycles, or even suicide ideation and attempts. Due to these symptoms, the quality of life of depression patients may be highly compromised, not only in terms of physical and psychological health, but also in work and socialization as well. What we hear the most about depression are probably selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT). These two terms reflect the what. current research and practice have focused most on depression. The former, as a biological method of intervention, is the most widely prescribed type of depression medication, which blocks the serotonin from being absorbed back to the presynaptic cell. The latter is a very common and effective psychological intervention of the disorder by challenging the maladaptive thoughts, regulating emotions, and developing positive coping strategies.

There is also attempt in deciphering the etiology of depression via immunological approaches, but it is largely overlooked in what we perceive as mainstream research (e.g., in terms of neurotransmitters or cognitive psychology). It is true that the immune system is more about how our body produces toxic chemicals or specifically designed antibodies to kill or eliminate what our body reckon as “harmful”, but this does not mean that the immune system has nothing to do with what happens in our brain. In fact, the immunological perspective has its own irreplaceable significance, as it views the development of depression as a result of the brain responding to immune system signals outside the blood-brain-barrier. There has been experimental evidence suggesting that chemicals produced by the immune system (like cytokines and chemokines) can move through the barrier into the brain, causing inflammation responses and thereby leading to depressive symptoms (Raison et al., 2009). The exact mechanism of cytokine effects is not clear yet, but there are already some hypotheses supported by rigorous experiments.

Cytokines can affect normal brain function. Source: TReAD Lab

Purely biologically, research has found that cytokines affect normal function of neurotransmitters. For example, one cytokine called IFN was found to cause transient depressive symptoms in 45% patients who used it as medical treatment, and the mechanism was later found out to be activating the NO-glutamate system and causing neurodegeneration (Moron et al., 2003). Research on IL1 and TNF (the most crucial cytokines leading to inflammation) found that they could promote serotonin transport in neurons, promoting reuptake of neurotransmitters in the synapses, exactly opposite of what an SSRI does (Zhu et al., 2006).

The picture becomes more interesting if we add stress into the discussion. In depression, stress mainly comes from the patient’s psychosocial life, and is represented in the brain as increased epinephrine and norepinephrine level, as a result of increased glucocorticoid around the body. The exact mechanism of how stress causes inflammation in the brain is not supported by experiments yet, but one hypothesis is that when stress activates the sympathetic nervous system under the condition of glucocorticoid resistance, microglia in the brain and macrophages (source of IL1 and TNF) in the blood are activated, leading to inflammatory states. In the meantime, stress also relates to the concentration of serotonin, as chronic stress would keep brain serotonin at a very low level. As low serotonin level is hypothesized to be a cause of depressive symptoms, the effect of chronic stress actually exacerbates the severity of depression to some extent. Chronic states of inflammation due to stress has an even more serious consequence, as not only they maintain the stress level, they would lead to decreased repair of neural damages and death of neural cells as well (Leonard, 2010).

A very intricate diagram of how cytokines actually affect the brain via stress. Source: Sino Biological

So, if inflammation response has such an effect on depression, would it be possible that anti-inflammatory medication help reduce depression severity? Yes. A meta-analysis on treatment effects of non-steroidal anti-inflammatory drugs and cytokine inhibitors showed that anti-inflammatory treatment could reduce not only clinically significant depressive symptoms, but the less severe subclinical ones as well. The study also offered the anti-inflammatory medication celecoxib, a cytokine inhibitor, as the best-performing treatment of depression due to its positive effects on responsiveness and remission control (Kohler et al., 2014).

There are more questions arising with the increasing research depth, such as what the actual psychoneuroimmunological mechanisms are, or how should the immunological treatment be clinically administered for the best treatment outcomes. However, despite the extreme complexity of the immune system, the nervous system, and their interactions, the immunological approach explaining and treating depression is very promising.


Kohler, O., Benros, M. E., Nordentoft, M., Farkouh, M. E., Iyengar, R. L., Mors, O., & Krogh, J. (2014). Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry71(12), 1381-1391.

Leonard, B. E. (2010). the Concept of Depression as a Dysfunction of the Immune System. Current Immunology Reviews6(3), 205-212.

Moron, J. A., Zakharova, I., Ferrer, J. V., Merrill, G. A., Hope, B., Lafer, E. M., … & Shippenberg, T. S. (2003). Mitogen-activated protein kinase regulates dopamine transporter surface expression and dopamine transport capacity. Journal of Neuroscience23(24), 8480-8488.

Raison, C. L., Borisov, A. S., Majer, M., Drake, D. F., Pagnoni, G., Woolwine, B. J., … & Miller, A. H. (2009). Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biological Psychiatry65(4), 296-303.

Zhu, C. B., Blakely, R. D., & Hewlett, W. A. (2006). The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology31(10), 2121.

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