What causes depression?
To be honest, scientists and psychologists can’t really say for sure. For a long time, the Monoamine Hypothesis and the Glutamate Hypothesis reigned supreme. They gave us SSRIs and SNRIs, and these two hypotheses (which many have argued are two sides of the same coin) influenced the ways that most people today think of depression–as a lack of transmission of certain neurotransmitters. But what leads to this lowered transmission? Are some people just deficient in serotonin (5-HT), a monoamine and the neurotransmitter that SSRIs upregulate in the brain?
A newer way of addressing these questions, among many others, is to look at the role of inflammation in depression.
So, what is inflammation exactly?
When you hear the word inflammation, you may picture the swelling of a sprained ankle, or the red sweaty face of a kid with a fever. But inflammation can be more broadly defined as a response triggered by damage–or perceived damage–to a living tissue. This response leads to the production of certain cytokines (proteins released by a cell) whose goal is to (a) remove the damaging agent and (b) remove the damaged tissue.
If you eat bad sushi and get food poisoning, it is an inflammatory response from your immune system that makes you puke and/or poop your brains out in order to eliminate the bad bacteria, or pathogens. (E. coli is just one example of a such a pathogen.) Sometimes, however, your immune system gets it wrong. Such is the case in people with autoimmune disorders, as these people’s immune systems attack their own cells, thinking that they are harmful. A less extreme example of the body getting it wrong would be allergies. Something like pollen really isn’t dangerous to your body, but people with seasonal allergies have immune systems that get a little confused and think it’s time to fight back.
The Inflammatory Hypothesis of Depression posits that depression is another example of your immune system getting it wrong.
There is an association between inflammation and depression.
If you would really like to dive in deep to this topic, I would recommend “The role of inflammation in depression: from evolutionary imperative to modern treatment target,” by Andrew H. Miller and Charles L. Raison (2016). Their review article is a great overview and provides links to approximately a bazillion other papers and studies. (And if you’d like a refresher on how to read scientific articles, here you go.) This article is also my primary source for what follows here.
Many patients with major depressive disorder (MDD) exhibit cardinal features of inflammatory response, including an increase in pro-inflammatory cytokines. A few specific cytokines are interleukin-6 and -8 (IL-6 and IL-8), interferon type I (type I IFN), and tumor necrosis factor (TNF). Administering such inflammatory cytokines (or their inducers/precursors) to an otherwise non-depressed person can actually induce depressive symptoms.
If there isn’t a specific pathogen attacking the body, though, how would these inflammatory factors end up in the body in increased concentrations naturally? One theory examined by this article was that inflammasomes may be responsible for inflammatory response to non-pathogenic, or “sterile,” stressors. The cystolic protein complexes that have been rather clunkily termed “inflammasomes” lead to the activation of the enzyme caspase-1, which then cleaves the precursor forms of cytokines and activate them.
I understand that I just threw a lot of very science-y jargon at you, and I apologize. Basically, the gist of all of this is that sterile stressors–such as public speaking or being chased by an angry dog–can increase inflammation in your body. Increased inflammation has also been associated with increased activation in parts of your brain associated with fear and emotional response, including the dorsal anterior cingulate cortex (dACC), insula, and amygdala.
There also exists a correlation between pro-inflammatory cytokines and reduced availability of certain monoamines. These monoamines are serotonin (5-HT), dopamine (DA), and norepinephrine/noradrenaline (NE). Increased expression and function of repuptake pumps cause the reduced availability of 5-HT, DA, and NE by clearing them out of the synapse. (A synapse is the area between neurons where neurotransmitters travel.) Here, you can see how the Inflammatory Hypothesis of depression can be used to explain the monoamine deficiency assumed by the Monoamine Hypothesis.
The evolutionary explanation for why we evolved to have bodies that are sort of stupid sometimes is called the “inflammatory bias.” An evolutionary biologist would tell you that back in ye olden days–like, the very very very olden days–people who could produce a greater inflammatory response were more likely to survive and reproduce because they wouldn’t die every time they got an infection. This view of inflammation can also explain the social avoidance and anhedonia that appear in people with depression. Both of these unpleasant side effects would allow you to better fight off an infection by conserving energy and preventing exposure to more pathogens. Similarly, a symptom of anxiety (which is often comorbid with depression) is hypervigilance, which would come in handy if you were trying to avoid doing something that could lead to another infection.
So why don’t we just start giving anti-inflammatory drugs to everyone with depression and call it a day? Well for one, suppressing people’s immune systems isn’t always the best idea. That’s how you end up dying from food poisoning, rather than just spending a day on the toilet. Furthermore, increased inflammatory response has only been identified in some people with depression. Plus, many of the antidepressant drugs already on the market, such as SSRIs and to a lesser extent SNRIs, already have some anti-inflammatory action. And they still don’t work for everyone. As with most things in science, more research is needed to figure out a way to use the association between inflammation and depression to actually help people.
That said, we do have some idea of the things that cause the inflammation that may cause depression.
This time, I will refer those of you who would like more in-depth coverage to “So depression is an inflammatory disease, but where does the inflammation come from?” by Michael Berk et al. (2013), another great review article. Most of the information I’m presenting in this section came from this article, plus what I had already learned from my past classes and reading on the subject.
The currently available evidence suggests that the following are all sterile stressors that can lead to an inflammatory response:
- Psychological stressors
- Poor diet
- Physical inactivity
- Altered gut permeability
- Genetic tendency to develop allergies and allergic diseases
- Poor dental care
- Sleep deprivation
- Vitamin D deficiency
Most of these are fairly self-explanatory, but I am going to dig a bit deeper into the role of diet and altered gut permeability in developing inflammation and depression in my next post. If you would like a bit of a primer on the gut’s role in mood and behavior, check out my (old) post on the subject.
Check back soon for a discussion of food, guts, and depression!