INL Article - Glutamate and Mental Health

INL Education: What is Glutamate, and how is it affecting your patient’s mental health?

In the 2017 Global Burden of Disease Study results estimated that one in ten people globally lived with a mental disorder of some description. Anxiety disorders accounted for almost 4% of these people, with the total number of people affected by anxiety considered around 264 million. (1)

Fast forward to the end of 2020, a year earmarked by the emergence of COVID-19 and the unique mental health challenges that the global pandemic has presented. Anxiety and other mental health hallmarks such as sleep disturbances have been at the forefront of symptoms our patients have been presenting within our clinics; in some cases, for the first time.

A recent study in Hong Kong released in May this year quantified this impact on mental health with a survey of 500 people aimed at evaluating anxiety and depression prevalence. 19% of the respondents included in the study had depression (PHQ-9 score above or equal to 10), and 14% had anxiety (GAD score above or equal to 10). More prominent in these results was 25.4% of the respondents who reported their mental health had deteriorated since the pandemic. (2)

Helping patients to manage anxiety in such extenuating circumstances is a challenge when it comes to differentiating between causal stress brought on by the pandemic and what’s commonly referred to as ‘generalised anxiety disorder.’

The term ‘anxiety’ covers nearly 12 different pathological states, including panic disorder, post-traumatic stress disorder, social phobia and specific phobias. With anxiety having such an early onset in comparison to other conditions, many people find their lives impaired for months, years or in worse cases, decades.

Therefore, looking at how we best manage the nuanced and intricate relationship between neurotransmitters, both excitatory and inhibitory, in anxiety, is an important consideration. Welcome then, to the stage, glutamate, the most abundant excitatory neurotransmitter in the central nervous system. (3)

Dietary glutamate is an endogenous amino acid found in everyday foods

Glutamate is often associated with food additives such as monosodium glutamate (MSG), the bound form of glutamate can be found in meat with the free form found in soy sauce and parmesan.

Although MSG has been classified as “safe” by the US FDA (4) dietary intake of MSG has been associated with somatic distress in both healthy and unwell individuals with chronic pain conditions. Specifically, MSG is connected with increased pain sensitivity as well as symptoms such as muscle tightness, headache, general weakness and arrhythmias. Research, though, is still inconsistent regarding how much may trigger symptoms. (5)

Glutamate plays a role in many different functions within the brain

Glutamate is the primary excitatory neurotransmitter in the brain and central nervous system. It plays many roles, most notably in neurodevelopment, key examples being differentiation; migration and development; (6) learning, such as long-term potentiation and depression. (7) It does this via mediating nerve signalling or passing chemical messages from one nerve cell to another. Under normal conditions, this can play an essential role in our day to day brain function.

Glutamate toxicity and inflammation are linked to depression and anxiety

So, what happens when it all goes wrong? There can be two different forms of dysregulation that can either appear independently or together. First, there can be too much glutamate that leads to an overexcitation of the nerve cell. Secondly, the receptor on the cell that it’s communicating with can be markedly oversensitive. This oversensitivity means it takes less glutamate to excite that cell hence the term, overexcitation. (8) If either or both of these things occur then glutamate can essentially excite cells to their death, a process referred to as “excitotoxicity.” (9)

It is in this increased glutamate receptor activity that we can begin to see the beginnings of conditions like anxiety and depression. One of the critical mediators of this is the relationship between glutamate, inflammation and serotonin or more importantly, the conversion of tryptophan into serotonin.

Besides the well-documented deficiency in serotonergic neurotransmission, evidence now points to the increased activation of the glutamate receptors in major depression (10) and anxiety (11).

In studies on major depression, the “immune activation” theory is moving to the forefront, and it seems one enzyme might be prominent in this new understanding. Via research in numerous conditions, we can now see the role that pro-inflammatory cytokines such as interleukin-2, interferon-γ, or tumour-necrosis factor-α can play in the activation of the tryptophan and serotonin-degrading enzyme, indoleamine 2,3-dioxygenase (IDO). (12), (13)

Increased activation of IDO and the following enzyme kynurenine monooxygenase by these pro-inflammatory cytokines leads to increased production of quinolinic acid, known to be a potent agonist of the NMDA receptor. Quinolinic acid is a strong-acting and robust excitotoxin, and prolonged exposure, even in average physiological concentrations is sufficient to cause excitotoxicity. (14) (15) In fact, even short term exposure of quinolinic acid can cause quick neuronal excitation via the activation of NMDA receptors. (16) This can build on itself as the quinolinic acid selectively induces further activation of the NMDA receptors in neurons found in the striatum, neocortex and hippocampus of the brain, leading to an increased excitotoxic burden within these regions. (17) We can then see the duel problem listed above. Too much glutamate production leads to too much excitation along with an oversensitivity of the receptor aggravating the situation. (18)

Downstream, an overproduction of glutamate and serotonin deficiency is caused by the enhanced consumption of tryptophan, causing more issues. (19) This is compounded by an immune response which sees tryptophan withdrawn from the inflammatory picture because of its essential role in the survival of infectious microbes; such as bacteria and their relationship with the consumption of tryptophan. (20) (21) (22)

Astrocytes are a vital part of the clearance of glutamate – it all comes down to transport

We have now explored one of the pathways leading to increased glutamate production, but another functional process necessary in glutamate homeostasis is the role of the astrocyte. Astrocytes make up the majority of the cells within the central nervous system (CNS) and perform a crucial role in the maintenance of the CNS. (23) One of the essential functions of the astrocyte is the balance of neurotransmitter regulation in the CNS via the uptake of synaptically released neurotransmitters such as glycine, GABA and importantly for our discussion, glutamate. (24)

Glutamate clearance in the CNS is mediated by glutamate uptake transporters expressed, mostly, by astrocytes. Therefore, astrocytes play an important role in glutamate homeostasis by preserving the balance between glutamate uptake and release to adjacent neurons. (25) For example, astrocytes convert glutamate into glutamine by glutamine synthase (26) and whilst other cells in the CNS participate in glutamate clearance, astrocytes are the most efficient in this process, as they remove around 90% of all released glutamate in the CNS! (27) (28)

It is easy to see now that with astrocytes important role in the management of glutamate that astrocyte dysfunction can lead to excitotoxicity as well as an imbalance between the inhibitory neurotransmitters such as GABA and excitatory neurotransmitters like glutamate. (29)