Here’s Why Functional Medicine and Naturopathic Doctors Do NOT Need to Pull Serotonin Precursors off their Supplement Shelves for Mood Disorders.

Introduction: Should We Consider Serotonin When Dealing with Depression?

It’s become obvious that we can’t treat depression solely based on serotonin levels.

Yet, does that mean we shouldn’t consider it all?

In this post, I will review why we need a new approach to mental health and all the factors that serve as a foundation for brain health.

Then, I will explore the current theories on what can contribute to depression and why serotonin shouldn’t be cast ahead as one of them.

If you or someone you love is affected by mental health, empower yourself with this essential information.

You may also want to share this article with your mental health provider and/or wellness team.

Why We Need a New Approach to Mental Health

An analysis of a review of studies was recently released that, according to headlines, officially “debunked” the whole serotonin hypothesis of depression. However, many psychologists and psychiatrists were not surprised by the findings. Most had been aware, for some time, of previous research that demonstrated that depression is not a simple theory with one cause.

Yet, the study ignited a hot debate. It cast a light on the fact that our approach to mental health, its interventions, and our understanding of psychiatric disorders in general are deficient. Specifically our treatment outcomes, access to them, and scientific evidence of their validity is lacking.

Complicating matters even more, our whole method of classification and diagnosis of psychiatric disorders are not defined by any confirmed, biologically accurate measurements. Rather, they are based on clusters of symptoms measured by surveys and scales that are not specific. This means we are attempting to alleviate psychological and emotional issues without addressing the health of the brain, which is responsible for producing them.

This would be akin to trying to treat every symptom of a heart problem without supporting cardiovascular health.

It is no wonder we have a national mental health crisis on our hands!

We must fully address the organ that is causing the symptoms if we truly want mental health sufferers to attain remission. Otherwise, we are trying to suppress the (non-agreed upon) symptoms with a pill that may, or may not, work.

The Integrative Approach to Mental Health

Though we may not have a reliable physiological marker for depression, we do have ways to assess and support brain function and its biochemistry.

Unfortunately, many are not aware that these integrative approaches exist. They incorporate a personalized approach to brain health. This means addressing all the brain health factors that contribute to any psychiatric disorder.

In fact, balancing these physiological aspects are the foundation for anyone struggling with mood or mental issues.

Integrative mental health clinicians also search the literature for newer, substantiated associative patterns that can impact their client’s or patient’s brain health. Several of these links to depression will be discussed later in this article.

The Many Factors of Mental Health

Brain health is multifactorial and complex. All biological processes impact the brain and the brain helps coordinate these physiological functions. This is why one can’t medicate depression away through manipulation of a single biochemical, such as serotonin, or any other neurotransmitter.

We must address brain health from a wider lens.

Here is a review of the foundational brain health factors to consider for any brain dysfunction:

• Inflammation and oxidative stress (e.g., several studies have shown IL-6, a cytokine marker of inflammation, to be elevated in depression)
• Nutrition and assimilation
• Dietary triggers and deficiencies (including cerebral folate deficiency)
• Mitochondrial dysfunction and imbalances
• Hormonal imbalances (Estrogen levels influence serotonin and progesterone impacts GABA.)
• Stress & cortisol levels
• The microbiome (The microbiome communicates through the vagal nerve to the brain via microbiota metabolites. This impacts mood and nervous system tone.)
• Environmental toxicants (Heavy metals are associated with cognitive issues.)
• Blood sugar levels
• Stealth infections
• Childhood adversity
• Emotional tone and spirituality
• History of brain trauma or brain impact
• Genetic variations impacting neurotransmitter efficacy (such as SNPs, single nucleotide polymorphisms, related to MTHFR, DRD2, DRD4, COMT, CBS, and serotonin transporters)
• Hyper or hypo-activity in a brain region
• Environmental stressors and technology overload
• Social support
• Mindset and beliefs
• Movement/exercise
• Sleep
• …and more!

How Depression Can be LINKED to Serotonin

I know that with my recent review and the new study, it appears that the serotonin hypothesis shouldn’t hold too much weight in mood disorders, but that’s not the full picture.

One of the biggest caveats of the study was the fact that the researchers were measuring a biological marker against symptoms. As noted, these scales were not equipped or validated to correlate with physiological effects.

Furthermore, the authors of the study did conclude that antidepressants did have some evidence of working for depression.

Finally, I and other integrative doctors have had success with clients and patients with psychological imbalances using serotonin precursors.

Why?

I’m going to dive into that now so my fellow integrative doctors can relax about recommending tryptophan and 5-HTP for serotonin repletion.

Three Ways Serotonin Relates to Brain Function

Here are three ways that serotonin is related to brain health and function.

They also explain why antidepressants and supplements may work for some people, and not others.

1. The Brain is Loaded with Serotonin Receptors

The brain is rich in serotonin receptors, especially in the cerebral cortex (the dorsal raphe nucleus). This innervation regulates the function of this brain region by activating these various serotonin receptor subtypes. (Note, there is more than the one serotonin transport receptor that was measured in the study review).

Furthermore, serotonin also interacts with neurons that modulate GABA, an inhibitory neurotransmitter, through acting on these receptors. This further influences other brain areas.

The work at Amen Clinics has led to the classification of seven types of depression based on brain function imaging. One specific type is linked to the activity in the cortex region. When this region has low blood flow, patients tend to respond favorably to serotonin precursors and antidepressants.

The other subtypes, whose cerebral cortex and serotonin receptors are functional, will not be served, and could even be harmed, by more serotonin interventions.

2. Methylation and Serotonin

Another link to the efficacy of serotonin interventions and medications for depression is the influence of the epigenome, or how our brain cells respond to various cues from our environment (e.g., food, toxins, stress, etc.).

The Walsh Institute, like the Amen Clinics, also works with personalizing brain health treatments. They classify depression into five types. One category is based on methylation, which is a process that impacts the epigenetic response.

Those who are classified as “undermethylated” are lacking in enough methyl factors to activate various neurotransmitter receptors. This results in low levels of serotonin, dopamine, and norepinephrine. Therefore, undermethylators will respond favorably to psychiatric medications and nutrients that boost serotonin.

One way to assess for methylation is histamine levels in the blood. Undermethylators will have high histamine markers because methyl groups help break down histamine.

Conversely, people who are classified as “overmethylated” will have lower histamine levels and higher amounts of these neurotransmitters. They will be aggravated by additional neurotransmitter stimulation. Antidepressants and serotonin precursors would not be good interventions to help them.

3. Inflammation and Serotonin

When there is inflammation in the body, the precursor to serotonin, tryptophan, is converted to a proinflammatory mediator vs. into serotonin and melatonin. This is to rev-up the body for defensive actions and to fight any invaders.

In this case, inflammation serves a protective function to prevent a pathogen or harmful substance from getting into the brain.

This conversion pathway explains why the study review found LOWER serotonin in patients taking antidepressants, although they had improved symptoms. These patient was likely inflamed, and their serotonin was being used up to make inflammatory mediators. Therefore, keeping their serotonin supply available with reuptake inhibitors was likely helpful for their mood.

Integrative doctors would address the root cause of what was contributing to low serotonin. In this case, it would be finding the triggers of the inflammation and taming it as they provide serotonin support.

Other Considerations with Depression in the Literature

Beyond serotonin and the brain health factors, below are some more recent connections to depression in the scientific literature.

The Dopamine – Depression Mismatch

One theory of depression is based on a mismatch between avoidant behavior and relief or pleasure seeking. This balance lies in the part of the brain rich with dopamine receptors, which can become depleted by stress and other factors. According to this theory, there is also an interaction between serotonin and dopamine levels in the brain, such that an imbalance in one of them can impact the other, influencing mood.

Interestingly, one recent trial reported that a drug that modulated dopamine may actually also lower inflammation. To take this one step farther, this means it could also be impacting serotonin, as mentioned above. This would unite the inflammation-serotonin-depression connection.

The study included 40 depressed results, who also had high levels of an inflammatory marker. As noted, the researchers found that the drug reversed inflammation and changed brain pathways. The authors reported the significance of these findings:

Felger says the study findings are critical for two reasons. First, they suggest depressed patients with high inflammation may specifically respond to drugs that increase dopamine. Second, Felger says these findings also provide additional evidence that functional connectivity in reward circuitry may serve as a reliable brain biomarker for the effects of inflammation on the brain.

Metabolic and Mitochondrial Dysfunction

Another current theory on depression is that the brain is displaying metabolic dysfunction and that mental health is a reflection of this imbalance. For example, one such factor contributing to this problem is insulin resistance, which compromises glucose availability to the brain and cells. Treating this systemically has been suggested to help reverse both blood sugar issues in the body and brain dysfunction.

Dr. Chris Palmer holds this theory which “integrates biological, psychological, and social factors and helps us understand the connections between mental health and physical health.”

Recent research supporting this theory was based on the evidence that older adults with major depression often have rapidly aging mitochondria. Mitochondria are key cellular structures that have a variety of functions, including energy production and fueling metabolic processes.

In the study, the blood protein, GDF-15, linked to poorly functioning, older mitochondria, was found to be elevated in those with depression. According to MedicalXpress, “This is the largest study to date providing a link between accelerated mitochondrial aging and depression in older adults…”

Summary: Serotonin’s Not the Golden Ticket for Curing Depression, But It’s Not Debunked Either

So, as you can see, depression and all brain disorders are complex.

We can’t say the serotonin hypothesis is “debunked” because the study itself to prove this was measuring a biological marker based on symptom scales that weren’t validated to correlate with it.

What we can say is that addressing the root cause of depression, or any mental disorder, is not a simple or short process. It takes some effort from both the practitioner and client. However, it’s the only way I ethically feel that I can support my client’s brain health.

We must fully address the health of the organ that is causing the symptoms, the brain. We cannot continue to try to suppress the (non-agreed upon) symptoms with a pill or only use talk therapy to balance emotions without addressing biochemistry.

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