Neurobiology of stress and neuroplasticity: Ketamine infusions to enhance neuroplasticity in depression | How does Ketamine work? Ketamine infusion Center Northern Virginia | Ketamine therapy for depression, anxiety, PTSD

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: 

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Rapid Anxiety Relief | 703-844-0184 | Fairfax, Virginia | Ketamine Treatment of AnXiEtY!

NOVA Health Recovery Ketamine Infusions

Contact NOVA Health Ketamine Center with the form below or call us at 703-844-0184 for anxiety treatment using ketamine:

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Ketamine has been found to be effective in Anxiety disorders, such as social anxiety and Generalized Anxiety Disorders. A recent study in The Journal of Psychopharmacology demonstrated that weekly injections of Ketamine at 0.5 to 1 mg/kg Subcutaneous reulted in anxiety score depression by 50%. The Hamilton anxiety score was used to rate anxiety levels.

Effect of midazolam and ketamine dose on mean Fear Questionnaire scores (a), Hamilton Anxiety Scale scores (b), and Clinician
Administered Dissociative States Scale scores (c).

Key points to the study:

(1) Dosing of 0.5 to 1 mg/kg SubQ worked best for anxiety when weekly administered.

(2) Effects were within hours and lasted for a week

NOVA Health Recovery offers IV, IM , oral, and nasal spray options for ketamine treatment. Call 703-844-0184 for an appointment. No referral is needed.

The Hamilton Anxiety Score is below:

703-844-0184 | Alexandria, Virginia Ketamine Infusion Provider | Sarcosine, Nitrous oxide, and buprenorphine for depression. Fairfax, Virginia Ketamine Infusion Center | Loudoun County Virginia Ketamine | IV Vitamin and Glutathione Center | IV NAD+ Virginia Center 22308

NOVA Health Recovery Ketamine Center | 703-844-0184 | CLick here for information

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Recent research has shown that ketamine has considerable promise for treating a wide range of treatment-refractory neuropsychiatric disorders, including obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), bipolar disorder, suicide ideation, addiction and, most notably, treatment-resistant major depressive disorder (MDD). Although this research has taken place almost exclusively within the past two decades, evidence of ketamine’s neuropsychiatric effects appeared long before this. For example, ketamine was used throughout the 1970s in Mexico as part of psychedelic therapy sessions that combined traditional healing practices with psychoanalytic techniques.

In 2000, researchers found that ketamine had strong, fast-acting, and long-term effects in depression. In a randomized, placebo-controlled, crossover design study, patients with depression received 0.5 mg/kg of ketamine or saline on the first day of testing. Treatments were switched 1 week later. Researchers found that the antidepressant effects of ketamine began within 4 hours, peaked at 72 hours, and lasted for 1 to 2 weeks thereafter.1 In a 2006 study, this finding was replicated in an independent group of 18 patients with major depressive disorder who were resistant to other treatments. Compared with participants who received placebo, those who received ketamine showed significant improvement in symptoms within 110 minutes, with 35% maintaining significant response for at least 1 week.

Many of today’s depression treatments are monoaminergic-based, including monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors. These treatments have been proven effective for a large number of patients. However, a significant subset of patients with major depressive disorder do not respond to these agents. Despite its undisputed value to the field, the monoamine hypothesis of depression cannot fully explain the heterogeneity of MDD. In the 1990s, animal models began to implicate glutamate – one of the major excitatory neurotransmitters in the mammalian central nervous system (CNS) – as well as its ionotropic NMDA receptor in the etiology and treatment of mood disorders .

Existing antidepressant treatments [MAOIs, TCAs, SSRIs, and serotonin-norepinephrine reuptake inhibitors (SNRIs)] are monoaminergic-based treatments. Although they have been in use for decades and have helped many patients, a significant subset of MDD patients showed little to no therapeutic benefit in response to these agents. For instance, the NIMH-funded, communitybased Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study of >4000 MDD patients found that, even after four unique medication trials, augmentation, or switch, 33% of the patients did not respond to standard monoaminergic-based treatments .

In 2000, Berman and colleagues discovered that ketamine exerted rapid, robust, and relatively sustained antidepressant effects in depressed patients . Using a randomized, placebo-controlled, crossover design, each patient received an i.v. infusion of 0.5 mg/kg of either ketamine or saline on the first test day. On the following test day, which took place at least 1 week later, treatments were switched. The authors found that ketamine exerted antidepressant effects that began within 4 h of the infusion, peaked at 72 h, and persisted for 1–2 weeks post-infusion. .Ketamine has also been shown to have distinct and independent antisuicidal and anti-anhedonic effects in patients with mood disorders .

Another limitation of currently available antidepressants is that their clinical effects take more time to reach their full therapeutic potential (for instance, the mean onset for paroxetine is 13 days). This is a substantial disadvantage during an acute depressive crisis. Furthermore, even when these agents do alleviate depressive symptoms, evidence regarding their ability to successfully reduce suicide ideation and behavior remains inconclusive . In contrast, a single dose (0.5 mg/kg) of i.v. ketamine exerts rapid and profound antidepressant effects within hours to days of administration . Ketamine also rapidly reduces suicidel ideation, an effect that appears to occur independently of its antidepressant properties . Ketamine has dose-dependent neuropsychological effects even at subanesthetic doses, with antidepressant properties peaking at 0.5–1.0 mg/kg.

Ketamine’s pan-therapeutic effects also include alleviating fatigue and anhedonia as well as improving sleep measures such as circadian rhythm and slow-wave activity in MDD patients .

The positive effects of Ketamine has led to research into other rapidly acting antisdepressants, including nasal ketamine. Lapidus and colleagues demonstrated that intranasal ketamine had antidepressant effects and led to sufficiently high ketamine plasma concentrations. We use a compounded intranasal ketamine miuxture in our office at NOVA Health Recovery. There is also an FDA approved version more recently, which has only the S-Ketamine in it . There are heavy restrictions and high costs to the FDA approved version, yet efficacy may not be any better.

Noitrois Oxide also has antidepressant effects. Like ketamine, it exhibits NMDA receptor antagonism, has partial agonism for mu, kappa, and delta opioid receptors, inhibits AMPA, kainite, and gamma-aminobutyric acid receptors A and C (GABAA, GABAC), affects serotonin-3 receptors (5-HT3), and releases dopamine . In a double-blind, placebo-controlled, crossover trial, depressive symptoms improved for participants receiving nitrous oxide within 2 h compared with those receiving placebo, an effect that remained significant at 1 day post-treatment. Phase I and II trials are ongoing to determine optimal dose, safety, and efficacy.

Sarcosine also has antidepressant effects. t, sarcosine (also known as N-methylglycine), is an amino acid that functions as a glycine transporter-1 inhibitor and a 6- week, double-blind, randomized, citalopram-controlled trial in 20 MDD patients found that sarcosine possessed superior antidepressant properties compared with citalopram after 2 weeks . Notably, and in contrast to ketamine, sarcosine did not result in rapid-acting effects on the timescale of several days. Sarcosine has co-agonistic properties at the NMDA receptor and is an agonist at the inhibitory glycine receptor. It also exhibits NMDA-enhancing properties, suggesting that AMPA-receptor-mediated or other downstream mechanisms might elicit antidepressant effects. NMDA receptor downregulation might also play a part .

Suboxone (Buprenorphine) also has antidepressant effects as well. Intrigued by the potential of nonaminergic antidepressant mechanisms, researchers have begun to re-evaluate the role of endogenous opioids in depression. For instance, buprenorphine (BUP), a drug currently used to treat opioid addiction and pain disorders, is being explored as a treatment for MDD. The compound has a wide variety of actions throughout the brain, including partial agonism at the mu opioid receptor and antagonism at the kappa and delta opioid receptors ; these are connected to intracellular signaling cascades that potentially mediate antidepressant effects Several open-label studies of BUP in MDD have shown promising preliminary results, and a double-blind, randomized, placebo-controlled trial examining the effect of low-dose BUP on suicidal ideation similarly yielded positive results .

NOVA Health Recovery has used buprenorphine succesfully in the treatment of depression.

Ketamine and Future Depression Treatments

1. Kraus C, Wasserman D, Henter ID, Acevedo-Diaz E, Kadriu B, Zarate CA Jr. The influence of ketamine on drug discovery in depression [published online August 2, 2019]. Drug Discov Today. doi: 10.1016/j.drudis.2019.07.007

2. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depressionArch Gen Psychiatry. 2006;63(8):856-64.

3. Nagele P, Duma A, Kopec M, et al. Nitrous oxide for treatment-resistant major depression: a proof-of-concept trialBiol Psychiatry. 2015;78(1):10-18.

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Looking at the results

Axsome reported strong results for its late-stage, experimental depression treatment, which met the primary endpoint for its phase 3 clinical trial. The drug, an NMDA receptor antagonist known as AXS-05, showed significant improvements in patients with major depressive disorder (MDD). More specifically, AXS-05 is a combination of two other well-known drugs, dextromethorphan and bupropion, which have independently been used, respectively, as a serotonin inhibitor and a nicotine antagonist. However, when put together, the two drugs showed strong results in helping patients with MDD.

In the phase 3 trial, 327 adult patients were split between the AXS-05 group and the placebo with a twice-per-day dose for a six-week period. Overall, the drug showed a significant reduction in the Montgomery-Asberg Depression Rating Scale (MADRS), a scoring system that evaluates the severity of symptoms in patients. In comparison to the placebo, which demonstrated an 11.9 average score reduction, patients on AXS-05 saw a 16.6 average point reduction in their MADRS scores.

Besides the fact that the clinical trial met all of its secondary endpoints as well, ASX-05 was well tolerated by patients, with the most common adverse reactions being nausea, headaches, and dizziness. These results confirm the already impressive results of a previous phase 2 study, where ASX-05 saw 47% of patients with MDD achieve complete remission, as opposed to the 16% of patients taking the placebo group at the time.

The depression market

Depression treatments are one of the largest healthcare markets in the U.S., with around 7.1% of adults — or 17.3 million — Americans experiencing MDD each year. Despite the lucrative potential of this market, a number of potential depression drug candidates have fallen by the wayside following further testing. One of the most recent was Sage Therapeutics‘ Sage 217 drug, which ended up failing in its late-stage clinical trial, a setback that sent the stock plummeting over 60% earlier this month.

It’s this historic difficulty in developing new depression treatments that make analysts and investors so excited about Axsome Therapeutics’ recent success. Conventional antidepressants work by changing the chemicals in your brain that influence your emotions, otherwise referred to as neurotransmitters. The most commonly prescribed type of antidepressant is selective serotonin reuptake inhibitors (SSRIs), which stop the reabsorption of serotonin in the brain.

However, these drugs often take several weeks before they kick in, and in many cases, patients need to try out a few different antidepressants before one works as intended. SSRIs also have their own unpleasant side effects, such as sexual dysfunction, which is prevalent in as many as 70% of patients taking these antidepressants. Both of these are reasons the demand for novel depression treatments remains so strong.

Is there any competition?

For the most part, there aren’t many drug candidates that can compete with AXS-05. The past year has seen many promising drug candidates either flop in their late-stage clinical trials or get rejected by the U.S. Food and Drug Administration. Besides the aforementioned Sage-217, Allergan‘s Rapastinel failed to show results in its clinical trials, while another depression drug developed by Alkermes also failed after the FDA ruled that it wanted more clinical data before reconsidering the treatment in the future. 

Sage Therapeutics has a postpartum depression drug called Zulresso, which received FDA approval back in April, but it caters to a niche market whereas AXS-05 has a wider-reaching patient base.

One of the few drugs that can compete with AXS-05 is Spravato, a nasal-spray drug candidate being developed by Johnson & Johnson. The drug received approval in March for use in patients with treatment-resistant depression. Since then, Johnson & Johnson submitted a New Drug Application for Spravato to be used in patients with MDD who have suicidal ideation, which could compete partially with AXS-05.

However, given the sheer size of the MDD market, AXS-05 only needs to capture a small portion of the patient population to become a blockbuster, something that seems quite likely should it receive FDA approval.

What’s the verdict?

All that’s left for Axsome Therapeutics now is to receive official approval from the FDA, and while nothing’s ever certain when it comes to health regulators, there haven’t been any major points of contention so far in AXS-05’s clinical results.

703-844-0184 | Ketamine Infusion Center Virginia | Ketamine Doctor | Seasonal Affective Disorder | SAD | New treatments for Depression | Ketamine infusions for depression | Ketamine Deppression Treatment | Ketamine Nasal Spray | Spravato | Loudoun Virginia Ketamine 703-844-0184 | 22308 | Arlington Ketamine

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Seasonal affective disorder (SAD) is a mood disorder that is characterized by symptoms that occur at the same time each year, usually during the darker, shorter days of fall and winter. Symptoms can include depression, fatigue, and social withdrawal. While this condition usually resolves within a few months, it can have a serious impact on how a person feels and functions.

It is not uncommon for people to experience seasonal fluctuation in moods. You may have noticed how a gray, rainy day makes you feel gloomy and tired, while a sunny day can leave you feeling cheerful and energized. The longer, sunnier days of summer are often associated with better moods, while the shorter, darker days that begin in late fall often align with an increase in SAD symptoms.

Shorter days combined with the stress of the winter holiday season can make the colder months of the year a trying time for many people. And with mood-boosting sunlight in such short supply, the added stresses of living up to our images of the picture-perfect holiday are just too much.

Insufficient exposure to sunlight has been associated with low levels of melatonin and serotonin, carbohydrate craving, weight gain, and sleep disturbance.

Symptoms

The symptoms of SAD occur cyclically with a return of symptoms each year during the winter months. These symptoms tend to be the typical symptoms of depression, including:

  • Increased sleep
  • Increased appetite and carbohydrate cravings
  • Weight gain
  • Irritability
  • Interpersonal difficulties (especially rejection sensitivity)
  • A heavy, leaden feeling in the arms or legs

Signs and Symptoms of SAD

Causes

Seasonal affective disorder is believed to be caused by a disturbance in the normal circadian rhythm of the body. Sunlight entering through the eyes influences this rhythm. When it’s dark, the pineal gland produces a substance called melatonin which is responsible for the drowsiness we feel each day after dusk. Light entering the eyes at dawn shuts off the production of melatonin.

During the shorter days of winter, when people may rise before dawn or not leave their offices until after sunset, these normal rhythms may become disrupted, producing the symptoms of SAD.

There is also evidence linking SAD to a reduced amount of the neurotransmitter serotonin. Serotonin is the feel-good substance that is increased by antidepressants called selective serotonin reuptake inhibitors (SSRIs).

This decrease in serotonin production may be responsible for many of the symptoms of SAD, such as depression and carbohydrate cravings.

Diagnosis

There is no laboratory test for SAD. It is diagnosed based upon a person’s symptom history using criteria set forth by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The DSM-5 does not consider SAD to be a separate disorder. Instead, it is a “specifier” of a major depressive episode diagnosis. In order to be diagnosed with SAD a person must, first of all, meet the criteria for a major depressive episode.

At least five of the symptoms listed below must be present most of the time during a two-week period. Further, at least one of the person’s symptoms must be one of the first two items listed. A depressed mood that is due to a medical condition or that is related to the content of a delusion or hallucination that the person is experiencing would not count.

  • Feelings of depression
  • Loss of interest in things once enjoyed
  • Changes in appetite or weight not associated with intentional dietary changes for the purpose of gaining or losing weight
  • Sleeping too much or too little
  • Psychomotor agitation or retardation
  • Fatigue or lost energy
  • Feelings of worthlessness or excessive guilt
  • Problems with concentration, thought, or decision-making
  • Thoughts of death or suicide 

Any symptoms which could be better explained by their connection to a medical condition, substance use, or grief would also not count. In addition, a psychotic disorder, such as schizoaffective disorder, would have to be ruled out as a cause for the symptoms.

If these criteria fit, the following criteria would also need to be met to obtain a seasonal pattern specifier:

  • A seasonal pattern of onset and cessation in major depressive episodes
  • Two major depressive episodes meeting all of the above criteria for the past two years without any episodes of major depression have occurred at other times of the year
  • A lifetime pattern of having mainly seasonally-related major depressive episodes

Treatment

Seasonal affective therapy responds well to treatment. The most commonly used treatments for SAD are:

  • Light therapy
  • Medication
  • Psychotherapy

LIGHT THERAPY

Light therapy using a device that gives off bright, white light is considered the best form of treatment for SAD at this time.

In fall 1998, a group of 13 Canadian specialists issued a set of professional consensus guidelines for the treatment of SAD. Among their conclusions:

  • The starting “dose” for light therapy using a fluorescent lightbox is 10,000 lux for 30 minutes per day. (Alternatively, lightboxes emitting 2,500 lux require two hours of exposure per day.)
  • Light therapy should be started in the early morning, upon awakening, to maximize treatment response.
  • Response to light therapy often occurs within one week, but some patients may require up to four weeks to show a response.
  • Common side effects of light therapy include headache, eyestrain, nausea, and agitation, but these effects are generally mild and transient or disappear with reducing the dose of light.

According to Dr. Michael Terman, head of the Winter Depression Program at Columbia-Presbyterian University, the consensus in the U.S. is that post-awakening bright light therapy, using a broad-spectrum white light source at 10,000 lux, is the first-line intervention. Drugs should be brought in as adjuvants only if light therapy is insufficient.

Optimum dosing of light is crucial since if done wrong it can produce no improvement, partial improvement, or even worsening of symptoms.The Best Light Therapy Lamps

In a study published in the Archives of General Psychiatry researchers exposed participants with SAD to bright lights that were 10 to 20 times brighter than normal indoor electrical lights. One group was exposed to these lights for approximately one and a half hours in the morning, while a second group was exposed in the evening. The third group received a placebo treatment. The participants who were exposed to the morning bright light treatments experienced full or near-full relief from depression.

Newer research published in the Journal of Nervous and Mental Disease has found that even a single, one-hour light session can rapidly improve symptoms of depression in people with SAD. And morning therapy, specifically, can help to correct any sleep-wake cycle issues contributing to the symptoms.

MEDICATIONS

On June 12, 2006, Wellbutrin XL (bupropion hydrochloride) became the first drug approved specifically for SAD in the U.S.

The effectiveness of Wellbutrin XL for the prevention of SAD episodes was established in three double-blind, placebo-controlled trials in adults with a history of major depressive disorder in fall and winter. Treatment began in the September through November timeframe, prior to the onset of symptoms. Treatment ended the first week of spring.

In these trials, the percentage of patients who were depression-free at the end of treatment was significantly higher for those on Wellbutrin XL than for those on placebo.

For all three studies combined, the overall rate of patients depression-free at the end of treatment was 84% for those on Wellbutrin XL, compared to 72% for those on placebo.

Wellbutrin XL is chemically unrelated to other common antidepressant medications like selective serotonin reuptake inhibitors (SSRIs). In fact, there is no conclusive evidence from randomized trials to support the use of SSRIs in the treatment of SAD.

PSYCHOTHERAPY

Cognitive-behavioral therapy (CBT) can also be an effective treatment for SAD, particularly if it is used in conjunction with light therapy and medication. CBT involves identifying negative thought patterns that contribute to symptoms and then replacing these thoughts with more positive ones. Best Online Resources for Depression

Coping

Healthy habits and lifestyle choices can also help reduce SAD symptoms. Things that you can do include:

  • Getting regular exercise
  • Getting enough sleep
  • Eating a healthy diet that includes plenty of fruits, vegetables, and protein

VITAMIN D

Research has found that people with SAD often have low vitamin D levels. Because of this, people with the condition are often encouraged to increase their intake of this vitamin either through diet, exposure to sunshine, or vitamin supplementation. However, research on effectiveness has been mixed. Some studies have suggested that it may be as effective as light therapy, while other studies have found no positive effect of vitamin D on SAD symptoms.

Always talk to your doctor before taking any medication, supplement, or herbal remedy to treat seasonal affective disorder.

MONITOR YOUR SYMPTOMS

Recognizing your tendency to experience seasonal depression can be helpful in aiding your treatment and coping. By knowing the signs, you’ll be able to reach out to your doctor and make lifestyle changes that may help you cope more effectively sooner.

The Center for Environmental Therapeutics (CET), a non-profit organization that provides educational materials about SAD, offers free, downloadable self-assessment questionnaires, as well as interpretation guides, to help you determine if you should seek professional advice.

Among the quizzes available are the AutoPIDS and AutoMEQ. Used together, the AutoPIDS helps you determine whether you have the symptoms of SAD and what your natural bedtime is, and the AutoSIGH tracks your current state of depression.

These tests should not be taken as a firm diagnosis, so be sure to discuss your results with your primary care physician or mental health professional prior to beginning any treatment.

Best Overall: Circadian Optics Lumine at Amazon

“Simple, modern design… filters out 99.9 percent of UV rays.”

Best Budget: Verilux HappyLight Compact Personal at Amazon

“Compact at just 1.5-lbs.”

Best Portable: Circadian Optics Lumos 2.0 at Amazon

“Produces an impressive 10,000 lux.”

Best for SAD: Carex Health Brands Day-Light at Amazon 

“Filters out more than 99% of UV rays.”

Best Blue Light: Philips goLITE BLU Energy at Amazon

“Has five light intensity settings.”

Best for Office: Carex Health Brands SunLite at Home Depot

“A lightweight product that you can use while you work.”

Best Alarm Clock: Philips Wake-Up Light at Amazon 

“Light therapy lamp and natural sunrise alarm clock.”

Best Floor Lamp: Lavish Home Natural Full Spectrum at Amazon 

“A flexible neck that you can adjust to any angle.”

Our Top Picks

1

Best Overall: Circadian Optics Lumine Light Therapy Lamp

Buy on Amazon

Light therapy lamps are a great option for helping with Seasonal Affective Disorder. Before buying a light therapy lamp, make sure to talk to your doctor. If you’re given the go-ahead, our favorite option is the Circadian Optics Lumine Light Therapy Lamp.

The simple, modern design will fit anywhere in your home. This light has an intensity of 10,000 lux in a pure white color that’s designed to imitate the sun at noon, and it boasts three adjustable brightness settings. It filters out 99.9 percent of UV rays to protect your eyes, and the LED bulbs have an impressive ​50,000-hour lifespan, so you won’t need to replace them anytime soon.

2

Best Budget: Verilux HappyLight Compact Personal, Portable Light Therapy Lamp

Buy on Amazon

High-end light therapy lamps can get quite expensive, but you don’t have to drain your bank account to get some relief from SAD. The Verilux HappyLight Compact Personal, Portable Light Therapy Energy Lamp is a best-selling item, and it costs significantly less than many other products.

The Verilux HappyLight is incredibly compact at just 1.5-lbs, and it produces light at an intensity of 5,000 lux, meaning you may need to sit in front of it for longer. It filters out UV rays to protect your eyes, and it’s easy to take with you to work or other destinations thanks to its compact design.

According to reviewers, this light therapy lamp is bright and effective, especially for its small size. Many write that they feel significantly better during the fall and winter when they sit in front of this light, and you can’t beat the affordable price.

3

Best Portable: Circadian Optics Lumos 2.0 Light Therapy Lamp

Buy on Amazon

Want a light therapy lamp that you can put in your bag and take with you on the go? Then the Circadian Optics Lumos 2.0 Light Therapy Lamp is just what you’re looking for.

This product measures just 2.25” wide, 3.25” deep, and 11.5” long, making it a compact, highly portable option for those with SAD. The design is adjustable, so it can be angled any way, and it produces an impressive 10,000 lux of pure white light using LED bulbs. The Circadian Optics Lumos 2.0 filters out harmful UV rays, and it has three brightness levels to choose from.

This light therapy lamp gets top marks from reviewers, many of whom say it’s one of the best products they’ve tried. Several note that the Lumos 2.0 has helped ease their seasonal depression​ and the compact size of this lamp is an added bonus.

4

Best for SAD: Carex Health Brands Day-Light Classic Therapy Lamp

Buy on Amazon

Seasonal affective disorder is no joke—it can cause loss of energy, difficulty concentrating, excessive fatigue and more unpleasant side effects. To optimally treat this seasonal condition, you need a clinically proven product like the Carex Health Brands Day-Light Classic Plus Bright Light Therapy Lamp.

While on the high-end side, this light therapy lamp meets all the expert criteria for treating SAD. The 12-inch lamp produces 10,000 lux of glare-free white light, filtering out more than 99 percent of UV rays. The height and angle of the light are adjustable, and the whole unit stands on a pedestal. There are two brightness settings to choose from, allowing you to customize your treatment.

Reviewers say this is an excellent therapy lamp for treating SAD, writing that they experienced a noticeable improvement in mood after using it. Some users also note that the light has lasted for several years, so it’s arguably worth the higher price point.5

Best Blue Light: Philips goLITE BLU Energy Light Therapy Lamp

Buy on Amazon

While most light therapy boxes emit white light, there are some people who prefer a blue light, which is supposed to be more energizing. If you’re looking for a blue light therapy lamp, you should consider the well-received Philips goLITE BLU Energy Light Therapy Lamp.

This compact lamp gives off a blue light that’s supposed to be as effective as 10,000 lux white light. It has five light intensity settings to choose from, and it filters out UV rays to protect your eyes.

Overall, reviewers have great things to say about the Philips goLITE BLU, writing that it seems to work just as well as standard white therapy lamps. Many note that the product’s portable design lets them bring it to the office in the winter and that they notice a significant difference in their mood and energy levels after using it.6

Best for Office: Carex Health Brands SunLite Bright Light Therapy Lamp

Buy on Home Depot

Sitting in a poorly-lit office building for eight hours a day certainly doesn’t help the winter blues. If you’re looking for a way to get a little extra light in your office, consider the Carex Health Brands SunLite Bright Light Therapy Lamp, a lightweight product that you can use while you work.

The SunLite Bright Light Therapy lamp is best for people with mild to moderate seasonal depression, as it provides 10,000 lux light from its 10-inch surface. The lamp filters out more than 99 percent of UV rays for safety and features “quick-change” bulbs for easy maintenance. It weighs just over 3 lbs, making it easy to transport to your office and back.

Reviewers say the SunLite Bright Light Therapy Lamp is a high-quality product with a durable construction. Several note it improved their SAD symptoms, and it comes at a reasonable price, to boot.7

Best Alarm Clock: Philips Wake-Up Light Alarm Clock

Buy on Amazon

Having trouble getting out of bed in the morning when it’s still dark out? This is a common problem during the winter, and a product like the Philips Wake-Up Light Alarm Clock can help!

This light therapy lamp and natural sunrise alarm clock is designed to improve your sleep and energy levels by waking you up gradually. The light has 20 brightness settings to choose from, and it turns on 30 minutes before your alarm, gradually getting brighter to wake you up gently. The light itself is UV-free, and the alarm clock features five wake-up sounds, FM radio capabilities, snooze, and even settings to help you fall asleep.

Reviewers agree that the Philips Wake-Up Light Alarm Clock does exactly what it claims, waking you up naturally to improve energy levels and banish lethargy. Many also note that the various brightness settings are beneficial, as it lets you customize the light to your preferences.8

Best Floor Lamp: Lavish Home Natural Full Spectrum Sunlight Therapy Floor Lamp

Buy on Amazon

Most light therapy lamps are tabletop designs, so you have to put them on a desk, table, or counter to use. If this is inconvenient to you, you might prefer ​a floor lamp, such as the Lavish Home Natural Full Spectrum Sunlight Therapy Lamp.

This product approximates natural light, providing bright white illumination that’s perfect for reading or working. The lamp has a flexible neck that you can adjust to any angle, and the product measures 60” tall.

Many people use the product for task lighting, but several note that it seems to improve their winter blues, as well. Overall, it’s a more convenient design than other light therapy lamps, and it comes at an unbeatable price.

703-844-0184 | Ketamine Infusions D.C. Maryland Virginia | Scopolamine I.V. for rapid depression relief | Northern Virgina Ketamine Infusion Center Fairfax, Va | 22304 |NAD Infusions | IV Vitamins |Ketamine Fairfax

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Scopolamine has been used in multiple forms (patches, tablets, nasal sprays, and IV)  for nausea, sea-sickness, and even depression.  It is a muscarinic acetylcholine receptor antagonist agent.

In 2006, Maura Fury, Ph.D. of the National Institutes of Mental Health treated anxiety and depression with I.V. Scopolamine with rapid results.Antidepressant-Efficacy-of-the-Antimuscarinic-drug-scopolamineDownload

In the trial they evaluated the role of the cholinergic
system in cognitive symptoms of depression and unexpectedly
observed rapid reductions in depression severity
following the administration of the antimuscarinic drug
scopolamine hydrobromide (4 μg/kg intravenously) compared
with placebo (P=.002) In this trial, 9 patients with treatment resistant depression and anxiety received infusions and had significant repsonses,

The cholinergic system is one of the neurotransmitter systems implicated in the pathophysiologic mechanism of mood disorders. Increasing cholinergic activity using physostigmine (an anticholinesterase inhibitor) provides a challenge uniquely capable of exacerbating depressive symptom in currently depressed patients with MDD and inducing depressive symptoms
in currently manic patients with Bipolar disorder.

The cholinergic system also is implicated in depression by evidence showing that polysomnographic responses to muscarinic receptor agonists and neuroendocrine and pupillary responses to cholinomimetics are exaggerated in depressed patients and that some muscarinic receptor gene polymorphisms are associated with an elevated incidence of depression. Elevated cholinergic function thus was hypothesized to participate in
the pathogenesis of mood disorders.Associations-of-acetylcholinesterase-activity-with-depression-and-anxiety-symptoms-among-adolescents-growing-up-near-pesticide-spray-sites-ScienceDirectDownload

In fact it has been noted that children growing up near sites of cholinergic pesticides have an increase rate of depression as the article above discusses.

A follow up study using Scopolamine was accomplished with 23 patinets and demonstrated rapid antidepressant and anti-anxiety effects with IV Scopolamine:Replication-of-Scopolamine’s-Antidepressant-Efficacy-in-Major-Depressive-Disorder-a-Randomized-Placebo-Controlled-Clinical-TrialDownload

In the study, 23 subjects were treated. Here are the results:

Results—Following the initial block the group receiving scopolamine first (S/P) showed a 32 percent reduction in MADRS scores (p<0.001) which exceeded the corresponding change of 6.5 percent under placebo (P/S) (p=0.009), confirming the a priori hypothesis. Improvement was
significant at the first evaluation that followed scopolamine administration (p=0.011). In block 2 the P/S group showed a 53 percent reduction in MADRS scores (p=0.001) following scopolamine versus placebo, while the reduction seen in S/P subjects who received scopolamine during block 1
persisted as they received placebo during block 2. Scopolamine induced drowsiness, blurred vision, dry mouth, light-headedness and reduced blood pressure, which were sufficiently well tolerated that no subject dropped out due to side effects.

The trial included Bipolar disorder and depressed patients and used a protocol of 4 mcg/kg over 15 minutes protocol. No patients dropped out.Patient improved within 3-5 days of the infusion. The improvement in the study lasted well over two weeks.

Moreover, the delay in the onset of the antidepressant response until well after the resolution of anticholinergic side effects appears compatible with an effect on transcription of “late response” genes or synaptic plasticity, rather than a direct action on muscarinic receptors.

One effect scopolamine shares with other somatic antidepressant treatments involves the modulation of N-methyl-D-aspartate receptor (NMDAR) function. Blocking muscarinic receptors via scopolamine administration reduces mRNA concentrations for NMDAR types
1A and 2A in the rat brain in vivo and protects hippocampal neurons from glutamatemediated neurotoxicity in vitro . Chronic administration of antidepressant drugs from various classes and repeated electroconvulsive shock reduce cortical NMDAR function ), and treatments associated with a rapid onset of antidepressant effects either exert direct
NMDAR antagonist effects (ketamine) or induce NMDR internalization (sleepdeprivation)). Taken together with evidence that abnormal glutamatergic transmission is involved in the pathophysiology of depression, these data suggest the hypothesis that scopolamine’s effect on NMDAR function plays a role in its antidepressant action.

Another possible mechanism that merits consideration is scopolamine’s paradoxical effect of enhancing parasympathetic autonomic outflow when administered in the low dose range that encompasses the doses used in this study.

While it remains unclear whether the effect of scopolamine (at 4.0
ug/kg iv) on parasympathetic activity plays any role in the antidepressant response, it is noteworthy that the pathophysiology of depression is associated with a reduction in the parasympathetic-to-sympathetic balance. Decreasing parasympathetic tone improves depression.

Side effects during the infusion:

  • Blurry vision
  • Dry Mouth
  • Lowered Blood pressure
  • Nausea
  • Some confusion for two hours may occur but no delirium

Small but statistically significant antidepressant effects were observed the day following the administration of scopolamine 0.4 mg i.m., which would have a bioavailability similar to that of about 2 ug/kg i.v.

In 2012, researchers in Iran led by Danial Khajavi, M.D.,
compared 40 patients with MDD randomly assigned to either
oral scopolamine plus citalopram or citalopram plus placebo.
Augmentation with scopolamine was significantly more
effective than placebo, with 65 percent of patients receiving
scopolamine showing higher rates of response at week 4 and
remission at week 6 than patients receiving placebo.

Oral Scopolamine Augmentation in Moderate to Severe Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Study:

Danial Khajavi, MD; Mehdi Farokhnia, MD; Amirhossein Modabbernia, MD; Mandana Ashrafi, MD; Seyed-Hesammedin Abbasi, MD; Mina Tabrizi, MD; and Shahin Akhondzadeh, PhD

Objective:To evaluate the antidepressant effect of oral scopolamine as an adjunct to citalopram.

Method:In this randomized double-blind placebo-controlled study, patients were assessed in the outpatient clinics of 2 large hospitals from November 2011 to January 2012. Forty patients (18–55 years) with major depressive disorder (DSM-IV-TR criteria) and 17-Item Hamilton Depression Rating Scale (HDRS) score ≥22 were randomly assigned to scopolamine hydrobromide (1 mg/d) (n=20) or placebo (n=20) in addition to citalopram for 6 weeks. HDRS score was measured at baseline and days 4, 7, 14, 28, and 42. The primary outcome measure was HDRS score change from baseline to week 6 in the scopolamine group versus the placebo group. Response was defined as ≥50% decrease in HDRS score; remission, as HDRS score ≤7.

Results: Augmentation with scopolamine was significantly more effective than placebo (F1,38=5.831, P=.021). Patients receiving scopolamine showed higher rates of response (65%, 13/20 at week 4) and remission (65%, 13/20 at week 6) than the placebo group (30%, 6/20 and 20%, 4/20, respectively; P=.027, P=.004, respectively). Patients in the scopolamine group showed higher rates of dry mouth, blurred vision, and dizziness than the placebo group.

Conclusions: Oral scopolamine is a safe and effective adjunct for treatment of patients with moderate to severe major depressive disorder.

General information regarding Treatment resistant Depression :Treatment-of-MDD-Treatment-ResistantDownload

Carlos Zarate also did a review on Scopolamine for depression therapy:Antidepressant-Efficacy-of-the-Antimuscarinic-drug-scopolamine-1Download

They review the data from a series of randomized, double-blind, placebo-controlled studies involving subjects with unipolar or bipolar
depression treated with parenteral doses of scopolamine. The onset and duration of the antidepressant response are considered in light of scopolamine’s pharmacokinetic properties and an emerging literature that characterizes scopolamine’s effects on neurobiological systems beyond
the cholinergic system that appear relevant to the neurobiology of mood disorders. Scopolamine infused at 4.0 μg/kg intravenously produced robust antidepressant effects versus placebo, which were evident within 3 days after the initial infusion. Placebo-adjusted remission rates were 56%
and 45% for the initial and subsequent replication studies, respectively. While effective in male and female subjects, the change in depression ratings was greater in female subjects. Clinical
improvement persisted more than 2 weeks following the final infusion. The timing and persistence of the antidepressant response to scopolamine suggest a mechanism beyond that of direct muscarinic cholinergic antagonism. These temporal relationships suggest that scopolamineinduced
changes in gene expression and synaptic plasticity may confer the therapeutic mechanism.

Interest in the muscarinic cholinergic system in mood disorders stemmed initially from evidence suggesting that hyper-sensitivity of the cholinergic system plays a role in the pathophysiology of depression. Researchers showed that increasing cholinergic activity using the anticholinesterase inhibitor, physostigmine, provided a challenge uniquely capable
both of exacerbating depressive symptoms in currently depressed subjects with major depressive disorder (MDD) and inducing depressive symptoms and reversing manic symptoms in manic subjects with bipolar disorder (BD) . The neuroendocrine and pupillary responses to physostigmine) also were abnormally increased in depressed individuals. The muscarinic cholinergic receptor system specifically was implicated by
evidence showing that polysomnographic responses to selective muscarinic agonists were exaggerated in depressed versus control samples, suggesting that muscarinic receptor supersensitivity exists in depressed individuals

The muscarinic receptor system, variation in the type 2 muscarinic (M2) cholinergic receptor gene (CHRM2) was associated with an elevated incidence or severity of unipolar depression and with abnormal
reductions in M2 receptor binding in bipolar depression.

Some abnormalities in cholinergic receptor function in mood disorders showed sex effects. For example, sex differences manifested in the baseline and cholinergically stimulated plasma hormone measures that differed between depressed and control samples, suggesting that heightened cholinergic sensitivity exists preferentially in premenopausal females with
MDD . Comings et al. found that genetic variation in CHRM2 gene (A/T
1890) was associated with MDD specifically in female subjects. In rodents, estrogen enhanced choline acetyltransferase activity and acetylcholine release , and M2 receptor stimulation mediated the estrogen-induced enhancement of N-methyl-D-aspartate receptor (NMDAR) function (24). These observations complement evidence reviewed
below that women are more likely than men to show an antidepressant response to scopolamine.

Putative animal models of depression also supported a role for elevated muscarinic cholinergic function. Flinders Sensitive Line rats, bred selectively for increased sensitivity of muscarinic receptors, showed putative behavioral analogs of depression such as lethargy,
reductions in self-stimulation, and increased behavioral despair in the forced swim test in response to agents that increase central cholinergic function . Moreover, antimuscarinic agents (including scopolamine) produced antidepressant-like effects by reducing the
behavioral despair induced via this test.

The timing of the antidepresant effects was after the third day of the infusion.


Scopolamine conceivably may alter synaptic plasticity or gene expression through a variety of direct or indirect mechanisms. In addition to producing antagonist effects at muscarinic receptors, scopolamine acutely increases acetylcholine release (via inhibi tion of releasecontrolling
muscarinic autoreceptors) and thereby increases cholinergic effects on nicotinic receptor systems to an extent that conceivably may contribute to antidepressant or antiinflammatory
effects. In addition, changes in muscarinic tone specifically have been
shown to affect other depression relevant systems, including the central dopamine serotonin, and neuropeptide Y transmitter systems and the innate immune system. Thus,
the antidepressant mechanism(s) of scopolamine potentially may involve a variety of systems.
One effect of scopolamine that is shared by some other somatic antidepressant treatments involves modulation of NMDAR function. The NMDAR gene expression is enhanced by muscarinic receptor stimulation in at least some brain structures , and thus, the elevated
muscarinic receptor sensitivity identified in mood disorders may contribute to an elevation in NMDAR transmission. Blocking muscarinic receptors via scopolamine administration reduces messenger RNA concentrations for NMDAR types 1A and 2A in the rat brain in vivo and protects hippocampal neurons from glutamate-mediated neurotoxicity
in vitro . Chronic administration of TCAs and repeated electroconvulsive shock reduce cortical NMDAR function, and treatments associated with a rapid onset of antidepressant effects exert direct NMDAR antagonist effects (ketamine) or induce NMDAR internalization (sleep deprivation) . Given evidence that abnormal glutamatergic transmission is involved in the pathophysiology of depression, these datasuggest that scopolamine’s effect on reducing NMDAR gene expression may play a role in
its antidepressant action.The-Role-of-the-Medial-Habenula-Cholinergic-System-in-Addiction-and-Emotion-Associated-BehaviorsDownloadScopolamine-Produces-Larger-Antidepressant-and-Antianxiety-Effects-in-Women-Than-in-MenDownload

In the above article, women have a more robust response to scopolamine than men do.

When comparing the baseline block to study end, the blockgender interaction (F¼12.6, p¼0.001) showed that the antianxiety response was greater in women. Men and women show a rapid antidepressant response following scopolamine, but the magnitude of response is larger in women than in men.

The bottom line: Scopolamine offers another route of treatment for depression and anxiety. We offer IV Scopolamine infusions at NOVA Health as well as scopolamine /Beta Blocker oral treatment dor dperession add on therapy and anxiety.



703-844-0184 | Ketamine Therapy for Depression | Fairfax, Virginia 22304 | Ketamine Therapy for OCD, PTSD, Bipolar , depression | Nasal Spray Ketamine Center Loudoun County, Virginia | Reston Ketamine |Ketamine Treatment Provider Virginia |

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NOVA Health Recovery Ketamine Infusion Center Fairfax, Virginia

Ketamine nasal spray can be used in a home environment for better depression and mood control. Call 703-844-0184 for an evaluation. No referral needed.

We use Ketamine with NAD therapy for patients who have low energy. fatigue, and depression. This can be combined with high dose Vitamin C and Glutathione for extra anti-oxidant effect.

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Suicide is preventable: How can we help our teens?

Every October, after school starts—and each May, as it ends—there is a spike in the number of teenagers who go to the Yale New Haven Children’s Hospital (YNHCH) emergency department because they are thinking about attempting suicide. They may or may not have struggled with a mental health issue before. But they often have a story: Bullies are harassing them, their parents are divorcing, the academic pressure is crushing them. For some, it’s gender concerns—they have come out as trans or non-binary, and their peers are shutting them out.

“It’s everything—all the pitfalls of being a teenager,” says Kirsten A. Bechtel, MD, a Yale Medicine specialist in the YNHCH, where she says 1,500 to 1,700 of the 40,000 patients a year come in for care for anxiety, depression, and other mental health and behavioral problems, and about 500 of those have suicidal thinking or behavior. In some cases, there may be no clear reason at all, she says.

Suicide is preventable, but rates of suicide are increasing worldwide, and it is now the second leading cause of death in adolescents and young adults (unintentional motor vehicle accidents are first).

Going to the emergency room may be the smartest thing these teenagers can do, Dr. Bechtel says. YNHCH is a Level 1 pediatric trauma center and provides subspecialty care for vulnerable children. Even a single attempt, not to mention an actual suicide, is a tragedy, she says, and a sign that there is a need for more prevention.

Why are teen suicides increasing?

Experts aren’t sure why there is an escalation in teen suicides, and an increase in mental illnesses, like depression and bipolar disorder, that are linked to suicide. One potential trigger may be what’s called “contagion”—when one suicide seems to prompt a chain reaction of suicides. Controversy has swirled around the Netflix series “13 Reasons Why,” which highlights the story of a girl who killed herself and left behind tapes to explain why. While some argue that the show has stimulated a positive conversation around the topic, a study in the Journal of the American Academy of Child and Adolescent Psychiatry showed a 28.9 percent increase in suicide rates in young people ages 10 to 17 in the month after the show’s release in April 2017. (In July 2019, producers followed advice from medical experts and cut a scene that portrayed the suicide.)

Social media also comes under discussion. “There is tantalizing data as far as the effects of social media, but I don’t think we have a good grip on that association,” says Yann Poncin, MD, a Yale Child Study Center psychiatrist, and medical director of the Children’s Day Hospital and In-Home Intensive Child & Adolescent Psychiatric Service. Dr. Poncin has noticed that many teenagers with depression—especially girls—turn to the online world. “I think the use of social media in a teenager with pre-existing concerns does fuel the fire a bit,” he says.

Although Dr. Bechtel has seen cases where social media has been used to alert friends that a teenager was in trouble, Facebook and Instagram can also drive a vulnerable teen to despair, she says. “The negative feedback teenagers get about what they said, what they wore, and who they are is so intense,” she says.

However, some of the biggest issues teens face are not new at all, Dr. Poncin says. A common one is loss—a romantic breakup, the end of a friendship, a death or divorce in the family—combined with underlying psychiatric disorders such as anxiety, depression, and bipolar disorder, which are also on the rise. Another is bullying: In a 2008 study, Yale researchers reviewed studies from 13 countries and found a connection between bullying and suicide.

How do you know a teenager is in trouble?

One thing experts agree on is that teenagers look at the world differently than adults do. “Psychologically, teenagers tend to have more absolutist views. They see things in starker, more rigid colors, and they see fewer gray areas,” says Eli Lebowitz, Ph.D., the director of the Program for Anxiety Disorders at the Yale Child Study Center. “This view can make a problem seem more daunting and a solution seem less likely, where a more mature person might be more accustomed to realizing that life has a combination of good and bad.”

Dr. Lebowitz tells parents who are worried to look at the teen’s ability to function. “‘Normal’ is ultimately the ability to function in way that is in line with expectations for someone of a similar age,” he says. For a teenager, that means attendance, performance, and the ability to get along with others at school, he explains. It is having a satisfying social life in and out of school, and the ability to participate in a reasonably functioning family life (whether or not it is devoid of conflict). It includes the “ability to eat, sleep, and get through a day feeling OK,” he says.

Jennifer Dwyer, MD, Ph.D., a psychiatrist at the Yale Child Study Center, says parents should pay attention if their teenager is chronically angry, cranky, or irritable, since teen depression may manifest through these behaviors rather than strictly through sadness or crying. But sadness can be a symptom too, she adds. Parents also should take note if teenagers are isolating themselves from friends, in constant conflict with the family or peers, having mood swings, giving away their belongings, or increasing their use of alcohol and drugs, she says.

Should you ask if they are thinking about suicide?

Suicidal ideation—essentially thinking about suicide—is not uncommon; in fact, most teenagers probably have thoughts, even if they don’t try it, Dr. Lebowitz says. But he says that many parents are hesitant to ask their teenager the direct question: Are you thinking about hurting yourself? “Not asking is usually a mistake. You are not likely to cause suicidal behavior if you ask about it,” he says. If the answer is yes, Dr. Lebowitz says the parent can follow up with additional questions:

  • How often do you think about it?
  • When do you think about it (all the time or only when you are really angry)?
  • Do you want to do it?
  • Do you have a specific plan?

If the teenager answers yes, the parent should seek help, Dr. Lebowitz says. “If the answer to the last two questions is yes, that would show the highest level of risk,” he adds. “Even if the answers to those are no, if a teenager thinks about it often, and not only when they are very angry or frustrated, then seeking help is recommended because it would indicate a high level of distress.”

These questions can also help diffuse the situation, Dr. Lebowitz says. “If you are alone thinking about suicide and you’re not able to talk about it, and nobody is asking you, that puts you at higher risk. If someone asks, even if you don’t like that person, it can reduce that sense of isolation. It’s just a fact in the life of a teenager that when somebody does care, it will reduce the risk,” he says.

Getting treatment to prevent suicide

Treatment for suicidal ideation starts with understanding the underlying concerns. Individual therapy, medication management, and the combination of the two could be appropriate, depending on the circumstances. Medicines that treat depression can often include a selective serotonin reuptake inhibitor (SSRI) such as Prozac or Zoloft. The medication can be combined with cognitive behavioral therapy (CBT), which involves regular meetings with a therapist to explore thoughts, feelings, and behaviors to better manage problems. “You can teach someone to recognize their own thinking patterns,” Dr. Lebowitz says. “It’s not instantaneous. But you can train the brain to recognize that pattern and say, “Oh, I’m falling into my thinking trap.””

“A lot of times the relationship with the therapist you are seeing is a good predictor of how therapy might work,” says Dr. Dwyer. “It should be someone the child and the parents feel comfortable bringing their concerns to, and who the child can stick with even when discussing difficult topics.”

Still, about 40 percent of teenagers fail to respond to medication, and half of that 40 percent don’t respond even when they switch to another medication and add psychotherapy, says Dr. Dwyer. “There aren’t a lot of great guidelines or algorithms after you’ve not had success with two medication trials and a trial of evidence-based psychotherapy,” she says.

Given the seriousness of adolescent treatment-resistant depression and suicide, novel treatments are currently being investigated. Ketamine is an anesthetic that has made headlines for its surprising antidepressant effects in adults. Esketamine, a related compound that is delivered as a nasal spray, was approved by the Food and Drug Administration (FDA) this year for treatment-resistant depression in adults. This medication works rapidly, within 24 hours, to reduce depressive symptoms compared to SSRIs, which take weeks to work. Ketamine is also associated with a reduction in suicidality in adults, even after controlling for any improvements in depressive symptoms.

Ketamine and esketamine are only now beginning to undergo rigorous testing for adolescents with treatment-resistant depression and suicidality. A small randomized clinical trial at Yale showed a positive effect of a single ketamine infusion in adolescents with treatment-resistant depression compared to a placebo, but this study only looked at short-term (two-week) outcomes.

Unfortunately, single doses of ketamine typically do not lead to sustained antidepressant responses, and Dr. Dwyer’s group is now conducting a trial looking at a limited number of repeated ketamine doses (which are associated with prolonged antidepressant effects in adults) in this population. But caution is warranted, Dr. Dwyer says, noting that some animal studies suggest that younger ages may be more susceptible to damage to the brain from a high dose of ketamine. It’s important to realize that ketamine is still considered an experimental treatment at this time for pediatric patients, she emphasizes. “I’m hopeful, but I’m also cautious about it, because I think the issues of effective and safe dosing paradigms in the population still need to be worked out,” says Dr. Dwyer.

What we are learning about the teenage brain

Meanwhile, neuroscientists are looking for clues in the brain which, in teens, is still developing. “Adolescence is a time when suicidal thoughts and behaviors can start to emerge,” says psychiatrist and neuroscientist Hilary Blumberg, MD, director of the Mood Disorders Research Program at Yale School of Medicine. She is using magnetic resonance imaging (MRI) to take pictures of the brains of adolescents and young adults with bipolar disorder who are at especially high risk—an estimated 50 percent of whom will attempt suicide at some point.

“We’re identifying the brain circuitry that underlies suicide thoughts and behaviors, how its trajectory of development differs in adolescents at risk for suicide, and how this can be helped,” says Dr. Blumberg, who has seen subtle variations in the prefrontal cortex of young people who have attempted suicide. (The prefrontal cortex has such executive functions as regulating emotions and impulses, and decision-making and planning. It can be compromised by various kinds of child abuse, substance abuse, and other stressors.) She and her research team have also observed subtle differences in the prefrontal structure in teens who go on to make a suicide attempt. “This provides us with new leads about how to generate targeted interventions to prevent suicide.”

Dr. Blumberg is also studying Social Rhythm Therapy (SRT), an approach that she says is showing early promise for normalizing brain circuitry and preventing suicide. SRT is designed to improve mood by regulating emotions and regularizing daily “rhythms”—an example of the latter is sleep patterns. “In order to help people have more regular sleep, you have to look at potential issues that may be causing the disruption. Their issues could be tied to social interactions and activity throughout the day, and a therapist can help them problem-solve around that,” Dr. Blumberg says. “We are encouraged by preliminary results where, after 12 weeks of regularizing daily rhythms, we see reductions in symptoms and suicide risk, and improvements in related brain circuitry.”

“The field has made important progress, but more research is needed,” Dr. Blumberg says. She is the U.S. lead of an international research consortium studying the brain scans of thousands of young people around the world who have suicidal thoughts and behaviors. She notes that the research is promising and may also turn out to be helpful to people who have bipolar disorder, as well as depression and other mental illnesses. “The future is very hopeful. We already have some strategies to prevent suicide, and it is especially hopeful that researchers from different disciplines are coming together in global efforts to discover new ways to reduce suicide.”

What if you are worried about suicide now?

Of course, many families need help immediately. If this is the case, Maryellen Flaherty-Hewitt, MD, a Yale Medicine pediatrician, recommends talking to the family pediatrician. “We routinely ask questions about access to guns, medications in the home, video games teenagers are using, and if they are exposed to violence,” says Dr. Flaherty-Hewitt. The pediatrician should be alert to teenagers who have had no history of mental illness, but who may be having difficulty coping with, say, feelings about sexuality, bullying at school or online, or the transition from one school to another, she says.

“When you have a child who has suicidal ideation, it’s a crisis, and pediatricians want to be part of this conversation. We want to make sure we bring the right people into the mix right away,” Dr. Flaherty-Hewitt says.

If the crisis warrants going to the emergency room, one of the first things that will happen is a counselor will sit with the teenager and listen to their concerns. In some cases, the patient will be admitted to the hospital or referred to YNHCH’s Partial Hospitalization Program. But, Dr. Bechtel says, “I’m always amazed how some of these kids are alright. Maybe they needed some respite, or maybe the biggest problem is that their behavioral health needs aren’t being met in the community,” she says.

For most young patients, thoughts of suicide are manageable, specialists say. “It may be a lifelong vulnerability, but there are many people who used to have an anxiety disorder or depression,” says Dr. Lebowitz. “We need to foster a belief in treatment and the understanding that having these problems can be part of life.”

Social Rhythm Therapy (SRT)Social-Rhythm-Therapies-for-Mood-Disorders-an-UpdateDownload

Magic Medicine?

Patients are turning to ketamine and other psychoactive drugs for mental health treatment

Sarah Jones, a 42-year-old stay-at-home mom in Woodstock, has struggled with depression since childhood. She’s tried multiple antidepressants and therapies over the years, and last fall, her medications once again quit working. Then Jones heard a radio ad about a new approach for depression — a drug called ketamine.

Ketamine is an anesthetic commonly used by veterinarians. It’s also used illegally as a club drug for its mind-altering, euphoric effects. And recently, it’s been touted for a new use: treating depression. 

Other psychoactive drugs like Ecstasy, LSD and magic mushrooms are also being considered as treatments for mental illnesses. Some of the drugs are under consideration for approval by the Food and Drug Administration (FDA).

Ketamine goes mainstream

Over the past several years, ketamine clinics, which deliver the drug to patients through intravenous (IV) infusions, have sprung up in Chicago and around the country to treat depression and other mental health conditions, including post-traumatic stress disorder (PTSD) and anxiety. 

Using the drug this way is considered an off-label use, meaning it’s used in a manner different from what’s been specified by the FDA. IV ketamine treatments for depression are not approved by the FDA and are often pricey. They are typically not covered by insurance. 

In March 2019, the FDA approved a nasal-spray version of ketamine, called esketamine (marketed as Spravato), to help the estimated 5 million Americans whose depression hasn’t responded to other treatments. Research shows that ketamine can more rapidly turn around depression than traditional antidepressants. Suicidal patients can find their urge to harm themselves quelled within 24 hours, rather than the weeks or months it takes a drug like Prozac to take effect, researchers have found.

It’s a bold move by the FDA to approve a completely new class of antidepressants and to open up a new realm of drugs that are considered psychedelics and psychoactive to be used as a medical treatment for something as common as depression,” says Bal Nandra, MD, an anesthesiologist and founder of IV Solution, which for almost three years has provided IV ketamine in downtown Chicago. 

Nandra hasn’t decided whether to offer the recently FDA-approved esketamine nasal spray in addition to IV ketamine. “It’s not nearly as effective or rapid acting as IV ketamine,” he says.

Lifting depression 

Jones received IV infusions of ketamine at Nandra’s South Dearborn Street clinic in November 2018. She followed Nandra’s typical regimen of six treatments given over a period of about two weeks, at a price of $500 to $600 per infusion. 

During these sessions, patients are seated in a private room, where they are hooked up to an IV for about 45 minutes, usually reclining on a medical lounge chair with the room darkened. Often, they wear an eye mask and listen to music. Patients are monitored by nurses or other staff for side effects, and those who become anxious may receive some sedation. After the infusion is over, patients are observed for about 30 to 45 minutes before being released. 

Ketamine can cause patients to feel dissociated from their bodies. The experience left Jones with a sense of the vastness of the universe and the idea that “there is something more out there than what we experience in our everyday life,” she says. “It almost takes you away from your suffering.” 

Most patients feel better after the first few ketamine infusions, Nandra says, though some take longer. Jones felt her depression lifting after her first treatment.  

It’s a bold move by the FDA … to open up a new realm of drugs that are considered psychedelics and psychoactive to be used as a medical treatment for something as common as depression.”

Jones returns to IV Solution every two months for one-session booster infusions to keep her depression at bay. 

She has been able to dramatically reduce her antidepressant use, while continuing in therapy. 

“Ketamine not only restored my brain to being able to function but also gave me insight into some life choices that were adding to my depression,” Jones says. Today, she adds, 

“I don’t remember what depression feels like. I’m so happy!” 

Gregory Teas, MD, a psychiatrist with the AMITA Health Behavioral Medicine Institute, says the clinic will likely start offering esketamine treatment starting this fall. Esketamine has a wholesale cost of $590 to $885 per dose, but the treatment may be covered by insurance, Teas says. Patients can’t take it at home but must go to a medical facility, where it is given under strict protocols, including two hours of monitoring afterward. 

Like other experts, Teas cautions that long-term studies on the use of ketamine and esketamine are needed. While the drug primarily works on receptors in the brain’s glutamate system, it also uses opioid and dopamine pathways, he says, which means it could be addictive for some patients.

Exploring other possibilities

Other psychoactive drugs may soon join ketamine as treatments for psychiatric conditions. The University of Chicago’s Human Behavioral Pharmacology Laboratory, directed by Harriet de Wit, PhD, has been studying MDMA (also known as Ecstasy) as a possible treatment.

MDMA, which causes people to feel loving toward themselves and others, may be helpful for people with PTSD and autism-related social anxiety, says researcher Anya Bershad, MD, PhD, who recently left the lab to complete a psychiatry residency at the University of California Los Angeles. 

A national phase 3 clinical trial of MDMA used in conjunction with psychotherapy for PTSD is underway, though Chicago is not a study site. If these trials go well, researchers expect the FDA might approve MDMA in 2021 for use with psychotherapy as a treatment for PTSD. 

Also being studied at the University of Chicago: microdosing with LSD to treat depression and anxiety. Study participants receive one-tenth or one-twentieth of a recreational dose, usually every three days, Bershad says. They don’t experience mind-altering psychedelic effects, but they do report feeling the “experience of unity,” even at those tiny doses, she says.

Other labs outside Illinois are studying psilocybin, or magic mushrooms, for their potential in treating anxiety, depression and eating disorders. Medical marijuana is also being researched for the treatment of PTSD, though studies differ so far on its effectiveness. 

As for ketamine, Nandra says in the years he’s been offering IV ketamine treatments he has seen many patients recover. “For these people, it lasts,” he says. “They do great. Their lives completely change. … It’s pretty amazing.”

Citocholine for Brain Health

Behind the Buzz: How Ketamine Changes the Depressed Patient’s Brain

The anesthetic-cum-party drug restores the ability to make connections among brain cells

The Food and Drug Administration’s approval in March of a depression treatment based on ketamine generated headlines, in part, because the drug represents a completely new approach for dealing with a condition the World Health Organization has labeled the leading cause of disability worldwide. The FDA’s approval marks the first genuinely new type of psychiatric drug—for any condition—to be brought to market in more than 30 years.

Although better known as a party drug, the anesthetic ketamine has spurred excitement in psychiatry for almost 20 years, since researchers first showed that it alleviated depression in a matter of hours. The rapid reversal of symptoms contrasted sharply with the existing set of antidepressants, which take weeks to begin working. Subsequent studies have shown ketamine works for patients who have failed to respond to multiple other treatments, and so are deemed “treatment-resistant.”

Despite this excitement, researchers still don’t know exactly how ketamine exerts its effects. A leading theory proposes that it stimulates regrowth of synapses (connections between neurons), effectively rewiring the brain. Researchers have seen these effects in animals’ brains, but the exact details and timing are elusive.

new study, from a team led by neuroscientist and psychiatrist Conor Liston at Weill Cornell Medicine, has confirmed that synapse growth is involved, but not in the way many researchers were expecting. Using cutting-edge technology to visualize and manipulate the brains of stressed mice, the study reveals how ketamine first induces changes in brain circuit function, improving “depressed” mice’s behavior within three hours, and only later stimulating regrowth of synapses.

As well as shedding new light on the biology underlying depression, the work suggests new avenues for exploring how to sustain antidepressant effects over the long term. “It’s a remarkable engineering feat, where they were able to visualize changes in neural circuits over time, corresponding with behavioral effects of ketamine,” says Carlos Zarate, chief of the Experimental Therapeutics and Pathophysiology Branch at the National Institute of Mental Health, who was not involved in the study. “This work will likely set a path for what treatments should be doing before we move them into the clinic.”

Another reason ketamine has researchers excited is that it works differently than existing antidepressants. Rather than affecting one of the “monoamine” neurotransmitters (serotonin, norepinephrine and dopamine), as standard antidepressants do, it acts on glutamate, the most common chemical messenger in the brain. Glutamate plays an important role in the changes synapses undergo in response to experiences that underlie learning and memory. That is why researchers suspected such “neuroplasticity” would lie at the heart of ketamine’s antidepressant effects.

Ketamine’s main drawback is its side effects, which include out-of-body experiences, addiction and bladder problems. It is also not a “cure.” The majority of recipients who have severe, difficult-to-treat depression will ultimately relapse. A course of multiple doses typically wears off within a few weeks to months. Little is known about the biology underlying depressive states, remission and relapse. “A big question in the field concerns the mechanisms that mediate transitions between depression states over time,” Liston says. “We were trying to get a better handle on that in the hopes we might be able to figure out better ways of preventing depression and sustaining recovery.”

Chronic stress depletes synapses in certain brain regions, notably the medial prefrontal cortex (mPFC), an area implicated in multiple aspects of depression. Mice subjected to stress display depressionlike behaviors, and with antidepressant treatment, they often improve. In the new study, the researchers used light microscopes to observe tiny structures called spines located on dendrites (a neuron’s “input” wires) in the mPFC of stressed mice. Spines play a key role because they form synapses if they survive for more than a few days.

For the experiment, some mice became stressed when repeatedly restrained, others became so after they were administered the stress hormone corticosterone. “That’s a strength of this study,” says neuroscientist Anna Beyeler, of the University of Bordeaux, France, who was not involved in the work, but wrote an accompanying commentary article in Science. “If you’re able to observe the same effects in two different models, this really strengthens the findings.” The team first observed the effects of subjecting mice to stress for 21 days, confirming that this resulted in lost spines. The losses were not random, but clustered on certain dendrite branches, suggesting the damage targets specific brain circuits.

The researchers then looked a day after administering ketamine and found that the number of spines increased. Just over half appeared in the same location as spines that were previously lost, suggesting a partial reversal of stress-induced damage. Depressionlike behaviors caused by the stress also improved. The team measured brain circuit function in the mPFC, also impaired by stress, by calculating the degree to which activity in cells was coordinated, a measure researchers term “functional connectivity.” This too improved with ketamine.

When the team looked closely at the timing of all this, they found that improvements in behavior and circuit function both occurred within three hours, but new spines were not seen until 12 to 24 hours after treatment. This suggests that the formation of new synapses is a consequence, rather than cause, of improved circuit function. Yet they also saw that mice who regrew more spines after treatment performed better two to seven days later. “These findings suggest that increased ensemble activity contributes to the rapid effects of ketamine, while increased spine formation contributes to the sustained antidepressant actions of ketamine,” says neuroscientist Ronald Duman, of the Yale School of Medicine, who was not involved in the study. Although the molecular details of what happens in the first hours are not yet fully understood, it seems a restoration of coordinated circuit activity occurs first; this is then entrenched by neuroplasticity effects in synapses, which then maintain behavioral benefits over time.

To prove that new synapses were a cause of antidepressant effects, rather than just coinciding with the improved behaviors, the team used a newly developed optogenetic technique, which allowed them to eliminate newly formed spines using light. Optogenetics works by introducing viruses that genetically target cells, causing them to produce light-sensitive proteins. In this case, the protein is expressed in newly formed synapses, and exposure to blue light causes the synapse to collapse. The researchers found that eliminating newly formed synapses in ketamine-treated mice abolished some of the drug’s positive effects, two days after treatment, confirming that new synapses are needed to maintain benefits. “Many mechanisms are surely involved in determining why some people relapse and some don’t,” Liston says, “ but we think our work shows that one of those involves the durability of these new synapses that form.”

And Liston adds: “Our findings open up new avenues for research, suggesting that interventions aimed at enhancing the survival of these new synapses might be useful for extending ketamine’s antidepressant effects.” The implication is that targeting newly formed spines might be useful for maintaining remission after ketamine treatment. “This is a great question and one the field has been considering,” Duman says. “This could include other drugs that target stabilization of spines, or behavioral therapies designed to engage the new synapses and circuits, thereby strengthening them.”

The study used three behavioral tests: one involving exploration, a second a struggle to escape, and a third an assessment of how keen the mice are on a sugar solution. This last test is designed to measure anhedonia—a symptom of depression in which the ability to experience pleasure is lost. This test was unaffected by deleting newly formed spines, suggesting that the formation of new synapses in the mPFC is important for some symptoms, such as apathy, but not others (anhedonia)—and that different aspects of depression involve a variety of brain circuits.

These results could relate to a study published last year that found activity in another brain region, the lateral habenula, is crucially involved in anhedonia, and injecting ketamine directly into this region improves anhedonia-related behavior in mice. “We’re slowly identifying specific regions associated with specific behaviors,” Beyeler says. “The factors leading to depression might be different depending on the individual, so these different models might provide information regarding the causes of depression.”

One caveat is that the study looked at only a single dose, rather than the multiple doses involved in a course of human treatment, Zarate says. After weeks of repeated treatments, might the spines remain, despite a relapse, or might they dwindle, despite the mice still doing well? “Ongoing effects with repeated administration, we don’t know,” Zarate says. “Some of that work will start taking off now, and we’ll learn a lot more.” Of course, the main caution is that stressed mice are quite far from humans with depression. “There’s no real way to measure synaptic plasticity in people, so it’s going to be hard to confirm these findings in humans,” Beyeler says.

Default Mode Network and Mood

The Default Mode Network (sometimes called simply the default network or the DMN) refers to an interconnected group of brain structures that are hypothesized to be part of a functional system. The DMN includes areas of the brain which researchers found to have higher activity when the mind was supposed to be at rest.  For example, when you are day dreaming, thinking about the future, replaying memories, etc. without a specific goal in mind.  Now, why would we care about this? The DMN is found to have increased activity in certain mood and pain disorders.  That being said, let’s look at our 3 reasons why you should know about the DMN. 

Reason #1: Increased DMN activity and functional connectivity is found in depression [1] as well as in pain disorders [2]. In these disorders, there is much rumination.  Rumination is where you have repetitive thoughts.  Those who deal with depression may replay depressing or sad memories over and over in their mind.  This prevents them from healing and creating room for more positive emotions and memories.  Additionally, those with pain may become fixated on the pain itself, or replay the events which lead to them having the pain.  This type of circular, overactive thinking occurs in the DMN. 

Reason #2:  Reducing activity in the DMN can decrease rumination, which in turn can reduce pain and depressed feelings.  In experienced meditators, there was decreased activity in the DMN, as well as increased connectivity in the regions of the brain responsible for self-monitoring and cognitive control [3]. Thus, giving us a scientific reason for the benefits of meditation.  We all have moments where we have unhelpful replays in our minds, and meditation can help us in breaking and reducing this ruminative behavior. 

Reason #3:  Ketamine reduces the functional activity in the DMN! A study showed that the connectivity of the DMN along with another portion of the brain, the dorsal nexus, was decreased after ketamine infusions [4]. So ketamine can effectively turn down the overactive areas in our mind, which can lead to an improved mood and less pain. 

In conclusion, you are much more than your mind, and before you can transcend something which does not serve you, you must know about it. Now that you know more about the default mode network, how your brain works, and rumination, what action will you take today

References:

  1. Hamilton, J. Paul, et al. “Default-Mode and Task-Positive Network Activity in Major Depressive Disorder: Implications for Adaptive and Maladaptive Rumination.” Biological Psychiatry, vol. 70, no. 4, 2011, pp. 327–333., doi:10.1016/j.biopsych.2011.02.003.
  2. Kucyi, A., et al. “Enhanced Medial Prefrontal-Default Mode Network Functional Connectivity in Chronic Pain and Its Association with Pain Rumination.” Journal of Neuroscience, vol. 34, no. 11, 2014, pp. 3969–3975., doi:10.1523/jneurosci.5055-13.2014.
  3. Brewer, J. A., et al. “Meditation Experience Is Associated with Differences in Default Mode Network Activity and Connectivity.” Proceedings of the National Academy of Sciences, vol. 108, no. 50, 2011, pp. 20254–20259., doi:10.1073/pnas.1112029108.
  4. Scheidegger, Milan et al. “Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action.” Ed. Stefano L. Sensi. PLoS ONE 7.9 (2012): e44799. PMC. Web. 23 June 2018.
  5. Sheline, Yvette I., et al. “The Default Mode Network and Self-Referential Processes in Depression.” Proceedings of the National Academy of Sciences, vol. 106, no. 6, 2009, pp. 1942–1947., doi:10.1073/pnas.0812686106.
  6. “Know Your Brain: Default Mode Network.” Neuroscientifically Challenged, 16 June 2015, www.neuroscientificallychallenged.com/blog/know-your-brain-default-mode-network.

NEUROGENESIS

When you break the word itself down, it comes in two parts: “neuro” as in neuron, and “genesis” as in creation. Neurogenesis broadly speaking is the process by which new neurons are created in the brain, thus allowing for increased plasticity of the brain and stronger synaptic connections. Adult neurogenesis is the process by which new neurons are created and integrated into existing brain circuitry when you are an adult. Adult neurogenesis can be seen in the olfactory bulb and the hippocampus.

The hippocampus is an S-shaped structure within the medial part of the temporal lobe and is densely packed with neurons. It a part of the limbic system, which also includes the hypothalamus and the amygdala. This region helps regulate emotion, memory, and arousal. Furthemore, the hippocampus is of particular interest because of its role in learning and motivation.

The monoamine hypothesis of depression states that antidepressants, a.k.a. selective serotonin reuptake inhibitors (SSRIs), work by increasing the levels of serotonin in the brain. It is thought that because SSRIs act on monoamine systems in the brain, which are involved in regulating emotion, therefore antidepressant results will be produced in individuals with depression.

However, treatment using SSRIs often take weeks to months to produce antidepressant effects, and sometimes they’re not even produced at all. People who have difficulty treating their depression with standard medical treatments are described as having treatment-resistant depression (TRD). Researchers are constantly working to find the mechanisms of depression and how it works in the brain.

Published in Neuropsychopharmacology in 2015, Hill and colleagues conducted a study on mice to measure whether inducing adult neurogenesis in the hippocampus positively affects anxious and depressive behaviors. Studies like these are often administered to mice first because they share similar biological and behavioral components to that of humans.

They found that when the mice were treated chronically with corticosterone (stress hormone secreted by the adrenal glands), increasing adult neurogenesis in the hippocampus does reduce anxiety and depression (1).

When we take these findings and circle back to ketamine, it makes sense. One of ketamine’s main mechanisms is increasing neurogenesis and synaptogenesis, allowing for neuroplasticity. Synaptogenesis is the process by which synaptic connections between the neurons in the brain are created. Increasing neuroplasticity allows for the brain to reorganize its connections more efficiently in response to stress and new changes in its environment. Essentially it is what keeps the brain resilient.

So ketamine increases neurogenesis, but why does it have the reputation of being a fast-acting antidepressant, especially for those with TRD? While we don’t have all of the answers to ketamine’s mechanisms, we do know this:

Ketamine Rapidly enhances the Maturation of Neurons

RATHER THAN INCREASING SEROTONIN, KETAMINE ACTS ON THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR AND THE GLUTAMATE NEUROTRANSMITTER

Ketamine increases the production of Brain Derived Neurotrophic Factor

Ketamine reduces the functional activity of the Default Mode Network

Beyond these multiple mechanisms of action, we also believe there is another level beyond the physical. Accordingly, we incorporate the bio-psycho-social-spiritual model of medicine at our clinic to take a holistic view for our patients!


References:

  1. Hill, A. S., Sahay, A., & Hen, R. (2015). Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors. Neuropsychopharmacology40(10), 2368–2378. doi: 10.1038/npp.2015.85

Researchers hypothesize that neurogenesis, or neuron growth, is an antidepressant action. This hypothesis is linked to the understanding that nearly all antidepressants increase birth of granule neurons in rodents. Ketamine, however, has such rapid antidepressant effects, suggesting that the mechanisms involved with ketamine are not involved with neuron birth. Instead, researchers hypothesized that ketamine’s rapid effects are due to it enhancing the maturation of neurons born previously.

To test this hypothesis, researchers injected rats with ketamine, assessing the effects of the ketamine on granule neurons. Researchers found that the ketamine rapidly affected the neurons, increasing mature neurons within two hours. A single injection of ketamine increased cell proliferation and functional maturation. For at least four weeks following the injection, depressive symptoms in rats were decreased.

In conclusion, ketamine has rapid, lasting effects on the recruitment of neurons into the hippocampal region of the brain. The hippocampus is believed to play a role in memory, spacial recognition, and avoidance-approach conflict processing. However, new neuron growth was independent of the antidepressant effects of the ketamine. The antidepressant effect may be due to ketamine’s work on neuron growth, but not on new neuron growth.

epression is among the most disabling conditions in our society. According to the World Health Organization, depression is the leading cause of ill health and disability worldwide. In America, 12.5% of individuals over the age of 12 have filled an antidepressant prescription.  Yet, the effectiveness of these medications are still lacking. Many patients don’t respond to antidepressant medications, and it can take months for the medicine to kick in. Unfortunately, many patients will regain their depression after being on medications long term.

Over 50 years ago, the hypothesis that low concentrations of serotonin in the central nervous caused depression was proposed.  This appealed to many doctors & scientists, because we finally had a potential biological mechanism to explain depression.  Accordingly, many antidepressants were developed to increase serotonin to help relieve depression. Although, it can work for some patients many patients do not respond or have significant side effects.  

SO WHAT IS A PERSON TO DO IF THEY HAVE TREATMENT-RESISTANT DEPRESSION?  

One cutting-edge option is targeting a completely different neurotransmitter – GLUTAMATE. Glutamate is an excitatory neurotransmitter and the most abundant neurotransmitter in the brain and central nervous system.  Ketamine works on the glutamate system by blocking it’s activity at the N-Methyl-D-Aspartate (NMDA) receptor.  

Ketamine raises brain derived neurotrophic factor (BDNF) levels, thereby enhancing connections between neurons and increasing neuroplasticity.  It’s literally changing the brain. In animal studies, the cascade of effects from ketamine created a rapid proliferation of dendritic spines that was associated with less depression. In a functional MRI brain study of humans, ketamine seemed to restore the functional connectivity in those patients with depression. 

Interestingly, ketamine is known to affect other receptors beyond the NMDA receptor, and have  anti-inflammatory as well as epigenetic effects. Also, the breakdown products of ketamine, like (S)-norketamine and (2R, 6R)-hydroxynorketamine, may also play a role in helping with depression. 

Even though we have some understanding of how ketamine works, we still don’t fully comprehend how ketamine is working exactly in patients with depression. 

“We live on an island surrounded by a sea of ignorance. As our island of knowledge grows, so does the shore of our ignorance.

— John A. Wheeler, Physicist

As we continue to learn more about ketamine and depression, more questions and unknowns will surely develop.

Therefore, it’s critical to expand our understanding of depression beyond the simple serotonin and even glutamate neurotransmitters.  The human body, brain, and consciousness is one of the most complex systems we have ever encountered. Although, we may never fully understand the intricacy of it all, we can still take action. 

We can be pragmatic and responsibly use ketamine for carefully selected patients. In addition to ketamine infusions, we can encourage psychotherapy, exercise, meditation, prayer, positive community, a good night’s rest, and a healthy diet to help people with depression.  

At Reset Ketamine, we utilize the bio-psycho-social-spiritual model that encompasses a whole person approach to health.  We believe health is not merely the absence of illness, but a state of physical, social, mental, and spiritual well-being.  We believe ketamine can be the catalyst to create paradigm shifts to help patients live a full life.

References:

Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019). Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron, 101(5), 774-778. doi:10.1016/j.neuron.2019.02.005

ccording to the World Health Organization, depression has now surpassed HIV, AIDS, malaria, diabetes, and war as the leading cause of disability. Current antidepressants may take weeks to months to be effective. Unfortunately, one-third of patients are still unresponsive, and are called “treatment-resistant.” However, there are other options available.

Ketamine, possibly the most widely used anesthetic agent in the world, has been shown by numerous studies to have rapid antidepressant effects when used off-label. The full mechanism by which ketamine induces these therapeutic effects is still a mystery. What researchers do understand is that increased levels of brain derived neurotrophic factor (BDNF), a protein that plays a role in the growth and maintenance of neurons, is involved. But how and where does ketamine increase BDNF?

A recent study in 2017 suggests that HDAC5, an enzyme affecting DNA and chromosomes, regulates the antidepressant effects of ketamine through a process called phosphorylation, which regulates protein function. Ketamine influences the transcription (the process by which DNA is turned into RNA) of BDNF and increases BDNF levels in the central nervous system.

Additionally, a study in 2015 demonstrated that the antidepressant effects of ketamine are based on the release of BDNF and the activation of the L-type voltage-dependent calcium channels (VDCC). Researchers found that the release of BDNF regulates the antidepressant effects of ketamine, further clarifying the underlying mechanisms that ketamine utilizes.

Furthermore, researchers observed in another 2015 study that dysfunctional levels of BDNF may be linked to depression, and that ketamine treatment can produce a positive effect within certain pathways of the brain, such as in the prefrontal cortex and nucleus accumbens. In this animal study, rats were divided into four groups: saline+deprived, saline+non-deprived, ketamine+deprived, and ketamine+non-deprived. Ketamine infusions were administered daily for 14 days. Researchers then observed the animals’ brain structures. They observed that the deprived rats had reduced levels of BDNF in the amygdala, hippocampus and nucleus accumbens. The ketamine reversed the levels of BDNF in the amygdala and nucleus accumbens. This is important because the amygdala plays a critical response in fear and strong emotions, while the nucleus accumbens is essential in motivation, aversion, reward, and learning.

In addition to ketamine’s effect on the default mode networkneuronsbrain wavesglutamate neurotransmitter, and inflammation, by understanding ketamine’s impact on BDNF, we can gain a deeper insight into the mystery of how our brain works. Ultimately, as Socrates once said, “To know thyself is the beginning of wisdom.”

References:

Choi, Miyeon, et al. “Ketamine Induces Brain-Derived Neurotrophic Factor Expression via Phosphorylation of Histone Deacetylase 5 in Rats.” Biochemical and Biophysical Research Communications, vol. 489, no. 4, 2017, pp. 420–425., doi:10.1016/j.bbrc.2017.05.157.

Lepack, A. E., et al. “BDNF Release Is Required for the Behavioral Actions of Ketamine.” International Journal of Neuropsychopharmacology, vol. 18, no. 1, 2014, doi:10.1093/ijnp/pyu033.

Réus, Gislaine, et al. “Ketamine Treatment Partly Reverses Alterations in Brain Derived- Neurotrophic Factor, Oxidative Stress and Energy Metabolism Parameters Induced by an Animal Model of Depression.” Current Neurovascular Research, vol. 12, no. 1, 2015, pp. 73–84., doi:10.2174/1567202612666150122122924.

Depression is among the most disabling conditions in our society. According to the World Health Organization, depression is the leading cause of ill health and disability worldwide. In America, 12.5% of individuals over the age of 12 have filled an antidepressant prescription.  Yet, the effectiveness of these medications are still lacking. Many patients don’t respond to antidepressant medications, and it can take months for the medicine to kick in. Unfortunately, many patients will regain their depression after being on medications long term.

Over 50 years ago, the hypothesis that low concentrations of serotonin in the central nervous caused depression was proposed.  This appealed to many doctors & scientists, because we finally had a potential biological mechanism to explain depression.  Accordingly, many antidepressants were developed to increase serotonin to help relieve depression. Although, it can work for some patients many patients do not respond or have significant side effects.  

SO WHAT IS A PERSON TO DO IF THEY HAVE TREATMENT-RESISTANT DEPRESSION?  

One cutting-edge option is targeting a completely different neurotransmitter – GLUTAMATE. Glutamate is an excitatory neurotransmitter and the most abundant neurotransmitter in the brain and central nervous system.  Ketamine works on the glutamate system by blocking it’s activity at the N-Methyl-D-Aspartate (NMDA) receptor.  

Ketamine raises brain derived neurotrophic factor (BDNF) levels, thereby enhancing connections between neurons and increasing neuroplasticity.  It’s literally changing the brain. In animal studies, the cascade of effects from ketamine created a rapid proliferation of dendritic spines that was associated with less depression. In a functional MRI brain study of humans, ketamine seemed to restore the functional connectivity in those patients with depression. 

Interestingly, ketamine is known to affect other receptors beyond the NMDA receptor, and have  anti-inflammatory as well as epigenetic effects. Also, the breakdown products of ketamine, like (S)-norketamine and (2R, 6R)-hydroxynorketamine, may also play a role in helping with depression. 

Even though we have some understanding of how ketamine works, we still don’t fully comprehend how ketamine is working exactly in patients with depression. 

“We live on an island surrounded by a sea of ignorance. As our island of knowledge grows, so does the shore of our ignorance.

— John A. Wheeler, Physicist

As we continue to learn more about ketamine and depression, more questions and unknowns will surely develop.

Therefore, it’s critical to expand our understanding of depression beyond the simple serotonin and even glutamate neurotransmitters.  The human body, brain, and consciousness is one of the most complex systems we have ever encountered. Although, we may never fully understand the intricacy of it all, we can still take action. 

We can be pragmatic and responsibly use ketamine for carefully selected patients. In addition to ketamine infusions, we can encourage psychotherapy, exercise, meditation, prayer, positive community, a good night’s rest, and a healthy diet to help people with depression.  

At Reset Ketamine, we utilize the bio-psycho-social-spiritual model that encompasses a whole person approach to health.  We believe health is not merely the absence of illness, but a state of physical, social, mental, and spiritual well-being.  We believe ketamine can be the catalyst to create paradigm shifts to help patients live a full life.

References:

Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019). Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron, 101(5), 774-778. doi:10.1016/j.neuron.2019.02.005

Researchers hypothesize that neurogenesis, or neuron growth, is an antidepressant action. This hypothesis is linked to the understanding that nearly all antidepressants increase birth of granule neurons in rodents. Ketamine, however, has such rapid antidepressant effects, suggesting that the mechanisms involved with ketamine are not involved with neuron birth. Instead, researchers hypothesized that ketamine’s rapid effects are due to it enhancing the maturation of neurons born previously.

To test this hypothesis, researchers injected rats with ketamine, assessing the effects of the ketamine on granule neurons. Researchers found that the ketamine rapidly affected the neurons, increasing mature neurons within two hours. A single injection of ketamine increased cell proliferation and functional maturation. For at least four weeks following the injection, depressive symptoms in rats were decreased.

In conclusion, ketamine has rapid, lasting effects on the recruitment of neurons into the hippocampal region of the brain. The hippocampus is believed to play a role in memory, spacial recognition, and avoidance-approach conflict processing. However, new neuron growth was independent of the antidepressant effects of the ketamine. The antidepressant effect may be due to ketamine’s work on neuron growth, but not on new neuron growth.


THETA BRAIN WAVES & THE ANTI-ANXIETY EFFECTS OF KETAMINE

According to a study published in the International Journal of Neuropsychopharmacology in 2018, specific brain waves are related to the anti-anxiety effects of ketamine. The brain waves involved in this function are called theta waves, found in the right frontal area of the brain. Ketamine can treat a wide variety of neurotic disorders, such as depressiongeneralized anxiety disorder, and PTSD, but researchers do not conclusively understand how ketamine works to relieve the symptoms of these disorders.

To better understand the therapeutic effects of ketamine, researchers studied the brain activity of patients given ketamine. Patients with generalized anxiety disorder and/or social anxiety disorder were administered ketamine and hooked up to a monitor measuring electrical brain activity (EEG). Ketamine affected the power of the brain waves by increasing the fast waves and decreasing the slow waves. However, only a single frequency band was related to therapeutic effects—the theta waves.

Human consciousness is believed to be related to neurons firing synchronously in various frequencies. Theta waves are in the 4 to 7 hertz rhythms. During meditation, theta waves predominated and were most abundant in the frontal and middle parts of the brain. Professor Jim Lagopoulos states, “These types of waves likely originate from a relaxed attention that monitors our inner experiences. Here lies a significant difference between meditation and relaxing without any specific technique. Previous studies have shown that theta waves indicate deep relaxation and occur more frequently in highly experienced meditation practitioners. When we measure mental calm, these regions signal to lower parts of the brain, inducing the physical relaxation response that occurs during meditation.”

So ketamine infusions seems to put the brain into a similar state that highly experienced meditators can achieve allowing for a calm, relaxed state of mind.

In conclusion, the anti-anxiety relief of ketamine may related to a very specific portion of electrical brain activity. This finding combined with the knowledge that ketamine blocks the NMDA glutamate receptor helps researchers understand how ketamine affects the brain. This preliminary study paves the way for future research on brain studies and ketamine.

Ketamines impact on BDNF

According to the World Health Organization, depression has now surpassed HIV, AIDS, malaria, diabetes, and war as the leading cause of disability. Current antidepressants may take weeks to months to be effective. Unfortunately, one-third of patients are still unresponsive, and are called “treatment-resistant.” However, there are other options available.

Ketamine, possibly the most widely used anesthetic agent in the world, has been shown by numerous studies to have rapid antidepressant effects when used off-label. The full mechanism by which ketamine induces these therapeutic effects is still a mystery. What researchers do understand is that increased levels of brain derived neurotrophic factor (BDNF), a protein that plays a role in the growth and maintenance of neurons, is involved. But how and where does ketamine increase BDNF?

A recent study in 2017 suggests that HDAC5, an enzyme affecting DNA and chromosomes, regulates the antidepressant effects of ketamine through a process called phosphorylation, which regulates protein function. Ketamine influences the transcription (the process by which DNA is turned into RNA) of BDNF and increases BDNF levels in the central nervous system.

Additionally, a study in 2015 demonstrated that the antidepressant effects of ketamine are based on the release of BDNF and the activation of the L-type voltage-dependent calcium channels (VDCC). Researchers found that the release of BDNF regulates the antidepressant effects of ketamine, further clarifying the underlying mechanisms that ketamine utilizes.

Furthermore, researchers observed in another 2015 study that dysfunctional levels of BDNF may be linked to depression, and that ketamine treatment can produce a positive effect within certain pathways of the brain, such as in the prefrontal cortex and nucleus accumbens. In this animal study, rats were divided into four groups: saline+deprived, saline+non-deprived, ketamine+deprived, and ketamine+non-deprived. Ketamine infusions were administered daily for 14 days. Researchers then observed the animals’ brain structures. They observed that the deprived rats had reduced levels of BDNF in the amygdala, hippocampus and nucleus accumbens. The ketamine reversed the levels of BDNF in the amygdala and nucleus accumbens. This is important because the amygdala plays a critical response in fear and strong emotions, while the nucleus accumbens is essential in motivation, aversion, reward, and learning.

In addition to ketamine’s effect on the default mode networkneuronsbrain wavesglutamate neurotransmitter, and inflammation, by understanding ketamine’s impact on BDNF, we can gain a deeper insight into the mystery of how our brain works. Ultimately, as Socrates once said, “To know thyself is the beginning of wisdom.”

References:

Choi, Miyeon, et al. “Ketamine Induces Brain-Derived Neurotrophic Factor Expression via Phosphorylation of Histone Deacetylase 5 in Rats.” Biochemical and Biophysical Research Communications, vol. 489, no. 4, 2017, pp. 420–425., doi:10.1016/j.bbrc.2017.05.157.

Lepack, A. E., et al. “BDNF Release Is Required for the Behavioral Actions of Ketamine.” International Journal of Neuropsychopharmacology, vol. 18, no. 1, 2014, doi:10.1093/ijnp/pyu033.

Réus, Gislaine, et al. “Ketamine Treatment Partly Reverses Alterations in Brain Derived- Neurotrophic Factor, Oxidative Stress and Energy Metabolism Parameters Induced by an Animal Model of Depression.” Current Neurovascular Research, vol. 12, no. 1, 2015, pp. 73–84., doi:10.2174/1567202612666150122122924.

Who should not get Ketamine?

Here are the 7 types of people who should NOT take ketamine:

  1. People with uncontrolled high blood pressure (hypertension). Ketamine is known to increase blood pressure, and in the setting of already high blood pressure the increase could get so high as to cause a heart attack or stroke. So it is important to have blood pressure monitored throughout your infusion.
  2. People with unstable heart disease (such as arrhythmias, congestive heart failure, coronary artery disease, etc.). Ketamine can increase heart rate and cardiac output (how hard your heart is working), which could worsen various heart conditions.
  3. People with untreated or uncontrolled thyroid disease (especially hyperthyroidism). In thyroid diseases such as hyperthyroidism, the body may already have an increased heart rate i.e. sympathetic overdrive which could be worsened with taking ketamine.
  4. People with active substance abuse. Ketamine can be used to treat addiction, however, infusions are given once the patient has detoxed or is off of the drugs the individual is addicted to. When a person is taking multiple drugs, the way their body may react may be unpredictable and potentially life threatening.
  5. People in an active manic phase of bipolar disorder. Ketamine can cause an altered mental state. If a person is already in an active manic state, ketamine could potentially worsen or enhance a worrisome emotional state.
  6. People with active delusions and hallucination symptoms (not taking prescription or while on street drugs). Similar to the point made in #5, a person can experience out of body experience or similar non ordinary state experiences when given ketamine. Ketamine could potentially enhance or worsen delusions and active hallucinations.
  7. Lastly, patients who have tried ketamine in the past and have had bad reactions to this medication.  If someone has been given ketamine for a procedure and had an adverse effect, we would suggest holding off. 

Psychedelic therapy, or at least the talk of them, is very popular as of this writing. Ketamine is currently the only legal and FDA approved psychedelic in the United States.  You may have heard about ketamine as a recreational drug or as an animal tranquilizer but not sure what to think about it. You may have depression, anxiety, OCD, or PTSD which is not being helped by standard treatments. You may even know of a loved one who could benefit from ketamine infusions. 

There is a lot of information out there. Some good and some not so good information in giving you a straight-forward understanding of ketamine as a treatment option for various mental health disorders. So welcome to our beginner’s guide, where we’ll cover the basics of what you need to know.

WHAT IS KETAMINE?

Ketamine was first synthesized in the 1960’s for use as a general anesthetic and FDA approved in 1970. Ketamine blocks the activity of glutamate (an excitatory neurotransmitter), which binds to and activates the NMDA receptor.  This NMDA receptor blockade is known to increase brain derived neurotrophic factor (BDNF).

Increases in BDNF results in increased neurogenesis and neuroplasticity. This helps those with chronic pain and depression to restore their neuronal activity and synaptic strength in the prefrontal cortex, restoring and resetting their brain back to a healthier state.

If you want to further learn how ketamine works check out: The 4 Mechanisms of How Ketamine Works

Ketamine has been traditionally used in the operating room and emergency departments for sedation and pain control.   Ketamine has a colorful history and is known to be used in veterinary medicine as a “animal tranquilizer” and even a recreational club drug of abuse.  However, ketamine is the most commonly medicine used worldwide for sedation and the World Health Organization (WHO) places ketamine in its List of Essential Medicines. 

Ketamine can be delivered into the body in several forms: oral (pill form), intranasal (insufflated into the nose), intramuscular (injected into the muscle), and intravenous (into the vein). Most ketamine clinics provide ketamine in the intravenous form as a slow infusion.  There are other clinics that may provide ketamine in the other forms in conjunction with psychotherapy. 

 WHY DOCTORS ARE USING KETAMINE?

Ketamine is effective in chronic pain, PTSD, depression, and other illnesses. Because of ketamine’s unique properties, many people are experiencing rapid, effective relief compared to traditional treatments, such as selective serotonin reuptake inhibitors (SSRIs) which can take months to take effect. 

When individuals are receiving ketamine for these treatments, ketamine is being used “off-label,” meaning that it is not being for the specific indication approved by the United States Food and Drug Administration (FDA). To get FDA approval for an indication, it requires multiple stages of research to evaluate the safety and efficacy for that specific use.  In 1970, ketamine was FDA approved for use as the,“sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.”  But all other uses are considered “off-label.” Fortunately, once a drug is FDA approved, physicians have the freedom to use their best clinical judgment in prescribing drugs for other purposes than originally intended.  

WHO SHOULDN’T GET KETAMINE?

To understand who should not get ketamine, you’ll need to understand the effect of ketamine on the body. Ketamine can increase the heart rate and blood pressure, and stress the cardiac function of anyone who has uncontrolled heart problems.  Ketamine is used during medical procedures and operations for analgesia (i.e. doctors can perform surgeries and procedures without causing pain to the patients) due to its dissociative property. This dissociative property is also, according to research, associated with better antidepressant effect during ketamine infusions. While this is a wonderful property, if a person has a mental disorder which is characterized by hallucinations or delusions, undergoing ketamine infusions could actually worsen these conditions. 

REVISITING THE HALLUCINOGENIC POTENTIAL OF KETAMINE

WE NOW KNOW WHY KETAMINE IS SO EFFECTIVE AT TREATING DEPRESSION

FIRST KETAMINE INFUSION CLINIC IN PALM SPRINGS, CA OPENS

FROM CHAOS TO CALM: A LIFE CHANGED BY KETAMINE

IS KETAMINE THE NEXT BIG DEPRESSION DRUG?

KETAMINE RELIEVES DEPRESSION BY RESTORING BRAIN CONNECTIONS

IS KETAMINE THE BEST HOPE FOR CURING MAJOR DEPRESSION?

KETAMINE DEPRESSION TREATMENT ‘SHOULD BE ROLLED OUT’

KETAMINE: THE FUTURE OF DEPRESSION TREATMENT?

ONCE IT FULLY CATCHES ON, KETAMINE COULD BE A REALLY IMPORTANT ANTIDEPRESSANT

TACKLING DEPRESSION WITH KETAMINE

ONETIME PARTY DRUG HAILED AS MIRACLE FOR TREATING SEVERE DEPRESSION

YALE SCIENTISTS EXPLAIN HOW KETAMINE VANQUISHES DEPRESSION WITHIN HOURS

WHAT IT’S LIKE TO HAVE YOUR SEVERE DEPRESSION TREATED WITH A HALLUCINOGENIC DRUG

KETAMINE INFUSIONS CUT MIGRAINE PAIN IN HALF IN NEW STUDY

FOR RECALCITRANT NEUROPATHIC PAIN, CONSIDER OUTPATIENT KETAMINE

KETAMINE RESETS SYSTEM FOR NORMAL PAIN PROCESSING IN COMPLEX SYNDROME PATIENTS

FIBROMYALGIA DOCTOR TOUTS KETAMINE FOR PAIN AND DEPRESSION

FIBROMYALGIA PATIENTS TREATED WITH INTRAVENOUS KETAMINE

THIS COULD BE BIG: INTRAVENOUS KETAMINE FOR FIBROMYALGIA

THE CURRENT MENTAL HEALTH CRISIS AND THE COMING KETAMINE REVOLUTION

YALE: ‘MAGIC’ ANTIDEPRESSANT MAY HOLD PROMISE FOR PTSD

IV KETAMINE RAPIDLY EFFECTIVE IN PTSD

KETAMINE MAY HELP EXTINGUISH FEARFUL MEMORIES

KETAMINE COULD PROVE USEFUL IN TREATMENT OF SEVERE SOCIAL ANXIETY

PSYCHEDELIC MEDICINE 101: THE CURIOUS CASE OF KETAMINE

Links to Academic Articles

RAPID AND LONGER-TERM ANTIDEPRESSANT EFFECTS OF REPEATED KETAMINE INFUSIONS IN TREATMENT-RESISTANT MAJOR DEPRESSION

SAFETY AND EFFICACY OF REPEATED-DOSE INTRAVENOUS KETAMINE FOR TREATMENT-RESISTANT DEPRESSION

NEUROBIOLOGY OF STRESS, DEPRESSION, AND RAPID ACTING ANTIDEPRESSANTS: REMODELING SYNAPTIC CONNECTIONS

NEW PARADIGMS FOR TREATMENT-RESISTANT DEPRESSION

ANTIDEPRESSANT EFFICACY OF KETAMINE IN TREATMENT-RESISTANT MAJOR DEPRESSION: A TWO-SITE RANDOMIZED CONTROLLED TRIAL

HIPPOCAMPAL VOLUME AND THE RAPID ANTIDEPRESSANT EFFECT OF KETAMINE

KETAMINE AND THE NEXT GENERATION OF ANTIDEPRESSANTS WITH A RAPID ONSET OF ACTION

DO THE DISSOCIATIVE SIDE EFFECTS OF KETAMINE MEDIATE ITS ANTIDEPRESSANT EFFECTS?

SYMPTOMATOLOGY AND PREDICTORS OF ANTIDEPRESSANT EFFICACY IN EXTENDED RESPONDERS TO A SINGLE KETAMINE INFUSION.

ANTIDEPRESSANT EFFECTS OF KETAMINE IN DEPRESSED PATIENTS

THE ROLE OF KETAMINE IN TREATMENT-RESISTANT DEPRESSION: A SYSTEMATIC REVIEW

IMPROVEMENT IN SUICIDAL IDEATION AFTER KETAMINE INFUSION: RELATIONSHIP TO REDUCTIONS IN DEPRESSION AND ANXIETY

USE OF KETAMINE IN ACUTE CASES OF SUICIDALITY

A POSSIBLE ROLE FOR KETAMINE IN SUICIDE PREVENTION IN EMERGENCY AND MAINSTREAM PSYCHIATRY

EFFICACY OF INTRAVENOUS KETAMINE FOR TREATMENT OF CHRONIC POST-TRAUMATIC STRESS DISORDER: A RANDOMIZED CLINICAL TRIAL

EFFICACY OF KETAMINE IN THE TREATMENT OF SUBSTANCE USE DISORDERS: A SYSTEMATIC REVIEW

KETAMINE REDUCES MUSCLE PAIN, TEMPORAL SUMMATION, AND REFERRED PAIN IN FIBROMYALGIA PATIENTS

KETAMINE IN CHRONIC PAIN MANAGEMENT: AN EVIDENCE-BASED REVIEW

RANDOMIZED CONTROLLED CROSSOVER TRIAL OF KETAMINE IN OBSESSIVE-COMPULSIVE DISORDER: PROOF-OF-CONCEPT

RAPID RESOLUTION OF OBSESSIONS AFTER AN INFUSION OF INTRAVENOUS KETAMINE IN A PATIENT WITH TREATMENT-RESISTANT OBSESSIVE-COMPULSIVE DISORDER: A CASE REPORT

ANALGESIC EFFECT OF SUBANESTHETIC INTRAVENOUS KETAMINE IN REFRACTORY NEUROPATHIC PAIN: A CASE REPORT

PAIN ANALYSIS IN PATIENTS WITH FIBROMYALGIA. EFFECTS OF INTRAVENOUS MORPHINE, LIDOCAINE, AND KETAMINE

KETAMINE FOR SOCIAL ANXIETY DISORDER: A RANDOMIZED, PLACEBO-CONTROLLED CROSSOVER TRIAL

NOVEL TREATMENT FOR LEVODOPA INDUCED MOTOR FLUCTUATIONS AND DYSKINESIA ASSOCIATED WITH PARKINSON’S DISEASE

KLEINE LEVIN SYNDROME (KLS) RESEARCH UPDATE IN LABORATORY OF DR. MIGNOT, STANFORD UNIVERSITY

703-844-0184 | Ketamine Therapy Virginia for depression | Fairfax irginia Ketamine Infusion Center | Suicide is preventable: How can we help our teens? | IV NAD therapy Center

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all 703-844-0184 for a phone consultation if you are interested in trying Ketamine for the treatment of depression, OCD, PTSD, or other mood disorders.

Suicide is preventable: How can we help our teens?

Every October, after school starts—and each May, as it ends—there is a spike in the number of teenagers who go to the Yale New Haven Children’s Hospital (YNHCH) emergency department because they are thinking about attempting suicide. They may or may not have struggled with a mental health issue before. But they often have a story: Bullies are harassing them, their parents are divorcing, the academic pressure is crushing them. For some, it’s gender concerns—they have come out as trans or non-binary, and their peers are shutting them out.

“It’s everything—all the pitfalls of being a teenager,” says Kirsten A. Bechtel, MD, a Yale Medicine specialist in the YNHCH, where she says 1,500 to 1,700 of the 40,000 patients a year come in for care for anxiety, depression, and other mental health and behavioral problems, and about 500 of those have suicidal thinking or behavior. In some cases, there may be no clear reason at all, she says.

Suicide is preventable, but rates of suicide are increasing worldwide, and it is now the second leading cause of death in adolescents and young adults (unintentional motor vehicle accidents are first).

Going to the emergency room may be the smartest thing these teenagers can do, Dr. Bechtel says. YNHCH is a Level 1 pediatric trauma center and provides subspecialty care for vulnerable children. Even a single attempt, not to mention an actual suicide, is a tragedy, she says, and a sign that there is a need for more prevention.

Why are teen suicides increasing?

Experts aren’t sure why there is an escalation in teen suicides, and an increase in mental illnesses, like depression and bipolar disorder, that are linked to suicide. One potential trigger may be what’s called “contagion”—when one suicide seems to prompt a chain reaction of suicides. Controversy has swirled around the Netflix series “13 Reasons Why,” which highlights the story of a girl who killed herself and left behind tapes to explain why. While some argue that the show has stimulated a positive conversation around the topic, a study in the Journal of the American Academy of Child and Adolescent Psychiatry showed a 28.9 percent increase in suicide rates in young people ages 10 to 17 in the month after the show’s release in April 2017. (In July 2019, producers followed advice from medical experts and cut a scene that portrayed the suicide.)

Social media also comes under discussion. “There is tantalizing data as far as the effects of social media, but I don’t think we have a good grip on that association,” says Yann Poncin, MD, a Yale Child Study Center psychiatrist, and medical director of the Children’s Day Hospital and In-Home Intensive Child & Adolescent Psychiatric Service. Dr. Poncin has noticed that many teenagers with depression—especially girls—turn to the online world. “I think the use of social media in a teenager with pre-existing concerns does fuel the fire a bit,” he says.

Although Dr. Bechtel has seen cases where social media has been used to alert friends that a teenager was in trouble, Facebook and Instagram can also drive a vulnerable teen to despair, she says. “The negative feedback teenagers get about what they said, what they wore, and who they are is so intense,” she says.

However, some of the biggest issues teens face are not new at all, Dr. Poncin says. A common one is loss—a romantic breakup, the end of a friendship, a death or divorce in the family—combined with underlying psychiatric disorders such as anxiety, depression, and bipolar disorder, which are also on the rise. Another is bullying: In a 2008 study, Yale researchers reviewed studies from 13 countries and found a connection between bullying and suicide.

How do you know a teenager is in trouble?

One thing experts agree on is that teenagers look at the world differently than adults do. “Psychologically, teenagers tend to have more absolutist views. They see things in starker, more rigid colors, and they see fewer gray areas,” says Eli Lebowitz, Ph.D., the director of the Program for Anxiety Disorders at the Yale Child Study Center. “This view can make a problem seem more daunting and a solution seem less likely, where a more mature person might be more accustomed to realizing that life has a combination of good and bad.”

Dr. Lebowitz tells parents who are worried to look at the teen’s ability to function. “‘Normal’ is ultimately the ability to function in way that is in line with expectations for someone of a similar age,” he says. For a teenager, that means attendance, performance, and the ability to get along with others at school, he explains. It is having a satisfying social life in and out of school, and the ability to participate in a reasonably functioning family life (whether or not it is devoid of conflict). It includes the “ability to eat, sleep, and get through a day feeling OK,” he says.

Jennifer Dwyer, MD, Ph.D., a psychiatrist at the Yale Child Study Center, says parents should pay attention if their teenager is chronically angry, cranky, or irritable, since teen depression may manifest through these behaviors rather than strictly through sadness or crying. But sadness can be a symptom too, she adds. Parents also should take note if teenagers are isolating themselves from friends, in constant conflict with the family or peers, having mood swings, giving away their belongings, or increasing their use of alcohol and drugs, she says.

Should you ask if they are thinking about suicide?

Suicidal ideation—essentially thinking about suicide—is not uncommon; in fact, most teenagers probably have thoughts, even if they don’t try it, Dr. Lebowitz says. But he says that many parents are hesitant to ask their teenager the direct question: Are you thinking about hurting yourself? “Not asking is usually a mistake. You are not likely to cause suicidal behavior if you ask about it,” he says. If the answer is yes, Dr. Lebowitz says the parent can follow up with additional questions:

  • How often do you think about it?
  • When do you think about it (all the time or only when you are really angry)?
  • Do you want to do it?
  • Do you have a specific plan?

If the teenager answers yes, the parent should seek help, Dr. Lebowitz says. “If the answer to the last two questions is yes, that would show the highest level of risk,” he adds. “Even if the answers to those are no, if a teenager thinks about it often, and not only when they are very angry or frustrated, then seeking help is recommended because it would indicate a high level of distress.”

These questions can also help diffuse the situation, Dr. Lebowitz says. “If you are alone thinking about suicide and you’re not able to talk about it, and nobody is asking you, that puts you at higher risk. If someone asks, even if you don’t like that person, it can reduce that sense of isolation. It’s just a fact in the life of a teenager that when somebody does care, it will reduce the risk,” he says.

Getting treatment to prevent suicide

Treatment for suicidal ideation starts with understanding the underlying concerns. Individual therapy, medication management, and the combination of the two could be appropriate, depending on the circumstances. Medicines that treat depression can often include a selective serotonin reuptake inhibitor (SSRI) such as Prozac or Zoloft. The medication can be combined with cognitive behavioral therapy (CBT), which involves regular meetings with a therapist to explore thoughts, feelings, and behaviors to better manage problems. “You can teach someone to recognize their own thinking patterns,” Dr. Lebowitz says. “It’s not instantaneous. But you can train the brain to recognize that pattern and say, “Oh, I’m falling into my thinking trap.””

“A lot of times the relationship with the therapist you are seeing is a good predictor of how therapy might work,” says Dr. Dwyer. “It should be someone the child and the parents feel comfortable bringing their concerns to, and who the child can stick with even when discussing difficult topics.”

Still, about 40 percent of teenagers fail to respond to medication, and half of that 40 percent don’t respond even when they switch to another medication and add psychotherapy, says Dr. Dwyer. “There aren’t a lot of great guidelines or algorithms after you’ve not had success with two medication trials and a trial of evidence-based psychotherapy,” she says.

Given the seriousness of adolescent treatment-resistant depression and suicide, novel treatments are currently being investigated. Ketamine is an anesthetic that has made headlines for its surprising antidepressant effects in adults. Esketamine, a related compound that is delivered as a nasal spray, was approved by the Food and Drug Administration (FDA) this year for treatment-resistant depression in adults. This medication works rapidly, within 24 hours, to reduce depressive symptoms compared to SSRIs, which take weeks to work. Ketamine is also associated with a reduction in suicidality in adults, even after controlling for any improvements in depressive symptoms.

Ketamine and esketamine are only now beginning to undergo rigorous testing for adolescents with treatment-resistant depression and suicidality. A small randomized clinical trial at Yale showed a positive effect of a single ketamine infusion in adolescents with treatment-resistant depression compared to a placebo, but this study only looked at short-term (two-week) outcomes.

Unfortunately, single doses of ketamine typically do not lead to sustained antidepressant responses, and Dr. Dwyer’s group is now conducting a trial looking at a limited number of repeated ketamine doses (which are associated with prolonged antidepressant effects in adults) in this population. But caution is warranted, Dr. Dwyer says, noting that some animal studies suggest that younger ages may be more susceptible to damage to the brain from a high dose of ketamine. It’s important to realize that ketamine is still considered an experimental treatment at this time for pediatric patients, she emphasizes. “I’m hopeful, but I’m also cautious about it, because I think the issues of effective and safe dosing paradigms in the population still need to be worked out,” says Dr. Dwyer.

What we are learning about the teenage brain

Meanwhile, neuroscientists are looking for clues in the brain which, in teens, is still developing. “Adolescence is a time when suicidal thoughts and behaviors can start to emerge,” says psychiatrist and neuroscientist Hilary Blumberg, MD, director of the Mood Disorders Research Program at Yale School of Medicine. She is using magnetic resonance imaging (MRI) to take pictures of the brains of adolescents and young adults with bipolar disorder who are at especially high risk—an estimated 50 percent of whom will attempt suicide at some point.

“We’re identifying the brain circuitry that underlies suicide thoughts and behaviors, how its trajectory of development differs in adolescents at risk for suicide, and how this can be helped,” says Dr. Blumberg, who has seen subtle variations in the prefrontal cortex of young people who have attempted suicide. (The prefrontal cortex has such executive functions as regulating emotions and impulses, and decision-making and planning. It can be compromised by various kinds of child abuse, substance abuse, and other stressors.) She and her research team have also observed subtle differences in the prefrontal structure in teens who go on to make a suicide attempt. “This provides us with new leads about how to generate targeted interventions to prevent suicide.”

Dr. Blumberg is also studying Social Rhythm Therapy (SRT), an approach that she says is showing early promise for normalizing brain circuitry and preventing suicide. SRT is designed to improve mood by regulating emotions and regularizing daily “rhythms”—an example of the latter is sleep patterns. “In order to help people have more regular sleep, you have to look at potential issues that may be causing the disruption. Their issues could be tied to social interactions and activity throughout the day, and a therapist can help them problem-solve around that,” Dr. Blumberg says. “We are encouraged by preliminary results where, after 12 weeks of regularizing daily rhythms, we see reductions in symptoms and suicide risk, and improvements in related brain circuitry.”

“The field has made important progress, but more research is needed,” Dr. Blumberg says. She is the U.S. lead of an international research consortium studying the brain scans of thousands of young people around the world who have suicidal thoughts and behaviors. She notes that the research is promising and may also turn out to be helpful to people who have bipolar disorder, as well as depression and other mental illnesses. “The future is very hopeful. We already have some strategies to prevent suicide, and it is especially hopeful that researchers from different disciplines are coming together in global efforts to discover new ways to reduce suicide.”

What if you are worried about suicide now?

Of course, many families need help immediately. If this is the case, Maryellen Flaherty-Hewitt, MD, a Yale Medicine pediatrician, recommends talking to the family pediatrician. “We routinely ask questions about access to guns, medications in the home, video games teenagers are using, and if they are exposed to violence,” says Dr. Flaherty-Hewitt. The pediatrician should be alert to teenagers who have had no history of mental illness, but who may be having difficulty coping with, say, feelings about sexuality, bullying at school or online, or the transition from one school to another, she says.

“When you have a child who has suicidal ideation, it’s a crisis, and pediatricians want to be part of this conversation. We want to make sure we bring the right people into the mix right away,” Dr. Flaherty-Hewitt says.

If the crisis warrants going to the emergency room, one of the first things that will happen is a counselor will sit with the teenager and listen to their concerns. In some cases, the patient will be admitted to the hospital or referred to YNHCH’s Partial Hospitalization Program. But, Dr. Bechtel says, “I’m always amazed how some of these kids are alright. Maybe they needed some respite, or maybe the biggest problem is that their behavioral health needs aren’t being met in the community,” she says.

For most young patients, thoughts of suicide are manageable, specialists say. “It may be a lifelong vulnerability, but there are many people who used to have an anxiety disorder or depression,” says Dr. Lebowitz. “We need to foster a belief in treatment and the understanding that having these problems can be part of life.”

Social Rhythm Therapy (SRT)Social-Rhythm-Therapies-for-Mood-Disorders-an-UpdateDownload

Magic Medicine?

Patients are turning to ketamine and other psychoactive drugs for mental health treatment

Sarah Jones, a 42-year-old stay-at-home mom in Woodstock, has struggled with depression since childhood. She’s tried multiple antidepressants and therapies over the years, and last fall, her medications once again quit working. Then Jones heard a radio ad about a new approach for depression — a drug called ketamine.

Ketamine is an anesthetic commonly used by veterinarians. It’s also used illegally as a club drug for its mind-altering, euphoric effects. And recently, it’s been touted for a new use: treating depression. 

Other psychoactive drugs like Ecstasy, LSD and magic mushrooms are also being considered as treatments for mental illnesses. Some of the drugs are under consideration for approval by the Food and Drug Administration (FDA).

Ketamine goes mainstream

Over the past several years, ketamine clinics, which deliver the drug to patients through intravenous (IV) infusions, have sprung up in Chicago and around the country to treat depression and other mental health conditions, including post-traumatic stress disorder (PTSD) and anxiety. 

Using the drug this way is considered an off-label use, meaning it’s used in a manner different from what’s been specified by the FDA. IV ketamine treatments for depression are not approved by the FDA and are often pricey. They are typically not covered by insurance. 

In March 2019, the FDA approved a nasal-spray version of ketamine, called esketamine (marketed as Spravato), to help the estimated 5 million Americans whose depression hasn’t responded to other treatments. Research shows that ketamine can more rapidly turn around depression than traditional antidepressants. Suicidal patients can find their urge to harm themselves quelled within 24 hours, rather than the weeks or months it takes a drug like Prozac to take effect, researchers have found.

It’s a bold move by the FDA to approve a completely new class of antidepressants and to open up a new realm of drugs that are considered psychedelics and psychoactive to be used as a medical treatment for something as common as depression,” says Bal Nandra, MD, an anesthesiologist and founder of IV Solution, which for almost three years has provided IV ketamine in downtown Chicago. 

Nandra hasn’t decided whether to offer the recently FDA-approved esketamine nasal spray in addition to IV ketamine. “It’s not nearly as effective or rapid acting as IV ketamine,” he says.

Lifting depression 

Jones received IV infusions of ketamine at Nandra’s South Dearborn Street clinic in November 2018. She followed Nandra’s typical regimen of six treatments given over a period of about two weeks, at a price of $500 to $600 per infusion. 

During these sessions, patients are seated in a private room, where they are hooked up to an IV for about 45 minutes, usually reclining on a medical lounge chair with the room darkened. Often, they wear an eye mask and listen to music. Patients are monitored by nurses or other staff for side effects, and those who become anxious may receive some sedation. After the infusion is over, patients are observed for about 30 to 45 minutes before being released. 

Ketamine can cause patients to feel dissociated from their bodies. The experience left Jones with a sense of the vastness of the universe and the idea that “there is something more out there than what we experience in our everyday life,” she says. “It almost takes you away from your suffering.” 

Most patients feel better after the first few ketamine infusions, Nandra says, though some take longer. Jones felt her depression lifting after her first treatment.  

It’s a bold move by the FDA … to open up a new realm of drugs that are considered psychedelics and psychoactive to be used as a medical treatment for something as common as depression.”

Jones returns to IV Solution every two months for one-session booster infusions to keep her depression at bay. 

She has been able to dramatically reduce her antidepressant use, while continuing in therapy. 

“Ketamine not only restored my brain to being able to function but also gave me insight into some life choices that were adding to my depression,” Jones says. Today, she adds, 

“I don’t remember what depression feels like. I’m so happy!” 

Gregory Teas, MD, a psychiatrist with the AMITA Health Behavioral Medicine Institute, says the clinic will likely start offering esketamine treatment starting this fall. Esketamine has a wholesale cost of $590 to $885 per dose, but the treatment may be covered by insurance, Teas says. Patients can’t take it at home but must go to a medical facility, where it is given under strict protocols, including two hours of monitoring afterward. 

Like other experts, Teas cautions that long-term studies on the use of ketamine and esketamine are needed. While the drug primarily works on receptors in the brain’s glutamate system, it also uses opioid and dopamine pathways, he says, which means it could be addictive for some patients.

Exploring other possibilities

Other psychoactive drugs may soon join ketamine as treatments for psychiatric conditions. The University of Chicago’s Human Behavioral Pharmacology Laboratory, directed by Harriet de Wit, PhD, has been studying MDMA (also known as Ecstasy) as a possible treatment.

MDMA, which causes people to feel loving toward themselves and others, may be helpful for people with PTSD and autism-related social anxiety, says researcher Anya Bershad, MD, PhD, who recently left the lab to complete a psychiatry residency at the University of California Los Angeles. 

A national phase 3 clinical trial of MDMA used in conjunction with psychotherapy for PTSD is underway, though Chicago is not a study site. If these trials go well, researchers expect the FDA might approve MDMA in 2021 for use with psychotherapy as a treatment for PTSD. 

Also being studied at the University of Chicago: microdosing with LSD to treat depression and anxiety. Study participants receive one-tenth or one-twentieth of a recreational dose, usually every three days, Bershad says. They don’t experience mind-altering psychedelic effects, but they do report feeling the “experience of unity,” even at those tiny doses, she says.

Other labs outside Illinois are studying psilocybin, or magic mushrooms, for their potential in treating anxiety, depression and eating disorders. Medical marijuana is also being researched for the treatment of PTSD, though studies differ so far on its effectiveness. 

As for ketamine, Nandra says in the years he’s been offering IV ketamine treatments he has seen many patients recover. “For these people, it lasts,” he says. “They do great. Their lives completely change. … It’s pretty amazing.”

Citocholine for Brain Health

Behind the Buzz: How Ketamine Changes the Depressed Patient’s Brain

The anesthetic-cum-party drug restores the ability to make connections among brain cells

The Food and Drug Administration’s approval in March of a depression treatment based on ketamine generated headlines, in part, because the drug represents a completely new approach for dealing with a condition the World Health Organization has labeled the leading cause of disability worldwide. The FDA’s approval marks the first genuinely new type of psychiatric drug—for any condition—to be brought to market in more than 30 years.

Although better known as a party drug, the anesthetic ketamine has spurred excitement in psychiatry for almost 20 years, since researchers first showed that it alleviated depression in a matter of hours. The rapid reversal of symptoms contrasted sharply with the existing set of antidepressants, which take weeks to begin working. Subsequent studies have shown ketamine works for patients who have failed to respond to multiple other treatments, and so are deemed “treatment-resistant.”

Despite this excitement, researchers still don’t know exactly how ketamine exerts its effects. A leading theory proposes that it stimulates regrowth of synapses (connections between neurons), effectively rewiring the brain. Researchers have seen these effects in animals’ brains, but the exact details and timing are elusive.

new study, from a team led by neuroscientist and psychiatrist Conor Liston at Weill Cornell Medicine, has confirmed that synapse growth is involved, but not in the way many researchers were expecting. Using cutting-edge technology to visualize and manipulate the brains of stressed mice, the study reveals how ketamine first induces changes in brain circuit function, improving “depressed” mice’s behavior within three hours, and only later stimulating regrowth of synapses.

As well as shedding new light on the biology underlying depression, the work suggests new avenues for exploring how to sustain antidepressant effects over the long term. “It’s a remarkable engineering feat, where they were able to visualize changes in neural circuits over time, corresponding with behavioral effects of ketamine,” says Carlos Zarate, chief of the Experimental Therapeutics and Pathophysiology Branch at the National Institute of Mental Health, who was not involved in the study. “This work will likely set a path for what treatments should be doing before we move them into the clinic.”

Another reason ketamine has researchers excited is that it works differently than existing antidepressants. Rather than affecting one of the “monoamine” neurotransmitters (serotonin, norepinephrine and dopamine), as standard antidepressants do, it acts on glutamate, the most common chemical messenger in the brain. Glutamate plays an important role in the changes synapses undergo in response to experiences that underlie learning and memory. That is why researchers suspected such “neuroplasticity” would lie at the heart of ketamine’s antidepressant effects.

Ketamine’s main drawback is its side effects, which include out-of-body experiences, addiction and bladder problems. It is also not a “cure.” The majority of recipients who have severe, difficult-to-treat depression will ultimately relapse. A course of multiple doses typically wears off within a few weeks to months. Little is known about the biology underlying depressive states, remission and relapse. “A big question in the field concerns the mechanisms that mediate transitions between depression states over time,” Liston says. “We were trying to get a better handle on that in the hopes we might be able to figure out better ways of preventing depression and sustaining recovery.”

Chronic stress depletes synapses in certain brain regions, notably the medial prefrontal cortex (mPFC), an area implicated in multiple aspects of depression. Mice subjected to stress display depressionlike behaviors, and with antidepressant treatment, they often improve. In the new study, the researchers used light microscopes to observe tiny structures called spines located on dendrites (a neuron’s “input” wires) in the mPFC of stressed mice. Spines play a key role because they form synapses if they survive for more than a few days.

For the experiment, some mice became stressed when repeatedly restrained, others became so after they were administered the stress hormone corticosterone. “That’s a strength of this study,” says neuroscientist Anna Beyeler, of the University of Bordeaux, France, who was not involved in the work, but wrote an accompanying commentary article in Science. “If you’re able to observe the same effects in two different models, this really strengthens the findings.” The team first observed the effects of subjecting mice to stress for 21 days, confirming that this resulted in lost spines. The losses were not random, but clustered on certain dendrite branches, suggesting the damage targets specific brain circuits.

The researchers then looked a day after administering ketamine and found that the number of spines increased. Just over half appeared in the same location as spines that were previously lost, suggesting a partial reversal of stress-induced damage. Depressionlike behaviors caused by the stress also improved. The team measured brain circuit function in the mPFC, also impaired by stress, by calculating the degree to which activity in cells was coordinated, a measure researchers term “functional connectivity.” This too improved with ketamine.

When the team looked closely at the timing of all this, they found that improvements in behavior and circuit function both occurred within three hours, but new spines were not seen until 12 to 24 hours after treatment. This suggests that the formation of new synapses is a consequence, rather than cause, of improved circuit function. Yet they also saw that mice who regrew more spines after treatment performed better two to seven days later. “These findings suggest that increased ensemble activity contributes to the rapid effects of ketamine, while increased spine formation contributes to the sustained antidepressant actions of ketamine,” says neuroscientist Ronald Duman, of the Yale School of Medicine, who was not involved in the study. Although the molecular details of what happens in the first hours are not yet fully understood, it seems a restoration of coordinated circuit activity occurs first; this is then entrenched by neuroplasticity effects in synapses, which then maintain behavioral benefits over time.

To prove that new synapses were a cause of antidepressant effects, rather than just coinciding with the improved behaviors, the team used a newly developed optogenetic technique, which allowed them to eliminate newly formed spines using light. Optogenetics works by introducing viruses that genetically target cells, causing them to produce light-sensitive proteins. In this case, the protein is expressed in newly formed synapses, and exposure to blue light causes the synapse to collapse. The researchers found that eliminating newly formed synapses in ketamine-treated mice abolished some of the drug’s positive effects, two days after treatment, confirming that new synapses are needed to maintain benefits. “Many mechanisms are surely involved in determining why some people relapse and some don’t,” Liston says, “ but we think our work shows that one of those involves the durability of these new synapses that form.”

And Liston adds: “Our findings open up new avenues for research, suggesting that interventions aimed at enhancing the survival of these new synapses might be useful for extending ketamine’s antidepressant effects.” The implication is that targeting newly formed spines might be useful for maintaining remission after ketamine treatment. “This is a great question and one the field has been considering,” Duman says. “This could include other drugs that target stabilization of spines, or behavioral therapies designed to engage the new synapses and circuits, thereby strengthening them.”

The study used three behavioral tests: one involving exploration, a second a struggle to escape, and a third an assessment of how keen the mice are on a sugar solution. This last test is designed to measure anhedonia—a symptom of depression in which the ability to experience pleasure is lost. This test was unaffected by deleting newly formed spines, suggesting that the formation of new synapses in the mPFC is important for some symptoms, such as apathy, but not others (anhedonia)—and that different aspects of depression involve a variety of brain circuits.

These results could relate to a study published last year that found activity in another brain region, the lateral habenula, is crucially involved in anhedonia, and injecting ketamine directly into this region improves anhedonia-related behavior in mice. “We’re slowly identifying specific regions associated with specific behaviors,” Beyeler says. “The factors leading to depression might be different depending on the individual, so these different models might provide information regarding the causes of depression.”

One caveat is that the study looked at only a single dose, rather than the multiple doses involved in a course of human treatment, Zarate says. After weeks of repeated treatments, might the spines remain, despite a relapse, or might they dwindle, despite the mice still doing well? “Ongoing effects with repeated administration, we don’t know,” Zarate says. “Some of that work will start taking off now, and we’ll learn a lot more.” Of course, the main caution is that stressed mice are quite far from humans with depression. “There’s no real way to measure synaptic plasticity in people, so it’s going to be hard to confirm these findings in humans,” Beyeler says.

Default Mode Network and Mood

The Default Mode Network (sometimes called simply the default network or the DMN) refers to an interconnected group of brain structures that are hypothesized to be part of a functional system. The DMN includes areas of the brain which researchers found to have higher activity when the mind was supposed to be at rest.  For example, when you are day dreaming, thinking about the future, replaying memories, etc. without a specific goal in mind.  Now, why would we care about this? The DMN is found to have increased activity in certain mood and pain disorders.  That being said, let’s look at our 3 reasons why you should know about the DMN. 

Reason #1: Increased DMN activity and functional connectivity is found in depression [1] as well as in pain disorders [2]. In these disorders, there is much rumination.  Rumination is where you have repetitive thoughts.  Those who deal with depression may replay depressing or sad memories over and over in their mind.  This prevents them from healing and creating room for more positive emotions and memories.  Additionally, those with pain may become fixated on the pain itself, or replay the events which lead to them having the pain.  This type of circular, overactive thinking occurs in the DMN. 

Reason #2:  Reducing activity in the DMN can decrease rumination, which in turn can reduce pain and depressed feelings.  In experienced meditators, there was decreased activity in the DMN, as well as increased connectivity in the regions of the brain responsible for self-monitoring and cognitive control [3]. Thus, giving us a scientific reason for the benefits of meditation.  We all have moments where we have unhelpful replays in our minds, and meditation can help us in breaking and reducing this ruminative behavior. 

Reason #3:  Ketamine reduces the functional activity in the DMN! A study showed that the connectivity of the DMN along with another portion of the brain, the dorsal nexus, was decreased after ketamine infusions [4]. So ketamine can effectively turn down the overactive areas in our mind, which can lead to an improved mood and less pain. 

In conclusion, you are much more than your mind, and before you can transcend something which does not serve you, you must know about it. Now that you know more about the default mode network, how your brain works, and rumination, what action will you take today

References:

  1. Hamilton, J. Paul, et al. “Default-Mode and Task-Positive Network Activity in Major Depressive Disorder: Implications for Adaptive and Maladaptive Rumination.” Biological Psychiatry, vol. 70, no. 4, 2011, pp. 327–333., doi:10.1016/j.biopsych.2011.02.003.
  2. Kucyi, A., et al. “Enhanced Medial Prefrontal-Default Mode Network Functional Connectivity in Chronic Pain and Its Association with Pain Rumination.” Journal of Neuroscience, vol. 34, no. 11, 2014, pp. 3969–3975., doi:10.1523/jneurosci.5055-13.2014.
  3. Brewer, J. A., et al. “Meditation Experience Is Associated with Differences in Default Mode Network Activity and Connectivity.” Proceedings of the National Academy of Sciences, vol. 108, no. 50, 2011, pp. 20254–20259., doi:10.1073/pnas.1112029108.
  4. Scheidegger, Milan et al. “Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action.” Ed. Stefano L. Sensi. PLoS ONE 7.9 (2012): e44799. PMC. Web. 23 June 2018.
  5. Sheline, Yvette I., et al. “The Default Mode Network and Self-Referential Processes in Depression.” Proceedings of the National Academy of Sciences, vol. 106, no. 6, 2009, pp. 1942–1947., doi:10.1073/pnas.0812686106.
  6. “Know Your Brain: Default Mode Network.” Neuroscientifically Challenged, 16 June 2015, www.neuroscientificallychallenged.com/blog/know-your-brain-default-mode-network.

NEUROGENESIS

When you break the word itself down, it comes in two parts: “neuro” as in neuron, and “genesis” as in creation. Neurogenesis broadly speaking is the process by which new neurons are created in the brain, thus allowing for increased plasticity of the brain and stronger synaptic connections. Adult neurogenesis is the process by which new neurons are created and integrated into existing brain circuitry when you are an adult. Adult neurogenesis can be seen in the olfactory bulb and the hippocampus.

The hippocampus is an S-shaped structure within the medial part of the temporal lobe and is densely packed with neurons. It a part of the limbic system, which also includes the hypothalamus and the amygdala. This region helps regulate emotion, memory, and arousal. Furthemore, the hippocampus is of particular interest because of its role in learning and motivation.

The monoamine hypothesis of depression states that antidepressants, a.k.a. selective serotonin reuptake inhibitors (SSRIs), work by increasing the levels of serotonin in the brain. It is thought that because SSRIs act on monoamine systems in the brain, which are involved in regulating emotion, therefore antidepressant results will be produced in individuals with depression.

However, treatment using SSRIs often take weeks to months to produce antidepressant effects, and sometimes they’re not even produced at all. People who have difficulty treating their depression with standard medical treatments are described as having treatment-resistant depression (TRD). Researchers are constantly working to find the mechanisms of depression and how it works in the brain.

Published in Neuropsychopharmacology in 2015, Hill and colleagues conducted a study on mice to measure whether inducing adult neurogenesis in the hippocampus positively affects anxious and depressive behaviors. Studies like these are often administered to mice first because they share similar biological and behavioral components to that of humans.

They found that when the mice were treated chronically with corticosterone (stress hormone secreted by the adrenal glands), increasing adult neurogenesis in the hippocampus does reduce anxiety and depression (1).

When we take these findings and circle back to ketamine, it makes sense. One of ketamine’s main mechanisms is increasing neurogenesis and synaptogenesis, allowing for neuroplasticity. Synaptogenesis is the process by which synaptic connections between the neurons in the brain are created. Increasing neuroplasticity allows for the brain to reorganize its connections more efficiently in response to stress and new changes in its environment. Essentially it is what keeps the brain resilient.

So ketamine increases neurogenesis, but why does it have the reputation of being a fast-acting antidepressant, especially for those with TRD? While we don’t have all of the answers to ketamine’s mechanisms, we do know this:

Ketamine Rapidly enhances the Maturation of Neurons

RATHER THAN INCREASING SEROTONIN, KETAMINE ACTS ON THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR AND THE GLUTAMATE NEUROTRANSMITTER

Ketamine increases the production of Brain Derived Neurotrophic Factor

Ketamine reduces the functional activity of the Default Mode Network

Beyond these multiple mechanisms of action, we also believe there is another level beyond the physical. Accordingly, we incorporate the bio-psycho-social-spiritual model of medicine at our clinic to take a holistic view for our patients!


References:

  1. Hill, A. S., Sahay, A., & Hen, R. (2015). Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors. Neuropsychopharmacology40(10), 2368–2378. doi: 10.1038/npp.2015.85

Researchers hypothesize that neurogenesis, or neuron growth, is an antidepressant action. This hypothesis is linked to the understanding that nearly all antidepressants increase birth of granule neurons in rodents. Ketamine, however, has such rapid antidepressant effects, suggesting that the mechanisms involved with ketamine are not involved with neuron birth. Instead, researchers hypothesized that ketamine’s rapid effects are due to it enhancing the maturation of neurons born previously.

To test this hypothesis, researchers injected rats with ketamine, assessing the effects of the ketamine on granule neurons. Researchers found that the ketamine rapidly affected the neurons, increasing mature neurons within two hours. A single injection of ketamine increased cell proliferation and functional maturation. For at least four weeks following the injection, depressive symptoms in rats were decreased.

In conclusion, ketamine has rapid, lasting effects on the recruitment of neurons into the hippocampal region of the brain. The hippocampus is believed to play a role in memory, spacial recognition, and avoidance-approach conflict processing. However, new neuron growth was independent of the antidepressant effects of the ketamine. The antidepressant effect may be due to ketamine’s work on neuron growth, but not on new neuron growth.

epression is among the most disabling conditions in our society. According to the World Health Organization, depression is the leading cause of ill health and disability worldwide. In America, 12.5% of individuals over the age of 12 have filled an antidepressant prescription.  Yet, the effectiveness of these medications are still lacking. Many patients don’t respond to antidepressant medications, and it can take months for the medicine to kick in. Unfortunately, many patients will regain their depression after being on medications long term.

Over 50 years ago, the hypothesis that low concentrations of serotonin in the central nervous caused depression was proposed.  This appealed to many doctors & scientists, because we finally had a potential biological mechanism to explain depression.  Accordingly, many antidepressants were developed to increase serotonin to help relieve depression. Although, it can work for some patients many patients do not respond or have significant side effects.  

SO WHAT IS A PERSON TO DO IF THEY HAVE TREATMENT-RESISTANT DEPRESSION?  

One cutting-edge option is targeting a completely different neurotransmitter – GLUTAMATE. Glutamate is an excitatory neurotransmitter and the most abundant neurotransmitter in the brain and central nervous system.  Ketamine works on the glutamate system by blocking it’s activity at the N-Methyl-D-Aspartate (NMDA) receptor.  

Ketamine raises brain derived neurotrophic factor (BDNF) levels, thereby enhancing connections between neurons and increasing neuroplasticity.  It’s literally changing the brain. In animal studies, the cascade of effects from ketamine created a rapid proliferation of dendritic spines that was associated with less depression. In a functional MRI brain study of humans, ketamine seemed to restore the functional connectivity in those patients with depression. 

Interestingly, ketamine is known to affect other receptors beyond the NMDA receptor, and have  anti-inflammatory as well as epigenetic effects. Also, the breakdown products of ketamine, like (S)-norketamine and (2R, 6R)-hydroxynorketamine, may also play a role in helping with depression. 

Even though we have some understanding of how ketamine works, we still don’t fully comprehend how ketamine is working exactly in patients with depression. 

“We live on an island surrounded by a sea of ignorance. As our island of knowledge grows, so does the shore of our ignorance.

— John A. Wheeler, Physicist

As we continue to learn more about ketamine and depression, more questions and unknowns will surely develop.

Therefore, it’s critical to expand our understanding of depression beyond the simple serotonin and even glutamate neurotransmitters.  The human body, brain, and consciousness is one of the most complex systems we have ever encountered. Although, we may never fully understand the intricacy of it all, we can still take action. 

We can be pragmatic and responsibly use ketamine for carefully selected patients. In addition to ketamine infusions, we can encourage psychotherapy, exercise, meditation, prayer, positive community, a good night’s rest, and a healthy diet to help people with depression.  

At Reset Ketamine, we utilize the bio-psycho-social-spiritual model that encompasses a whole person approach to health.  We believe health is not merely the absence of illness, but a state of physical, social, mental, and spiritual well-being.  We believe ketamine can be the catalyst to create paradigm shifts to help patients live a full life.

References:

Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019). Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron, 101(5), 774-778. doi:10.1016/j.neuron.2019.02.005

ccording to the World Health Organization, depression has now surpassed HIV, AIDS, malaria, diabetes, and war as the leading cause of disability. Current antidepressants may take weeks to months to be effective. Unfortunately, one-third of patients are still unresponsive, and are called “treatment-resistant.” However, there are other options available.

Ketamine, possibly the most widely used anesthetic agent in the world, has been shown by numerous studies to have rapid antidepressant effects when used off-label. The full mechanism by which ketamine induces these therapeutic effects is still a mystery. What researchers do understand is that increased levels of brain derived neurotrophic factor (BDNF), a protein that plays a role in the growth and maintenance of neurons, is involved. But how and where does ketamine increase BDNF?

A recent study in 2017 suggests that HDAC5, an enzyme affecting DNA and chromosomes, regulates the antidepressant effects of ketamine through a process called phosphorylation, which regulates protein function. Ketamine influences the transcription (the process by which DNA is turned into RNA) of BDNF and increases BDNF levels in the central nervous system.

Additionally, a study in 2015 demonstrated that the antidepressant effects of ketamine are based on the release of BDNF and the activation of the L-type voltage-dependent calcium channels (VDCC). Researchers found that the release of BDNF regulates the antidepressant effects of ketamine, further clarifying the underlying mechanisms that ketamine utilizes.

Furthermore, researchers observed in another 2015 study that dysfunctional levels of BDNF may be linked to depression, and that ketamine treatment can produce a positive effect within certain pathways of the brain, such as in the prefrontal cortex and nucleus accumbens. In this animal study, rats were divided into four groups: saline+deprived, saline+non-deprived, ketamine+deprived, and ketamine+non-deprived. Ketamine infusions were administered daily for 14 days. Researchers then observed the animals’ brain structures. They observed that the deprived rats had reduced levels of BDNF in the amygdala, hippocampus and nucleus accumbens. The ketamine reversed the levels of BDNF in the amygdala and nucleus accumbens. This is important because the amygdala plays a critical response in fear and strong emotions, while the nucleus accumbens is essential in motivation, aversion, reward, and learning.

In addition to ketamine’s effect on the default mode networkneuronsbrain wavesglutamate neurotransmitter, and inflammation, by understanding ketamine’s impact on BDNF, we can gain a deeper insight into the mystery of how our brain works. Ultimately, as Socrates once said, “To know thyself is the beginning of wisdom.”

References:

Choi, Miyeon, et al. “Ketamine Induces Brain-Derived Neurotrophic Factor Expression via Phosphorylation of Histone Deacetylase 5 in Rats.” Biochemical and Biophysical Research Communications, vol. 489, no. 4, 2017, pp. 420–425., doi:10.1016/j.bbrc.2017.05.157.

Lepack, A. E., et al. “BDNF Release Is Required for the Behavioral Actions of Ketamine.” International Journal of Neuropsychopharmacology, vol. 18, no. 1, 2014, doi:10.1093/ijnp/pyu033.

Réus, Gislaine, et al. “Ketamine Treatment Partly Reverses Alterations in Brain Derived- Neurotrophic Factor, Oxidative Stress and Energy Metabolism Parameters Induced by an Animal Model of Depression.” Current Neurovascular Research, vol. 12, no. 1, 2015, pp. 73–84., doi:10.2174/1567202612666150122122924.

Depression is among the most disabling conditions in our society. According to the World Health Organization, depression is the leading cause of ill health and disability worldwide. In America, 12.5% of individuals over the age of 12 have filled an antidepressant prescription.  Yet, the effectiveness of these medications are still lacking. Many patients don’t respond to antidepressant medications, and it can take months for the medicine to kick in. Unfortunately, many patients will regain their depression after being on medications long term.

Over 50 years ago, the hypothesis that low concentrations of serotonin in the central nervous caused depression was proposed.  This appealed to many doctors & scientists, because we finally had a potential biological mechanism to explain depression.  Accordingly, many antidepressants were developed to increase serotonin to help relieve depression. Although, it can work for some patients many patients do not respond or have significant side effects.  

SO WHAT IS A PERSON TO DO IF THEY HAVE TREATMENT-RESISTANT DEPRESSION?  

One cutting-edge option is targeting a completely different neurotransmitter – GLUTAMATE. Glutamate is an excitatory neurotransmitter and the most abundant neurotransmitter in the brain and central nervous system.  Ketamine works on the glutamate system by blocking it’s activity at the N-Methyl-D-Aspartate (NMDA) receptor.  

Ketamine raises brain derived neurotrophic factor (BDNF) levels, thereby enhancing connections between neurons and increasing neuroplasticity.  It’s literally changing the brain. In animal studies, the cascade of effects from ketamine created a rapid proliferation of dendritic spines that was associated with less depression. In a functional MRI brain study of humans, ketamine seemed to restore the functional connectivity in those patients with depression. 

Interestingly, ketamine is known to affect other receptors beyond the NMDA receptor, and have  anti-inflammatory as well as epigenetic effects. Also, the breakdown products of ketamine, like (S)-norketamine and (2R, 6R)-hydroxynorketamine, may also play a role in helping with depression. 

Even though we have some understanding of how ketamine works, we still don’t fully comprehend how ketamine is working exactly in patients with depression. 

“We live on an island surrounded by a sea of ignorance. As our island of knowledge grows, so does the shore of our ignorance.

— John A. Wheeler, Physicist

As we continue to learn more about ketamine and depression, more questions and unknowns will surely develop.

Therefore, it’s critical to expand our understanding of depression beyond the simple serotonin and even glutamate neurotransmitters.  The human body, brain, and consciousness is one of the most complex systems we have ever encountered. Although, we may never fully understand the intricacy of it all, we can still take action. 

We can be pragmatic and responsibly use ketamine for carefully selected patients. In addition to ketamine infusions, we can encourage psychotherapy, exercise, meditation, prayer, positive community, a good night’s rest, and a healthy diet to help people with depression.  

At Reset Ketamine, we utilize the bio-psycho-social-spiritual model that encompasses a whole person approach to health.  We believe health is not merely the absence of illness, but a state of physical, social, mental, and spiritual well-being.  We believe ketamine can be the catalyst to create paradigm shifts to help patients live a full life.

References:

Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019). Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron, 101(5), 774-778. doi:10.1016/j.neuron.2019.02.005

Researchers hypothesize that neurogenesis, or neuron growth, is an antidepressant action. This hypothesis is linked to the understanding that nearly all antidepressants increase birth of granule neurons in rodents. Ketamine, however, has such rapid antidepressant effects, suggesting that the mechanisms involved with ketamine are not involved with neuron birth. Instead, researchers hypothesized that ketamine’s rapid effects are due to it enhancing the maturation of neurons born previously.

To test this hypothesis, researchers injected rats with ketamine, assessing the effects of the ketamine on granule neurons. Researchers found that the ketamine rapidly affected the neurons, increasing mature neurons within two hours. A single injection of ketamine increased cell proliferation and functional maturation. For at least four weeks following the injection, depressive symptoms in rats were decreased.

In conclusion, ketamine has rapid, lasting effects on the recruitment of neurons into the hippocampal region of the brain. The hippocampus is believed to play a role in memory, spacial recognition, and avoidance-approach conflict processing. However, new neuron growth was independent of the antidepressant effects of the ketamine. The antidepressant effect may be due to ketamine’s work on neuron growth, but not on new neuron growth.


THETA BRAIN WAVES & THE ANTI-ANXIETY EFFECTS OF KETAMINE

According to a study published in the International Journal of Neuropsychopharmacology in 2018, specific brain waves are related to the anti-anxiety effects of ketamine. The brain waves involved in this function are called theta waves, found in the right frontal area of the brain. Ketamine can treat a wide variety of neurotic disorders, such as depressiongeneralized anxiety disorder, and PTSD, but researchers do not conclusively understand how ketamine works to relieve the symptoms of these disorders.

To better understand the therapeutic effects of ketamine, researchers studied the brain activity of patients given ketamine. Patients with generalized anxiety disorder and/or social anxiety disorder were administered ketamine and hooked up to a monitor measuring electrical brain activity (EEG). Ketamine affected the power of the brain waves by increasing the fast waves and decreasing the slow waves. However, only a single frequency band was related to therapeutic effects—the theta waves.

Human consciousness is believed to be related to neurons firing synchronously in various frequencies. Theta waves are in the 4 to 7 hertz rhythms. During meditation, theta waves predominated and were most abundant in the frontal and middle parts of the brain. Professor Jim Lagopoulos states, “These types of waves likely originate from a relaxed attention that monitors our inner experiences. Here lies a significant difference between meditation and relaxing without any specific technique. Previous studies have shown that theta waves indicate deep relaxation and occur more frequently in highly experienced meditation practitioners. When we measure mental calm, these regions signal to lower parts of the brain, inducing the physical relaxation response that occurs during meditation.”

So ketamine infusions seems to put the brain into a similar state that highly experienced meditators can achieve allowing for a calm, relaxed state of mind.

In conclusion, the anti-anxiety relief of ketamine may related to a very specific portion of electrical brain activity. This finding combined with the knowledge that ketamine blocks the NMDA glutamate receptor helps researchers understand how ketamine affects the brain. This preliminary study paves the way for future research on brain studies and ketamine.

Ketamines impact on BDNF

According to the World Health Organization, depression has now surpassed HIV, AIDS, malaria, diabetes, and war as the leading cause of disability. Current antidepressants may take weeks to months to be effective. Unfortunately, one-third of patients are still unresponsive, and are called “treatment-resistant.” However, there are other options available.

Ketamine, possibly the most widely used anesthetic agent in the world, has been shown by numerous studies to have rapid antidepressant effects when used off-label. The full mechanism by which ketamine induces these therapeutic effects is still a mystery. What researchers do understand is that increased levels of brain derived neurotrophic factor (BDNF), a protein that plays a role in the growth and maintenance of neurons, is involved. But how and where does ketamine increase BDNF?

A recent study in 2017 suggests that HDAC5, an enzyme affecting DNA and chromosomes, regulates the antidepressant effects of ketamine through a process called phosphorylation, which regulates protein function. Ketamine influences the transcription (the process by which DNA is turned into RNA) of BDNF and increases BDNF levels in the central nervous system.

Additionally, a study in 2015 demonstrated that the antidepressant effects of ketamine are based on the release of BDNF and the activation of the L-type voltage-dependent calcium channels (VDCC). Researchers found that the release of BDNF regulates the antidepressant effects of ketamine, further clarifying the underlying mechanisms that ketamine utilizes.

Furthermore, researchers observed in another 2015 study that dysfunctional levels of BDNF may be linked to depression, and that ketamine treatment can produce a positive effect within certain pathways of the brain, such as in the prefrontal cortex and nucleus accumbens. In this animal study, rats were divided into four groups: saline+deprived, saline+non-deprived, ketamine+deprived, and ketamine+non-deprived. Ketamine infusions were administered daily for 14 days. Researchers then observed the animals’ brain structures. They observed that the deprived rats had reduced levels of BDNF in the amygdala, hippocampus and nucleus accumbens. The ketamine reversed the levels of BDNF in the amygdala and nucleus accumbens. This is important because the amygdala plays a critical response in fear and strong emotions, while the nucleus accumbens is essential in motivation, aversion, reward, and learning.

In addition to ketamine’s effect on the default mode networkneuronsbrain wavesglutamate neurotransmitter, and inflammation, by understanding ketamine’s impact on BDNF, we can gain a deeper insight into the mystery of how our brain works. Ultimately, as Socrates once said, “To know thyself is the beginning of wisdom.”

References:

Choi, Miyeon, et al. “Ketamine Induces Brain-Derived Neurotrophic Factor Expression via Phosphorylation of Histone Deacetylase 5 in Rats.” Biochemical and Biophysical Research Communications, vol. 489, no. 4, 2017, pp. 420–425., doi:10.1016/j.bbrc.2017.05.157.

Lepack, A. E., et al. “BDNF Release Is Required for the Behavioral Actions of Ketamine.” International Journal of Neuropsychopharmacology, vol. 18, no. 1, 2014, doi:10.1093/ijnp/pyu033.

Réus, Gislaine, et al. “Ketamine Treatment Partly Reverses Alterations in Brain Derived- Neurotrophic Factor, Oxidative Stress and Energy Metabolism Parameters Induced by an Animal Model of Depression.” Current Neurovascular Research, vol. 12, no. 1, 2015, pp. 73–84., doi:10.2174/1567202612666150122122924.

Who should not get Ketamine?

Here are the 7 types of people who should NOT take ketamine:

  1. People with uncontrolled high blood pressure (hypertension). Ketamine is known to increase blood pressure, and in the setting of already high blood pressure the increase could get so high as to cause a heart attack or stroke. So it is important to have blood pressure monitored throughout your infusion.
  2. People with unstable heart disease (such as arrhythmias, congestive heart failure, coronary artery disease, etc.). Ketamine can increase heart rate and cardiac output (how hard your heart is working), which could worsen various heart conditions.
  3. People with untreated or uncontrolled thyroid disease (especially hyperthyroidism). In thyroid diseases such as hyperthyroidism, the body may already have an increased heart rate i.e. sympathetic overdrive which could be worsened with taking ketamine.
  4. People with active substance abuse. Ketamine can be used to treat addiction, however, infusions are given once the patient has detoxed or is off of the drugs the individual is addicted to. When a person is taking multiple drugs, the way their body may react may be unpredictable and potentially life threatening.
  5. People in an active manic phase of bipolar disorder. Ketamine can cause an altered mental state. If a person is already in an active manic state, ketamine could potentially worsen or enhance a worrisome emotional state.
  6. People with active delusions and hallucination symptoms (not taking prescription or while on street drugs). Similar to the point made in #5, a person can experience out of body experience or similar non ordinary state experiences when given ketamine. Ketamine could potentially enhance or worsen delusions and active hallucinations.
  7. Lastly, patients who have tried ketamine in the past and have had bad reactions to this medication.  If someone has been given ketamine for a procedure and had an adverse effect, we would suggest holding off. 

Psychedelic therapy, or at least the talk of them, is very popular as of this writing. Ketamine is currently the only legal and FDA approved psychedelic in the United States.  You may have heard about ketamine as a recreational drug or as an animal tranquilizer but not sure what to think about it. You may have depression, anxiety, OCD, or PTSD which is not being helped by standard treatments. You may even know of a loved one who could benefit from ketamine infusions. 

There is a lot of information out there. Some good and some not so good information in giving you a straight-forward understanding of ketamine as a treatment option for various mental health disorders. So welcome to our beginner’s guide, where we’ll cover the basics of what you need to know.

WHAT IS KETAMINE?

Ketamine was first synthesized in the 1960’s for use as a general anesthetic and FDA approved in 1970. Ketamine blocks the activity of glutamate (an excitatory neurotransmitter), which binds to and activates the NMDA receptor.  This NMDA receptor blockade is known to increase brain derived neurotrophic factor (BDNF).

Increases in BDNF results in increased neurogenesis and neuroplasticity. This helps those with chronic pain and depression to restore their neuronal activity and synaptic strength in the prefrontal cortex, restoring and resetting their brain back to a healthier state.

If you want to further learn how ketamine works check out: The 4 Mechanisms of How Ketamine Works

Ketamine has been traditionally used in the operating room and emergency departments for sedation and pain control.   Ketamine has a colorful history and is known to be used in veterinary medicine as a “animal tranquilizer” and even a recreational club drug of abuse.  However, ketamine is the most commonly medicine used worldwide for sedation and the World Health Organization (WHO) places ketamine in its List of Essential Medicines. 

Ketamine can be delivered into the body in several forms: oral (pill form), intranasal (insufflated into the nose), intramuscular (injected into the muscle), and intravenous (into the vein). Most ketamine clinics provide ketamine in the intravenous form as a slow infusion.  There are other clinics that may provide ketamine in the other forms in conjunction with psychotherapy. 

 WHY DOCTORS ARE USING KETAMINE?

Ketamine is effective in chronic pain, PTSD, depression, and other illnesses. Because of ketamine’s unique properties, many people are experiencing rapid, effective relief compared to traditional treatments, such as selective serotonin reuptake inhibitors (SSRIs) which can take months to take effect. 

When individuals are receiving ketamine for these treatments, ketamine is being used “off-label,” meaning that it is not being for the specific indication approved by the United States Food and Drug Administration (FDA). To get FDA approval for an indication, it requires multiple stages of research to evaluate the safety and efficacy for that specific use.  In 1970, ketamine was FDA approved for use as the,“sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.”  But all other uses are considered “off-label.” Fortunately, once a drug is FDA approved, physicians have the freedom to use their best clinical judgment in prescribing drugs for other purposes than originally intended.  

WHO SHOULDN’T GET KETAMINE?

To understand who should not get ketamine, you’ll need to understand the effect of ketamine on the body. Ketamine can increase the heart rate and blood pressure, and stress the cardiac function of anyone who has uncontrolled heart problems.  Ketamine is used during medical procedures and operations for analgesia (i.e. doctors can perform surgeries and procedures without causing pain to the patients) due to its dissociative property. This dissociative property is also, according to research, associated with better antidepressant effect during ketamine infusions. While this is a wonderful property, if a person has a mental disorder which is characterized by hallucinations or delusions, undergoing ketamine infusions could actually worsen these conditions. 

REVISITING THE HALLUCINOGENIC POTENTIAL OF KETAMINE

WE NOW KNOW WHY KETAMINE IS SO EFFECTIVE AT TREATING DEPRESSION

FIRST KETAMINE INFUSION CLINIC IN PALM SPRINGS, CA OPENS

FROM CHAOS TO CALM: A LIFE CHANGED BY KETAMINE

IS KETAMINE THE NEXT BIG DEPRESSION DRUG?

KETAMINE RELIEVES DEPRESSION BY RESTORING BRAIN CONNECTIONS

IS KETAMINE THE BEST HOPE FOR CURING MAJOR DEPRESSION?

KETAMINE DEPRESSION TREATMENT ‘SHOULD BE ROLLED OUT’

KETAMINE: THE FUTURE OF DEPRESSION TREATMENT?

ONCE IT FULLY CATCHES ON, KETAMINE COULD BE A REALLY IMPORTANT ANTIDEPRESSANT

TACKLING DEPRESSION WITH KETAMINE

ONETIME PARTY DRUG HAILED AS MIRACLE FOR TREATING SEVERE DEPRESSION

YALE SCIENTISTS EXPLAIN HOW KETAMINE VANQUISHES DEPRESSION WITHIN HOURS

WHAT IT’S LIKE TO HAVE YOUR SEVERE DEPRESSION TREATED WITH A HALLUCINOGENIC DRUG

KETAMINE INFUSIONS CUT MIGRAINE PAIN IN HALF IN NEW STUDY

FOR RECALCITRANT NEUROPATHIC PAIN, CONSIDER OUTPATIENT KETAMINE

KETAMINE RESETS SYSTEM FOR NORMAL PAIN PROCESSING IN COMPLEX SYNDROME PATIENTS

FIBROMYALGIA DOCTOR TOUTS KETAMINE FOR PAIN AND DEPRESSION

FIBROMYALGIA PATIENTS TREATED WITH INTRAVENOUS KETAMINE

THIS COULD BE BIG: INTRAVENOUS KETAMINE FOR FIBROMYALGIA

THE CURRENT MENTAL HEALTH CRISIS AND THE COMING KETAMINE REVOLUTION

YALE: ‘MAGIC’ ANTIDEPRESSANT MAY HOLD PROMISE FOR PTSD

IV KETAMINE RAPIDLY EFFECTIVE IN PTSD

KETAMINE MAY HELP EXTINGUISH FEARFUL MEMORIES

KETAMINE COULD PROVE USEFUL IN TREATMENT OF SEVERE SOCIAL ANXIETY

PSYCHEDELIC MEDICINE 101: THE CURIOUS CASE OF KETAMINE

Links to Academic Articles

RAPID AND LONGER-TERM ANTIDEPRESSANT EFFECTS OF REPEATED KETAMINE INFUSIONS IN TREATMENT-RESISTANT MAJOR DEPRESSION

SAFETY AND EFFICACY OF REPEATED-DOSE INTRAVENOUS KETAMINE FOR TREATMENT-RESISTANT DEPRESSION

NEUROBIOLOGY OF STRESS, DEPRESSION, AND RAPID ACTING ANTIDEPRESSANTS: REMODELING SYNAPTIC CONNECTIONS

NEW PARADIGMS FOR TREATMENT-RESISTANT DEPRESSION

ANTIDEPRESSANT EFFICACY OF KETAMINE IN TREATMENT-RESISTANT MAJOR DEPRESSION: A TWO-SITE RANDOMIZED CONTROLLED TRIAL

HIPPOCAMPAL VOLUME AND THE RAPID ANTIDEPRESSANT EFFECT OF KETAMINE

KETAMINE AND THE NEXT GENERATION OF ANTIDEPRESSANTS WITH A RAPID ONSET OF ACTION

DO THE DISSOCIATIVE SIDE EFFECTS OF KETAMINE MEDIATE ITS ANTIDEPRESSANT EFFECTS?

SYMPTOMATOLOGY AND PREDICTORS OF ANTIDEPRESSANT EFFICACY IN EXTENDED RESPONDERS TO A SINGLE KETAMINE INFUSION.

ANTIDEPRESSANT EFFECTS OF KETAMINE IN DEPRESSED PATIENTS

THE ROLE OF KETAMINE IN TREATMENT-RESISTANT DEPRESSION: A SYSTEMATIC REVIEW

IMPROVEMENT IN SUICIDAL IDEATION AFTER KETAMINE INFUSION: RELATIONSHIP TO REDUCTIONS IN DEPRESSION AND ANXIETY

USE OF KETAMINE IN ACUTE CASES OF SUICIDALITY

A POSSIBLE ROLE FOR KETAMINE IN SUICIDE PREVENTION IN EMERGENCY AND MAINSTREAM PSYCHIATRY

EFFICACY OF INTRAVENOUS KETAMINE FOR TREATMENT OF CHRONIC POST-TRAUMATIC STRESS DISORDER: A RANDOMIZED CLINICAL TRIAL

EFFICACY OF KETAMINE IN THE TREATMENT OF SUBSTANCE USE DISORDERS: A SYSTEMATIC REVIEW

KETAMINE REDUCES MUSCLE PAIN, TEMPORAL SUMMATION, AND REFERRED PAIN IN FIBROMYALGIA PATIENTS

KETAMINE IN CHRONIC PAIN MANAGEMENT: AN EVIDENCE-BASED REVIEW

RANDOMIZED CONTROLLED CROSSOVER TRIAL OF KETAMINE IN OBSESSIVE-COMPULSIVE DISORDER: PROOF-OF-CONCEPT

RAPID RESOLUTION OF OBSESSIONS AFTER AN INFUSION OF INTRAVENOUS KETAMINE IN A PATIENT WITH TREATMENT-RESISTANT OBSESSIVE-COMPULSIVE DISORDER: A CASE REPORT

ANALGESIC EFFECT OF SUBANESTHETIC INTRAVENOUS KETAMINE IN REFRACTORY NEUROPATHIC PAIN: A CASE REPORT

PAIN ANALYSIS IN PATIENTS WITH FIBROMYALGIA. EFFECTS OF INTRAVENOUS MORPHINE, LIDOCAINE, AND KETAMINE

KETAMINE FOR SOCIAL ANXIETY DISORDER: A RANDOMIZED, PLACEBO-CONTROLLED CROSSOVER TRIAL

NOVEL TREATMENT FOR LEVODOPA INDUCED MOTOR FLUCTUATIONS AND DYSKINESIA ASSOCIATED WITH PARKINSON’S DISEASE

KLEINE LEVIN SYNDROME (KLS) RESEARCH UPDATE IN LABORATORY OF DR. MIGNOT, STANFORD UNIVERSITY

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Ketamine Study Reveals How to Make It an Even Better Depression Treatment

In early March, the FDA approved a nasal spray for depression based on ketamine, a substance once known only as a rave drug. Despite its reputation, ketamine is so promising as an anti-depressant that it will soon be available in licensed clinics throughout the country. A study published in Science on Thursday proposes the new treatment can be made even better.

In their paper, a team of scientists at Weill Cornell’s Medicine’s Feil Family Brain and Mind Research Institute show that ketamine can help the brain reform synapses, crucial connections between neurons, that can alleviate depressive symptoms. Ketamine is already famous for working quickly to relieve depressive symptoms — within days or hours — co-author Conor Liston, Ph.D., tells Inverse, but maintaining those crucial connections is key to extending its effects.

“Our study shows that the formation of new connections (synapses) between brain cells is required for sustaining ketamine’s antidepressant effects in the days after treatment,” says Liston, also professor of neuroscience at Weill Cornell. “Ketamine is an exciting new treatment for depression that differs from drugs like SSRIs in that it relieves symptoms rapidly. However, those effects are not always sustained.”

upset, depressed
Ketamine-based nasal spray is a new FDA-licensed drug for treatment-resistant depression.

Growing Back Dendritic Spines

In a mouse model, Liston and his co-authors demonstrated that doses of ketamine helped mouse brains regrow dendritic spines, small protrusions on neurons that help them pick up signals rom other cells that, crucially, degrade during exposure to chronic stress. These dendritic spines are a key part of synapse formation.

The degradation of these spines is not a perfect analog to human depression, but humans have them as well, and Liston points out that some of the most important features of depression in humans are also present in chronically stressed mice.

To create depression-like conditions, the team degraded the dendritic spines in their mice using stress hormones. Then, they gave one group a dose of ketamine, which they expected to have anti-depressive effects.

dendritic spine
A dendritic spine helps form a synapse — a connection to another neuron.

The dose of ketamine not only changed the mice’s behavior — they tried harder to escape their cages — it also helped reform the dendritic spines in their brains. Interestingly, the ketamine didn’t form random dendritic spines but actually seemed to replace the old ones that had been degraded by constant stress. Of the new spines formed, 47.7 percent grew within two micrometers of where the old ones once were.

Why Dendritic Spines Are Important

The new dendritic spines serve an important purpose in the mouse brains. Within three hours of treatment, previously damaged circuits in the prefrontal cortex were starting to come back online, but this happened before new synapses form. At the end of the experiment, an estimated 20.4 to 31.0 percent of the lost synapses were restored after the mice took ketamine.

The fact that the circuits were restored before the synapses reformed suggests that ketamine jump-starts a two-step process that fights depression. The first step is the rapid anti-depressant effect that is seen in so many studies. The second step — regrowing the spines and restoring synapses — occurs more slowly, which means it’s the one scientists should focus on if they’re looking to make ketamine’s effects on depression last longer, Liston says.

When Liston used blue light to artificially remove the newly grown spines in a follow-up experiment, the mice relapsed into depressive symptoms. It suggested that maintaining these dendritic spines is important in keeping depression at bay.

“Our results suggest that interventions aimed at enhancing the survival of newly formed connections in prefrontal brain circuits could be useful for augmenting ketamine’s antidepressant effects by increasing their durability in the days and weeks after treatments.”

The FDA’s approval of a ketamine-based drug to treat depression was groundbreaking in itself, especially since it works differently than other anti-depressant drugs. But just because it’s been approved doesn’t mean there aren’t ways to improve it. Depression can be alleviated with ketamine, but for now the illness constantly threatens individuals with remission. Preventing the potential for a relapse with the promise of longer-lasting effects is one way to make this already remarkable drug even more helpful.

tructured Abstract

INTRODUCTION

Depression is an episodic form of mental illness, yet the circuit-level mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood. Ketamine relieves depressive symptoms rapidly, providing an opportunity to study the neurobiological substrates of transitions from depression to remission and to test whether mechanisms that induce antidepressant effects acutely are distinct from those that sustain them.

RATIONALE

Contrasting changes in dendritic spine density in prefrontal cortical pyramidal cells have been associated with the emergence of depression-related behaviors in chronic stress models and with ketamine’s antidepressant effects. But whether and how dendritic spine remodeling is causally involved, or whether it is merely correlated with these effects, is unclear. To answer these questions, we used two-photon imaging to study how chronic stress and ketamine affect dendritic spine remodeling and neuronal activity dynamics in the living prefrontal cortex (PFC), as well as a recently developed optogenetic tool to manipulate the survival of newly formed spines after ketamine treatment.

RESULTS

The induction of depression-related behavior in multiple chronic stress models was associated with targeted, branch-specific elimination of postsynaptic dendritic spines and a loss of correlated multicellular ensemble activity in PFC projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predicted motivated escape behavior. Unexpectedly, ketamine’s effects on behavior and ensemble activity preceded its effects on spine formation, indicating that spine formation was not required for inducing these effects acutely. However, individual differences in the restoration of lost spines were correlated with behavior 2 to 7 days after treatment, suggesting that spinogenesis may be important for the long-term maintenance of these effects. To test this, we used a photoactivatable probe to selectively reverse the effects of ketamine on spine formation in the PFC and found that the newly formed spines play a necessary and specific role in sustaining ketamine’s antidepressant effects on motivated escape behavior. By contrast, optically deleting a random subset of spines unrelated to ketamine treatment had no effect on behavior.

CONCLUSION

Prefrontal cortical spine formation sustains the remission of specific depression-related behaviors after ketamine treatment by restoring lost spines and rescuing coordinated ensemble activity in PFC microcircuits. Pharmacological and neurostimulatory interventions for enhancing and preserving the rescue of lost synapses may therefore be useful for promoting sustained remission.

Why is ketamine an antidepressant?

A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine’s antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants.

Structured Abstract

INTRODUCTION

Depression is an episodic form of mental illness, yet the circuit-level mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood. Ketamine relieves depressive symptoms rapidly, providing an opportunity to study the neurobiological substrates of transitions from depression to remission and to test whether mechanisms that induce antidepressant effects acutely are distinct from those that sustain them.

RATIONALE

Contrasting changes in dendritic spine density in prefrontal cortical pyramidal cells have been associated with the emergence of depression-related behaviors in chronic stress models and with ketamine’s antidepressant effects. But whether and how dendritic spine remodeling is causally involved, or whether it is merely correlated with these effects, is unclear. To answer these questions, we used two-photon imaging to study how chronic stress and ketamine affect dendritic spine remodeling and neuronal activity dynamics in the living prefrontal cortex (PFC), as well as a recently developed optogenetic tool to manipulate the survival of newly formed spines after ketamine treatment.

RESULTS

The induction of depression-related behavior in multiple chronic stress models was associated with targeted, branch-specific elimination of postsynaptic dendritic spines and a loss of correlated multicellular ensemble activity in PFC projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predicted motivated escape behavior. Unexpectedly, ketamine’s effects on behavior and ensemble activity preceded its effects on spine formation, indicating that spine formation was not required for inducing these effects acutely. However, individual differences in the restoration of lost spines were correlated with behavior 2 to 7 days after treatment, suggesting that spinogenesis may be important for the long-term maintenance of these effects. To test this, we used a photoactivatable probe to selectively reverse the effects of ketamine on spine formation in the PFC and found that the newly formed spines play a necessary and specific role in sustaining ketamine’s antidepressant effects on motivated escape behavior. By contrast, optically deleting a random subset of spines unrelated to ketamine treatment had no effect on behavior.

CONCLUSION

Prefrontal cortical spine formation sustains the remission of specific depression-related behaviors after ketamine treatment by restoring lost spines and rescuing coordinated ensemble activity in PFC microcircuits. Pharmacological and neurostimulatory interventions for enhancing and preserving the rescue of lost synapses may therefore be useful for promoting sustained remission.