This winter, I’ve had three colds. Apart from the icky symptoms of the infection itself, I am especially tired of the side-effects that happen when your body is sick: the fatigue, the loss of appetite, being unable to concentrate, and not wanting to do the things you usually like. You know the drill, when everything feels like cold soup in your brain and even getting out of bed feels like too much effort. These pesky side symptoms that pop up during infections are generally called “sickness behaviour”, and it’s not just humans who exhibit them, as they have a big evolutionary advantage – they make us rest so our bodies can heal, and they keep us away from our social groups so we don’t infect anyone else.

Or, that’s the theory, anyway.

Evolution hasn’t really prepared us for the many responsibilities of modern life that make it hard for us to get that sorely needed rest, just as it hasn’t prepared us for a lot of other challenges we face today. While sickness behaviour in reaction to an infection can still be a good thing, it turns into a problem when it becomes chronic, in which case these behavioural patterns suddenly sound a lot like a symptom checklist for major depression. And in fact, there may be a bigger link than previously thought between our immune system and brain circuits that are related to mood disorders like depression.

How evolution made us want to stay in bed

First, let’s go way back in our hypothetical evolutionary history, long before apps that may tell us if we’re at risk for developing depression based on our recent activity in social media. While our ancestors didn’t yet know the particular stress induced by having a very public Facebook argument with a distant relative on Hillary vs. Donald, they still had to deal with grievances of their own, mostly in the form of interactions with predators or rivals. These stressors had a high risk of injury and, therefore, pathogen exposure for the individual, so it was adaptive in terms of survival and reproduction chances to activate a variety of immunological and behavioural responses to them, such as the above mentioned sickness behaviour: the link between stress, inflammation and behaviour was born.

Fast-forward to more modern times, when humans started to move to more sanitised urban environments, where our primary stressors don’t usually come hand in hand with the risk of infection, but are increasingly of a psychosocial nature. Inflammation and sickness behaviour triggered by these stressors suddenly isn’t so helpful anymore, and the cause of stress is often long-term and cannot be eradicated by simply staying in bed for a few days until we feel better. The result is an increase of autoimmune, allergic, and inflammatory diseases, as well as – you guessed it – depression.

Thanks a bunch, evolution.

Body to brain: engage sickness behaviour

We’ve explored how the brain and the immune system communicate in a previous post already. Pro-inflammatory cytokines act as a signal of inflammation in the blood stream. These cytokines can cause symptoms of depression in healthy people, and a subgroup of patients with depression show elevated levels of cytokines in their blood in reaction to psychosocial stress. Production of cytokines can be triggered by protein complexes or other molecules that form in response to injury, infection, and, most notably, psychosocial stress, both in animals and in humans. Once in the blood, these cytokines can reach the brain via different mechanisms, where they signal: Hey, brain, there’s an inflammation going on down here, you need to help out.

The brain is nothing if not dutiful, and responds by curbing the production of important neurotransmitters such as serotonin, noradrenaline, and dopamine, while increasing glutamate levels. These neurotransmitters, in turn, have a hand in the activity of specific brain regions that are responsible for motivation and motor activity and may be involved in the anhedonia and social avoidance characteristics of depression. Other targets are brain regions which are connected to agitation, anxiety and alarm, symptoms that often occur hand-in-hand with depression. Lastly, cytokines can also mess around with the hippocampus, possibly causing difficulties in memory and learning, which can also be symptoms of depression.

Get well soon?

So now we know that stress can lead to inflammation which can lead to depression. The first avenue to explore is, of course, treatment. Anti-inflammatory therapies could well replace or supplement conventional antidepressants for those patients who do indeed show increased inflammation, with careful consideration of the potential side-effects. Non-pharmacological treatment options like diet and exercise might be an important complement to both anti-inflammatory and psychotherapeutic interventions for these patients, and having effective coping mechanisms for stress could down-regulate both the inflammatory response as well as the depressive symptoms.

Apart from providing us with potential new treatment avenues that might be especially relevant for otherwise treatment-resistant patients, knowing about this particular three-way link could also be helpful in the diagnostic process, for example by doing blood tests and identifying specific inflammatory markers in the blood or in our genes that are tied to an increased risk of depression. These markers might also tell us something about how the patient in question might respond to different kinds of treatments in the future, making it easier to devise an individual treatment plan.

And in the end… 

It’s April now, and hopefully the cold season is over for me and all the other unlucky people out there who suffered a similar fate this winter. As annoying as it is to be ill, though, I can’t help but be grateful that my body has an in-built mechanism that is designed to help me get better by making me get the rest that I need. Perhaps depressive symptoms are, in that way, a similar effort of our brain to protect us from chronic stress, even if they don’t actually help us tackle the cause of the stress. If only our immune system were as effective at combating mental illness as it is when fighting off an infection! But who knows – maybe one day someone will come up with a vaccine for depression?