Most of us have some sense of what depression is, at least in terms of the symptoms. For me it feels like somebody jammed a syringe into my head, that releases a dark cloud over my mind, casting everything through an overly negative and pessimistic lens. The relentless, anxious, worrying, second guessing everything.

But what does depression really look like, biologically speaking?

I’m pretty sure these irrational symptoms aren’t just “all in my head”, even if they technically originate upstairs.  What would depression look like if we put it under a microscope? To find out what scientists currently know about depression, I headed to Centre for Addiction and Mental Health (CAMH), in Toronto.

It turns out we’re in the midst of a technological revolution when it comes to depression. According to Etienne Sibille, Senior Scientist at CAMH, before the advent of brain-scanning technology “all we knew about depression was indirect. People would mostly talk about ‘chemical imbalance,’ referring to fluctuating levels of neurotransmitters like serotonin, dopamine and norepinephrine, known to play a role in regulating our mood and cognition. Antidepressants were largely discovered by chance in the 1950s, when scientists invented new medications for conditions tuberculosis and schizophrenia that ended up augmenting the function of these neurotransmitters. Some patients would report improvement in their moods, and thus antidepressant pharmaceuticals exploded. Unfortunately, antidepressants don’t work for the majority of patients, upwards of 50%.

Perhaps this is because brain chemicals are only one piece of the puzzle. Brain-scanning technology allows researchers to better understand how depression actually affects the brain. Jeffrey Meyer, the head of CAMH’s Neurochemical Imaging Program gave me a tour of the PET (Positron Emission Tomography) scanner. By injecting patients with a dyed tracer that can target specific sites in the brain, researchers can look virtually anywhere within the brain and identify brain changes that might happen during clinical depression.

Dr. Meyer discovered that depressed patients have increased levels of inflammation – in other words our body’s response to infection or trauma. It had been previously known that diseases that present with inflammatory symptoms, such as Alzheimer’s, arthritis or diabetes will often have sad mood, which encouraged Dr. Meyer’s team to target a certain marker that goes up when the brain makes an inflammatory response.

The team compared 20 healthy people, and 20 people in the midst of a clinical depression and found a 30% rise in this marker for inflammation, which they found all over the gray matter of the brain.

What could this inflammation be saying? “Our study shows that it happens when the depression is present, it doesn’t tell us what caused what. However, since we know when you provoke inflammation, you can cause sad mood, most likely some level of causality between having inflammation and some depressive symptoms.” In other words, some depression could be the by-product of another disease that causes inflammation.

“Our study shows that it happens when the depression is present, it doesn’t tell us what caused what. However, since we know when you provoke inflammation, you can cause sad mood, most likely some level of causality between having inflammation and some depressive symptoms.”

Dr. Jeffrey Meyer, CAMH Toronto

But what if you’re depressed, but you don’t have an inflammatory disease playing a role in causing it? Researchers know there can be multiple triggers of depression, including genetics and trauma. Another scientist at CAMH, Dr. Yuliya Nikolova concentrated her research on the impact stress (from traumatic experience) can on the brain, and specifically the part of the brain that regulates our response to stress and fear: the amygdala.

“Stress is a very common trigger of depression. More often than not, depressive episodes come in the wake of some sort of stressful life event.”

This gave Dr. Nikolova the hunch to study this densely connected part of the brain. The amygdala evolved millions of years ago and it’s key to recognizing threats in the environment, and responding to them very quickly.  The coordinated “fight or flight” response it triggers in our body is supposed to only occur when there’s real danger — like a sabre-toothed tiger attack — boosting our heart rate and breathing, to catapult us to safety. However scientists believe the amygdala might be over-active in the brains of people predisposed to depression. Yuliya believes “this hyperactivity might predate the development of depression and anxiety.”

In other words, it’s as if the brains of those of us predisposed to depression and anxiety brains are more sensitive to threats in general. Modern day triggers such as stressful work environments, deaths in the family or relationship issues can be enough to activate the response.

To find out the consequences of this overactive amygdala, Dr. Nikolova and her team compared the brains of mice having experienced prolonged stress against healthy controls. Not only did they notice the amygdala network getting larger in their brains, but it also grew more connected with other brain regions that regulate instinctive behaviour. She also observed a decrease in connections with the pre-frontal cortex, the part of our conscious brain designed to regulate that instinctive behaviour and her team replicated these findings in humans who experienced traumatic childhoods.

What this means is that the brain becomes over-specialized with dealing with stressors and threats, “which comes at the expense of other potentially behaviorally and clinically relevant functions”. It’s as if the amygdala is hijacking our brain and becoming the driver of our behaviour. Maybe this re-wiring explains why worrisome anxious thoughts can feel so out of control.

Chronic stress can rewire our brains to prioritize instinctive regions.

And that isn’t the only way depression affects our brain. If depression gets worse, it can even affect our hippocampus, which in turn regulates our formation of memories. Several studies indicate that depression leads to a shrinking depression, and it gets worse with more depressive episodes.

“Because of the involvement of the hippocampus in memory function, if your hippocampus gets smaller, chances are your memory performance will suffer.”

I’ve certainly experienced cloudy and unreliable memory, which is consistently reported as a symptom by people suffering depression.

The hippocampus is also supposed to put the brakes on that overactive amygdala. “When the hippocampus shrinks it can become even less effective at shutting down the stress response, so you end up in this vicious perpetual cycle,” says Yuliya. Why this happens is a mystery, but perhaps our brains are adapting to protect us from the emotional experiences we find so traumatic.

So is there anything we can do to stop this, armed with this biological information? Alas, depression is a complex and very individual disease. What might be observed in one person’s brain may not be the same as what we might see in another.

Dr. Meyer believes there “could be 5-10 common, different biologies that can occur in clinical depression” such as the shrinking hippocampus and inflammation, and we could have any combination of them. That said, the neuroscientists is hopeful: “if we can identify the key ones, there might be better, targeted treatments”. Through better understanding of this biology, it will lead to more individually targeted and “biologically informed treatments”.

Right now doctors don’t have a standardized blood test to tell us what kind of depression we have so it’s more on us to monitor our own brains so to speak.

We all have a unique story of depression, which likely means one of these unique brain biologies.  The more we know about our own case and symptoms, how long we’ve had the depression, the more we can reverse engineer what might be causing it and which therapies could work best with a little trial and error.

How to reverse engineer your depression. Easier said then done!

Sounds simple right? Well…. not exactly. But at least by wondering, we’re gaining some insight, and that’s a step in the right direction.

For more information about the brain biology and causes of depression, check out this Harvard resource.

For other mental health resources, check out our charity partner, Healthy Minds Canada: