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The Intersection of Ketamine, Microglia, and the Kynurenine Pathway

In today's post, I dive into the literature to learn more about the connection between microglia, ketamine, and the kynurenine pathway. One of the labs I will often assess as part of a comprehensive functional psychiatry assessment is an organic acid test (OAT), which is a tool that evaluates the levels of various organic acids, the small molecules produced during the body's energy generation and metabolic processes.

The organic acid test is akin to checking the 'waste products' of our body's internal factory to see how well different parts are working. From a mental health perspective, it examines substances involved in mood, attention, and cognition. The organic acid test includes information about an individual's kynureine pathway. This pathway is involved in the metabolism of the amino acid tryptophan, can affect mental health as its dysregulation can lead to an imbalance in neuroactive compounds (kynurenic acid and quinolinic acid), potentially contributing to conditions such as depression and anxiety.

My questions of curiosity are: 1) What impact does ketamine have on microglia 2) Do we have biomarkers that we can use to measure this and 3) Can we get a better idea of who might benefit from ketamine therapy? So let's dive in. 🤠

Neuroinflammation, Microglia, and Depression

Recent years have seen an increased appreciation for the link between inflammation and depression (Miller & Raison, 2016). Microglia, the primary immune cells of the brain, are an essential interface between the immune system and the brain. Chronic inflammation, as seen in conditions like Major Depressive Disorder (MDD), leads to microglial activation, which in turn increases inflammatory biomarkers like IL-1β, IL-6, TNF, and C-reactive protein (CRP) (Enache, Fakra, & Lépine, 2019).

This inflammation triggers a diversion of tryptophan metabolism towards the kynurenine pathway, resulting in decreased serotonin synthesis, a significant feature of depression (Dantzer, O'Connor, Freund, Johnson, & Kelley, 2008).

Ketamine and the Kynurenine Pathway

The kynurenine pathway produces two key metabolites: kynurenic acid and quinolinic acid. Quinolinic acid, an N-Methyl-D-Aspartate (NMDA) receptor agonist, has roles in neuroinflammation and neurodegeneration. On the other hand, kynurenic acid acts as an NMDA receptor antagonist and has neuroprotective properties (Savitz, 2020).

Importantly, the balance between these two metabolites, known as the kynurenic to quinolinic acid ratio, has been shown to predict ketamine response in patients (Savitz, 2020). Ketamine, a potent NMDA receptor antagonist, has demonstrated potential as a rapid and effective treatment for depression, including treatment-resistant depression (Duman, Aghajanian, Sanacora, & Krystal, 2016).

Kynurenine Pathway

One groundbreaking study about how ketamine may lessen inflammation related to major depressive disorder is the one conducted by Verdonk and his team.

Their research explored the effects of ketamine in a mouse model of depression induced by lipopolysaccharide (LPS), a molecule known to stimulate an immune response. They found that a single dose of ketamine reversed the depressive-like behaviors in these mice. The changes were reflected in decreased anxiety and improved self-care behaviors, a reduction in the production of cytokines (proteins important in cell signaling) in the brain tissue, modulation of microglial reactivity, and a decrease in the production of quinolinic acid by microglia1.

This last point is particularly relevant to our earlier discussion on the kynurenine pathway. As we know, an excess of quinolinic acid, a neurotoxic metabolite in this pathway, can contribute to depressive symptoms. The ability of ketamine to reduce the production of quinolinic acid offers a new pathway through which it might alleviate depression.

Importantly, Verdonk et al's study did not just focus on mice. In a translational approach, they also found that the ratio of kynurenic acid to quinolinic acid could predict a patient's response to ketamine treatment for treatment-resistant depression. Additionally, a reduction in quinolinic acid levels following a ketamine infusion was found to be a predictor of the decrease in MADRS score, a measure of depression severity.

This research signifies a promising lead in the field of psychiatry, opening new avenues for the use of ketamine as an immunomodulatory agent to treat depression. Further research is needed to fully understand the underlying mechanisms, but the potential benefits are promising. Understanding the interplay between ketamine, microglia, and the kynurenine pathway could yield more effective treatments for depression, particularly for those patients who have found little relief in conventional therapies.

Other Factors that can Affect the Kynurenic to Quinolinic Acid Ratios

Various factors can influence the kynurenic acid to quinolinic acid ratio, and thus potentially mental health status. These include:

  1. Stress: Chronic stress can activate the immune system and increase the production of pro-inflammatory cytokines. This can subsequently drive tryptophan metabolism more towards the production of quinolinic acid via the kynurenine pathway, which can contribute to neurodegeneration and depressive symptoms.

  2. Diet and Nutrition: Deficiencies in certain vitamins, such as B6, can hinder the enzymatic conversion of kynurenine to kynurenic acid, leading to a higher quinolinic acid ratio and potentially contributing to depressive symptoms. Additionally, a diet high in processed foods can lead to chronic inflammation, again potentially shifting the kynurenine pathway balance unfavorably.

  3. Genetic Factors: Some individuals might have a genetic predisposition that affects the enzymes involved in the kynurenine pathway, influencing the ratio of kynurenic acid to quinolinic acid and potentially contributing to mental health disorders.

  4. Gut Microbiome: The gut microbiota can influence the immune system and inflammation levels in the body, which in turn can influence the kynurenine pathway. Dysbiosis of the gut microbiota has been linked to alterations in the kynurenine pathway and mental health disorders.

  5. Tickborne Diseases: Tick-borne diseases can indeed influence the kynurenic acid to quinolinic acid ratio, affecting mental health. When a tick bites a host, it can transmit a variety of pathogens, including bacteria and viruses, that can cause diseases such as Lyme disease, babesiosis, or anaplasmosis. These infections trigger a robust immune response in the body, leading to inflammation.

  6. Lifestyle factors: Lack of physical activity, poor sleep, and smoking can cause systemic inflammation, thereby potentially influencing the pathway and the kynurenic:quinolinic acid ratio.

Applications in Integrative Psychiatry and Considerations for Pondering and Research

In integrative psychiatry, a comprehensive approach to patient health is essential. This approach may include (depending on the patient), understanding and measuring the kynurenic to quinolinic acid ratio to assess depression severity and predict response to ketamine treatment (Savitz, 2020).

As we continue to refine our understanding of depression and expand the therapeutic toolkit, more targeted and effective treatments utilizing the kynureric: quinolinic acid ratio as a biomarker for psychiatric disorders that address inflammation seems potentially valuable. Do we know if this ratio can guide treatment decisions about who may benefit most from ketamine therapy? Not yet, but let's stay tuned.

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