Rethinking Depression: Understanding Multifaceted Causes Beyond ‘Chemical Imbalance’

For years, the "chemical imbalance" theory has been the de facto explanation for depression and other mental health conditions. This theory suggests that depression is caused by a deficiency or excess of certain neurotransmitters, such as serotonin or dopamine. However, recent research has unveiled a rather inconvenient truth: this theory lacks solid scientific support. It would seem that depression and other mental health conditions are not solely caused by a simple chemical imbalance, or low serotonin levels in the brain.

Let’s delve into the myth of the chemical imbalance and explore underlying root causes of depression recognized by functional and integrative medicine.

Interested in the functional medicine approach to treating depression? Learn more.

The Chemical Imbalance Myth: Unraveling the Truth

The chemical imbalance theory suggests that conditions like depression result from imbalances in certain neurotransmitters, especially serotonin. The idea is that if we could "correct" these imbalances with long-term drug treatment—such as with the use of selective serotonin reuptake inhibitors (SSRIs)—we could effectively treat these conditions. However, this serotonin theory has crumbled under scientific scrutiny.

'No Consistent Evidence'

In 2022, an umbrella review of available evidence turned the serotonin hypothesis on its head. It found that the main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by low serotonin activity (1). The studies included in the review involved tens of thousands of participants.

Moreover, researchers noted there was convincing evidence that long-term antidepressant use actually reduced serotonin levels.

It is true that some depressed patients have reduced serotonin and norepinephrine activity, but the majority do not, according to available evidence. An estimated 25 percent of people who suffer from depression actually have low activity of these neurotransmitters (2).  

Beyond Neurotransmitters

Ultimately, reviews have failed to establish a concrete link between depression and chemical imbalances in the brain. The brain's biochemical processes are incredibly intricate and multifaceted, making it unlikely that a few neurotransmitters are solely responsible for complex mental health conditions.

Mental health conditions, including depression, manifest differently among individuals, suggesting that there is no one-size-fits-all "imbalance."

Read more about the integrative approach to anxiety & depression.

9 Possible Underlying Causes of Depression

Let's explore several of the underlying root causes of depression that functional and integrative medicine recognize.

Note: Treatment for depression should be highly individualized, and not all root causes apply to every patient. You should work with your doctor to determine the best treatment for you. This means the use of SSRIs or other medication may indeed be a necessary part of your treatment plan.

1. Inflammation

Inflammation is increasingly linked to depression. Chronic inflammation in the body can lead to the production of pro-inflammatory cytokines that affect the brain. This immune system activation might play a substantial role in depressive symptoms.

It appears that inflammatory agents in the blood can break down the barrier between the body and the brain, causing neuroinflammation and altering key neural communication. In people at risk for depression, inflammation may be a trigger for the disorder (3). Reducing systemic inflammation might be a useful treatment for depressive symptoms, regardless of the cause of the inflammation (4). 

Read: The Warning Signs of Chronic Inflammation

2. Hormonal Imbalances

Hormonal fluctuations, particularly in thyroid hormones and sex hormones (estrogen and testosterone), can contribute to depression. Hormonal imbalances often go hand in hand with mood disturbances (5).

Women are at twice the risk for anxiety and depression disorders as men are, and hormonal fluctuations may be a factor in this increased risk.

3. Chronic Illness

Chronic illnesses such as hypothyroidism, inflammatory bowel disease, and autoimmune disorders can cause widespread inflammation, resulting in depression (6). Immune dysregulation is very common in depressed patients, and makes it less likely that some forms of treatment will be successful.

Related: Reducing A High Toxic Burden & Other Causes of Immune Dysregulation

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4. Nutritional deficiencies

Certain mineral and vitamin deficiencies can contribute to depression. For example, low levels of vitamin D have been linked to depression (7). Vitamin D plays a critical role in brain health, and its deficiency is associated with impaired mood, cognitive function, and immunity. There is also some evidence to suggest that long-term use of selective serotonin reuptake inhibitors may contribute to certain nutrient deficiencies (8).

Additionally, the deficiency of magnesium, zinc, and omega-3 fatty acids has been linked to depression.

5. Gut health

The gut-brain connection is a significant focus in functional medicine. An imbalance in gut bacteria may lead to inflammation, affecting mood regulation (9). 

The gut microbiome, which refers to the community of microbes that reside in our gut, has a profound impact on our mental health. There is strong evidence that imbalance of gut flora is associated with mood disorders such as depression and anxiety. This is because the gut microbiome actively communicates with the brain through the gut-brain axis. Feeding your gut the right food can help regulate mood and improve overall health.

6. Stress & Trauma

Trauma is a distressing event or experience that can have long-lasting effects on mental and physical health. Childhood traumas such as abuse, neglect, and personal loss have been linked to the development of depression (10). Stressful life events affect the HPA axis, which can lead to chronic activation of the stress response system and ultimately result in depression.

Stress is a major factor in the development and persistence of major depression (11). Moreover, evidence suggests chronic stress impairs the body’s ability to produce neurotransmitters, which are crucial in regulating mood.

Functional medicine takes into account the psychological and emotional aspects of a person’s health when treating depression.

7. Sleep Deprivation & Circadian Rhythm Dysfunction

As we struggle to sync with our natural sleep and wake cycles, our physical and mental health often take a hit. Lack of sleep is linked to mood disorders, particularly depression.

Circadian rhythm disruption can result from inadequate exposure to natural light and overexposure to artificial light at night. This can cause hormonal imbalances, leading to depressive symptoms (12).

8. Medications

Certain medications, such as birth control pills and benzodiazepines, have been linked to an increased risk of depression.

Birth control pills can disrupt normal hormone production and affect mood regulation (13). Oral contraceptives also deplete nutrients that support a balanced mood, such as B vitamins and magnesium. 

Benzodiazepines increase the risk of depression, and long-term use can lead to tolerance and dependence (14). 

Read: B Vitamins for Cellular Health, Metabolism, & Longevity

9. Environmental toxins

Environmental toxins such as pollutants, heavy metals, and pesticides can affect mood and contribute to depression (15). They can cause inflammation in the brain, which is linked to major depressive disorder. Additionally, environmental toxins can disrupt the endocrine system, which can affect mood regulation and lead to depression.

What to Remember

If you struggle with symptoms of depression, consider reaching out to a functional or integrative medicine practitioner at CentreSpringMD who can help you identify and address the underlying causes. Remember that there is always hope and a path forward towards better health and well-being.

The “chemical imbalance” theory has long dominated our understanding of depression and mental health conditions. However, a growing body of research demonstrates that this theory is fundamentally flawed. Depression is a multifaceted condition with a multitude of potential root causes, each requiring a personalized approach.

Functional and integrative medicine embrace this complexity. By addressing factors like inflammation, gut health, nutrition, hormones, stress, environment, and lifestyle, practitioners can offer holistic and effective solutions for individuals struggling with depression. It’s time we move past the chemical imbalance myth and embrace a more comprehensive, patient-centered approach to mental health.


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