Bild Blog alisha

Inflammation and Mental Illness

Recent research points to a new perspective on a common disorder. Depression is a major cause of disability worldwide and yet we only begin to understand how multifaceted depression actually is. This is an attempt to get one’s head around what there is to learn about the interactions between stress, the immune system, and the brain.

There’s this small moment prior to any big challenge - be it holding a speech, having a job interview, or jumping from a high cliff into the cold blue. With intentions set, time stands still for this brief moment and one is fully awake, ready to pull through. The heart pulses faster and palms begin to sweat - the classical fight-or-flight response working at its best. Something else, however, takes place inside one’s cells. In response to psychological stress, inflammatory processes can get activated too. This seems counterintuitive. Why should the body turn on inflammation in the absence of infection or damage to cells? Interestingly, stress and inflammation are more closely interconnected than one may think. Quick, sweet periods of stress, like stepping out of one’s comfort zone, can inspire and prompt favorable feelings. If the stress becomes chronic and one constantly feels overwhelmed, however, inflammatory processes can get hyperactivated, eventually leading to a mental state that shapes the lives of many: depression. Grasping and understanding the biological roots of depression is crucial for developing and choosing effective treatment options. I invite you on a journey of untangling the story of depression and appreciating the mind-boggling interconnectedness of our body’s stress response, immune system, and nervous system.

The bridge between stress and the immune system

Three major ways describing how stress can result in an immune response stand out from recent research. One pathway involves a cleverly assembled complex of proteins, called inflammasome. The inflammasome can be activated by psychological stressors (such as holding a presentation in front of people) and is thus thought to act as a bridge between stress and immune system activation. The protein complex acts by bringing inflammatory proteins into their active form and therefore promotes inflammation. In addition to the inflammasome, two other systems linking stress and immunity have been studied extensively: the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. Perturbation of these pathways leading to hyperactive inflammatory processes is tightly associated with depressive symptoms. In fact, inflammation is a very robust risk factor for the development of depression. This means that if people show certain inflammatory markers, it is likely that they will experience symptoms of depression in the future. Why would inflammation predict and accompany depression? Nothing can be thoroughly comprehended if not looked at in the light of evolution. Let us therefore ascertain what evolutionary factors may explain this co-occurrence of immune responses and state of low mood.

An evolutionary eye on depression

Humans have spent most of their time on planet Earth hunting for meat and gathering berries. Back in those days, a simple cut could be detrimental; in many cases even fatal if bacteria entered the wound. In fact, half of the people lost their lives due to infections before adulthood. Evolutionary pressure thereby fostered certain behavioral and physiological responses. For example, sickness behaviors such as social avoidance and anhedonia – the reduced ability to experience pleasure — promoted survival. Why? These behaviors conserved energy to fight infection and heal wounds, and helped “flattening the curve” - a principle we all know too well. In other words, depressive symptoms increased the chances of survival as an individual and as a species. This is one of the core concepts of the pathogen host defense theory, which provides us with an idea about why depressive symptoms might have evolved to attend inflammation. How inflammation is translated into depression points to another piece of our puzzle. In this context, researchers have found that inflammatory molecules can disturb the balance of certain neurotransmitters (signaling molecules of neurons) involved in mood regulation. One set of affected neuromodulators are monoamine neurotransmitters.

The monoamine hypothesis

Monoamines are a type of neurotransmitters with a particular chemical structure. Examples include serotonin, dopamine and noradrenaline. If a person runs low on certain monoamines, the chances that they are depressed are rather high. Some researchers even go as far as saying that a deficit in these neurotransmitters is the main cause of depression. A reduced availability of monoamines can be caused by inflammatory molecules. For example, certain inflammatory proteins prevent monoamines from being synthesized. While low levels of serotonin & co promote depression, an inverted picture can be seen in the case of glutamate.

When glutamate overdoes it

Glutamate is an amino acid that also functions as a neurotransmitter. Actually, it is the most abundant excitatory neurotransmitter there is in the brain. You don’t want your glutamate signaling getting out of balance as high levels of glutamate are linked to depressive symptoms. An enzyme produced in response to inflammation called indoleamine-pyrrole 2,3-dioxygenase, or just IDO, partly bears the blame. The enzyme indirectly increases glutamate release, which ultimately promotes depression.

What could the future look like?

Knowing that depression can have inflammatory causes paves the way to a whole new branch of treatment approaches. For example, drugs that specifically target inflammatory molecules could be used to treat depressive symptoms. It’s challenging though: the wide operation spectrum of inflammatory molecules in the body make it difficult to accurately target certain, but not other pathways. Different treatment approaches utilize the fascinating capacity of our bodies to reduce inflammation via certain T cell responses. So called regulatory T cells are especially skilled at dealing with the too loud parties inflammatory molecules are enjoying. Possible treatment options eliciting anti-inflammatory T-cell responses include the administration of bacteria or parasites.

While there are many possibilities for using anti-inflammatory strategies to treat depression, these only work for subgroups of patients. They are particularly useful for people who actually show increased inflammation (for example individuals with osteoarthritis). Importantly, for patients with no evidence of inflammation, this kind of treatment may avail to nothing or can even be detrimental.

Slowing down

Developing drugs to help people with depression is one side of the story. At least equally important are lifestyle choices that actively counteract the development of depression. Recovery and relaxation are crucial aspects promoting health and prevent entering the stress-inflammation-depression vicious cycle. After mastering that scary presentation or jumping off that high cliff, it’s vital to let the stress dwindle away. For some this may mean enjoying a cup of coffee or tea, others find peace in nature - approaches to shift into a calm mode vary from person to person.



Miller, Andrew H., and Charles L. Raison. "The role of inflammation in depression: from evolutionary imperative to modern treatment target." Nature reviews immunology 16.1 (2016): 22-34.


We welcome useful feedback. The comments are moderated.