Ketamine infusion therapy can be effective in treatment resistant depression with a 70% response in patients who have failed multiple other therapies including ECT and TMS. Some patients simultaneously get TMS treatment (transcutaneous magnetic stimulation) with ketamine infusions and find the combination to be even more effective. We combine IV B complex and IV vitamin therapies with the infusions to produce even better results as the vitamins allow the underlying enzymes that produce serotonin (the happiness molecule) and dopamine (the molecule of reward) to have improved efficacy. IV scopolamine prior to the ketamine enhances results as well. Scopolamine has studies demonstrating an antidepressant effect as well as promoting calmness and preventing nausea. No referral for treatment is needed. We don’t alter your medication regimen initially, but generally initiate the ketamine infusions, nasal sprays, and oral ketamine treatments to augment your current medications. For those with medication side-effects, you can use ketamine infusions to wean off your medications. Ketamine infusions generally are done as a series of 6 infusions either twice or three times a week with monthly maintenance infusions as needed. Patients who respond generally start a home-based ketamine nasal spray or oral ketamine regime for aftercare at NOVA Health Ketamine Treatment Center in Fairfax, Virginia. Ketamine is effective in depression treatment, OCD, PTSD, chronic pain, bipolar disorder, and several other conditions. If you are looking for a ketamine treatment provider near me or a ketamine clinic, call us today for an immediate appointment. 

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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The Neurobiology of Stress | How does Ketamine treat depression?

Neurobiology of stress and antidepressants- synaptic connections 

Depression: 

  • Economic costs $100 billion a year 
  • 17% of the population suffers from depression 
  • Women affected twice as often as men 
  • Most treatments require weeks to months to work 
  • Neuronal atrophy and loss of neurotrophic factor support play a major role in depression 

There is loss of brain tissue in depressed patients: 

  • Decreased prefrontal cortex (PFC) volume (involved with decision making and executive functioning) and hypofunction is noted with correlation to disease severity clinically in bipolar patients and depressed patients 
  • Decreased size in the hippocampus (the area of memory) The volume of the hippocampus is reduced more and more with longer duration of depression. This can be reversed with antidepressant treatment. 

There is both structural loss and changes in Major depressive disorder (MDD) as well as neurochemical changes. These are reversible with treatment. 

What contributes to the loss of volume in MDD?  

  • Stress can influence the PFC and hippocampus in terms of synapse connections, apical dendrites, and neurogenesis. There is a retraction of synapses rapidly with stress and depression. Decreased synapses is seen in the PFC of patients who committed suicide. 
  • Loss of connections decreases control of mood, cognition, and emotional dysregulation. The result is depression. 

The atrophy of neurons and loss of synapses leads to emotional dysregulation. 

What is the impact of antidepressants? 

Most antidepressants block monoamine reuptake such as serotonin and norepinephrine, but they don’t directly impact spine number and function. They can block the effects of stress, but this can take months for them to work. They are only effective in 1/3 of patients on the first trial. It may take years to get the treatment right. 1/3 of patients are treatment resistant (MDD). 

SSRIs influence second messenger systems too SLOWLY modulate the responses of neurons with neuroplasticity and neurogenesis. 

Drugs acting through glutamatergic neurotransmitter systems directly act on the AMPA and NMDA receptors to rapidly gain effect as an antidepressant. An example is Ketamine. 

Ketamine is a rapid-acting antidepressant. In a study by Berman in 2000, a single dose of ketamine resulted in an antidepressant effect within 72 hours of administration. Link to the graph. 

Ketamine blocks the NMDA receptor at the GABA interneuron and allows for a glutamate brief burst to produce Brain derived neurotrophic factor (BDNF) that increases neuroplasticity.  

Several other studies replicated this including Carlos Zarate in 2006 demonstrated reduction of depression in 2 hours to a single ketamine dose given IV. This is rapid and lasted 7 days after a single dose, but many relapse back after that point.   

In Bipolar depression, Zarate (2012) demonstrated rapid improvement in depression in 40 minutes lasting 7 days at least.  

Suicidal ideation is decreased rapidly as well as demonstrated by Price et al (2009) and Larkin (2011) which showed that there was a rapid reversal of suicidal ideation even 10 days after a single IV ketamine dose.  

  • 36,000 individuals die a year from suicide and 23% of these patients were on antidepressants at the time of the suicide. 

Multiple replication studies have demonstrated the same improvement in depression with ketamine infusions. 

Image from: Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ. Ketamine for depression: where do we go from here?. Biol Psychiatry. 2012;72(7):537-547. doi:10.1016/j.biopsych.2012.05.003 

Ketamine causes: 

  • Rapid remodeling of synapses in response to glutamate activity 
  • Typical antidepressants do NOT affect the synapses directly 
  • Ketamine affects the number and function of synaptic spines. 

Stressed and depressed patients have dendritic spines that are fewer in number than in non-depressed individuals. 

Glutamate is involved in learning and memory. Ketamine, through regulation of glutamate, causes increase synapse formation.  

Ketamine rapidly increases neuronal connections. 

The size of the spine and the bigger the connection creates greater function at the synapse. In a study by Li et al (Science 2010) it was shown that ketamine rapidly increases synaptic protein formation in the prefrontal cortex (PFC – the C.E.O of the brain) by increasing spine number and the number of mushroom or high-quality spines. Proteins involved in the synapse production included GluR1, PSD95, and Syn1. 

Ketamine: 

  • Increases the size of the spines (mushroom spines) 
  • Increases spine density 

Proteins required to form these spines include: (These proteins are required to build synapses and spines) 

  • GluR1 
  • PSD95 (post synaptic density protein 95) 
  • Syn1 (Synapsin) 

These proteins can be measured after a single dose of ketamine and were found to be increased. This occurs within 2 hours of the ketamine administration. This lines up with clinical effects as seen in Zarate et al (2006) in which the antidepressant effect of ketamine is noted at 2 hours. 

The increase in the synaptic connections occurs at the same time as the therapeutic responses. This response is present even at day 7, but drops off at day 14, as does the therapeutic response.  

Ketamine has rapid actions in rodent models. Models that measure helplessness and despair include the forced swim test and learned helplessness model of depression. Stress leads to anhedonia and depression in rodents. This is shown by decreased intake of sucrose by rodents after stress or giving up in a swim test when forced to swim in a beaker. So chronic unpredictable stress causes depressive symptoms in mice and decreases synapses on histological sectioning.  

Ketamine reverses the depressive symptoms and increases the synapse numbers.  

Ketamine rapidly reverses spine and behavioral deficits caused by chronic stress (3 weeks or more). The pathophysiology and treatment of depression is associated with the number and function of synaptic connections. Ketamine reverses depression and anhedonia. 

What is the mechanism by which ketamine increases spine number and function

Ketamine influences GABA inhibitory neurons that actively control glutamate release. Ketamine turns off the GABA interneurons to allow the Glutamate release from presynaptic neurons and thus produces the antidepressant effect. 

MTOR (mammalian target of Rapamycin) mediates the protein synthesis dependent learning and initiates the translation of proteins in the brain to increase synaptic spines. MTOR is present in dendrites.  

Ketamine upregulates mTOR and causes the production of synaptic proteinsspine number, and eventually antidepressant behavior. The synaptic proteins include GluA1 and PSD95. 

A major neurotrophic factor in the brain is Brain Derived Neurotrophic factor (BDNF). It guides neurons and allows them to survive. In the adult brain BDNF regulates neuronal functionneuronal growth and survival. This is important in learning and memory. 

  • BDNF is decreased in depression 
  • Other neurotrophic factors are decreased in depression such as VEGF (vascular endothelial growth factor) and fibroblast growth factor. These all increase with antidepressant treatment. 

The BDNF Val66/met polymorphism is a SNP (single nucleotide polymorphism) that can decrease the production of BDNF and is present in 25% of the population. The BDNF Met SNP results in decreased BDNF and is associated with reduced episodic memory, reduced memory performance, and decreased executive functioning. There is also decreased hippocampal volume in normal subjects with this allele as well as in MDD and Bipolar patients.  

There is an increased vulnerability for depression in people with stress and the BDNF Met allele, especially with early life exposure. The Met allele decreases the release of BDNF from the terminals, however the total production of BDNF is normal. Ketamine induction of dendritic spines and its antidepressant behavior is blocked in BDNF Met mice

The Met/Met allele blocks the release of BDNF. The Met carriers had a 50% reduction response compared to Val carriers in one study. So, the Val66Met allele can be used as a marker to identify people who may respond to ketamine or not. 

The ketamine response requires BDNF release to produce its antidepressant response. Control of mood and emotion require synaptic integrity of PFC neurons. Ketamine produces nascent spines in the PFC and restores spines lost due to stress and depression. 

Relapse is associated with the loss of synaptic connections. There may be ways to keep the effect of the response stabilized with add-on therapy.  

The control of mood and emotions requires synaptic integrity with the PFC and inhibitory connections with the amygdala and other brain regions. Regions like the amygdala are involved in fear and anxiety. The PFC also interacts with the dorsal raphe and nucleus accumbens (a mesolimbic region of reward) to regulate mood as well as the hippocampus (involved with memory) 

Side effects of ketamine: 

  • Produces psychomimetic effects acutely 
  • Nausea 

These effects are transient within the first hour. The antidepressant effect can last a week from a single infusion. 

What mediates neuronal atrophy in stress? Relatively mild stress can cause neuronal atrophy within a week. The consequences include MDD. PTSD, cognitive deficits, and other mood disorders. 

Summary: 

  • Stress decreases BDNF and mTOR signaling resulting in decreased synaptogenesis and spine formation 
  • Increases in REDD1 will decrease the activity of mTOR thus decreasing BDNF production. Stress and activation of the HPA axis produce the increase of REDD1. 
  • Ketamine can reverse this by increasing mTOR 
  • Exercise, enrichment, and coping strategies can help maintain synaptic homeostasis 
  • After a ketamine infusion, there can be another loss of spines that coincides with the relapse of depression after a single infusion.  
  • Repeat ketamine therapies and other interventions may maintain the spine number and function. 

For an appointment at NOVA Health Recovery for Ketamine therapy or other medical issues, call us at 703-844-0184 or email us below with your phone number:

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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 

Ketamine Provider | Ketamine near me | Psychedelic assisted therapy | Mushrooms | Ketamine assisted psychotherapy | Ketamine psychedelic therapy | KAP | K hole | New depression Treatments | Areas we serve: 

Ketamine Provider | Ketamine near me | Psychedelic assisted therapy | Mushrooms | Ketamine assisted psychotherapy | Ketamine psychedelic therapy | KAP | K hole | New depression Treatments | Areas we serve: 

Maryland (MD): 

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Fairfax, Va 

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Front Royal 22630 

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