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

Depression casts a profound shadow over millions of lives worldwide. According to the World Health Organization (WHO), depression stands as a major cause of disability globally, underscoring the urgent need for effective intervention and support. However, its manifestations are as diverse as the individuals it affects, demanding nuanced, multifaceted approaches to diagnosis and treatment. 

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What Is Major Depressive Disorder?

Depression is a mood disorder characterized by persistent feelings of sadness, hopelessness, and loss of interest or pleasure in activities. It affects how you think, feel, and handle daily activities and can lead to various emotional and physical problems. 

There are several types of depressive disorders. Major depressive disorder (MDD), which is also called major depression and clinical depression, is one of the most common and severe forms of depression. MDD is diagnosed when a person experiences symptoms of depression that interfere with daily activities nearly every day for at least two weeks.

Major Depressive Disorder Signs & Symptoms

The symptoms and severity of depression can vary between affected individuals, and may include:

• Sad and anxious feelings
• Feelings of irritability, frustration, or restlessness
• Feelings of worthlessness, guilt, or helplessness
• Losing the desire to partake in activities that used to be fun
• Difficulty concentrating, making decisions, and remembering details
• Thoughts of self-harm or suicide

Physical symptoms that often accompany depression include: 

• Sleep disturbances
• Fatigue
• Changes in appetite
• Unintentional changes in weight 
• Low libido
• Muscle and joint pain
• Headaches
• Heart palpitations 
• Shortness of breath
• Digestive symptoms
• Dizziness

Root Causes of Major Depressive Disorder

Depression is viewed as a result of complex interactions between genetics, biochemical, environmental, and psychological factors. Factors that have been identified as increasing the risk of developing depression include: 

• A family history of depression
• History of trauma or other stressful events
• Planned or unplanned major life changes
• Medical problems, including cancer, stroke, and chronic pain syndromes
• Certain medications
• Drug and alcohol use

Biological Factors

Certain nutrients play vital roles in brain function and mood regulation. Deficiencies in nutrients like omega-3 fatty acids, amino acids, B vitamins (especially folate and B12), vitamin D, magnesium, zinc, and iron have been linked to an increased risk of depression. These nutrients are essential for neurotransmitter synthesis, neuronal function, and neuroplasticity – all critical for maintaining mental health.

Hormones like cortisol (the stress hormone), thyroid hormones, and sex hormones (estrogen, progesterone, and testosterone) can influence mood and emotional well-being. Elevated cortisol levels due to chronic stress, imbalances in thyroid function, or hormonal fluctuations during the postpartum period or menopause have been associated with depressive symptoms.

Neurotransmitters like serotonin, dopamine, and norepinephrine play key roles in mood regulation. Imbalances in these neurotransmitters have long been implicated in depression.

The gut-brain axis refers to the bidirectional communication between the gut and the brain, involving neural, hormonal, and immunological pathways. The gut microbiota plays a crucial role in this communication. Disruptions in the gut microbiota composition (dysbiosis) or intestinal inflammation can influence neurotransmitter production, hormone regulation, and nutrient absorption, thus impacting mood and mental health.

For example, certain gut bacteria produce neurotransmitters like serotonin and gamma-aminobutyric acid (GABA), which regulate mood. Imbalances in gut bacteria may lead to alterations in neurotransmitter levels. Additionally, gut dysbiosis and inflammation can compromise the integrity of the intestinal barrier, allowing toxins and inflammatory molecules to enter the bloodstream and potentially affect the brain, contributing to neuroinflammation and depressive symptoms.

Environmental & Psychological Factors

Poor diet, lack of exercise, inadequate sleep, and chronic stress can disrupt physiological processes and exacerbate biochemical imbalances associated with depression (59). 

Alcohol or substance abuse is a risk factor for depression. Findings from one study revealed that 20% of adults who struggle with ongoing alcohol addiction also met the diagnostic criteria for major depression. A destructive cycle ensues between depression and substance misuse; as many as one-third of individuals clinically diagnosed with depression resort to drug or alcohol abuse. (5) 

People who take medications with listed side effects of depression or suicidal thoughts are more likely to be depressed or suicidal. Medicines that can cause depression include proton pump inhibitors, allergy medications, estrogen-containing birth control, and antihypertensives. (52)  

How to Diagnose Major Depressive Disorder

An accurate diagnosis of MDD relies on a comprehensive evaluation of the individual's symptoms, medical history, and psychological functioning by a qualified healthcare professional.

Step 1: Use the DSM-5 Criteria

The Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) diagnostic criteria for MDD include the presence of five or more of the following symptoms during the same two-week period, which represent a change from previous functioning, with at least one of the symptoms being either depressed mood or loss of interest or pleasure:

• Depressed mood most of the day, nearly every day
• Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day
• Significant weight loss when not dieting, weight gain, or decrease or increase in appetite nearly every day
• Insomnia or hypersomnia nearly every day
• Psychomotor agitation or retardation nearly every day (observable by others)
• Fatigue or loss of energy nearly every day
• Feelings of worthlessness or excessive or inappropriate guilt nearly every day
• Diminished ability to think or concentrate, or indecisiveness, nearly every day
• Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

According to the DSM-5, the symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. They must not be attributable to the physiological effects of a substance or another medical condition. (37) 

The U.S. Preventive Services Task Force (USPSTF) recommends screening all adults older than 18 years for depression. The PHQ-2 and PHQ-9 are validated depression screening tools used in clinical practice. The PHQ-2 comprises two questions assessing depressed mood and lack of pleasure over the past two weeks, with higher scores indicating increased depression risk. The PHQ-9 is a more comprehensive tool with nine questions based on DSM-5 criteria, evaluating various depressive symptoms. 

Step 2: Rule Out Organic Causes

Laboratory studies should be ordered to exclude organic causes of depressive symptoms. These studies might include: 

• Complete blood count (CBC)
• Comprehensive metabolic panel (CMP)
• Thyroid panel, including TSH, free T3, and free T4
• Serum cortisol
• Ferritin
• Vitamin B12

Step 3: Order Additional Testing to Identify the Root Causes of Depression

Once clinical depression has been diagnosed and other diagnoses have been ruled out, specialty tests assist doctors in uncovering imbalances leading to depressive symptoms and, ultimately, making effective treatment recommendations. 

Organic acid testing (OAT) is a comprehensive metabolic test that analyzes urine samples to assess the levels of organic acids produced as intermediate products of metabolism. OAT is an excellent starting point for specialty testing for MDD because it casts a wide net to screen for imbalances in energy production, neurotransmitter metabolism, detoxification, oxidative stress, and nutritional status – all of which have implications for mental health. 

• Organic Acids (OAT) by Mosaic Diagnostics
• Organix by Genova Diagnostics
• Organic Acids Profile by US BioTek 

Abnormal results from the OAT can direct additional testing for specific body systems to get a more detailed picture of the biochemical, biological, and physiological variations that allow depression to set in. Some examples may include: 

• Micronutrient analysis to assess the levels of vitamins, minerals, and other essential nutrients that can influence mental health
• Neurotransmitter testing to identify specific neurotransmitter imbalances to increase the efficacy of pharmacologic and nutritional interventions
• Comprehensive stool analysis as a means to evaluate the gut-brain axis 
• Comprehensive hormone panels, which provide in-depth measurements of the production and metabolism of stress and sex hormones
• Genetic testing offers insights into an individual's unique genetic makeup and how it may influence their response to medications, a field known as pharmacogenomics.

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Treatment Plan for Major Depressive Disorder

One in three patients with MDD treated with medication alone have treatment-resistant depression. The following outline provides a framework for a treatment protocol emphasizing precision medicine, breaking free of the one-size-fits-all approach to treating depression.

1. Assess Risk of Suicidality 

Here's Why This Is Important: 

Assessing the risk of suicidality ensures patient safety and guides treatment decisions that match each patient's risk level. 

How Do You Do This?

Commonly used evidence-based suicide risk assessment tools include:

• Columbia Suicide Severity Rating Scale (C-SSRS)
• Beck Scale for Suicide Ideation (BSS)
• Suicide Assessment Five-Step Evaluation and Triage (SAFE-T)

These assessment tools help stratify patients into low, moderate, or high-risk categories to guide intervention planning and determine the appropriate level of care. 

Doctors should collaboratively develop safety plans with patients at risk for suicide to mitigate immediate risk and enhance coping skills. Safety plans typically include strategies for managing suicidal thoughts, accessing support networks, and seeking professional help during crises.

2. Reduce Depressive Symptoms

Here's Why This Is Important:

Reducing depressive symptoms enhances motivation, increases hope, and fosters a sense of agency and empowerment in individuals with depression, thereby facilitating their commitment to and engagement in the treatment process.

How Do You Do This?

Pharmacotherapy and psychotherapy are first-line treatments for depression. Antidepressant medications, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs), modulate neurotransmitter levels to induce a mood-boosting effect. 

The American Psychological Association (APA) recommends one of seven types of psychotherapy for treating depression, including:

• Behavioral therapy
• Cognitive therapy
• Cognitive-behavioral therapy (CBT)
• Interpersonal psychotherapy  (IPT)
• Mindfulness-based cognitive therapy (MBCT)
• Psychodynamic therapy
• Supportive therapy

There are a number of dietary and botanical supplements that have evidence-based antidepressant properties, including:

• St. John's Wort 900 mg daily
• Omega-3 Fatty Acids at least 1,000 mg daily
• Saffron 30 mg daily
• Lavender oil 80-160 mg daily
• Vitamin D 20,000-40,000 IU per week

3. Support the Gut-Brain Axis

Here's Why This Is Important:

Nutrient deficiencies, hormonal imbalances, and neurotransmitter imbalances often result from gastrointestinal dysfunction. Addressing the gut-brain axis by optimizing digestive function, restoring intestinal barrier function, and promoting a balanced gastrointestinal microbiome can inherently and simultaneously tackle these issues. 

How Do You Do This?

The composition of the gut microbiota is heavily influenced by diet. 

• Eat a Mediterranean-style diet rich in fiber, fruits, vegetables, healthy fats, lean proteins, and fermented foods, which promotes the growth of beneficial bacteria.
• Limit and Avoid foods high in processed foods, sugar, and saturated fats, which favor the growth of harmful bacteria.
• Reduce inflammation by incorporating anti-inflammatory foods, such as berries, dark leafy greens, fatty fish, herbs, and spices.
• Regulate blood sugar by balancing carbohydrates with a lean protein and fiber source with every meal. 

Aerobic exercise improves the diversity and abundance of beneficial gut bacteria. This may be one reason for the link between exercise's positive effects on mental health. Research suggests that walking, jogging, yoga, and strength training may be the most effective forms of exercise for treating 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, including Lactobacillus helveticus, Bifidobacterium longum, and Bifidobacterium breve, in doses ranging from 10-20 billion CFU daily, have shown promise in treating depression. (60)

Smoking significantly increases the risk of depression and perpetuates dysbiosis (26, 57). Patients who smoke should be encouraged to quit, and everyone should limit their exposure to secondhand smoke. 

4. Refine and Maintain

Here's Why This Is Important:

Assessing the patient's response to the treatment plan and modifying it accordingly follows personalized medicine principles. It ensures optimal treatment efficacy and improves long-term treatment outcomes. 

How Do You Do This?

This portion of the treatment plan is highly customizable and should be guided by the patient's medical history and lab results. Examples of treatment plan modifications to expedite symptom improvement and enhance mood include:

• Supplement with specific neurotransmitter precursors, such as tryptophan and vitamin B6, to support serotonin synthesis 
• Prescribe additional supplements to optimize specific micronutrients to their optimal range
• If labs indicate hormonal imbalances, balance estrogen, progesterone, and testosterone levels. B vitamins, zinc, and chasteberry exert their effects through distinct mechanisms to regulate hormonal pathways (28). 
• Make referrals for acupuncture, chiropractic adjustments, and massage therapy (59) 

The Risks of Untreated Major Depressive Disorder

Untreated depression takes a toll emotionally and physically. Potential complications include increased risk of: 

• Chronic diseases
• Substance abuse
• Self-harm and suicidal ideation
• Mortality 

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Key Takeaways:

• Timely and accurate diagnosis of depression is crucial for effective treatment. Healthcare professionals should be vigilant in recognizing symptoms and risk factors, utilizing standardized screening tools when appropriate.
• Depression is a multifaceted condition influenced by biological, psychological, and social factors. A comprehensive assessment should consider the patient's medical history, psychosocial context, and potential contributing factors to tailor treatment strategies accordingly.
• There is no one-size-fits-all approach to treating depression. Treatment plans should be personalized based on the severity of symptoms, treatment preferences, and patient-specific considerations. Options may include psychotherapy, pharmacotherapy, lifestyle modifications, and complementary therapies.
• If you or someone you know is struggling with suicidal thoughts, please reach out for help immediately. Contact a suicide hotline or mental health professional for support and guidance. You are not alone, and there are people who care and want to help you through this difficult time.