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A Root Cause Medicine Protocol for Patients With Depression: Comprehensive Lab Testing, Therapeutic Diet, and Supplements

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A Root Cause Medicine Protocol for Patients With Depression: Comprehensive Lab Testing, Therapeutic Diet, and Supplements

One in six people (16.6%) will experience depression at some time in their life. Those who suffer from or have a loved one struggling with depression can appreciate the toll this mental health disorder has on personal fulfillment and quality of life. Sadly, about one-third of people with depression suffer silently without seeking medical treatment. Functional medicine aims to lessen the stigma associated with mental health disorders, bringing awareness to a multifaceted approach that combines conventional and complementary therapies that address the underlying causes and offer tailored solutions for this prevalent ailment.


What Is Depression?

Depression is a mental health disorder characterized by persistent feelings of sadness, emptiness, and a lack of interest or pleasure in activities that one used to enjoy. It goes beyond normal sadness and can significantly impact a person's daily life, relationships, and overall well-being.

The term depression is often used to encompass a range of depressive disorders, including, but not limited to, major depressive disorder, persistent disruptive disorder (dysthymia), seasonal affective disorder (SAD), and postpartum depression (PPD). The various depressive disorders are differentiated based on the specific criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), a widely used classification system for mental health disorders. These criteria consider each disorder's duration, severity, and specific symptoms for diagnosis. (4

Depression Signs & Symptoms

The types and severity of symptoms of depression can vary from person to person. A diagnosis of major depressive disorder requires the presence of several symptoms that persist for at least two weeks and significantly affect a person's daily functioning. Here are the common symptoms of depression:

  • Depressed Mood: Feeling sad, down, or empty most of the day, nearly every day
  • Loss of Interest or Pleasure: A marked decrease in interest or enjoyment in activities that were once pleasurable or engaging
  • Changes in Appetite or Weight: Significant weight loss or gain, or changes in appetite (overeating or loss of appetite)
  • Sleep Disturbances: Insomnia (difficulty falling asleep or staying asleep) or hypersomnia (excessive sleeping)
  • Fatigue: Feeling tired, sluggish, or lacking energy, even after a restful sleep
  • Feelings of Worthlessness or Excessive Guilt: Ongoing feelings of inadequacy, guilt, or worthlessness
  • Difficulty Concentrating: Trouble focusing, making decisions, or remembering details
  • Suicidal Thoughts or Intent: Recurrent thoughts of death, suicidal ideation, or a specific plan for suicide
  • Physical Symptoms: Various physical symptoms such as headaches, stomachaches, or other physical aches that don't have a clear medical cause and don't resolve with treatment

Depression Possible Causes 

From a functional medicine perspective, depression is viewed as a result of complex interactions among genetic predispositions, biochemical imbalances, lifestyle factors, and environmental stressors. A family history of depression or other mood disorders increases the risk of developing depression (17). 

Depression is often linked to disruptions in key physiological systems, such as the gut-brain axis, immune system, and hormonal balance. Factors such as chronic inflammation, gut dysbiosis (imbalanced gut bacteria), and nutrient deficiencies can contribute to depressive symptoms. For example, the gut-brain connection highlights how imbalances in the gut can affect neurotransmitter production and mood regulation. Neurotransmitters (chemical messengers in the brain) are crucial in regulating mood. An imbalance of neurotransmitters, such as serotonin, norepinephrine, and dopamine, can contribute to depressive symptoms.

Changes in hormonal balance, such as those occurring during pregnancy, postpartum, menopause, or thyroid disorders, can impact mood and increase the risk of depression (12).

Furthermore, functional medicine emphasizes the impact of lifestyle choices on mental health. Poor diet, lack of exercise, inadequate sleep, and chronic stress can disrupt physiological processes and exacerbate biochemical imbalances associated with depression (28). Alcohol or drug abuse can contribute to or exacerbate depression. Additionally, withdrawal from certain substances can lead to depressive symptoms. Some medications, such as certain antihypertensives or corticosteroids, can have depression as a side effect. (17

Stressful life events, such as the loss of a job, a relationship breakdown, or financial hardship, can disrupt emotional equilibrium, triggering biological responses that affect neurotransmitter balance and brain function, potentially paving the way for depressive episodes. Similarly, the impact of childhood adversity, encompassing experiences like abuse, neglect, or dysfunctional family dynamics, can leave lasting emotional imprints that shape cognitive patterns, self-perception, and coping mechanisms, contributing to a heightened vulnerability to depression in later life. Furthermore, chronic illnesses can lead to a cascade of physiological changes, including inflammation and hormonal disturbances, which are closely intertwined with mood regulation, potentially precipitating or aggravating depressive symptoms. (17

Functional Medicine Labs to Test for Root Cause of Depression

Functional medicine labs help to uncover biochemical imbalances contributing to depression, helping providers create integrative treatment plans that incorporate lifestyle and nutritional interventions to support mental health.

Organic Acid Test

An organic acid test (OAT) is a great functional medicine testing option that can act as a preliminary screening test that casts a wide net on various contributory factors to depression. This panel measures cellular byproducts that evaluate for neurotransmitter status, dysbiosis, inflammation, and nutrient deficiencies.

Nutrient Profile 

Nutrient deficiencies can also be detected through a comprehensive nutritional assessment, which examines intracellular and extracellular levels of essential vitamins, minerals, antioxidants, amino acids, and fatty acids, which can exacerbate neuroinflammation and mood disorders when outside of the ideal range. 

Hormone Panel

Blood, saliva, and urine tests can measure various hormones and their metabolites, including estrogen, progesterone, testosterone, thyroid hormones, and cortisol. Popular test options include Vibrant America's serum hormones panel, Precision Analytical's DUTCH Plus, and Doctor's Data's thyroid profile.

Comprehensive Stool Analysis

A comprehensive stool test offers a snapshot into the gut-brain axis by measuring various gastrointestinal-related biomarkers related to digestion and absorption, inflammation, immune function, and the gut microbiome. 


Conventional Treatment for Depression

The conventional treatment approach for depression typically involves a combination of psychotherapy and pharmaceutical antidepressants. Psychotherapy (talk therapy) involves working with a trained mental health professional, such as a psychologist, psychiatrist, or therapist, to explore and address the underlying thoughts, emotions, and behavioral patterns contributing to depression. Antidepressant medications are commonly prescribed to regulate brain chemistry and alleviate depressive symptoms. The most common types of antidepressants include selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Medication is typically prescribed with psychotherapy for more comprehensive and effective treatment. (9

Other less commonly used treatments, often reserved for patients with treatment-resistant depression (TRD), include repetitive transcranial magnetic stimulation (rTMS), light therapy, transcranial direct stimulation, vagal nerve stimulation, deep brain stimulation, and sleep deprivation treatment (9).

Functional Medicine Treatment Protocol for Depression

A functional medicine approach to treating the root causes of depression includes extensive testing for biochemical and physiologic imbalances, followed by an individualized and integrative plan consisting of nutritional interventions, eliminating allergens, hormone replacement, and lifestyle changes as indicated by lab results.

Therapeutic Diet and Nutrition Considerations for Depression

Diet is an important component of mental health. A dietary pattern characterized by a high intake of fruit, vegetables, whole grains, fish, olive oil, low-fat dairy, antioxidants, and a low intake of animal foods has been associated with a reduced risk of depression. Conversely, a dietary pattern characterized by high consumption of red/processed meat, refined grains and sugars, high-fat dairy, and low intakes of fruits and vegetables is associated with an increased risk of depression. (14

The Mediterranean diet has garnered significant attention for its positive impact on mental health, including its role in managing and preventing depression. Rooted in the dietary patterns of countries bordering the Mediterranean Sea, this diet emphasizes nutrient-dense whole foods, healthy fats, and lean proteins that provide essential vitamins, minerals, and antioxidants that support brain and gut health and function. Several studies have suggested that adherence to the Mediterranean diet is associated with a lower risk of developing depression and a reduced prevalence of depressive symptoms. (24

Supplements Protocol for Depression

The following supplements may provide additional benefits in treating and preventing depression. You should always speak to your functional medicine healthcare provider before starting any new supplement, as many drug-nutrient interactions pose a risk for side effects.

Emotion Balance Support

Emotion Balance Support is a formula by Thorne that combines mood-enhancing nutrients and botanicals. Here is a highlight of some of the ingredients included in this formula and how they help to treat depression: 

B vitamins are essential for the healthy production and metabolism of neurotransmitters for mood regulation. Vitamins B6, B9 (folate), and B12 (cobalamin) are just a few of over 20 nutrients that have been linked to depression when deficient (10). Additionally, research studies support using B vitamins for treating depression, linking a higher intake of B vitamins with lower depression scores.

Tyrosine and tryptophan are amino acids that play important roles in synthesizing serotonin, dopamine, and norepinephrine, neurotransmitters associated with mood regulation, focus, and motivation (20). These neurotransmitter levels can be supported by supplementing with their amino acid precursors, as supported by research like this 2017 study, which showed the combination of tyrosine and tryptophan supplemented in women after giving birth reduced the risk of postpartum depression.

Rhodiola is an adaptogenic herb with anti-stress and antidepressant effects. A 6-week study concluded that daily dosing of a standardized rhodiola extract in patients with mild-to-moderate depression improved symptoms of depression, insomnia, and emotional instability. 

Dose: 2 capsules twice daily

Duration: at least six weeks

Vitamin D

Vitamin D deficiency is linked to mood changes, such as anxiety and depression. Studies show that vitamin D improves depressive symptoms to a similar or greater effect than pharmaceutical antidepressants when given in doses that improve and normalize serum vitamin D status.  

Dose: 1,000-4,000 IU daily, or 50,000 IU once weekly

Duration: 2-12 months

Omega-3 Fatty Acids (Fish Oil)

Omega-3 fatty acids are essential polyunsaturated fats found in high concentrations in fatty fish, walnuts, and flaxseeds. A 2016 meta-analysis associated a higher intake of omega-3 fatty acids with a reduced risk of depression. Supplementation is most effective when formulas contain higher doses of EPA than DHA.

Dose: 1,000-1,500 mg daily (combined EPA and DHA, with greater than 60% EPA)

Duration: 4-6 months


Saffron is a spice derived from the flower of Crocus sativus. It has a long history of use in traditional medicine and cooking, and it has been studied for its potential effects on mood and mental health, including depression. Several studies have explored using saffron extract as a possible natural remedy for depression. The active compounds in saffron, including crocin and safranal, are believed to influence neurotransmitter systems in the brain, particularly serotonin and dopamine. These compounds may help regulate mood and alleviate depressive symptoms. (18

Dose: 15-30 mg daily

Duration: 6-8 weeks


The link between gut health and mental well-being has generated increased interest in utilizing probiotics to address depression. Probiotics are designed to reinstate a harmonious equilibrium of gut bacteria, which could impact brain functionality and mood regulation by modulating the immune system, mitigating inflammation, and influencing serotonin production. Various probiotic strains have shown promise in treating depression, including Lactobacillus helveticus, Bifidobacterium longum, and Bifidobacterium breve. (29)

Dose: 10-20 billion CFU daily

Duration: 4 weeks

When To Retest Labs

Per clinical guidelines for treating depression, an improvement in depressive symptoms is expected 4-8 weeks after initiating treatment. At this time, a thorough review of patient symptoms and reordering labs to monitor patient progress can be performed, followed by necessary adjustments to medications, supplements, and lifestyle modifications. (9

Learning More About Depression



Functional medicine treatment options can typically be implemented safely alongside conventional interventions for a holistic approach to treating depression. By delving beyond surface symptoms and into the root causes of this multifaceted condition, functional medicine offers a personalized and holistic approach to depression that resonates with the uniqueness of each individual. 

The information provided is not intended to be a substitute for professional medical advice. Always consult with your doctor or other qualified healthcare provider before taking any dietary supplement or making any changes to your diet or exercise routine.
Learn More

Lab Tests in This Article


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