Functional Medicine Testing for Depression

What is Functional Medicine and Functional Assessment of Organic Acids?

Functional medicine involves the assessment of a person’s physiological health as a unique individual by inquiring about their lifestyle, genetic predispositions, nutrition, and metabolism. The practice of functional medicine includes investigating environmental factors and stressful events that may contribute to poor health and disease. Integrating all these areas and using the best available evidence can lead to a personalized nutritional intervention supporting recovery from illness.

To look at how metabolic health status can affect physiology and overall health, we test for organic acids (a group of metabolites), some of which may be used as biomarkers that reveal metabolic imbalances and may play an important role in pathophysiological pathways in disease. We use the NutrEval (by Genova Diagnostics), a functional and nutritional assessment of organic acid levels and other metabolites in the plasma and urine. These are functional indicators of health status across multiple domains. Here, we review a few organic acids that can be analyzed using the NutrEval assessment of organic acids to determine the presence of specific organic acids that can be potentially used as inflammatory markers of depression, which will allow us to create a nutritional plan tailored to your specific metabolic needs and therefore improve your health.

What is Depression?

Depression, also clinically known as Major Depressive Disorder, is a mental condition that an individual may experience due to many possible factors that may include psychosocial stress, early childhood adversity, genetic predispositions (single-nucleotide polymorphisms), metabolic and nutritional imbalances, neurotransmitter and neuroendocrine imbalances, inflammation, among many other possible factors [1].

Many studies have demonstrated that inflammation plays a significant role in the development of depression and other psychiatric disorders such as dementia, amyotrophic lateral sclerosis, multiple lateral sclerosis, Alzheimer’s Disease, and Parkinson’s Disease [2]. In addition to the causal link between inflammation and depression, there is a relationship between inflammation and digestive disorders, including Celiac disease, Crohn’s disease, inflammatory bowel disorder, and irritable bowel syndrome- all associated with depression. Furthermore, depression due to inflammatory causes can co-exist with increased BMI, diabetes, cardiovascular disease, and cancer. We will further focus on the contribution of inflammation in depression and identify a few specific organic acids that may potentially inform us about the presence of inflammation in an individual experiencing depression.

Depression at the Neurobiological Level and Known Biomarkers of Depression

It has been well-established that psychosocial stress is one of the primary causes of depression. Psychosocial stress initiates the release of widely known neuroendocrine factors highly involved in chronic dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis associated with MDD, including the glucocorticoid cortisol, which induces an inflammatory response.

Other common biomarkers involved in pathophysiological pathways of depression that are also affected by inflammatory signals include 5-hydroxytryptamine (5-HT, serotonin) and its receptor, kynurenine, kynurenic acid, and quinolinic acid. At the biological and molecular level, serotonin has been well-established as the neurotransmitter responsible for symptoms of depression when its levels are out of balance based on the monoamine hypothesis of depression.

Serotonin is synthesized from the precursor amino acid L-tryptophan, and upon release, it binds to the 5-HT receptor to exert its neurobiological effects. However, serotonin levels can be decreased by being degraded, which can occur through the overactivation of the enzyme indoleamine 2,3-dioxygenase (IDO) upon stimulation of inflammatory signals from the peripheral system. IDO breaks down L-tryptophan to kynurenine through the kynurenine pathway, driving tryptophan pools away from serotonin synthesis. Elevated levels of kynurenine can result and are then converted to kynurenic acid and quinolinic acid, thus dysregulating the brain’s kynurenic acid to quinolinic acid ratio. The overactivation of IDO in microglia from peripheral inflammatory signals is one of the initial mechanisms of neuroinflammation and neurotoxicity in depression and other psychiatric disorders [3].

What is the Role of Inflammation in Depression?

Now that we understand the crosstalk between the kynurenine pathway and inflammatory pathways, we can dive deeper into the mechanisms that make inflammation one of the many crucial hallmarks of depression. The Cytokine Hypothesis states that a root cause of depression is the abundance of proinflammatory signals such as cytokines and interleukins [4]. Cytokine signaling from the peripheral system alters the metabolism of neurotransmitters and neuroendocrine factors involved in depression.

The initial release of cytokines is caused by psychosocial stress leading to the secretion of catecholamines. Catecholamines include epinephrine and norepinephrine, which are involved in the fight-or-flight response, among other monoamines such as dopamine. The release of catecholamines into the sympathetic nervous system induces the production of monocytes in the bone marrow. These monocytes released into the peripheral system then encounter DAMPs (damage-associated-molecular-patterns), activating pro-inflammatory macrophages [5,6]. The activation of pro-inflammatory macrophages, cells of the innate immune system, is associated with decreased oxidative phosphorylation in the mitochondria and increased glycolysis, reflecting the repurposing of mitochondria from a metabolic organelle into a cell signaling organelle in pro-inflammatory macrophage activation [5,7,8,9].

These metabolic shifts are linked to elevated levels of the mitochondrial metabolite succinic acid and the glycolytic metabolite lactic acid, both organic acids [10]. Along with elevated levels of these two metabolites, there are attenuated levels of a-ketoglutaric acid and pyruvic acid [11,12,13,14,15]. The elevated levels of succinic acid in the pro-inflammatory activation of macrophages cause inflammation by producing IL-1b [16], a pro-inflammatory cytokine involved in activating the IDO enzyme.

Potential Biomarkers of Inflammation During Depression

We can therefore look at the succinic acid to a-ketoglutaric acid ratio and pyruvic acid to lactic acid ratio to potentially determine the inflammatory status of an individual experiencing depression. If the succinic acid to a-ketoglutaric acid ratio increases and the pyruvic acid to lactic acid ratio decreases, this may indicate inflammation. Indeed, research studies show elevated secretion of succinic acid in the inflammation from arthritis and liver damage [17,18]. Furthermore, this assessment can be confirmed along with the patient’s kynurenic acid to quinolinic acid ratio and levels of the serotonin downstream metabolite 5-hydroxyindoleacetic acid (5-HIAA), all organic acids also detected by the NutrEval test. Finally, the NutrEval test can also test for branched-chain amino acids (BCAAs) and branched-chain a-keto acids (BCKAs), frequently elevated in depression and other psychiatric disorders [19].

Testing for Organic Acids to Offer Nutritional Interventions for Improving Depression

Identifying organic acids potentially involved in the mechanisms of inflammation in depression and treating inflammation through nutritional interventions shows excellent promise in treating depression. This means that inflammatory foods would be a focus in the recovery of a patient experiencing depression. In addition to consuming a Mediterranean Diet and anti-inflammatory nutrients, it may also be wise to avoid food sources that cause inflammation, such as wheat, specifically gluten [20,21].

Another possible cause of inflammation is the excess intake of sugars and carbohydrates. Finally, there are beneficial anti-inflammatory herbs [22]. If used with a nutritional plan individualized to a patient, an increase in physical activity and a safe environment to inhibit re-exposure and re-traumatization from the psychosocial stressors at cause will support recovery from depression.

Lastly, supplementation with omega-3 essential fatty acids can improve symptoms of depression. Specifically, the omega-3 fatty acid, eicosapentaenoic acid (EPA), has been extensively shown to relieve symptoms of depression. Several studies show EPAs drive tryptophan away from the kynurenine pathway and toward the production of serotonin [23,24,25]. EPA levels can be increased by supplementation of fish oil and cod liver oil. Finally, some studies show aerobic exercise drives kynurenine away from its conversion to quinolinic acid in the central nervous system, thus contributing to a reduction in symptoms of inflammation and depression [26,27].

Article written in collaboration with Aracely Acevedo

David Wiss

David became a Registered Dietitian Nutritionist (RDN) in 2013 and founded Nutrition in Recovery, a group practice of RDNs specializing in treating eating and substance use disorders. In 2017, David received the “Excellence in Practice” award at the National Food and Nutrition Conference and Expo. The California Academy of Nutrition and Dietetics awarded him the “Emerging Dietetic Leader Award” in 2020.

He earned his Ph.D. from UCLA’s Fielding School of Public Health in the Community Health Sciences department (with a minor in Health Psychology) by investigating the links between adverse childhood experiences and various mental health outcomes among socially disadvantaged men.

His treatment philosophy is based on a biopsychosocial model which incorporates an understanding of biological mechanisms, psychological underpinnings, and contextual factors that integrate the social determinants of health. Wise Mind Nutrition’s website offers a fully online interactive treatment program in Spring 2023.