What is the immune system’s role in mental health and depression?

Throughout the past century, researchers have attributed many odd, potential causes to mental health problems such as vaccines or cold, unloving mothers causing autism. Today, such explanations seem (or should seem) ridiculous but there are other scientific areas that started off being seemingly ridiculous, yet turned out to be highly relevant. One of the most recent scientific endeavours concentrates on the role of the immune system in mental health and brain functioning and, using the example of depression, I’m going to outline why this is something that is highly exciting indeed.

A very basic overview about the immune system

To understand how the immune system might affect the brain and mental health, I need to give a short overview on how the immune system works. The immune system’s role is defending the body against dangerous pathogens such as viruses or bacteria. To offer such defence, the immune system fights off pathogens by way of two major systems called the innate and the adaptive immune system. To understand these systems, it might be helpful to regard them as political policies for fighting terrorism as they can be considered in very similar ways. Just as the immune system fights bacteria and viruses, terrorism will be fought using general and specific policies that conform to innate and adaptive immune systems, respectively.

Looking at general policies, a government can instruct police officers to apply one of different crude rules for spotting terrorists. An obvious one could be “If you see someone with a bomb, shoot them down because bombs are dangerous”. While this might prove effective in preventing a handful of terrorist attacks, we would probably all agree that there are ways to get around such weak enforcement. On the other end of the spectrum, a government might give instructions to prevent people from certain “terrorist-prone” countries to enter a country in the first place. While this might (emphasising the “might” here…) work in preventing terror attacks, it will predominantly mean not letting in a lot of the “good guys” and, most importantly, this is a huge douchebag strategy.

Translating this back to the general policies of our immune system, the innate immune system also applies crude rules such as “target anything that looks like a bad bacteria or vicious virus”. If done properly, it will fight off all of the bad stuff entering our bodies without doing too much damage to our own cells. If not done properly, it will let in too many of the “bad guys” or fight off too many of the good guys, so it’s easy to see that balance is key here.

Next we can look at specific policies and at the adaptive immune system. If we go back to the terror defence analogy, specific policies might be formed by intelligence agencies that have the resources to make more fine-grained investigations than police officers on the ground. So, for example after a terror attack occurs, an intelligence agency will look at how the terrorists organised their attack, who was in contact with whom etc. Hopefully, this will then lead the agency to develop new, smarter policies for police officers on the ground such as “since terrorist John Doe bought ingredients X, Y, and Z to construct a bomb, we will shoot everyone buying these ingredients at a hardware store” (for the sake of the analogy, we’ll go ahead with killing everyone here and not bother with arresting the suspect).

The specific, adaptive immune system will also set up policies based on very fine-grained criteria such as very specific bacterial or viral molecular signatures. Based on these signatures, it will then let the innate immune system enforce these new policies afterward. Again, it is important to note that even though such finer policies sound better, there can still be meaningful mistakes. On the terror defence level, this might be killing off all chemistry teachers that simply wanted to buy their ingredients for tomorrow’s lesson and, on the immune level, it is the reason why we require “may contain traces of nuts” indications on labels (because the immune system goes berserk against harmless substances).

So why is the immune system important in psychological terms: isn’t there something called the Blood-Brain-Barrier?

It’s correct that the brain has long been considered distinct from the immune system due to an extra layer of protection called the Blood-Brain-Barrier. Rather than a protective bubble surrounding the brain, the Blood-Brain-Barrier, or short BBB, functions as a protective wall surrounding individual blood vessels in the nervous system. Thereby, it shields the brain against potentially toxic materials. While normal blood vessels in the rest of the body have small pores that allow traffic of many molecules and proteins, blood vessels in the brain have tight junctions that only allow water, some gases, and certain molecules to pass through. Additionally, important immune cells such as macrophages (macrophages are the pathogen-eating infantry of the immune system) do not exist inside the brain. So going back to the terror defence example, the brain can be compared to central political buildings like Westminster Palace or the White House: Since decisions of major importance are made there, it would be a massive security threat to let a random guy off the street enter at his/her will.

So considering this disparity between brain and body, why do researchers bother making such a fuss about the immune system’s involvement in mental health and psychological disorders? After all, if emotions are regulated by the brain and the brain is shielded from the immune system, there shouldn’t be any immune effect on our psychological well-being. Now this is where it starts getting exciting as  scientists have discovered different mechanisms by which these systems do, in fact, interact. First, while macrophages do not exist in the brain, cells called microglia take up their role in the nervous system and are responsible for clearing up plaques and other toxic materials there. Second, immune messenger cells called cytokines can be actively transported across the BBB. Once inside, these cells can relay signals for other cells like microglia indicating to “calm down as things are going alright” or to “brace yourselves since pathogens are coming”. Third, during times of increased immune activity, which happens, for example, when being sick, the BBB can become leaky, thus allowing access for other immune cells and more messengers. So these three examples show that there is quite a bit of crosstalk between the immune system and the brain.

The immune system, mental health, and depression

Approaching the final piece of the puzzle, researchers started wondering whether the crosstalk between the immune system and the brain had some real-world implications for people’s mental health and some clues already suggested that this is the case.

When we’re sick, and sick translates to increased innate (or general) immune activity, we feel very badly. We don’t want to get out of our beds, we don’t really feel like eating, things we usually enjoy don’t seem pleasurable anymore, and we might sleep too much or cannot get enough sleep. These bad feelings, which have been termed sickness behaviour in scientific literature, are actually very similar to symptoms experienced by individuals suffering from major depressive disorder. Now this isn’t rocket science and even though it seems like a ridiculous point to make, there are some very important implications to be taken from this. Now what if everyone who suffered from depression was merely exhibiting these symptoms because the immune system’s sickness mode was falsely activated?

Unfortunately, it doesn’t only boil down too such an easy explanation but several studies do suggest that this hypothesis at least matters to an extent. First, clinicians do actually see that states of increased immune activation are associated with depressive symptoms. For example, patients who require immune-activating treatment like interferon medication (used to treat hepatitis C) have a 25% chance of developing depressive symptoms as a consequence. Similarly, patients with a chronic inflammatory condition (meaning generally increased immune activation) such as inflammatory bowel disease report depressive symptoms much more frequently than healthy people. Second, people who do not suffer any major medical disease but do suffer from major depressive disorder have a greater amount of cytokines (remember: the immune messenger cells) relaying the signal “brace yourselves, the pathogens are coming” in their blood, so that their immune systems are more active than normal.

Third, new evidence shows that treatment reducing activity of the immune system might actually work for improving symptoms of depression: Charles Raison and colleagues from Emory University conducted a study in which they compared medication lowering immune activity against a placebo pill for treating people suffering major depressive disorder. While the immune-medication did not show effects in all patients, those who exhibited increased immune-activity before treatment responded well to medication.

Along the same lines, we also recently published what’s called a systematic review and meta-analysis, in which we summarised information from many different studies on immune-lowering medication in chronic inflammatory conditions. In these studies, researchers had often measured depressive symptoms in addition to the general disease symptoms and we wanted to figure out whether immune activity-lowering drugs were helpful in treating depression. Looking at this, it did indeed seem to be the case that depressive symptoms decreased significantly after medication intake and this was not only the case because patients’ primary disease was improved (we checked!).

So combining our findings with those of Raison and colleagues, it seems that treatment lowering immune activity might be a promising alternative for some patients with major depressive disorder, and specifically those with increased immune activity. This is stressed even more by findings that this subgroup also appears to benefit less from usual treatment options such as common antidepressant drugs, so that there might actually be a unique form of immune-related depression. If this form exists, future researchers need to identify it and provide such patients with alternative treatment options such as immunotherapy. Here, it will be really important to develop specific clinical guidelines on when to deviate from normal antidepressant treatment and provide immunotherapy, also especially because some immune-medications have strong side-effects and should only be used when absolutely necessary. All things considered, however, this might mean that we might be able to treat patients suffering from depression, who are not yet helped by common therapies.

I very much hope that this article brought across why the immune system is a very fascinating target of psychiatry research and while this article focused on depression and the innate immune system, there is more immune-related research on other disorders like schizophrenia, autism, or Alzheimer’s disease. With the start of PsychoTransmitter we will hopefully be able to feature some more research on this exciting area!

References

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  9. Raison, C. L., Rutherford, R. E., Woolwine, B. J., Shuo, C., Schettler, P., Drake, D. F., . . . Miller, A. H. (2013). A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry, 70(1), 31-41. doi:10.1001/2013.jamapsychiatry.4
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Nils Kappelmann

I'm a PhD student at the Max-Planck-Institute of Psychiatry in Munich, Germany, investigating potential biomarkers in the psychotherapeutic treatment of depression.

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