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From street drug to depression therapy

Ketamine offers a new option for people with stubborn depression that doesn’t respond to other medications.

703-844-0184 | Ketamine Treatment Center in Alexandria, Va 22306

 

Many people know of ketamine as a hallucinogenic and addictive street drug, which, when abused, can put people in medical peril. But today, doctors are increasingly looking to ketamine as a potentially lifesaving treatment for people with severe, treatment-resistant depression, who may be at high risk for suicide.

“Ketamine has been shown to be effective in people who have not responded to antidepressant treatment,” says Dr. Cristina Cusin, an assistant professor of psychiatry at Harvard Medical School. The fast-acting treatment has shown promise — sometimes improving depressive symptoms within hours of the first intravenous treatment.

While ketamine can offer hope to some, it’s not for everyone. The use of ketamine to treat depression is still controversial in some circles. “Some prescribers would never consider the use of a controlled substance for this purpose, because of the potential for abuse,” says Dr. Cusin. “But as with opiates, a drug is not good or bad, per se.” Still, ketamine does need to be carefully matched to the right patient for the right use to avoid harm, and treatment should be closely monitored over time.

A variety of uses

The use of ketamine in medicine isn’t new. It’s routinely used in hospitals both for anesthesia and for pain relief.

Currently, the use of ketamine for depression is “off label.” This means that although ketamine is approved by the FDA for some medical purposes, it’s not approved specifically to treat depression. However, that may soon change. Under its “fast track” drug approval process, the FDA is reviewing the results of clinical trials of esketamine, a ketamine-based nasal spray, to treat depression, says Dr. Cusin.

For now, people who undergo ketamine treatment for depression typically receive the drug at specialized clinics, either intravenously or as a nasal spray. Effects from the nasal spray last for a single day or a few days, while the intravenous treatment may last for a few weeks to a month. In both instances the dose is significantly lower than would be used for anesthesia or when used illicitly.

How ketamine works

Studies have shown that ketamine is effective in treating people whose depression has not responded to other interventions, says Dr. Cusin. Such treatment-resistant depression is estimated to affect from 10% to 30% of people diagnosed with the condition.

Experts believe that ketamine works through a unique mechanism, directly modulating the activity of a brain chemical called glutamate. Glutamate is believed to play a role in stimulating the growth of new brain connections that may help alleviate depressive symptoms.

People who have taken ketamine to treat their depression experience varying success, depending on their personal history—how long they’ve been depressed, how severe their symptoms are, and how many drugs they’ve tried without seeing improvement, says Dr. Cusin.

For people with less severe depression, ketamine may be effective in as many as 60% of those who try it. Among those with more persistent and significant disease, a smaller number, 30% to 40%, may experience relief, says Dr. Cusin. “The expectation should not be that it will magically cure depression in everybody,” she says. “Ketamine is not a perfect fix. It’s like any other medication.” In other words, it works for some people, and it won’t work for others.

To be effective, treatment with ketamine must typically continue indefinitely and involve careful monitoring. Clinicians who prescribe ketamine for depression should screen patients carefully to ensure the drug is appropriate for the individual, says Dr. Cusin. “Not everybody who wishes to try ketamine will be a good candidate,” she says.

Among those who should not use ketamine are people with

  • a history of substance abuse
  • a history of psychosis
  • elevated blood pressure
  • an uncontrolled medical condition.

Who can benefit?

Because ketamine is a newer treatment, there are still a lot of questions surrounding its use, says Dr. Cusin. For instance:

  • Which people respond best to treatment?
  • How much should be given, and how often?
  • What are the long-term effects of treatment?

Because the medication is being used off label for depression, there are no clearly defined safety recommendations either for home use or for its use in specialized clinics, she says. This means that it’s up to individual providers to guide the patient in making informed decisions about treatment. Choosing a qualified provider is essential. JAMA Psychiatrypublished a statement in 2017 outlining best practices for doctors to follow in ketamine treatment, such as performing a comprehensive assessment, obtaining informed consent, and documenting the severity of depression before starting the medication. These guidelines are aimed at increasing the safe use of ketamine for depression, and providers can use them to help ensure that the treatment is a good match for your condition.

As with any other medical intervention, anyone considering ketamine should also consider the drawbacks of treatment along with the potential benefits. Ketamine’s drawbacks include these:

http://maientertainmentlaw.com/?search=where-to-purchase-real-cialis Cost. It’s expensive and not covered by insurance. “The cost ranges from $400 to $1,200 per dose for the intravenous drug, and you may need as many as 12 to 18 doses a year,” says Dr. Cusin.

propecia in woman Unknowns. Ketamine hasn’t been used to treat depression for long enough for doctors to know whether there are any harmful long-term consequences of taking the medication. More time and study are needed to truly understand how it affects people over the long term.

acquistare levitra online sicuro Palermo Treatment failure. Many people with treatment-resistant depression view ketamine treatment as their last option, so if this therapy fails to improve their depression, they can be emotionally devastated. Realistic expectations and follow-up support are essential.

Even if ketamine does produce results, it’s still important to understand what it can and can’t do. “-Ketamine isn’t going to eliminate all frustrations and stress from your life. While it may lift some symptoms of depression, the life stressors will still be there,” says Dr. Cusin. You’ll still need support to help you manage them.

follow Side effects. While ketamine is viewed as safe in a controlled setting, it can frequently increase blood pressure or produce psychotic-like behavior, which may result in delusions or hallucinations. Serious adverse events are rare because the drug is used at such low doses, says Dr. Cusin.

However, provided you are an appropriate candidate for the treatment and your doctor monitors you closely, you could find that it improves your mood. “Ketamine could make a huge difference in the quality and duration of life and can be very effective for people who are thinking about suicide,” says Dr. Cusin.

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The VA Recognizes Ketamine As An Emergency Treatment For PTSD And Depression Patients At High Suicide Risk

CLEARWATER, Fla., Sept. 27, 2018 /PRNewswire/ — Long used as an safe and effective sedative for surgery, Ketamine has found new life as a treatment for severe depression, PTSD and suicidal ideation. Praised by some mental health experts, the drug so far has achieved very good results in clinical trials. The military now recognizes its’ potential, and last fall Brooke Army Medical Center in San Antonio became part of study on its effects. BAMC will treat active-duty troops with Ketamine, while a VA hospital near Yale will treat veterans. Another study is currently underway at a Veterans Affairs medical center in Cleveland, Ohio. The VA is trying to stem the tide of rising suicide rates among veterans, which average 22 per day – that’s one suicide every 65 minutes.

A staff psychiatrist at the Louis Stokes Cleveland VA Medical Center in Ohio, Dr. Punit Vaidya stated “30% of individuals with major depression don’t respond to traditional medications, so people can become desperate for things that work, because they can have a huge impact on their quality of life, and their overall functioning. The effects of the ketamine infusion can often be seen within a day, if not hours,” Vaidya explained. “If you look at their depression ratings and suicidal ratings given right before treatment and even four hours later you can see a significant reduction and I think that’s really quite remarkable,” Vaidya said.

Dr. Ashraf Hanna, a board certified physician and director of pain management at the Florida Spine Institute in Clearwater, Florida discusses PTSD and Treatment-Resistant Depression: “There are many forms of depression that can be treated by a psychiatrist with various modalities, anti-depressants and psychotherapy. IV Ketamine therapy is only reserved for those patients that have Treatment-Resistant Depression that have failed conventional therapy. IV Ketamine infusion therapyhas offered a new hope to patients that had no hope.”

When asked what prompted his use of IV Ketamine for PTSD and Depression and if any universities were involved in its development, Dr. Hanna went on to say: “There have been multiple universities involved in the research such as Harvard, Yale and Stanford that have proven the success rate of IV Ketamine for treatment-resistant depression. Since I was already successfully using IV Ketamine for CRPS/RSD,FibromyalgiaNeuropathy, and Post-Treatment Lyme Disease Syndrome, with over 10,000 infusions to date, I wanted to expand the treatment for PTSD, Depression, bipolar and Obsessive Compulsive Disorders. Since I am not a psychiatrist, I do not treat depression, but I work with qualified psychiatrists, and if he or she feels the patient has failed other treatment modalities, I then administer IV Ketamine for treatment-resistant depression.”

Dr. Bal Nandra and Ketamine patient Jason LaHood on how Ketamine is redefining the way patients are treated for depression

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Links for Ketamine Articles

  1. NYMag.com – What It’s Like to Have Your Severe Depression Treated With a Hallucinogenic Drug
    http://nymag.com/scienceofus/2016/03/what-its-like-to-treat-severe-depression-with-a-hallucinogenic-drug.html
  2. Huffington Post – How Ketamine May Help Treat Severe Depression
    http://www.huffingtonpost.com.au/2017/04/05/how-ketamine-may-help-treat-severe-depression_a_22027886/
  3. Murrough, Iosifescu, Chang et al. Antidepressant Efficacy in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial  Am J Psychiatry. 2013 Oct 1, 170(10): 1134-1142
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992936/
  4. Murrough, Perez, Pillemer, et al.. Rapid and Longer0Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression Biol Psychiatry 2013 Aug 15; 74(4): 250-256
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725185/
  5. Murrough, Burdick, Levitch et al. Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial Neuropsychopharmacology 2015 Apr; 40(5): 1084-1090
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367458/
  6. Feder, Parides, et al. Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder A Randomized Clinical Trial Jama Psychiatry 2014 June;71(6): 681-8
    http://jamanetwork.com/journals/jamapsychiatry/fullarticle/1860851
  7. Schwartz, Murrough, Iosifescu Ketamine for treatment-resistant depression: recent developments and clinical applications Evid Based Ment Health 2016 May; 19(2):35-8
    http://ebmh.bmj.com/content/ebmental/19/2/35.full.pdf
  8. Rodriguez, Kegeles, et al Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept Neuropsychopharmacology 2013 Nov; 38(12): 2475-2483
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799067/pdf/npp2013150a.pdf
  9. Singh, Fedgchin, Daly et al. A Double-Blind, Randomized, Pacebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression American Journal of Psychiatry 2016 August; 173(8): 816-826
    http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2016.16010037
  10. Taylor,  Landeros-Weisenberger, Coughlin et al. Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial  Neuropsychopharmacology 2017 August;
    https://www.ncbi.nlm.nih.gov/pubmed/28849779

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WHAT CAN I EXPECT AT AN INFUSION VISIT?

We will ask you to fast for 8 hours before your infusion. Once you have checked in, you will complete a questionnaire to assess your current status. The IV will be started in your hand or your arm using a small catheter. This may feel like a sting from a small bug bite. The Ketamine will be administered through your IV over a period of 40 minutes. We will take your vital signs before, during, and after the infusion. After resting for an additional 15-20 minutes after the infusion, you will be discharged home with your driver.

  1. What is Ketamine? 
    Ketamine is an anesthetic drug that has been available since the 1960’s. In high doses, it can cause a ‘dissociative anesthesia” which induces hypnosis like states as well as unconsciousness. Around 2000, scientists started looking at Ketamine IV infusions carefully when its clinical usefulness was expanded to include a role in the management of mood disorders as well as chronic pain.
  2. Why can I not drive the day of the infusion?
    Ketamine is a potent anesthetic. As with any anesthetic, we advise our patients to NOT operate any heavy machinery for the remainder of the day due to potential residual effects.
  3. What are the side effects?
    Less than 2% of people will experience side effects. Some of the common side effects are: drowsiness, nausea, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Most of these symptoms dissipate after the first hour of receiving the infusion.
  4. Are there certain conditions that are contra-indications for Ketamine treatment?
    Yes. If you have a history of cardiovascular disease, uncontrolled hypertension, history of psychosis, history of failed Ketamine infusion treatment, history of substance abuse or dependence within the year (patients will undergo a screening process) you will not qualify for Ketamine infusion treatments.
  5. How will I know if I need a booster infusion and how frequently will I require them?
    The duration of antidepressant efficacy after the initial treatment is different for everyone. The studies show that the variance can be 15 days to indefinitely. This is quite a range and unfortunately, there are no predictors for the duration.
  6. Is there a guarantee that this will work for me?
    Unfortunately, we cannot give guarantees.  Studies have shown that 70% of people will obtain efficacy.  After the first 2 infusions, we will be able to ascertain whether the infusions will work for you. We will not advise you to continue your treatment after the first 2 infusions if we do not see a certain amount of improvement.
  7. Isn’t Ketamine addictive? 
    Ketamine has the potential to be addictive. Studies have shown that at these doses and frequency, Ketamine is not addictive.
  8. Do I have to continue my current treatments for depression? 
    Yes. We advise that you alert your current health care provider that you are undergoing these treatments and that you maintain your current regimen.  It can be dangerous to stop taking your medications without the care of a physician. Our patients have a brighter outlook and a positive drive after their treatment that has allowed them to have higher success rates with psychotherapy. We will be happy to work with your current health care provider to provide the optimal outcome.

_____________________________________

VA Using Ketamine for PTSD and Depression

Ketamine for Depresion | Obsessive-compulsive disorder| Fairfax, Va | 703-844-0184 | Ketamine doctors | IV ketamine | Ketamine treatment center | 22306

NOVA Health Recovery  <<< Ketamine Treatment Center Fairfax, Virginia

CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

email@novahealthrecovery.com  << Email for questions to the doctor

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Ketamine

The drug Ketamine is considered a breakthrough treatment for depression and some other neuropsychiatric conditions. Below are excerpts from recent articles discussing this revolutionary treatment and the links to the full articles.

Ketamine For Depression: the Highs and Lows.

The Lancet Psychiatry. VOLUME 2, ISSUE 9, P783–784, SEPTEMBER 2015

Long used as an anaesthetic and analgesic, most people familiar with ketamine know of it for this purpose. Others know it as a party drug that can give users an out-of-body experience, leaving them completely disconnected from reality. Less well known is its growing off-label use in the USA for depression, in many cases when other options have been exhausted.

David Feifel, a professor of psychiatry at the University of California, San Diego, was one of the first clinicians to use ketamine off-label to treat depression at UCDS’s Center for Advanced Treatment of Mood and Anxiety Disorders, which he recently founded. “Currently approved medications for depression all have about the same, very limited efficacy. A large percentage of patients with depression do not get an adequate level of relief from these antidepressants even when they have tried several different ones and even when other drugs known to augment their effects are added to them”, Feifel tells The Lancet Psychiatry. “The stagnation in current antidepressant medication on the one hand, and the tremendous number of treatment-resistant patients, has propelled me to explore truly novel treatments like ketamine.”

Compelling published study results and case reports exist of patients’ depression—in some cases deeply entrenched depression that has lasted months or even years—alleviating within hours of use of ketamine. However, critics have warned that the drug has not been studied sufficiently (at least outside clinical trials), and also emphasized the cost. Patients can pay more than $1000 per session for treatment that must usually be repeated several times. That cost is rarely covered by the patient’s medical insurance.

Advocates of ketamine use in depression are excited because it has a different mechanism of action to standard antidepressants, which affect signalling by monoamine neurotransmitters such as serotonin, noradrenaline, or dopamine. Ketamine is thought to act by blocking N-methyl-d-aspartate (NMDA) receptors in the brain, which interact with the amino acid neurotransmitter glutamate.

Feifel states that he has patients who have been receiving ketamine treatments every 2–4 weeks for long periods, some for around 3 years, and has not yet seen any safety issues arise.

Pharmaceutical companies are entering this exciting arena by attempting to develop new drugs based on ketamine without similar side-effects. Feifel dismisses the notion that the dissociative so-called trip induced by ketamine is actually an important negative side-effect. “Although I have had a couple patients have unpleasant ‘trips’, it’s exceedingly rare, usually dose related, and very transitory due to ketamine’s rapid metabolism.” Feifel says that, more often than not, patients find the trip to be positive, or even spiritual, and believe it is an important component of the antidepressant effect they experience afterwards. “There is no doubt the dissociative effect represents a logistical issue, requiring monitoring—and this should be addressed in any approval given for ketamine”, he adds.

Feifel says that it is not for him, but for his patients to decide where the balance of risks and benefits lies in trying ketamine to treat their depression”One could make a compelling argument that it’s unethical to withhold ketamine treatments from someone who has chronic, severe treatment resistant depression. But I know this from the patients who tell me they would not be in this world right now if it were not for the ketamine.”

Feifel concludes that it is straightforward to talk to TRD patients about ketamine. “I tell them all the relevant information. The efficacy rates, time to onset of benefits, duration limitations, alternatives, lack of insurance coverage, and other information. My job is to make sure they understand the parameters of the treatment, not to decide whether they should do it.”

Full article: The Lancet

Ketamine for depression the highs and lows b

Onetime Party Drug Hailed as Miracle for Treating Severe Depression

Washington Post, Feb 2, 2016

Ketamine, popularly known as the psychedelic club drug Special K, has been around since the early 1960s. It is a staple anesthetic in emergency rooms, regularly used for children when they come in with broken bones and dislocated shoulders. It’s an important tool in burn centers and veterinary medicine, as well as a notorious date-rape drug, known for its power to quickly numb and render someone immobile. Since 2006, dozens of studies have reported that it can also reverse the kind of severe depression that traditional antidepressants often don’t touch.

Experts are calling it the most significant advance in mental health in more than half a century. They point to studies showing ketamine not only produces a rapid and robust antidepressant effect; it also puts a quick end to suicidal thinking.  “This is the next big thing in psychiatry,” says L. Alison McInnes, a San Francisco psychiatrist who over the past year has enrolled 58 severely depressed patients in Kaiser’s San Francisco clinic. The excitement stems from the fact that it’s working for patients who have spent years cycling through antidepressants, mood stabilizers and various therapies. “Psychiatry has run out of gas” in trying to help depressed patients for whom nothing has worked, she says. “There is a significant number of people who don’t respond to antidepressants, and we’ve had nothing to offer them other than cognitive behavior therapy, electroshock therapy and transcranial stimulation.”

Ketamine does, however, have one major limitation: Its relief is temporary. Clinical trials at NIMH have found that relapse usually occurs about a week after a single infusion.

A study published in the journal Science in 2010 suggested that ketamine restores brain function through a process called synaptogenesis. Scientists at Yale University found that ketamine not only improved depression-like behavior in rats but also promoted the growth of new synaptic connections between neurons in the brain.

Patients often describe a kind of lucid dreaming or dissociative state in which they lose track of time and feel separated from their bodies. Many enjoy it; some don’t. But studies at NIMH and elsewhere suggest that the psychedelic experience may play a small but significant role in the drug’s efficacy.

As a drug once known almost exclusively to anesthesiologists, ketamine now falls into a gray zone. As the use of ketamine looks likely to grow, many psychiatrists say that use of ketamine for depression should be left to them. “The bottom line is you’re treating depression,” says psychiatrist David Feifel, director of the Center for Advanced Treatment of Mood and Anxiety Disorders at the University of California at San Diego. “And this isn’t garden-variety depression. The people coming in for ketamine are people who have the toughest, potentially most dangerous depressions. I think it’s a disaster if anesthesiologists feel competent to monitor these patients.”

Full article: The Washington Post

Onetime party drug hailed as miracle for treating severe depression


A Ketamine intravenous drip being prepared. (Amarett Jans/Courtesy of Enrique Abreu)

February 1, 2016

It was November 2012 when Dennis Hartman, a Seattle business executive, managed to pull himself out of bed, force himself to shower for the first time in days and board a plane that would carry him across the country to a clinical trial at the National Institute of Mental Health (NIMH) in Bethesda.

After a lifetime of profound depression, 25 years of therapy and cycling through 18 antidepressants and mood stabilizers, Hartman, then 46, had settled on a date and a plan to end it all. The clinical trial would be his last attempt at salvation.

For 40 minutes, he sat in a hospital room as an IV drip delivered ketamine through his system. Several more hours passed before it occurred to him that all his thoughts of suicide had evaporated.

“My life will always be divided into the time before that first infusion and the time after,” Hartman says today. “That sense of suffering and pain draining away. I was bewildered by the absence of pain.”

Ketamine could be speedy depression treatment

Ketamine is being used by researchers at The National Institutes of Health as a treatment for major depression. 

Ketamine, popularly known as the psychedelic club drug Special K, has been around since the early 1960s. It is a staple anesthetic in emergency rooms, regularly used for children when they come in with broken bones and dislocated shoulders. It’s an important tool in burn centers and veterinary medicine, as well as a notorious date-rape drug, known for its power to quickly numb and render someone immobile.

Since 2006, dozens of studies have reported that it can also reverse the kind of severe depression that traditional antidepressants often don’t touch. The momentum behind the drug has now reached the American Psychiatric Association, which, according to members of a ketamine task force, seems headed toward a tacit endorsement of the drug for treatment-resistant depression.

Experts are calling it the most significant advance in mental health in more than half a century. They point to studies showing ketamine not only produces a rapid and robust antidepressant effect; it also puts a quick end to suicidal thinking.

Traditional antidepressants and mood stabilizers, by comparison, can take weeks or months to work. In 2010, a major study published in JAMA, the journal of the American Medical Association, reported that drugs in a leading class of antidepressants were no better than placebos for most depression.

A growing number of academic medical centers, including Yale University, the University of California at San Diego, the Mayo Clinic and the Cleveland Clinic, have begun offering ketamine treatments off-label for severe depression, as has Kaiser Permanente in Northern California.

The ‘next big thing’

“This is the next big thing in psychiatry,” says L. Alison McInnes, a San Francisco psychiatrist who over the past year has enrolled 58 severely depressed patients in Kaiser’s San Francisco clinic. She says her long-term success rate of 60 percent for people with treatment-resistant depression who try the drug has persuaded Kaiser to expand treatment to two other clinics in the Bay Area. The excitement stems from the fact that it’s working for patients who have spent years cycling through antidepressants, mood stabilizers and various therapies.

“Psychiatry has run out of gas” in trying to help depressed patients for whom nothing has worked, she says. “There is a significant number of people who don’t respond to antidepressants, and we’ve had nothing to offer them other than cognitive behavior therapy, electroshock therapy and transcranial stimulation.”

McInnes is a member of the APA’s ketamine task force, assigned to codify the protocol for how and when the drug will be given. She says she expects the APA to support the use of ketamine treatment early this year.

The guidelines, which follow the protocol used in the NIMH clinical trial involving Hartman, call for six IV drips over a two-week period. The dosage is very low, about a tenth of the amount used in anesthesia. And when it works, it does so within minutes or hours.

“It’s not subtle,” says Enrique Abreu, a Portland, Ore., anesthesiologist who began treating depressed patients with it in 2012. “It’s really obvious if it’s going to be effective.

“And the response rate is unbelievable. This drug is 75 percent effective, which means that three-quarters of my patients do well. Nothing in medicine has those kind of numbers.”

So far, there is no evidence of addiction at the low dose in which infusions are delivered. Ketamine does, however, have one major limitation: Its relief is temporary. Clinical trials at NIMH have found that relapse usually occurs about a week after a single infusion.

Ketamine works differently from traditional antidepressants, which target the brain’s serotonin and noradrenalin systems. It blocks N-methyl-D-aspartate (NMDA), a receptor in the brain that is activated by glutamate, a neurotransmitter.

In excessive quantities, glutamate becomes an excitotoxin, meaning that it overstimulates brain cells.

“Ketamine almost certainly modifies the function of synapses and circuits, turning certain circuits on and off,” explains Carlos Zarate Jr., NIMH’s chief of neurobiology and treatment of mood disorders, who has led the research on ketamine. “The result is a rapid antidepressant effect.”

Rapid effect

study published in the journal Science in 2010 suggested that ketamine restores brain function through a process called synaptogenesis. Scientists at Yale University found that ketamine not only improved depression-like behavior in rats but also promoted the growth of new synaptic connections between neurons in the brain.

mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.

Psychedelic-Assisted Psychotherapy A Paradigm Shift in Psychiatric Research and Development

Psychedelics Promote Structural and Functional Neural Plasticity.

Even a low-dose infusion can cause intense hallucinations. Patients often describe a kind of lucid dreaming or dissociative state in which they lose track of time and feel separated from their bodies. Many enjoy it; some don’t. But studies at NIMH and elsewhere suggest that the psychedelic experience may play a small but significant role in the drug’s efficacy.

“It’s one of the things that’s really striking,” says Steven Levine, a Princeton, N.J., psychiatrist who estimates that he has treated 500 patients with ketamine since 2011. “With depression, people often feel very isolated and disconnected. Ketamine seems to leave something indelible behind. People use remarkably similar language to describe their experience: ‘a sense of connection to other people,’ ‘a greater sense of connection to the universe.’ ”

Although bladder problems and cognitive deficits have been reported among long-term ketamine abusers, none of these effects have been observed in low-dose clinical trials. In addition to depression, the drug is being studied for its effectiveness in treating obsessive-compulsive disorder, post-traumatic stress disorder, extreme anxiety and Rett syndrome, a rare developmental disorder on the autism spectrum.

Booster treatments

The drug’s fleeting remission effect has led many patients to seek booster infusions. Hartman, for one, began his search before he even left his hospital room in Bethesda.

Four years ago, he couldn’t find a doctor in the Pacific Northwest willing to administer ketamine. “At the time, psychiatrists hovered between willful ignorance and outright opposition to it,” says Hartman, whose depression began creeping back a few weeks after his return to Seattle.

It took nine months before he found an anesthesiologist in New York who was treating patients with ketamine. Soon, he was flying back and forth across the country for bimonthly infusions.

Upon his request, he received the same dosage and routine he’d received in Bethesda: six infusions over two weeks. And with each return to New York, his relief seemed to last a little longer. These days, he says that his periods of remission between infusions often stretch to six months. He says he no longer takes any medication for depression besides ketamine.

“I don’t consider myself permanently cured, but now it’s something I can manage,” Hartman says, “like diabetes or arthritis. Before, it was completely unmanageable. It dominated my life and prevented me from functioning.”

In 2012 he helped found the Ketamine Advocacy Network, a group that vets ketamine clinics, advocates for insurance coverage and spreads the word about the drug.

And word has indeed spread. Ketamine clinics, typically operated by psychiatrists or anesthesiologists, are popping up in major cities around the country.

Levine, for one, is about to expand from New Jersey to Denver and Baltimore. Portland’s Abreu recently opened a second clinic in Seattle.

Depression is big business. An estimated 15.7 million adults in the United States experienced at least one major depressive episode in 2014, according to the NIMH.

“There’s a great unmet need in depression,” says Gerard Sanacora, director of the Yale Depression Research Program. “We think this is an extremely important treatment. The concern comes if people start using ketamine before CBT [cognitive behavioral therapy] or Prozac. Maybe someday it will be a first-line treatment. But we’re not there yet.”

Many unknowns

Sanacora says a lot more research is required. “It’s a medication that can have big changes in heart rate and blood pressure. There are so many unknowns, I’m not sure it should be used more widely till we understand its long-term benefits and risks.”

While a single dose of ketamine is cheaper than a $2 bottle of water, the cost to the consumer varies wildly, running anywhere between $500 and $1,500 per treatment. The drug itself is easily available in any pharmacy, and doctors are free to prescribe it — as with any medication approved by the Food and Drug Administration — for off-label use. Practitioners attribute the expense to medical monitoring of patients and IV equipment required during an infusion.

There is no registry for tracking the number of patients being treated with ketamine for depression, the frequency of those treatments, dosage levels, follow-up care and adverse effects.

“We clearly need more standardization in its use,” Zarate says. “We still don’t know what the proper dose should be. We need to do more studies. It still, in my opinion, should be used predominantly in a research setting or highly specialized clinic.”

As a drug once known almost exclusively to anesthesiologists, ketamine now falls into a gray zone.

“Most anesthesiologists don’t do mental health, and there’s no way a psychiatrist feels comfortable putting an IV in someone’s arm,” Abreu says.

It’s a drug, in other words, that practically demands collaboration. Instead, it has set off a turf war. As the use of ketamine looks likely to grow, many psychiatrists say that use of ketamine for depression should be left to them.

“The bottom line is you’re treating depression,” says psychiatrist David Feifel, director of the Center for Advanced Treatment of Mood and Anxiety Disorders at the University of California at San Diego. “And this isn’t garden-variety depression. The people coming in for ketamine are people who have the toughest, potentially most dangerous depressions. I think it’s a disaster if anesthesiologists feel competent to monitor these patients. Many of them have bipolar disorder and are in danger of becoming manic. My question [to anesthesiologists] is: ‘Do you feel comfortable that you can pick up mania?’ ”

But ketamine has flourished from the ground up and with little or no advertising. The demand has come primarily from patients and their families; Zarate, for instance, says he receives “at least 100 emails a day” from patients.

Nearly every one of them wants to know where they can get it.

 

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Ketamine has ‘truly remarkable’ effect on depression and is effective in elderly patients, scientists say

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Ketamine can have a “truly remarkable” effect on people with depression, researchers have said after a new study showed promising results among elderly patients.

Colleen Loo, a professor at the University of New South Wales in Australia, led the world’s first randomised control trial into the drug’s effect on people over 60 with treatment-resistant depression.

“This trial has shown ketamine can be used safely in the elderly and it tends to be effective,” she told The Independent, adding that a similar effect was observed in this age group as in younger patients.

It is important to test how people of different ages respond to a new treatment before it can be offered by doctors, she said: “Sometimes depression in the elderly can be harder to treat, especially with medication.

“Also, they tend to have more medical problems, which can interfere with medication.”

Ketamine was discovered in 1962 and is licenced for medical use in the UK as an anaesthetic, but is also used illegally as a recreational drug.

Of the study’s 16 participants, 11 reported an improvement in their condition while being treated with the drug, according to the research published in the American Journal of Geriatric Psychiatry.

After six months, 43 per cent of the subjects said they had no significant symptoms of depression – a high rate given that the participants had not responded to previous treatment, said Professor Loo.

“It is truly remarkable the way ketamine can work,” she said. “Other people have also found you get a rapid and powerful effect after a single dose of ketamine.”

“Some people mistakenly think we are inducing a temporary, drug-induced euphoria and people are ‘out of it’, which is why they’re not depressed.

“But the effects take place in the first hour, and they’re not euphoric at all. In fact, all of our research participants disliked them. They considered them adverse effects.

“The antidepressant effect kicks in a few hours later and are maximised about 20 hours later, when you’re fully alert and in your usual state of mind.”

While research into the use of ketamine to treat mental health problems is still in its early stages, scientists at Oxford University have said their studies show the drug can provide relief to patients with severe depression “where nothing has helped before”.

Rupert McShane, the consultant psychiatrist who is leading Oxford’s ketamine treatment programme, told The Independent it was “good to see that, contrary to some reports, some older people do respond to ketamine.”

“This study highlights that ketamine can be given in a variety of ways (not just intravenous), that it’s a good idea to adjust the dose, and that the more resistant someone’s depression is, the higher the dose that they are likely to need,” he said.

Professor Loo and her colleagues delivered ketamine to the patients using a small injection under the skin – similar to the insulin jabs given to diabetes patients.

This makes the drug easier and quicker to administer than the intravenous infusions used in other trials, which require a machine pump to regulate the dose and takes up to an hour to complete.

Participants received increasing doses of ketamine over a period of five weeks, with the dose personalised for each patient.

However, she warned that while the research is one step closer to providing a model for how doctors could prescribe ketamine as a treatment for depression in future, it would still be “premature to jump into clinical practice”.

“There are ‘super-responders’, who after a single treatment can be well for several months,” said Professor Loo, giving the example of a subject who, in 2014, remained free of depressive symptoms for five months after just one dose of ketamine.

But “most people are well but then they relapse over around three to seven days,” she said. “That’s where repeated dosing comes in.”

Ketamine Injections May Help Older Adults With Depression

Repeated subcutaneous injections of ketamine significantly improved symptoms in a small group of older adults with treatment-resistant depression, researchers found in a pilot study published online in The American Journal of Geriatric Psychiatry.

The randomized controlled trial is the first to assess the efficacy and safety of ketamine in the geriatric patient population.

“These findings take us a big step forward as we begin to fully understand the potential and limitations of ketamine’s antidepressant qualities,” said lead author Colleen Loo, MD, a professor in the School of Psychiatry at the University of New South Wales, Sydney, Australia.

Psychiatrists Issue ‘Much-needed’ Consensus on Ketamine for Mood Disorders

“Not only was ketamine well-tolerated by participants, with none experiencing severe or problematic side effects, but giving the treatment by a simple subcutaneous injection (a small injection under the skin) was also shown to be an acceptable method for administering the drug in a safe and effective way.”

Overall, the response and remission rate for older adults receiving ketamine was 68.8%.

Australian researchers tested individualized dosing of ketamine using a dose-titration method in 16 adults age 60 and older. Participants received increasing doses over 5 weeks. The double-blind, placebo-controlled trial included 1 session in which participants received an active treatment substitute that, similar to ketamine, caused sedation.

Why Not Make Ketamine a First-line Treatment?

After the randomized controlled trial, participants received 12 ketamine doses in an open-label phase.

At a 6-month follow-up, 7 of 14 older adults who had completed the randomized controlled trial had depression remission — 5 of whom remitted at doses below the common ketamine dose of 0.5 mg/kg, researchers reported. Repeated treatments, they added, resulted in a higher likelihood of remission or a longer time to relapse.

“Elderly patients with severe depression face additional barriers when seeking treatment for the condition. Many medications may cause more side effects or have lower efficacy as the brain ages,” said researcher Duncan George, MBBS, School of Psychiatry, University of New South Wales. “Older people are also more likely to have comorbidities like neurodegenerative disorders and chronic pain, which can cause further complications due to ketamine’s reported side effects.

“Our results indicate a dose-titration method may be particularly useful for older patients, as the best dose was selected for each individual person to maximize ketamine’s benefits while minimizing its adverse side effects.”

—Jolynn Tumolo

References

George D, Gálvez V, Martin D, et al. Pilot randomized controlled trial of titrated subcutaneous ketamine in older patients with treatment-resistant depression. The American Journal of Geriatric Psychiatry. 2017 June 13;[Epub ahead of print].

World-first ketamine trial shows promise for geriatric depression [press release]. Sydney, Australia: University of New South Wales; July 24, 2017.

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Poster Number: EI 5
Ketamine in Late Life Treatment-Resistant Depression
Erika Heard, MD1
; Yousuf Sohail, MD1
; Anusuiya Nagar, MD1
; Oliver M. Glass, MD2
; Adriana P. Hermida, MD1

Introduction: Ketamine is a dissociative anesthetic, which provides antagonism on the N-methyl-D-aspartate (NMDA)
receptor. Several studies have demonstrated rapid anti-depressant and anti-suicidal effects from the administration of ketamine
in adult patients but studies in late life patients are lacking. While ketamine may increase sympathetic stimulation and cause
decreased respiratory rate in geriatric patients, it is still nonetheless considered a safe agent. Low-dose intravenous infusion of
ketamine is gaining popularity in the treatment for treatment-resistant depression (TRD) in late life patients. We provide a case
report on a patient in late life who suffered from TRD and was treated with ketamine.
Methods: A case report of the use of intravenous ketamine to treat a geriatric patient with TRD along with a literature review
of the subject.
Results: A 76-year-old female with a history of hypertension and arthritis presented with worsening depressive symptoms for the
past two years. She endorsed neuro-vegetative symptoms of depressed mood, poor appetite, unintentional 25-pound weight loss,
and conflicted feelings about wanting to live. She also reported difficulties with concentration and memory, feelings of
worthlessness, and psychomotor retardation. Her daughter stated she was more vegetative and had a strong desire not to live alone.
QIDS (Quick Inventory of Depressive Symptomatology) baseline was 23. She had previous trials of multiple medications including
paroxetine, fluoxetine, sertraline, escitalopram, buproprion, and venlafaxine. This patient showed poor tolerance to all the
medications and at the time of assessment was taking mirtazapine 7.5 mg and duloxetine 60 mg. Electroconvulsive therapy (ECT)
was recommended; however, the patient was found to be not a good candidate as per anesthesiology due to multiple comorbidities.
As a result, mirtazapine was titrated to 15 mg nightly while duloxentine was continued at 60 mg daily. Patient was started on
intravenous ketamine infusions of 20 mg (0.5 mg/kg) over 40 minutes. Patient tolerated the acute course of ketamine, which was
administered twice per week. Patient and daughter reported clinicial improvement after the first infusion with noticeable
improvement in QIDS (23 to 12) after 6 acute sessions without adverse effects. Improved symptoms included brighter affect,
increased energy, decreased anhedonia, increased daily activity, improved appetite (gained 40lbs), and being more engaged in the
community. Additionally, she began to take care of herself again. She has received 17 ketamine treatments with latest QIDS score of
1. After 6 acute infusion sessions, she was tapered to once per week, then once per 10 days, once per 2 weeks and then to a once
every three week schedule before discontinuing. The patient continued to report improvements. The literature on intravenous
ketamine infusions has shown effectiveness in reducing depressive symptoms in cases of TRD. The patient presented in this study
demonstrates promise of the use of ketamine in late life depression patients. This case also highlights that ketamine can be an
alternative option for elderly patients with TRD who do not qualify for ECT. Within the geriatric population, comorbid medical
conditions and polypharmacy may increase the chance of morbidity and mortality. Ketamine infusions at a low dose must be
monitored closely over a course of time. Therefore, ketamine infusions should only be administered to TRD patients in facilities
where appropriate medical monitoring can occur. Geriatric patients who are given ketamine infusions should be assessed for the
development of dependency, and addiction given its abuse potential. Further research on this novel therapy will yield greater
knowledge of how to best utilize ketamine infusions in geriatric patients.
Conclusions: The literature on intravenous ketamine infusions has shown effectiveness in reducing depressive symptoms in cases of
TRD. Similarly, our patient had a decline in depressive symptoms and a positive outcome. The case highlights that ketamine can be
used as an alternative for the TRD population that may not qualify for ECT. Within the geriatric population, comorbid pathology
and poly-pharmacy increase the chance of morbidity and mortality. Ketamine infusions at a low dose can be a potential treatment if
monitored closely over a course of time. Therefore, ketamine infusions offer a safe and effective alternative option for TRD patients
in psychiatric facilities where close monitoring can occur. Patients on ketamine treatments should be continually monitored for
addiction potential and adverse effects to ketamine infusions, none of which were seen with our current patient. Further research on
this novel therapy will yield greater knowledge of how to best utilize ketamine infusions for the general population and more
specifically for the geriatric subset that encompasses the majority of TRD patients.

___________________________________________________________________________________

Exploring Ketamine Use in Geriatric Patients Suffering From Treatment-Resistant Depression

Introduction: Ketamine is a glutamate NMDA receptor antagonist and is commonly used as an anesthetic. Low-dose
subanesthetic intravenous ketamine is fairly new and an increasingly popular treatment for treatment-resistant depression
(TRD) in the adult population; however, there is a scarcity of evidence of ketamine’s use among geriatric patients. Previously,
psychotropics and electroconvulsive therapy (ECT) have been used in the geriatric TRD population. Ketamine provides a
possible new treatment modality for those patients concerned with ECT-induced cognitive effects and may also allow for use in
patients with significant cardiovascular co-morbidities, who would likely not quality for ECT.
Methods: We provide a literature review on the use of ketamine for TRD in the geriatric population.
Results: Studies and case series have shown the use of ketamine as a monotherapy and augmented therapy with
electroconvulsive therapy in the adult and geriatric population. Literature supports efficacy with monotherapy and questionable
benefit from augmentative therapy. Dosing ranges from 0.2 mg/kg to 0.5 mg/kg, with evidence showing remittance with
ketamine dosing less than 0.5 mg/kg. Some studies have shown cognitive protection as compared to other TRD treatment
modalities, while the majority of studies have not thoroughly analyzed systemic adverse risk profiles including cognitive and
cardiovascular effects.

Conclusions: There is evidence in the literature for the use of intravenous ketamine in the TRD geriatric population. Larger
randomized control trials are needed to provided guidance regarding dosing, cognitive and systemic effects, and treatment
response.

USe of Ketamine in agitated delirium in the ELderly:

Treatment of Behavior Disturbances with Ketamine in a Patient Diagnosed with Major Neurocognitive Disorder

Ketamine has been shown to be beneficial for some
depressed patients, but it is not known whether it could
be beneficial for agitated demented patients who are
not depressed.

_____________________________________________________

Augmentation of response and remission to serial intravenous ketamine in TRD

Background: Ketamine has been showing high efficacy and rapid antidepressant effect. However, studies of ketamine infusion wash subjects out from prior antidepressants, which may be impractical in routine practice. In this study, we determined antidepressant response and remission to six consecutive ketamine infusions while maintaining stable doses of antidepressant regimen. We also examined thetrajectory of response and remission, and the time to relapse among responders.

Methods: TRD subjects had at least 2-month period of stable dose of antidepressants. Subjects completed
six IV infusions of 0.5 mg/kg ketamine over 40 min on a Monday–Wednesday–Friday schedule during a
12-day period participants meeting response criteria were monitored for relapse for 4 weeks

.
Results: Fourteen subjects were enrolled. Out of twelve subjects who completed all six infusions, eleven(91.6%) achieved response criterion while eight (66.6%) remitted. After the first infusion, only three andone out of twelve subjects responded and remitted, respectively. Four achieved response and sixremitted after 3 or more infusions. Five out of eleven subjects remain in response status throughout the 4weeks of follow-up. The mean time for six subjects who relapsed was 16 days.Limitations: Small sample and lack of a placebo group limits the interpretation of efficacy.

Conclusions: Safety and efficacy of repeated ketamine infusions were attained without medication-free state in patients with TRD. Repeated infusions achieved superior antidepressant outcomes as compared to a single infusion with different trajectories of response and remission. Future studies are needed to elucidate neural circuits involved in treatment response to ketamine.

 

_____________________________________________________

Why Treat Depression besides feeling better? It is associated with increased risk of DEATH:

Anxiety, Depression Linked With Higher Cardiovascular Risk

Adults with mood disorders like anxiety and depression may be more likely to have a heart attack or stroke than people without mental illness, a new study suggests.

Researchers enrolled 221,677 people age 45 and older without any history of heart attack or stroke and tracked them for an average of nearly five years.

More than 90% of participants were ages 45 to 79. In this age group, compared to men without mental health issues at the start, men with moderate psychological distress were 28% more likely to have a heart attack during the study and 20% more likely to have a stroke. Men in this age group with high levels of distress were 60% more likely to have a heart attack and 44% more likely to have a stroke.

Women ages 45 to 79 with moderate psychological problems were 12% more likely to have a heart attack and 28% more likely to have a stroke than women without any mental distress. Women with high psychological distress were 24% more likely to have a heart attack and 68% more likely to have a stroke.

“The stronger association between psychological distress and heart attack in men compared to women could be due to women being more likely than men to seek primary care for mental and physical health problems, thus partly negating the possible physical effects of mental health problems,” said lead study author Caroline Jackson of the University of Edinburgh in the U.K.

“Alternatively, it could reflect the known hormonal protection against heart disease in women since the study population included a large number of younger women,” Jackson said by email. “We did however find a strong association between psychological distress and stroke in women, perhaps suggesting different mechanisms exist between psychological distress and different types of cardiovascular disease in women.”

Overall, the study participants suffered 4,573 heart attacks and 2,421 strokes.

The study wasn’t designed to prove whether or how depression or anxiety might directly cause heart attacks or strokes, researchers note in Circulation: Cardiovascular Quality Outcomes.

Another limitation is that researchers assessed psychological factors at a single point in time, making it impossible to know if worsening cardiovascular health contributed to mood disorders or if mental illness caused heart problems.

However, it’s possible that lifestyle factors like poor eating and exercise habits, smoking, or inactivity might independently influence both the risk of mental health problems and heart issues, the study authors note.

“It is also possible that symptoms of depression or anxiety directly affect the body’s physiology through mechanisms such as hormonal pathways, inflammatory processes in arteries and increased risk of blood clotting,” Jackson said. “It is vital that further research seeks to identify the underlying mechanisms so that we can better understand the link between mental health and subsequent physical health and inform intervention strategies.”

Researchers assessed psychological distress using a standard set of questions designed to reveal symptoms of mood disorders. The questions asked, for example, how often people felt tired for no reason, how often they felt restless or fidgety, and how frequently they felt so sad that nothing could cheer them up.

Overall, about 16% of the study participants had moderate psychological distress and roughly 7% had high or very high levels of mental distress.

SOURCE: http://bit.ly/2PfAJjd    Psychological Distress and Risk of Myocardial Infarction and Stroke in the 45 and Up Study

Psychological Distress and Risk of MI and stroke in the 45 and up study

 

Circulation: Cardiovascular Quality and Outcomes 2018.

________________________________________________

Psychological distress, physical illness, and risk of coronary heart disease 2005

depressed-patients-likely-experience-mi-stroke

 

Resistance Training Reduces Depressive Symptoms

Weightlifting and muscle training significantly reduced depressive symptoms among adults regardless of their age and health status, the amount of training, and whether they grew stronger, researchers found in a meta-analysis.

The study, published online in JAMA Psychiatry, spanned 33 randomized clinical trials with more than 1800 participants.

The best improvement appeared to be in participants with mild or moderate depression, suggesting resistance training could be an alternative or add-on treatment option.

Trivia: How Much Exercise Is Needed to Prevent Depression?

“For general feelings of depression and the beginning phases of major depression, antidepressants and medications may not be very effective. There also is a shift toward finding options that do not require someone to start a drug regimen they may be on for the rest of their lives,” said researcher Jacob Meyer, PhD, assistant professor of kinesiology at Iowa State University in Ames.

“Understanding that resistance training appears to have similar benefits to aerobic exercise may help those wading through daunting traditional medication treatment options.”

The meta-analysis did identify smaller reductions in depressive symptoms in randomized clinical trials with blinded allocation or assessment. Better quality trials that compare resistance training with other proven treatments for depression are needed, researchers advised.

—Jolynn Tumolo

References

Gordon BR, McDowell CP, Hallgren M, Meyer JD, Lyons M, Herring MP. Association of efficacy of resistance exercise training with depressive symptoms. JAMA Psychiatry. 2018 May 9;[Epub ahead of print].

Motivation to move may start with being mindful [press release]. Ames, Iowa: Iowa State University; May 14, 2018.

Resistance exercise training may reduce symptoms of depression. Psychiatric News Alert. May 15, 2018.

__________________________________

Neurologic Changes and Depression

KEY POINTS
 The assessment of late-life depression with comorbid cognitive impairment can be challenging and requires a clear clinical history and a thorough medical and cognitive assessment.

 There are several neuropsychological changes associated with late-life depression, ranging from subjective cognitive complaints to mild cognitive impairment to dementia.

 Changes on neuroimaging and in several biomarkers (eg, apolipoprotein E e4 allele, beta amyloid, tau, neurotrophins, and so forth) have been associated with late-life depression.

 Multiple psychotherapeutic techniques have been found effective in the treatment of late life depression as well as holistic/nontraditional, pharmacologic, and brain-stimulation
approaches.

______________________________________________________

Why Does Ketamine Work?

Ketamine and Ketamine Metabolite Pharmacology Insights into Therapeutic Mechanisms.

Abstract

Ketamine, a racemic mixture consisting of (S)- and (R)-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine’s pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of N-methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

Mechanisms of ketamine action as an antidepressant.

Ketamine administration during a critical period after forced ethanol abstinence inhibits the development of time-dependent affective disturbances.

Article Link::

Ketamine administration during a critical period after forced ethanol abstinence inhibits the development of time-dependent affective disturbances

We find
that ketamine prevents the development of affective disturbances
when administered at the onset of forced abstinence, and not
shortly thereafter (2–6 days).Studies suggest that the GluN2B subunit of the N- methyl- Daspartate
(NMDA) receptor participates in regulating affect and in
the antidepressant actions of ketamine [9, 14, 16]. Chronic ethanol
administration and early withdrawal increase expression of
GluN2B in several brain areas, particularly within the central
nucleus of the amygdala and bed nucleus of the stria terminalis
(BNST) [17], both of which are heavily involved in regulating affect
[18–21]. Previously, we found that knockdown of GluN2B-within
the BNST produces antidepressant-like actions similar to ketamine
[22] and that GluN2B is necessary for long-term potentiation (LTP) within the BNST [23]. Furthermore, we have previously shown that
non-contingent chronic intermittent ethanol enhances LTP within
the BNST which is dependent on the GluN2B subunit [23].
However, no studies have looked at LTP within the BNST during
withdrawal after contingent 2-bottle choice ethanol drinking. Here
we show that withdrawal from 2BC ethanol drinking decreases the
early component of LTP within the BNST. Further, administration
of ketamine at the onset of forced abstinence, but not shortly
thereafter (2–6 days) facilitated later LTP induction.

Ketamine administered at the onset of
abstinence, but not 6 days later rescued the STP deficit and overall increased the capacity for plasticity within the BNST. Our results suggest, for the first time to our knowledge, that ketamine may need to be administered at a specific time point during abstinence in order to effectively treat and manage alcohol use dependent affective disturbances. These data thus suggest a “critical period” during which ketamine is effective in preventing the development of alcohol abstinence induced affective
disturbances.

_____________________________________________________________

Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive-Like Behavior During Forced Abstinence From Alcohol Drinking

Introduction: Ketamine has emerged as a safe and effective treatment option for treatment refractory depression (TRD) and
suicidal ideation. Electroconvulsive therapy (ECT) is a well established treatment for refractory depression, but this treatment is often deferred or terminated before response due tolerability or medical concerns.
Methods: We present a case series of TRD patients who were unable to receive ECT and offered intravenous ketamine at a dose
of 0.5 mg/kg infused over the course of forty minutes for up 3 treatment sessions within two weeks. Most of these patients
were hospitalized older patients with sufficient medical conditions that increased ECT risks.

Results: Ketamine appears to be a safe and effective alternative for these patients, leading to resolution of suicidality, adherence
to antidepressant treatment, and prompt hospital discharge.

Conclusions: In conclusion, for TRD patients unable to undergo ECT, availability of intravenous ketamine, as an adjunct to
an ECT service, can not only avert the prospect of a prolonged and costly course of hospitalization, but also quickly improve
patients’ quality of life.

___________________________________________

Why magnesium is important in treating depression:

Magnesium for treatment-resistant depression A review and hypothesis

Sixty percent of cases of clinical depression are considered to be treatment-resistant depression (TRD). Magnesium-deficiency causes N-methyl-D-aspartate (NMDA) coupled calcium channels to be biased towards opening, causing neuronal injury and neurological dysfunction, which may appear to humans as major depression. Oral administration of magnesium to animals led to anti-depressant-like effects that were comparable to those of strong anti-depressant drugs. Cerebral spinal fluid (CSF) magnesium has been found low in treatment-resistant suicidal depression and in patients that have attempted suicide. Brain magnesium has been found low in TRD using phosphorous nuclear magnetic resonance spectroscopy, an accurate means for measuring brain magnesium. Blood and CSF magnesium do not appear well correlated with major depression. Although the first report of magnesium treatment for agitated depression was published in 1921 showing success in 220 out of 250 cases, and there are modern case reports showing rapid terminating of TRD, only a few modern clinical trials were found. A 2008 randomized clinical trial showed that magnesium was as effective as the tricyclic anti-depressant imipramine in treating depression in diabetics and without any of the side effects of imipramine. Intravenous and oral magnesium in specific protocols have been reported to rapidly terminate TRD safely and without side effects. Magnesium has been largely removed from processed foods, potentially harming the brain. Calcium, glutamate and aspartate are common food additives that may worsen affective disorders. We hypothesize that – when taken together – there is more than sufficient evidence to implicate inadequate dietary magnesium as the main cause of TRD, and that physicians should prescribe magnesium for TRD. Since inadequate brain magnesium appears to reduce serotonin levels, and since anti-depressants have been shown to have the action of raising brain magnesium, we further hypothesize that magnesium treatment will be found beneficial for nearly all depressives, not only TRD.

___________________________________________________________________

Does oral administration of ketamine accelerate response to treatment in MDD

Conclusion:

Altogether, our results suggest that oral ketamine may be considered as suitable adjuvant to sertraline
in relieving depressive symptoms.

Patients received sertraline (150 mg a day). As an adjuvant, they
received either 50 mg/day ketamine or placebo. Formulation of ketamine capsules used in this study is delineated elsewhere. Different doses of oral ketamine have been used in previous studies; a number of studies have used a fixed dose 0.5 mg/kg or 150 mg/day (Irwin et al., 2013; Jafarinia et al., 2016) whereas others titrated the drug in a rangefrom 0.5 mg/kg to 0.7 mg/kg or 25–300 mg/day (Al Shirawi et al., 2017; Hartberg et al., 2017). The frequency of administration also varies from once daily usage to three times a day (Irwin et al., 2013;
Jafarinia et al., 2016). For IV administration, previous trials recommendan injection once every two or three days (Andrade, 2017).
Here, we used ketamine as an adjuvant and thus a fixed low dose was chosen to minimize adverse effects. Sertraline was initiated at 25 mg/day and increased by 25 mg every three days. The maximum dose reached 150 mg. Ketamine prescription started with initial dose ofsertraline and was prescribed at 25 mg twice daily. During the course of the trial, patients were not allowed to participate in psychotherapeutic sessions or receive any other medication, such as other antidepressants, anxiolytics or hypnotics. They were followed for six weeks and were asked to inform their therapist in case they experienced any adverse effects. Vital signs were recorded and physical examination was performed at the screening session and at each of the post-baseline visits. Upon high clinical suspicion for cardiovascular disease, electrocardiogram monitoring was performed and positive findings were excluded.