The purpose of this research paper is to understand the role the glutamate receptor N-Methyl D-Aspirate (NMDA) has in the pathological condition of major depressive disorder. Over the past couple of decades, it has been shown the NMDA receptor antagonist ketamine can rapidly relieve depression symptoms in 30 minutes. This is a significant improvement over current first line treatment for Major Depressive Disorder (MDD) which are Selective Serotonin Reuptake Inhibitors (SSRI’s). In the past it has been thought that dysfunction in the brains monoamine system of signaling was the source of diseases such as MDD and Generalized Anxiety Disorder (GAD). This article will look at some of the most recent studies about the NMDA receptor and its role in MDD. It can be reasonably concluded that pharmaceutical agents that are allosteric modulators or antagonists of the NMDA receptor may improve depression symptoms.
Keywords: NMDA receptor, Major Depressive Disorder, Glutamatergic Signaling
Major Depressive Disorder (MDD) is characterized by long term depressed mood with symptoms such as: agitation, anxiety, somnolence, suicidal ideation, rapid weight gain or weight loss, apathy, guilt, hopelessness, restlessness, insomnia and difficulty concentrating. MDD is currently considered one of the worlds 4 most important health problems (Stasiuk, Weronika, Monika Prendecka, Krzysztof Chara, & Teresa Małecka-Massalska. 2018). With current depression rates on the rise within the next decade MDD will rank second (after cardiovascular disease) as a leading cause of disability world-wide (Stasiuk et al. 2018).
Major Depressive Disorder is very common among first world countries around the world. For the last 50 years it has been thought by the medical community that Major Depressive Disorder is caused by a low concentration of monoamines in the synaptic cleft. One monoamine, serotonin, when in low concentrations was thought to be the cause of MDD. Most treatments of the last half century have focused on this theory. Most antidepressants aim to increase the levels of serotonin in the synaptic cleft. Many of them do this by blocking the reuptake of serotonin. Blocking the reuptake effectively increases the level in the cleft. The most used medications for this purpose are Selective Serotonin Reuptake Inhibitors such as Prozac, Paxil, Celexa, Zoloft, Lexapro and Latuda. These medications are effective at increasing serotonin levels however, it is a strain on the body’s neurons because they depend on the materials recycled from the reuptake to create more serotonin. This means that many times the benefits of such medications are short lived.
Since the introduction of Selective Serotonin Reuptake Inhibitors (SSRI’s) there hasn’t been a novel approach derived in the treatment of Major Depressive Disorder (MDD). It is estimated that only 60-70% of people treated with current methods obtain any relief from their symptoms (Stasiuk et al. 2018). Of those only an estimated 30% receive complete remission from their symptoms. Of those who only receive partial relief from their symptoms tend to relapse. Also those who are on SSRI treatment experience many unwanted side effects, creating new problems for patients. This shows that we have great need for new, novel approaches to treating depression.
Ketamine, a well-known party drug called “Special K” has shown in studies that it has the ability to rapidly reduce symptoms of depression (Stasiuk et al. 2018). Ketamine has no action on the monoamine system of brain signaling such as SSRI’s and older antidepressants. Its primary target is the N-Methyl D-Aspirate (NMDA) glutamate receptor in the brain. The brain has several main sources of synaptic signaling. The Monoamine system is more well known and as discussed earlier has been the main target for antidepressant treatments, specifically serotonin (a monoamine). Another, the glutamate system which is primarily responsible for neuronal excitability, is the target of drugs like Ketamine. Ketamine acts as an antagonist of the NMDA receptor and effectively blocks the binding of glutamate which will dampen the neurons excitability making it more difficult to fire an action potential. This rapidly relieves depression symptoms (in a way that is still investigational) and is also showing promise in reducing the depressive symptoms of those with bipolar disorder. It’s also thought that Ketamine is effective for treating depression by not only reducing the function of the NMDA receptor but also enhancing the ability of the AMPA receptor (another glutamate receptor). It is also thought that Ketamine’s ability to cause “induction of the CREB transcription agent (c-AMP response element-binding)” (Stasiuk et al. 2018) helps create the long-lasting antidepressant effect.
Amentadine, another NMDA receptor antagonist has shown antidepressant effects similar to that of ketamine. We can conclude from this information provided by Stasiuk et al. that an antagonistic effect on NMDA receptor can reduce the symptoms of depression. The effect that this has on the neuron is that it is less excitable because the action of glutamate is blocked. We may reasonably conclude from this information that depression may be caused by overstimulation of the neuron via the NMDA receptor. It also posits the question, why doesn’t GABA enhancement also have the same antidepressant-like effect?
GABA is the primary inhibitory neurotransmitter of the glutamatergic system of signaling. Increased amounts of GABA should have a similar effect to that of decreased glutamate concentration. This is not the case. No GABA increasing agent has shown to relieve symptoms of depression. Perhaps there is a particular effect that drugs such as Ketamine and Amentadine have on the NMDA receptor that GABA agents cannot replicate. It has been shown that blocking the release of glutamate may help relieve depression symptoms. Drugs such as lamotrigine which block sodium channels reducing the release of glutamate have shown the ability to relieve depression symptoms (Deutschenbaur, L., Beck, J., Kiyhankhadiv, A., Mühlhauser, M., Borgwardt, S., Walter, M., Lang, U. E. 2016).
There are other several other medications already on the market that act as an NMDA receptor antagonist other than ketamine and amantadine. One of these is dextromethorphan which is commonly found in over the counter cold medicines (Deutschenbaur 2016) Dextromethorphan intervention is mostly conjecture and hasn’t been studied for this purpose. Another medication known as memantine which blocks the NMDA receptor in a similar fashion as amantadine has been investigated as an antidepressant. Memantine has failed to prove that it is effective as an antidepressant at this point (Deutschenbaur et al. 2016). Another medication pioglitazone, an NMDA receptor antagonist, has shown a decrease in depression among studies of mice. Deutschenbaur et al. (2016) list many other investigational medications that are showing in studies that they have an effect on the NMDA receptor that reduces depression symptoms.
To fully understand why some medications that effect the NMDA receptor and relieve depression symptoms and others don’t we need to understand the anatomy of the receptor itself. The NMDA receptor is made of many different subunits and receptor binding sites. There are three main categories of NMDA binding sites. The first category is the NR1 binding sites with subunits A,B,C and D which bind glycine. The second category is the NR2 binding sites, with subunits of A,B,C and D where glutamate is bound. The third is the NR3 binding sites which are divided into two subunits, A and B which bind glycine as well as the NR1 sites. A study published in Brain Behavior Research by Francija, E., Petrovic, Z., Brkic, Z., Mitic, M., Radulovic, J., & Adzic, M. (2018) has developed a way to specifically target the NR2A binding site to see if it elicits an antidepressant effect. In their experiment they induce lipopolysaccharide depressive behavior in mice. The article states that lipopolysaccharide induced depression is mediated by the NMDA receptor (Francija et al. 2018).
The way Francija et al. tested their theory is that they created mice that had a knockout of the NR2A gene. This means that the mice no longer had the NR2A binding site because the gene for the subunit had been spliced out of the mice’s genes (a knockout of the gene). They then induced lipopolysaccharide depression in the knockout mice along with mice who had not been genetically altered. The attempt was to see if depression could still be induced in either type of mice. They were not able to induce depression in the knockout mice. This indicates that the NR2A binding site of the NMDA receptor is a key target in inflammation induced depression.
The NMDA receptor is complicated and has many parts. It is clear that simple antagonism of the receptor might not always create the antidepressant effects sought. Another study by Soichiro Ide, Yuiko Ikekubo, Masayoshi Mishina, Kenji Hashimoto, & Kazutaka Ikeda (2017) and published in the Journal of Pharmacological Sciences sought to find the role of another subunit of the NMDA receptor (2017). Similar to the last experiment Soichiro et al. sought to identify the role of the NR2D binding site in antidepressant effects. They tested this theory by taking out the NR2D gene in a group of mice. Without the gene the mice would not be able to produce NR2D subunit and binding site of the NMDA receptor. They then took this group of mice and a group of wild mice (the control) and tested if ketamine’s enantiomers (molecules that are mirror images of ketamine) still produced an antidepressant effect. According to their results (RS)-ketamine and (S)-ketamine still reduced depression symptoms robustly for up to 96 hours, however, (R)-ketamine only produced an antidepressant effect in the wild mice. This lead Soichiro et al. to conclude that the NR2D binding site is key to the antidepressant effects of (R)-ketamine but not to that of (RS) or (S)-ketamine.
What we can conclude from this article is that the enantiomers of ketamine work on different binding sites of the NMDA receptor. (R)-Ketamine depends on the NR2D binding site while (RS) and (S)-ketamine do not depend on it. It would seem that antagonizing either NR2D or NR2A will produce antidepressant effects. Investigations into the other binding sites is still ongoing. It is worth noting that another drug in development called Rapastinel (previously GLYX-13) has shown robust antidepressant effects as an allosteric modulator (binding of a molecule to make a conformational change in the protein) of the glycine site of the NMDA receptor (J.W. Murrough 2015).
As discussed above the NMDA receptor has binding sites for glutamate and glycine, but we failed to discuss that it also binds magnesium (2+). Magnesium (2+) is very important in regulating our NMDA receptors. Magnesium acts as a natural antagonist of the receptor. The NMDA receptor blockade produced by magnesium is removed when the neuron is depolarized. It is said that this effect plays an important role in synaptic plasticity (creating new neuronal connections) as well as long term potentiation (Ghasemi, M., Phillips, C., Trillo, L., De Miguel, Z., Das, D., & Salehi, A. 2014). This could indicate that a deficiency in magnesium intake could produce depression symptoms. Hypomagnesemia (low blood magnesium) is an issue in the United States and may play a role in rising depression rates.
A study by Harald Murck (2013) agrees that magnesium levels play a crucial role when targeting the NMDA receptor for depression therapy. According to Murck, magnesium plays an extremely similar role to that of Ketamine since they both block (antagonize) the NMDA receptor. He claims that intracellular magnesium levels could indicate the effectiveness of NMDA targeting drugs such as Ketamine. He states that Ketamine could be taking over the function of magnesium in magnesium deficient patients. This could mean that instead of treating the cause of affective disorders we are merely treating the symptoms with medications such as ketamine. According to this study’s results, intracellular magnesium levels should be the first thing looked at when considering the source of affective disorders.
There have also been studies concerning the effect zinc levels have on the NMDA receptor and consequently depression. Zinc has been shown to act like that of magnesium only it’s binding site is different (Matthew A. Petrilli, Thorsten M. Kranz, Karine Kleinhaus, Peter Joe, Mara Getz, Porsha Johnson, Dolores Malaspina. 2017). It has been shown that a deficiency of zinc can lead to symptoms of depression and other mental conditions. When there is a low amount of zinc and magnesium, the NMDA receptor is not being regulated correctly. This allows too much calcium to flow into the neuron creating issues that lead to depression (Patrilli et al. 2017).
The previous two studies used indicate that mineral deficiencies can lead to mental disabilities involving the NMDA receptor. This highlights the need for first world countries to include these important elements in their diet. Many people’s diets in the United States are often deficient of both nutrients (magnesium and zinc) and could play a very important role in the rising rates of affective disorders. A conclusion from these two articles could be that magnesium and zinc levels should be among the first things investigated by psychiatrists when treating a new case of an effective disorder. Supplements of magnesium and zinc are cheap and if used correctly can effectively return the bodies mineral levels to normal.
For many years studies have shown that affective disorders such as depression have a link to the increase of excitatory neurotransmitters. More specifically, mood disorders have been linked to an increase in excitatory neurotransmitters such as glutamate (Ghasemi et al. 2014). These increased levels have been found in both Bipolar Disorder as well as Major Depressive Disorder. Ghasemi et al. have theorized that the relationship between the glutamatergic system and mood disorders could have to do with the destruction of oligodendrocytes in the prefrontal cortex of the brain of people with Major Depressive Disorder and Bipolar Disorder. He says that the destruction of the oligodendrocytes could lead to excitotoxicity which is now connected with MDD and BPD. Ghasemi et al. state that when the NMDA system is disrupted that calcium ion influx is increased. We know that increased intracellular levels of calcium causes permeability issues within the mitochondria. This results in the release of free radicals which could terminate the cell.
The NMDA receptor also has a lesser known role in the symptoms of depression. As discovered by Vásquez, C. E., Riener, R., Reynolds, E., & Britton, G. B. Brain Derived Neurotropic Factor plays a large role in depressed patient’s symptoms (2014). Brain Derived Neurotropic Factor (BDNF for short) is a protein that helps facilitate the creation of new memories. BDNF also plays a crucial role in learning. What it does is help the neurons in the brain and sometimes in the periphery create new neuronal connections. BDNF also helps stimulate and regulate neurogenesis (creation of new neurons). Thus, it is not only crucial in creating new neuronal connections but also creating new neurons. Vásquez et al. have found that depressed patients have low levels of BDNF in the hippocampus and pre-frontal cortex. These areas of the brain are responsible for memory and higher thinking. Vásquez et al. (2014) explain that low levels of BDNF are related to calcium dysregulation in the brain. Specifically, they are related to hyperstimulation of the glutamate system of signaling. They found that overstimulation of the NMDA receptor by glutamate created issues with BDNF being synthesized in the neuron and released. This harms the brains ability to learn and create new memories. It was suggested by the study authors that antagonism of the NMDA receptor may help restore the balance needed in the glutamate signaling system, thus relieving many symptoms of depression.
Ghasemi et al. (2014) also explain that research has discovered a genetic link between depression and dysfunction of the NMDA receptor. Some single nucleotide polymorphisms (appreciable degree of point mutations within a specific population) have been found in the GRIN1, GRIN2A, and GRIN2B genes which code for the NR1, NR2A and NR2B binding sites on the NMDA receptor. These mutations could cause the receptor to be dysfunctional, leading to symptoms of depression. This genetic mutation could be an explanation as to why some people still don’t receive remission from their depressive symptoms through NMDA receptor antagonism because the interventions may be attempting to bind to a receptor site that isn’t there. There have been some inconsistencies with this information as it has been contradicted by other studies. Further research needs to be done to show the link between genetic inconsistencies, their effect on the NMDA receptor and incidence of depression in such individuals.
Beyond simple genetics, researchers have found an epigenetic component to depression and linked it to the NMDA receptor. Kaut, O., Schmitt, I., Hofmann, A., Hoffmann, P., Schlaepfer, T. E., Wüllner, U., & Hurlemann, R. (2015) have discovered that connection. In an article they published they explain the link that they have found. Kaut et al. explain that specific genes have been hypermethylated and turned off through epigenetic means. They took hippocampus and prefrontal cortex samples from depressed patients and tested the DNA for signs of methylation. They found that the GRIN2A gene had been hypermethylated. As mentioned before, the GRIN2A gene codes for the NR2A subunit of the NMDA receptor. This is further evidence of the key role of the NR2A subunit in depressive disorders. It also tells us that there is a key environmental factor. Something environmental is causing the hypermethylation of the GRIN2A gene.
When all of these studies are taken into consideration it is abundantly clear that dysfunction or hyperstimulation of the NMDA receptor leads to depression symptoms. These studies have shown us that through antagonization (blocking), or allosteric modulation of the NMDA receptor that depression symptoms can often be relieved. They have shown this by introducing interventions that antagonize or allosterically modulate the NMDA receptor and have shown through objective study that these interventions reduce depression symptoms. One of the key highlights of this overview is the apparent necessity of minerals such as magnesium and zinc in the proper function of the NMDA receptor. As mentioned before the rise of affective disorders could be connected to the worsening deficiency of these minerals. It is clear that targeting the NMDA receptor with new pharmaceutical interventions would be an effective way for the industry to head. Larger studies of current NMDA effecting drugs are called for. These studies can provide a guide to psychiatrists as to which of these drugs may be used safely with patients.
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