How does Ketamine work for depression? Glutamate and neuroplasticity. Ketamine infusions for depression Northern Virginia

NOVA Health Recovery Ketamine Infusion Center Fairfax, Virginia

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Glutamate is the single most powerful neurotransmitter in the brain. It is also the most common neurotransmitter in the brain.  

Glutamate is involved with: 

  • Learning 
  • Cognition 
  • Increased Synapse formation 
  • Neuronal plasticity 
  • Glutamate is neurotoxic in excess 

The core therapeutic effect of antidepressants is neuronal plasticity and increased synapse formation. 

Astrocytes play a critical role in brain health maintenance and function: 

The non-neuronal cells (I.e., astrocytes ) are extremely important mediators of brain health and function – the astrocytes and microglial cells play an incredible role in brain health maintenance. Astrocytes and glutamate play a role in: 

Neurological disorders: autism, Down’s syndrome, fragile x syndrome, chronic traumatic encephalopathy 

Neurodegeneration: Wernicke’s encephalopathy and Korsakoff syndrome (low thiamine) and stroke 

Psychiatric disorders: Depression, addiction, schizophrenia 

Interestingly enough, the supporting cells, the glial cells, are the major players in brain health and function. 

Glutamate is complex. It is an amino acid that is everywhere and considered non-essential since our body can manufacture it. It is excitatory and is synthesized in axon terminals of glutamatergic neurons and produced from alpha-ketoglutarate from the TCA cycle or from the amino acid Glutamine. Of note, Glutamate autoregulates itself in that Glutamate produces GABA, which is an inhibitory neurotransmitter. 

Glutamate cycling is complex as the diagram below demonstrates: 

Glutamate is derived from glutamine or alpha ketoglutarate and also arginineproline, and histidine. It is synthesized in the axon terminals of glutamatergic neurons. The presynaptic transporters concentrate glutamate into vesicles through a packaging protein VGLUT. The inrush of calcium causes the vesicle to release the glutamate into the synaptic cleft where the post synaptic neuron receptors interact with the glutamate or else the glial cells take up the glutamate and recycle it to the presynaptic neuron. 

The vesicular glutamate transporter (VGLUT) is a transport protein that allows glutamate to be packaged and released to interact with one of three ionotropic receptors:  AMPA, NMDA, or Kainate receptors. Glutamate receptors are located on pre-synaptic neurons, post-synaptic neurons, and glial cells in the synapse. 

The EAAT (excitatory amino acid transporter) takes up synaptic glutamate and transports it into the glial cells and neurons to be converted to glutamine (GLN)  for transport back to the pre-synaptic neurons, where it is converted back to excitatory Glutamate. Excess free glutamate is toxic to neurons and should not “stay around” for long. 

Of note, our taste buds’ sense of umami is a reaction with glutamate and mediates the appetitive response to protein-rich food. Glutamate plays a fundamental role in evaluating the nutritional value of food. 

Glutamate is a great coordinator in neuronal function and its release results in the production of mTOR (mammalian target of rapamycin- involved with protein production), Brain Derived Neurotrophic Factor (BDNF- involved with synapse formation), and PSD-95 (post-synaptic density protein- a major scaffolding protein for neurons and dendrites. 

MTOR is a kinase (an enzyme) that generates proteins necessary for the production of new synapses (synaptogenesis), new nerve cell formation (neurogenesis), and dendrite formation. Dendrites are critical for information processing in that a neuron can have 100,000 connections via dendrites. These dendrites are made through the function of the scaffolding protein PSD-95

Rapid acting antidepressants increase synapse numbers and function through increased BDNF release. The rapid acting antidepressants increase synaptic proteins, PSD95, and GluA1 to accomplish synaptogenesis. 

The main players of this are the receptors of which there are ionotropic and metabotropic receptors. Ionotropic receptors are immediate acting, opening ionic channels, whereas matabotrophic channels take time to get results. NMDA, AMPA, and Kainate receptors are ionotropic and are members of the Glutamate receptors. 

There are two type of Glutamate release: 

  • Burst Glutamate release 
  • Drip Glutamate release 

Extracellular glutamate has two functional pools: 

  • Synaptic Glutamate from a transient burst of Glutamate from the presynaptic neuron 
  • Ambient extracellular Glutamate from steady background Glutamate from the glia that fills the extracellular space at a low level of glutamate. 

There is a baseline Glutamate that comes from our glial cells. 

NMDA receptor: 

The NMDA receptors contain 4 subunits of a combination of NR1, NR2, and NR3: Generally, it is composed of 2 NR1 and 2 NR2 subunits, and occasionally an NR3 subunit. This results in diverse electrophysiological and pharmacological responses. 

There is a binding place in the channel pore for magnesium and at resting membrane potential, the Magnesium attaches to the binding site and blocks ion flow through the channel. 

AMPA Receptor (AMPAR): 

  • AMPARs are activated by glutamate as well, inducing a fast excitatory synaptic signal involved with early glutamatergic effects in the synapse. 
  • AMPArs are co-expressed with NMDAR 
  • This results in neuroplasticity and neural protection. 
  • AMPA has less affinity for Glutamate and so there is a rapid dissociation of glutamate from AMPA and they deactivate rapidly.  
  • AMPA activation results in the inward flow of sodium 

NMDA and AMPA work together.  AMPA looks like NMDA as it has four subunits (GluR1,2,3,4).  

AMPA activation is needed for improvement in depression due to increased BDNF. Ketamine-induced BDNF release is dependent on the activation of glutamate-AMPA receptors and L-type voltage dependent calcium channels. 

Within 15 minutes of signaling AMPA, we see synaptic plasticity and neurogenesis – in 15 minutes! This is faster than ECT. 

Glutamate and Glycine are both important. There are Glutamate and Glycine receptors inside the NMDA receptors. Both are needed to make the receptor work. You can modulate glycine and glutamate to make the system work. 

The NMDA receptor is ionotropic glutamate receptor for controlling neuronal plasticity and memory function. Glutamate binds to the agonist site on the NMDA receptor, while glycine and D-serine bind to a glycine modulatory site, while magnesium blocks the receptor in a voltage sensitive manner. Both Glycine and Glutamine need to bind the NMDA receptor to make it open to allow sodium and calcium into the neuron and Potassium out. 

So again, Glycine receptor must also be activated to activate the NMDA receptor.  

Glycine is an NMDA agonist. It is an important amino acid released by glial cells and glutamatergic neurons to cause synaptic responses. Activation of the Glycine receptor (GlyR) contributes to the glycine-induced NMDAR endocytosis and suppresses NMDAR function as well.  

The net effect of glycine is to decrease NMDA response. 

Glutamate modulation (such as with ketamine) enhances synaptogenesis.  

Stress causes dendritic spines and connections to come apart, but Ketamine, an NMDA antagonist, upregulates AMPA and causes the production of BDNF, PSD-95, and mToR activation. This rapidly causes the production of dendritic spines and neuroplasticity. 

Optimizing glutamate is important for synaptic plasticity, cognition, learning, and mood. Not too much and not too little – but just enough glutamate is what works. 

Glutamate issues in Psychiatric disorders

Astrocyte (a supporting cell) pathology in Depression is more severe than neuronal changes. Depression may primarily reside in the supporting cells of the brain. 

In Major depression (MDD), we get astrocyte dysfunction and atrophy, with decreased astrocytes and GFAP expression and decreased glutamate uptake with increased inflammation. We see altered (decreased) secretion of growth factors and increased cytokines as well as charges in gap junctional connectivity. The result is abnormal connectivity in neuronal networks and neurotransmission imbalance. 

Mechanisms of Glutamate

  1. Presynaptic release of glutamate 
  1. Postsynaptic ionotropic receptors activated (NMDA and AMPA receptors) 
  1. Reuptake of glutamate by glial glutamate membrane transporters 
  1. Glutamate metabolism and recycling by glutamate/glycine cycle 

With stress we can get: 

  • Increased glutamate release 
  • Altered expression and function of ionotropic glutamate receptors 
  • Altered clearing of glutamate from the synapse 
  • Reduced glutamine/glutamate cycling and decreased glial cell density 

Anything from release of Glutamate to the glial cells functioning and glutamate trafficking can and are impaired in depression. 

Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017;4(5):409-418. doi:10.1016/S2215-0366(17)30015-9 

Humans who suffer from MDD, peripheral blood levels of glutamate show that there are significant abnormalities in glutamate levels, with glutamate levels being higher in MDD patients. 

Glutamate and inflammation go together.  Excess amounts of glutamate cause microglia to produce IL-6, TNF-alpha and this leads to CNS inflammation and loss of synaptogenesis and loss of neuronal plasticity.  

Treatment resistant depression (TRD) :  Non-response to two or more antidepressant (AD)  agents at an adequate dose for 6 weeks. If you fail one antidepressant, the chance of a second agent producing remission is less than 20%. TRD patients are more severely impaired than non-TRD patients in that they will suffer for a longer duration from depression, have more hospitalizations along with higher rates of job loss and financial distress. 

Factors associated with TRD include

  • High levels of anxiety 
  • Age of onset 
  • Intensity 
  • Personality Disorders 
  • Social Phobia 
  • Current suicidal risk 
  • Nonresponse to first AD treatment 
  • Melancholic features 

Factors to consider in a patient who fails trials of antidepressants include: 

  • Is it the correct diagnosis? 
  • Treatment adherence 
  • Adequate duration of treatment 
  • Adequate dosing of treatment 
  • Comorbid medical issues that may interfere with treatment 
  • Appropriate drug choice 
  • Comorbid psychiatric conditions 
  • How severe is the illness? 

Many patients do not adhere to the treatment and many patients are not on the appropriate therapy, thus leading to TRD. 

Glutamate- based treatment of depression is the key to Treatment resistant of depression. 

Glutamate targets for mental health treatment: 

  •  NMDA receptor antagonists such as ketamine, magnesium, zinc, and NR2B subunit antagonists. 
  • AMPA modulators 
  • EAAT2 enhancer such as ceftriaxone 
  • Glycine receptor agonists 
  • Inhibitor of glutamate release, antagonist of NMDA, AMPA, Kainate receptors (riluzole) 

Ketamine is available currently and is highly effective in the treatment of depression. At the NMDA receptor, ketamine interacts with the GluN1/GluN2A subunits rather than the GluN1/GluN2B subunit and this is what produces the psychomimetic effects. The NMDA receptor is made of subunits. 

This is a matter of optimization of the NMDA functioning – there is an optimal activation/antagonism of the receptor to get functioning just right: Agonism and antagonism of the NMDA receptor are both clinical approaches to treating major depression. 

Recall how ketamine works: 

If we change the level of inhibition of the glutamate neuron, we can get surges of glutamate coming from the presynaptic neuron that occupy the AMPA receptors primarily in the postsynaptic neuron. This block of NMDA receptor of the glutamate neuron results in MORE Glutamate which results in AMPA activation and the TRKB  receptor activation by BDNF. Ketamine is an NMDA antagonist and this results in a brief release of Glutamate that activates AMPA. 

Sanacora G, Schatzberg AF. Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders? [published correction appears in Neuropsychopharmacology. 2015 Apr;40(5):1307]. Neuropsychopharmacology. 2015;40(2):259-267. doi:10.1038/npp.2014.261  

Here are the steps again

  1. Ketamine blocks the NMDA receptor of the GABA interneuron that generally inhibits glutamate release 
  1. This results in a surge in glutamate release and cycling 
  1. There is an increase activation of AMPA receptors 
  1. This results in increased BDNF which binds to TrkB receptors to activate mTOR leading to transphosphorylation and activation of extracellular signal-related kinase (ERK) and suppression of glycogen synthase kinase (GSK-3_ and synaptogenesis. Through increased protein synthesis and synapse number. 
  1. The effect is improved depression! 

The end results of the manipulation of glutamate signaling are intracellular activation of mTOR and the production of BDNF, activation of PSD-95, scaffolding proteins, synaptogenesis, and inhibition of GSK-3 (this is anti-inflammatory). These changes occur in 2-3 hours. 

Dwyer JM, Duman RS. Activation of mammalian target of rapamycin and synaptogenesis: role in the actions of rapid-acting antidepressants. Biol Psychiatry. 2013;73(12):1189-1198. doi: 10.1016/j.biopsych.2012.11.011 

A single infusion of ketamine can produce remission in one-third of TRD in a single day in contrast to traditional monoaminergic based treatments that take 10-14 weeks of continuous use. The onset of action is 4 hours to 1 day and again, ketamine can produce remission in one-thrid of patients. 

SSRIs produce only antidepressant effects whereas ketamine also targets: 

  • Anhedonia 
  • Fatigue 
  • Suicidal Ideations (independent of ketamine’s antidepressant effects) 

Glutamate impacts both depression and wellnessThere is an absence of mental wellness in cognition and executive functioning in many depressed patients. Also, ketamine enhances wellness traits such as: 

  • Happiness (less worry) 
  • Calmness 
  • Energy (less fatigue) 
  • Self-esteem (less worthlessness feelings) 

Ketamine is a broad-spectrum antidepressant therapy unlike any other medication used in psychiatry. 

Even one dose of ketamine can be anti-suicidal as reviewed in one study that utilized 10 other studies as a metanalysis. Depression may a result of a glial-based disease and is more related to loss of synaptogenesis and neuroplasticity. Depression is not necessarily related to monoamines and not related only to neuronal disorders.  

Esketamine is the S-enantiomer of ketamine applied intranasally in a new medication called Spravato. Ketamine exists as R- and S- ketamine, which are mirror images of each other. Most clinics use this form of ketamine (a racemic mixture as a combination of R- and S- ketamine).  

  • Ketamine is made up of a racemic mixture of R-Ketamine and S-ketamine 

Esketamine has been shown to be effective in depression and is FDA approved as a nasal spray for depression. Esketamine benefits are

  • 4-fold affinity for the NMDA receptor 
  • 2-fold greater potency 
  • Rapid clearance 
  • Less cognitive impairment or agitation 

Esketamine (Spravato)  was administered with traditional antidepressants initially twice a week for the first month and then weekly thereafter and demonstrated high effectivenessIntranasal ketamine worked for depression and suicidality within 4 hours by decreasing depression and suicidality substantially. There was not only reduction but also remission of suicidality for up to 24 hours in the initial studies.  

Glutamate interventions work in TRD, Anti-suicidality, PTSD, Bipolar depression, and OCD

Most patients with TRD also have severe anxiety and ketamine can also be effective in refractory anxiety disorders. Patients with general anxiety disorder (GAD) and social anxiety disorder (SAD) when given one or two weekly ketamine doses at 1mg/kg SQ for three months had a 50% decrease in Fear (fear questionnaire ratings) and the Hamilton anxiety score. Maintenace ketamine may be a therapeutic option in treatment refractory GAD/SAD. Repeated treatments of intranasal ketamine (racemic) may also be effective in TRD as well. 


  • Ketamine’s mechanisms of action are complex 
  • Chronic stress, medical illness, elevated cortisol from the HPA axis results in the destruction of dendritic spines, decreased synapse formation, and depression as well as other mental health conditions. This is associated with inflammation. 
  • A single dose of ketamine can be anti-suicidal and is a rapid antidepressant. 
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NOVA Health Recovery is a Ketamine Treatment Center in Fairfax, Virginia (Northern Virginia Ketamine) that specializes in the treatment of depression, anxiety, bipolar disorder, OCD, and chronic pain such as CRPS, cluster headaches, and fibromyalgia using Ketamine therapies, both infusion and home-based ketamine nasal spray and oral tablets. We also offer addiction treatment services with Suboxone, Vivitrol, and Sublocade therapies for opiate addiction as well as alcohol treatment regimens. Contact us at 703-844-0184 or at this link: NOVA Health Recovery Ketamine Infusion Center 

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