Top functional medicine pro, Dr. Will Cole recently shared his take on the emerging research around serotonin, depression, and SSRIs, the most commonly prescribed antidepressants on the market.

According to Cole, after decades of exhaustive studies there remains “no clear evidence that serotonin levels or serotonin activity are responsible for depression.” This news represents an important tide change in the way we treat depression, a condition that effects more than 13% of adults in the U.S. We asked Cole to expand upon his recent statement, and he provided us with this insightful piece… 

There’s no questioning it: brain health problems have become an epidemic in our society. Everything from brain fog to depression is on the rise with zero sign of slowing down.

While depression has long been considered one of the byproducts of low serotonin, new research is questioning everything we thought we knew about the origin of this mental health problem.

In my telehealth functional medicine clinic, I have spent years consulting patients all around the world about their health. Although this new research may come as a surprise to a lot of people, in functional medicine, it is finally bringing to light greater connections we have long seen regarding the mind-body connection.

The Latest Research On Depression And Serotonin

A review of multiple studies recently published in Molecular Psychiatry, found no correlation between a chemical imbalance of serotonin and rates of depression. This discovery is so significant because it calls into question antidepressants—specifically serotonin reuptake inhibitors (SSRI)—as the go-to method for treating depression and how often they should be prescribed moving forward to correct low serotonin levels.

While this discovery is a step in the right direction, it actually leaves us back at square one in terms of finding effective treatment methods and uncovering the root causes of depression in the first place.

This is where functional medicine and bio-individuality come into play. In functional medicine we understand that there is rarely a “one-size-fits-all” treatment to someone’s health problems. In that same vein, people rarely ever have the same underlying triggers, even if they have the same diagnoses. That said, there is one common factor among the many when it comes to modern day brain problems, depression included: autoimmune-inflammation in the brain.

The Autoimmune-Inflammation Connection

As I mentioned earlier, brain problems are on the rise. Do you know what else is also on the rise? You guessed it—autoimmune conditions. In fact, close to 50 million Americans have been diagnosed with an autoimmune disease. Today there are 100 recognized autoimmune conditions and at least 40 more disease processes that likely have an autoimmune component (at least that we know about now!).

A whole new area of research known as the “cytokine model of cognitive function” is dedicated to looking at how inflammation can damage the brain’s protective blood-brain barrier (BBB) and possibly lead to brain problems such as what is now referred to as neurological autoimmunity.

So what does depression have to do with inflammation? As it turns out, a lot. Inflammation has the potential to trigger depression, exacerbate it, and even be the root cause. This inflammation activates the brain’s immune microglia cells, which can trigger an inflammatory-autoimmune response. In other words, people’s immune systems might be attacking their brain and nervous tissue in response to inflammation that could have started somewhere else entirely, such as in the gut. A study published in Frontiers in Immunology found that depression was associated with increased inflammatory activation of the immune system that ends up affecting the central nervous system.
Interestingly enough, research has also shown that depression and anxiety are more common in patients with autoimmune diseases than chronic degenerative conditions, likely due to the direct effect of inflammatory cytokines on the central nervous system. Further, someone with one autoimmune disease has a higher chance of suffering an immune system attack on another system, such as the brain.

Here’s where it gets really interesting, in the same study published in Frontiers in Immunology, they actually explain that antidepressants have been shown to decrease inflammation, and that higher levels of inflammation in a patient at baseline is often a predictor of how well depression treatments will work. We might not have been initially targeting inflammation with antidepressants, but we can see how they worked in our favor once we began to understand their  mechanisms.

The Gut-Brain Connection

If studies are seeing the connection between brain inflammation and depression, where did serotonin come into play at all?

Your gut and brain are actually formed from the same fetal tissue when you were growing in your mother’s womb, and continue their special bond throughout your whole life through what is known as the gut-brain axis. The same proteins that govern gut permeability also determine the permeability of your blood-brain barrier. Basically, what affects one, affects the other.

One of the greatest examples of this is serotonin gut health. Surprisingly, close to 95% of this neurotransmitter is made and stored in your gut—not your brain! No wonder the medical literature often refers to your gut as your “second brain”. Therefore, it makes sense that if you are experiencing inflammation in your gut and brain, it can affect your serotonin levels for the worse.

Because of this new study, we now understand that depression has less to do with the level of serotonin in your brain than the level of inflammation you’re experiencing and what that is doing to your serotonin signaling. More studies need to be done, but one could hypothesize that serotonin signaling could be off because of inflammation in the brain. Your body might actually have enough serotonin, but chronic inflammation keeps it from using it effectively.

Putting it All Together

In functional medicine, we look at every symptom as a “check engine light”, a sign that something deeper is going on beneath the surface. Depression is no different. By continuing to study the mechanisms by which inflammation can trigger health problems—and even further, what triggers inflammation in people—we can begin to treat the root cause of this brain health problem.

Chronic infections from mold and biotoxins, hormone imbalances like thyroid problems, poor diet, stress, unresolved trauma and more can all be inflammatory triggers in someone’s health journey. Ultimately, it’s up to us in functional medicine to put together all the pieces of a person’s health puzzle and form a plan of action to address depression and other health problems. I go into a deep dive of this topic in my upcoming book Gut Feelings, for preorder now.

While we are still learning more about depression, we can make connections, and take the information we do know and apply it in a way that facilitates whole-body healing—mental, physical, and emotional.