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NOVA Health Recovery | Alexandria, Va 22306 | Call for esketamine and nasal ketamine as well as IV Ketamine for depression, PTSD, anxiety  703-844-0184 < Link

Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

From Popular Anesthetic to Antidepressant, Ketamine Isn’t the Drug You Think It Is

An hour before we spoke, Darragh O’Carroll, an emergency room physician from Hawaii, had just given an elderly patient a sedating shot of ketamine. The man had pneumonia and was acting confused and fidgety, making him hard to treat.

“Not only it was a pain control for him when I was putting needles into his neck, but it also kept him still,” O’Carroll says. “And with very minimal risk of lowering his blood pressure.”

Ketamine’s use as an anesthetic — and not as a party drug — is widespread, though not commonly known. In fact, the World Health Organizationestimates ketamine is the most widely used anesthetic in the world and keeps it on their list of essential medicines, a category of drugs that all developed countries should have on hand.

O’Carroll has described ketamine as his “favorite medicine of all time” in an article for Tonic, not only because the anesthetic is incredibly safe and effective, but also because of its versatility. It’s most widely used in surgery, but could also help treat severe asthma, chronic pain, and may even possess anti-tumor properties. In the last two decades, ketamine has also emerged as a potent antidepressant, able to treat symptoms of some mental illnesses in less than 72 hours.

“I think the more research that goes into ketamine, the more uses that we find for it,” O’Carroll says.

From PCP to Painkiller

Ketamine’s story begins with a drug called PCP. Yes, that PCP — phencyclidine or so-called “angel dust,” a drug that when smoked can cause a trance-like state, agitation and out-of-body hallucinations. After it was first synthesized by medicinal chemist Victor Maddox in 1956, the drug was briefly approved as an anesthetic by the FDA for its sedative properties. In tests with a wild rhesus monkey, for example, researchers put their fingers in the previously aggressive animal’s mouth and watched its jaw remain slack.

But while it was safe and effective for pain relief, the side effects of PCP soon became too obvious to ignore.

Some patients under the influence of PCP would feel like they lost their arms or legs or that they were floating in space. It could also cause seizures and delirium. Scientists began seeking a shorter-acting anesthetic without convulsant properties. In 1962, chemistry professor Calvin Stevens discovered a PCP analogue that fit the bill: ketamine.

Ketamine is a potent, sedating painkiller that can cause amnesia and is mostly used in surgery and veterinary medicine. During the Vietnam Invasion, ketamine saw widespread use in the U.S. military because it has several advantages over opioids. First, unlike morphine, ketamine doesn’t suppress blood pressure or breathing. It also doesn’t need to be refrigerated, making it useful in the field or in rural areas that don’t have access to electricity.

Ketamine’s benefits extend beyond use as an anesthetic, though — in some cases it can serve as a balm for the mind as well. A 2008 analysis found that burn victims who were given ketamine were less likely to develop symptoms of post-traumatic stress disorder, even if their injuries were more severe. Those findings have been replicated, such as a 2014 clinical trial of 41 patients, who saw their PTSD symptoms diminish within 24 hours, an effect that lasted for two weeks.

“When somebody gets one of their limbs dramatically blown off or is shot in the face, it’s a very traumatic event,” O’Carroll says. In such a situation, giving ketamine not only provides instant pain relief, it could prevent long-lasting trauma.

Because its chemical structure is so similar to PCP, ketamine can still give lucid hallucinations, such as feeling that your mind has separated from the body — a dissociative state users sometimes call a “K-hole.” One recent study based on users’ written reports even indicated that this kind of experience might be a close analogue to a near-death experience. However, these dissociative states only happen at high doses — the amount of ketamine used to for surgery and to treat depression is typically much lower.

But ketamine’s side effects are less common and easier to manage than PCP. In fact, ketamine is one of the safest drugs used in medicine today and can even be given to young children. For example, ketamine was used to sedatethe boys’ soccer team trapped in a cave in Thailand last year. Putting the kids in a tranquilized state made it easier to rescue them, and ketamine is safer than the opioids or benzodiazepines that are also commonly used as sedatives.  

Ketamine as Antidepressant

But it wasn’t until the 1990s that what could turn out to be ketamine’s most important function was discovered. A team from Yale University School of Medicine was examining the role of glutamate, a common neurotransmitter, in depression, and discovered something remarkable: ketamine could rapidly relieve depression symptoms.

“To our surprise, the patients started saying, they were better in a few hours,” Dennis Charney, one of the researchers, told Bloomberg. This rapid relief was unheard of in psychiatry.

Glutamate is associated with neural plasticity, our brain’s ability to adapt and change at the level of the neuron. Ketamine blocks certain glutamate receptors, but not others, and the end effect could be to promote the growth of new neurons while protecting old ones. This could explain how ketamine can help reset the brain, though the theory hasn’t yet been definitively proven.

The prescription meds currently on the market for depression have some major drawbacks. Drugs like Prozac or Wellbutrin can take a few weeks or months to kick in while worsening symptoms in the short term — not a good combination, especially for someone who is extremely depressed, or even suicidal.

It took around a decade for mainstream science to take notice of these early ketamine-depression studies. But once it did, ketamine clinics began popping up all across North America, offering fast relief for depression, anxiety and other mental illnesses. Patients are given an infusion — an IV drip that lasts about an hour — and many people, but not everyone, have seen rapid relief of their symptoms.

Suddenly, ketamine infusions became trendy, though the science to back up some of the medical claims is still inconclusive, according to STAT. However, ketamine infusions are rarely covered by insurance, although that is changing. A typical session can run $700, with many patients taking six sessions or more. But many of these patients have so-called treatment-resistant depression. They’ve tried other medications or therapies without success and some see ketamine as a last resort.

Steven Mandel, a clinical psychologist and anesthesiologist, has used ketamine on patients since it first came on the market around 50 years ago. In 2014, he began using it for patients with depression and opened Ketamine Clinics of Los Angeles, one of the oldest and largest clinics in the country. They’ve done over 8,000 infusions so far.

“Our success rate is better than 83 percent,” Mandel says. For his clinic, success means a 50 percent improvement of depression symptoms for longer than three months.

Ketamine’s success as an antidepressant couldn’t help but attract the attention of major pharmaceutical companies as well. In 2009, Johnson & Johnson began developing their own version of the drug they called esketamine. Rather than an infusion through a vein, it’s dispensed through a nasal spray. The FDA approved their formulation in early March. It was thefirst drug in 35 years to fight depression using a different approach than traditional drugs.

“Esketamine is a giant step forward,” Mandel says. “It means we’re not going to be demonizing mind-altering substances used for therapeutic purposes. It opens the door to research on LSD, on psilocybin, on MDMA and many other agents that could possibly relieve a great deal of suffering.”

But many clinicians have raised concerns about long-term side effects, such as heart and bladder toxicity. Others have been critical of esketamine, saying there isn’t enough data yet to suggest the drug is safe or effective. Husseini Manji, a neuroscientist who helped develop the drug for Johnson & Johnson at their subsidiary Janssen, has pushed back against these claims.

“When you line up the totality of the studies, it was really an overwhelming amount of data that was all in the same direction,” Manji says in a call. Though just two of the five late-state clinical trials showed significant results, the changes in mood in the three that fell short were “almost identical in magnitude” to the others, Manji says. It was enough for the drug to meet standards for FDA approval.

We can probably expect other ketamine-related drugs to come to market soon. ATAI Life Sciences, a company funding research on the use of magic mushrooms for depression, is developing their own ketamine depression drug. The pharmaceutical company Allergan also developed rapastinel, another ketamine-like drug, though it failed to show any real benefits for patients in later trials. Manji says this is unfortunate for people who could be helped by these kinds of drugs.

“From a patient standpoint, we were hoping it would work,” he says, even though he was not involved in rapastinel’s development. “But sometimes if you really haven’t got the mechanism right and you haven’t really threaded the needle, then sometimes you don’t see these results.”

Drug of Abuse?

Even though ketamine’s medical uses are well-established, most people have only heard of ketamine in the context of a party drug. Because of this bad reputation — and what’s perceived as growing misuse of the drug — several countries, such as China and the UK, have tried to place greater restrictions on ketamine. This would make it harder to study and more expensive in clinical use.

“If it was to ever be rescheduled, places that would be first affected would be you know places that need it most,” O’Carroll says. The WHO has asked at least four times for countries to keep access to ketamine open. “The medical benefits of ketamine far outweigh potential harm from recreational use,” Marie-Paule Kieny, assistant director general for Health Systems and Innovation at WHO, said in 2015.

So far, no countries have put greater restrictions on ketamine, and that’s probably a good thing. Ketamine has a rich history, but its future is still being written.



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Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

VA to offer new ketamine-based nasal spray to help combat depression

The newest FDA-approved medication to treat severe depression, a nasal spray based on the anesthetic (and misused hallucinogenic party drug) ketamine, will soon be available to veterans treated within the Department of Veterans Affairs.

In a move that may help thousands of former service members with depression that has not improved with other treatments, VA officials announced Tuesday that the department’s doctors are now authorized to prescribe Spravato, the brand name for esketamine, a molecular variation of ketamine.

The decision to offer a drug hailed by many as a breakthrough in treatment for its speedy results — often relieving symptoms in hours and days, not weeks — shows the VA’s “commitment to seek new ways to provide the best health care available for our nation’s veterans,” Secretary Robert Wilkie said in a release.

“We’re pleased to be able to expand options for Veterans with depression who have not responded to other treatments,” Wilkie added.

The treatment will be available to veterans based on a physician’s assessment and only will be administered to patients who have tried at least two antidepressant medications and continue to have symptoms of major depressive disorder.

An estimated 16 million Americans have had at least one major episode of depression, and of those, 1 in 3 are considered treatment-resistant. In the veteran population of 20 million, the estimated diagnosis rate of depression is 14 percent — up to 2.8 million veterans. Between one-third and half of those veterans may be treatment-resistant.

The lack of effective medications for difficult-to-treat patients prompted the Food and Drug Administration to place esketamine on a fast track, expediting its review of the drug to ensure that it went to patent as soon as safely possible, according to administration officials.

“Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process, including a robust discussion with our external advisory committees, were important in our decision to approve this treatment,” said Dr. Tiffany Farchione, acting director of the FDA’s Center for Drug Evaluation and Research Division of Psychiatry Products, in a release.

As with any other medication, there are risks. Spravato carries a boxed warning for side effects that include misuse, the reason it is administered under a doctor’s supervision. The list of side effects includes sedation and blood pressure spikes and disassociation, such as feelings of physical paralysis and out-of-body experiences. It also can cause suicidal thoughts and behaviors.

Acknowledging the dangers, FDA made esketamine available only through a restricted distribution system.

A veteran prescribed Spravato would inhale the nasal spray at a medical facility while under supervision of a medical provider, and would be monitored for at least two hours after receiving the dose. A typical prescription includes twice-weekly doses the first month, followed by a single dose weekly or biweekly as needed. Spravato cannot be dispensed for home use.

Spravato is made by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. It is the first major antidepressant medication to hit the market in 30 years.



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VA uses ketamine to treat PTSD effectively

The San Francisco Veterans Affairs Medical Center is administering ketamine to veterans with post-traumatic stress disorder and depression.

Tobias Marton, the director of the ketamine infusion program at the center, said that since the program first launched two years ago, they have treated about 40 patients who had virtually exhausted all other options.

“They’ve done everything we’ve asked them to do and they remain with very severe symptoms and with a poor or impaired quality of life,” he said. “Despite (past treatments), there remains a high risk of suicide (with some veterans).”

While it was not clear where the 40 patients are from, the option is something that is available to Humboldt County veterans who are suffering from PTSD or depression.

Marton said that in general, about a third of people diagnosed with depression don’t respond to first, second and third lines of treatment.

In contrast, ketamine infusion has yielded “impressive outcomes.”

Many people know of ketamine as a party drug, often referred to as Special K, but it is mainly used medically for anesthesia or pain treatment.

Miracle of medicine

“We know ketamine has rapid and powerful anti-suicide properties,” he said. “To have another tool, a potentially powerful tool to have an impact on suicide rates is really exciting.”

While Marton is proceeding with “cautious optimism,” Boris Nikolov, the CEO of Neurosciences Medical Clinic in Miami, Florida, which has a ketamine clinic, believes the application might be a medical breakthrough.

It’s one of the greatest discoveries in the field of depression,” he said. “This is one of the miracles in medicine.

Nikolov’s clinic has treated 120 patients with ketamine, including his wife who has PTSD as a result of severe child abuse.

“Ketamine really helped her,” he said. “That was a really big part of her recovery.”

Nikolov said most medicines that treat depression take from two to four weeks to start working. Ketamine begins working within hours after it is administered, a process which usually involves an IV infusion over the course of about an hour.

“What’s most important is the strong and fast effect of ketamine in patients who are very seriously depressed, or want to hurt themselves,” he said. “When they finish treatment, they’re totally different people. There is no other medication that does that.”

Brad Burge, the director of strategic communication at the Multidisciplinary Association for Psychedelic Studies, or MAPS, said there has been “an explosion of treatment that’s outpaced research.”

“It means that people are going to have another option, an alternative to conventional medications,” he said.

According to Burge, MAPS believes the best form of ketamine infusion involves pairing with other forms of psychotherapy such as group or individual counseling.

Ketamine availability

While ketamine is an FDA-approved drug which has been used as an anesthetic as well as a pain reliever, it isn’t officially sanctioned by the FDA to be used for treating mental health disorders. However, Marton said that ketamine has been administered in this fashion for over 18 years now.

A company is currently in the process of trying to get an intranasal product approved by the FDA which would administer ketamine through the nasal passage, according to Marton. He expects the FDA’s decision to be announced sometime around March 2019.

If the product is approved, he said, VA clinics in rural communities like the one in Eureka would likely be able to start offering ketamine treatments as well.

For now, only the location in San Francisco is able to offer the treatment, but Marton said anyone within their service realm, which includes Humboldt County, is invited to consult with the VA about seeking treatment.

“We want to be as thoughtful as we can,” he said. “As we understand more about it … (we) might be able to start helping people who we haven’t been able to help despite throwing everything we have at them.”

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New Drug Combo Shows Promise for Treatment of Depression and Addiction

Drug Combo Shows Promise for Depression and Addiction
Ketamine Treatment for alcoholism | Call 703-844-0184 | Alexandria, Va 22306 | NOVA Health Recovery

The combination of naltrexone and ketamine can help treat both symptoms of addiction and depression, a preliminary study by Yale University researchers suggests.

Substance abuse and depression are common in many patients, and efforts to treat both conditions simultaneously have had limited success. One recent study suggested that the antidepressant effects of ketamine might blunted by administration of naltrexone, used to limit cravings of those addicted to opioid drugs and alcohol.

A preliminary study of five patients suffering from both depression and substance abuse disorders suggest that isn’t the case. The study was published Jan. 9 in the journal JAMA Psychiatry.

The results “raise the possibility that for people who have depression complicated by substance abuse disorders, the combination of ketamine and naltrexone may be a strategy to explore in the effort to optimally treat both conditions,” said senior author John Krystal, Yale’s Robert L. McNeil Jr. Professor of Translational Research; professor of psychiatry, neuroscience, and psychology; and chair of the Department of Psychiatry.

Krystal and lead author Gihyun Yoon, assistant professor of psychiatry, treated the five patients suffering from depression and alcohol use disorder with a long-lasting form of naltrexone and then administered ketamine. Four of the five responded to the first ketamine dose and all five found relief from depression after multiple doses.

The study also challenges the idea that ketamine might produce antidepressant effects by stimulating opiate receptors.

Krystal cautioned that larger studies are needed to confirm beneficial effects of the combination treatment.

Krystal and Yoon have provisional patents on the use of ketamine and naltrexone to treat comorbid depression and substance abuse.

The study was primarily funded by the U.S. Department of Veterans Affairs.

Publication: Gihyun Yoon, et al., “Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder,” JAMA Psychiatry, 2019; doi:10.1001/jamapsychiatry.2018.3990

At NOVA Health Recovery, we do use Ketamine and other combinations to treat Alcoholism and Opioid and Pain pill addiction using Ketamine Treatment. Dr. Sendi is Board Certified in Addiction Medicine. Call 703-844-0184 Today. Fairfax, Va 22304.



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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:

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.

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.

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.

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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Ketamine and Psychedelic Drugs Change Structure of Neurons

ummary: A new study reveals psychedelics increase dendrites, dendritic spines and synapses, while ketamine may promote neuroplasticity. The findings could help develop new treatments for anxiety, depression and other related disorders.

Source: UC Davis.

A team of scientists at the University of California, Davis is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety, and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

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Fairfax | NOVA Ketamine IV Ketamine for depression | Fairfax, Va 22306 | 703-844-0184

Ketamine and Psychedelic Drugs Change Structure of Neurons

Summary: A new study reveals psychedelics increase dendrites, dendritic spines and synapses, while ketamine may promote neuroplasticity. The findings could help develop new treatments for anxiety, depression and other related disorders.

Source: UC Davis.

A team of scientists at the University of California, Davis is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety, and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

image shows neurons under psychedelics and ketamine

Psychedelic drugs such as LSD and ayahuasca change the structure of nerve cells, causing them to sprout more branches and spines, UC Davis researchers have found. This could help in “rewiring” the brain to treat depression and other disorders. In this false-colored image, the rainbow-colored cell was treated with LSD compared to a control cell in blue. NeuroscienceNews.com image is credited to Calvin and Joanne Ly.

Behavioral studies also hint at the similarities between psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder (PTSD), and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.

These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.

“Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives,” Olson said.

 

Psychedelic drugs, ketamine change structure of neurons

Psychedelic drugs, ketamine change structure of neurons

Psychedelics as Possible Treatments for Depression and PTSD

A team of scientists at the University of California, Davis, is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety and related disorders.

In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines) and the number of connections between neurons (synapses). These structural changes could suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

Behavioral studies also hint at the similarities between psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder, or PTSD, and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.

These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.

“Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives,” Olson said.

Additional co-authors on the Cell Reports “Psychedelics Promote Structural and Functional Neural Plasticity.” study are Calvin Ly, Alexandra Greb, Sina Soltanzadeh Zarandi, Lindsay Cameron, Jonathon Wong, Eden Barragan, Paige Wilson, Michael Paddy, Kassandra Ori-McKinney, Kyle Burbach, Megan Dennis, Alexander Sood, Whitney Duim, Kimberley McAllister and John Gray.

Olson and Cameron were co-authors on the ACS Chemical Neuroscience paper along with Charlie Benson and Lee Dunlap.

The work was partly supported by grants from the National Institutes of Health.

Psychedelics Promote Structural and Functional
Neural Plasticity

Below is the Intro and Discussion for the article:

Psychedelics Promote Structural and Functional neural Plasticity

Authors:

Calvin Ly, Alexandra C. Greb,
Lindsay P. Cameron, …,
Kassandra M. Ori-McKenney,
John A. Gray, David E. Olson
Correspondence
deolson@ucdavis.edu

In Brief
Ly et al. demonstrate that psychedelic
compounds such as LSD, DMT, and DOI
increase dendritic arbor complexity,
promote dendritic spine growth, and
stimulate synapse formation. These
cellular effects are similar to those
produced by the fast-acting
antidepressant ketamine and highlight
the potential of psychedelics for treating
depression and related disorders.

  • Highlights
     Serotonergic psychedelics increase neuritogenesis,
    spinogenesis, and synaptogenesis
  •  Psychedelics promote plasticity via an evolutionarily
    conserved mechanism
  •  TrkB, mTOR, and 5-HT2A signaling underlie psychedelicinduced
    plasticity
  •  Noribogaine, but not ibogaine, is capable of promoting
    structural neural plasticity

SUMMARY
Atrophy of neurons in the prefrontal cortex (PFC)
plays a key role in the pathophysiology of depression
and related disorders. The ability to promote
both structural and functional plasticity in the PFC
has been hypothesized to underlie the fast-acting
antidepressant properties of the dissociative anesthetic
ketamine. Here, we report that, like ketamine,
serotonergic psychedelics are capable of robustly
increasing neuritogenesis and/or spinogenesis both
in vitro and in vivo. These changes in neuronal structure
are accompanied by increased synapse number
and function, as measured by fluorescence microscopy
and electrophysiology. The structural changes
induced by psychedelics appear to result from stimulation
of the TrkB, mTOR, and 5-HT2A signaling
pathways and could possibly explain the clinical
effectiveness of these compounds. Our results underscore
the therapeutic potential of psychedelics
and, importantly, identify several lead scaffolds for
medicinal chemistry efforts focused on developing
plasticity-promoting compounds as safe, effective,
and fast-acting treatments for depression and
related disorders.

INTRODUCTION
Neuropsychiatric diseases, including mood and anxiety disorders,
are some of the leading causes of disability worldwide
and place an enormous economic burden on society (Gustavsson
et al., 2011; Whiteford et al., 2013). Approximately
one-third of patients will not respond to current antidepressant
drugs, and those who do will usually require at least 2–4 weeks
of treatment before they experience any beneficial effects
(Rush et al., 2006). Depression, post-traumatic stress disorder
(PTSD), and addiction share common neural circuitry (Arnsten,
2009; Russo et al., 2009; Peters et al., 2010; Russo and
Nestler, 2013) and have high comorbidity (Kelly and Daley,
2013). A preponderance of evidence from a combination of
human imaging, postmortem studies, and animal models suggests
that atrophy of neurons in the prefrontal cortex (PFC)
plays a key role in the pathophysiology of depression and
related disorders and is precipitated and/or exacerbated by
stress (Arnsten, 2009; Autry and Monteggia, 2012; Christoffel
et al., 2011; Duman and Aghajanian, 2012; Duman et al.,
2016; Izquierdo et al., 2006; Pittenger and Duman, 2008;
Qiao et al., 2016; Russo and Nestler, 2013). These structural
changes, such as the retraction of neurites, loss of dendritic
spines, and elimination of synapses, can potentially be counteracted
by compounds capable of promoting structural and
functional neural plasticity in the PFC (Castre´ n and Antila,
2017; Cramer et al., 2011; Duman, 2002; Hayley and Litteljohn,
2013; Kolb and Muhammad, 2014; Krystal et al., 2009;
Mathew et al., 2008), providing a general solution to treating
all of these related diseases. However, only a relatively small
number of compounds capable of promoting plasticity in the
PFC have been identified so far, each with significant drawbacks
(Castre´ n and Antila, 2017). Of these, the dissociative
anesthetic ketamine has shown the most promise, revitalizing
the field of molecular psychiatry in recent years.
Ketamine has demonstrated remarkable clinical potential as a
fast-acting antidepressant (Berman et al., 2000; Ionescu et al.,
2016; Zarate et al., 2012), even exhibiting efficacy in treatmentresistant
populations (DiazGranados et al., 2010; Murrough
et al., 2013; Zarate et al., 2006). Additionally, it has shown promise
for treating PTSD (Feder et al., 2014) and heroin addiction
(Krupitsky et al., 2002). Animal models suggest that its therapeutic
effects stem from its ability to promote the growth of dendritic
spines, increase the synthesis of synaptic proteins, and
strengthen synaptic responses (Autry et al., 2011; Browne and
Lucki, 2013; Li et al., 2010).

Like ketamine, serotonergic psychedelics and entactogens
have demonstrated rapid and long-lasting antidepressant and
anxiolytic effects in the clinic after a single dose (Bouso et al.,
2008; Carhart-Harris and Goodwin, 2017; Grob et al., 2011;
Mithoefer et al., 2013, 2016; Nichols et al., 2017; Sanches
et al., 2016; Oso´ rio et al., 2015), including in treatment-resistant
populations (Carhart-Harris et al., 2016, 2017; Mithoefer et al.,
2011; Oehen et al., 2013; Rucker et al., 2016). In fact, there
have been numerous clinical trials in the past 30 years examining
the therapeutic effects of these drugs (Dos Santos et al., 2016),
with 3,4-methylenedioxymethamphetamine (MDMA) recently
receiving the ‘‘breakthrough therapy’’ designation by the Food
and Drug Administration for treating PTSD. Furthermore, classical
psychedelics and entactogens produce antidepressant
and anxiolytic responses in rodent behavioral tests, such as
the forced swim test (Cameron et al., 2018) and fear extinction
learning (Cameron et al., 2018; Catlow et al., 2013; Young
et al., 2015), paradigms for which ketamine has also been shown
to be effective (Autry et al., 2011; Girgenti et al., 2017; Li et al.,
2010). Despite the promising antidepressant, anxiolytic, and
anti-addictive properties of serotonergic psychedelics, their
therapeutic mechanism of action remains poorly understood,
and concerns about safety have severely limited their clinical
usefulness.
Because of the similarities between classical serotonergic
psychedelics and ketamine in both preclinical models and clinical
studies, we reasoned that their therapeutic effects might
result from a shared ability to promote structural and functional
neural plasticity in cortical neurons. Here, we report that serotonergic
psychedelics and entactogens from a variety of chemical
classes (e.g., amphetamine, tryptamine, and ergoline) display
plasticity-promoting properties comparable to or greater than
ketamine. Like ketamine, these compounds stimulate structural
plasticity by activating the mammalian target of rapamycin
(mTOR). To classify the growing number of compounds capable
of rapidly promoting induced plasticity (Castre´ n and Antila,
2017), we introduce the term ‘‘psychoplastogen,’’ from the
Greek roots psych- (mind), -plast (molded), and -gen (producing).
Our work strengthens the growing body of literature indicating
that psychoplastogens capable of promoting plasticity
in the PFC might have value as fast-acting antidepressants
and anxiolytics with efficacy in treatment-resistant populations
and suggests that it may be possible to use classical psychedelics
as lead structures for identifying safer alternatives.

DISCUSSION
Classical serotonergic psychedelics are known to cause
changes in mood (Griffiths et al., 2006, 2008, 2011) and brain
function (Carhart-Harris et al., 2017) that persist long after the
acute effects of the drugs have subsided. Moreover, several
psychedelics elevate glutamate levels in the cortex (Nichols,
2004, 2016) and increase gene expression in vivo of the neurotrophin
BDNF as well as immediate-early genes associated with
plasticity (Martin et al., 2014; Nichols and Sanders-Bush, 2002;
Vaidya et al., 1997). This indirect evidence has led to the
reasonable hypothesis that psychedelics promote structural
and functional neural plasticity, although this assumption had
never been rigorously tested (Bogenschutz and Pommy,
2012; Vollenweider and Kometer, 2010). The data presented
here provide direct evidence for this hypothesis, demonstrating
that psychedelics cause both structural and functional changes
in cortical neurons.

Prior to this study, two reports suggested
that psychedelics might be able
to produce changes in neuronal structure.
Jones et al. (2009) demonstrated that DOI
was capable of transiently increasing the
size of dendritic spines on cortical neurons,
but no change in spine density was
observed. The second study showed
that DOI promoted neurite extension in a
cell line of neuronal lineage (Marinova
et al., 2017). Both of these reports utilized
DOI, a psychedelic of the amphetamine
class. Here we demonstrate that the ability
to change neuronal structure is not a
unique property of amphetamines like
DOI because psychedelics from the ergoline,
tryptamine, and iboga classes of compounds also promote
structural plasticity. Additionally, D-amphetamine does not increase
the complexity of cortical dendritic arbors in culture,
and therefore, these morphological changes cannot be simply
attributed to an increase in monoamine neurotransmission.
The identification of psychoplastogens belonging to distinct
chemical families is an important aspect of this work because
it suggests that ketamine is not unique in its ability to promote
structural and functional plasticity. In addition to ketamine, the
prototypical psychoplastogen, only a relatively small number of
plasticity-promoting small molecules have been identified previously.
Such compounds include the N-methyl-D-aspartate
(NMDA) receptor ligand GLYX-13 (i.e., rapastinel), the mGlu2/3
antagonist LY341495, the TrkB agonist 7,8-DHF, and the muscarinic
receptor antagonist scopolamine (Lepack et al., 2016; Castello
et al., 2014; Zeng et al., 2012; Voleti et al., 2013). We
observe that hallucinogens from four distinct structural classes
(i.e., tryptamine, amphetamine, ergoline, and iboga) are also
potent psychoplastogens, providing additional lead scaffolds
for medicinal chemistry efforts aimed at identifying neurotherapeutics.
Furthermore, our cellular assays revealed that several
of these compounds were more efficacious (e.g., MDMA) or more potent (e.g., LSD) than ketamine. In fact, the plasticity-promoting
properties of psychedelics and entactogens rivaled that
of BDNF (Figures 3A–3C and S3). The extreme potency of LSD
in particular might be due to slow off kinetics, as recently proposed
following the disclosure of the LSD-bound 5-HT2B crystal
structure (Wacker et al., 2017).
Importantly, the psychoplastogenic effects of psychedelics in
cortical cultures were also observed in vivo using both vertebrate
and invertebrate models, demonstrating that they act through an
evolutionarily conserved mechanism. Furthermore, the concentrations
of psychedelics utilized in our in vitro cell culture assays
were consistent with those reached in the brain following systemic
administration of therapeutic doses in rodents (Yang
et al., 2018; Cohen and Vogel, 1972). This suggests that neuritogenesis,
spinogenesis, and/or synaptogenesis assays performed
using cortical cultures might have value for identifying
psychoplastogens and fast-acting antidepressants. It should
be noted that our structural plasticity studies performed in vitro
utilized neurons exposed to psychedelics for extended periods
of time. Because brain exposure to these compounds is often
of short duration due to rapid metabolism, it will be interesting
to assess the kinetics of psychedelic-induced plasticity.
A key question in the field of psychedelic medicine has been
whether or not psychedelics promote changes in the density of
dendritic spines (Kyzar et al., 2017). Using super-resolution
SIM, we clearly demonstrate that psychedelics do, in fact, increase
the density of dendritic spines on cortical neurons, an effect
that is not restricted to a particular structural class of compounds.
Using DMT, we verified that cortical neuron spine
density increases in vivo and that these changes in structural
plasticity are accompanied by functional effects such as
increased amplitude and frequency of spontaneous EPSCs.

We specifically designed these experiments
to mimic previous studies of ketamine
(Li et al., 2010) so that we might
directly compare these two compounds,
and, to a first approximation, they appear
to be remarkably similar. Not only do they
both increase spine density and neuronal
excitability in the cortex, they seem to
have similar behavioral effects. We have
shown previously that, like ketamine,
DMT promotes fear extinction learning
and has antidepressant effects in the
forced swim test (Cameron et al., 2018). These results, coupled
with the fact that ayahuasca, a DMT-containing concoction, has
potent antidepressant effects in humans (Oso´ rio et al., 2015;
Sanches et al., 2016; Santos et al., 2007), suggests that classical
psychedelics and ketamine might share a related therapeutic
mechanism.
Although the molecular targets of ketamine and psychedelics
are different (NMDA and 5-HT2A receptors, respectively), they
appear to cause similar downstream effects on structural plasticity
by activating mTOR. This finding is significant because ketamine is
known to be addictive whereas many classical psychedelics are
not (Nutt et al., 2007, 2010). The exact mechanisms by which these
compounds stimulate mTOR is still not entirely understood, but
our data suggest that, at least for classical psychedelics, TrkB
and 5-HT2A receptors are involved. Although most classical psychedelics
are not considered to be addictive, there are still significant
safety concerns with their use in medicine because they
cause profound perceptual disturbances and still have the potential
to be abused. Therefore, the identification of non-hallucinogenic
analogs capable of promoting plasticity in the PFC could
facilitate a paradigm shift in our approach to treating neuropsychiatric
diseases. Moreover, such compounds could be critical to
resolving the long-standing debate in the field concerning whether
the subjective effects of psychedelics are necessary for their therapeutic
effects (Majic et al., 2015  ). Although our group is actively
investigating the psychoplastogenic properties of non-hallucinogenic
analogs of psychedelics, others have reported the therapeutic
potential of safer structural and functional analogs of ketamine
(Moskal et al., 2017; Yang et al., 2015; Zanos et al., 2016).
Our data demonstrate that classical psychedelics from several
distinct chemical classes are capable of robustly promoting the
growth of both neurites and dendritic spines in vitro, in vivo, and across species. Importantly, our studies highlight the similarities
between the effects of ketamine and those of classical serotonergic
psychedelics, supporting the hypothesis that the clinical
antidepressant and anxiolytic effects of these molecules might
result from their ability to promote structural and functional plasticity
in prefrontal cortical neurons. We have demonstrated that
the plasticity-promoting properties of psychedelics require
TrkB, mTOR, and 5-HT2A signaling, suggesting that these key
signaling hubs may serve as potential targets for the development
of psychoplastogens, fast-acting antidepressants, and anxiolytics.
Taken together, our results suggest that psychedelics
may be used as lead structures to identify next-generation neurotherapeutics
with improved efficacy and safety profiles.

Also below is a great article on DMT and neuroplasticity:

 

Dark Classics in Chemical Neuroscience N,N-Dimethyltryptamine DMT

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Ketamine has much support in the use of hard-to-treat depression and suicidal behaviors. Below are studies and their links, including a meta-analysis, which demonstrate the effect of Ketamine. Also a recent trial by Carlos Zarate shows the heterogenous nature of response to Ketamine . It is difficult to say who is going to be lifted from their depression completely or partially respond, but in the study, Dr. Zarate showed that patients with a long history of suicidal thinking and self-harm will have less of a response in some cases.

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Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients << Article link 

Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients

Repeat intravenous treatment with low doses of the anesthetic drug ketamine quickly reduced suicidal thoughts in a small group of patients with treatment-resistant depression. In their report receiving Online First publication in the Journal of Clinical Psychiatry, a team of Massachusetts General Hospital (MGH) investigators report the results of their study in depressed outpatients who had been experiencing suicidal thought for three months or longer.

“Our finding that low doses of ketamine, when added on to current antidepressant medications, quickly decreased suicidal thinking in depressed patients is critically important because we don’t have many safe, effective, and easily available treatments for these patients,” says Dawn Ionescu, MD, of the Depression Clinical and Research Program in the MGH Department of Psychiatry, lead and corresponding author of the paper. “While several previous studies have shown that ketamine quickly decreases symptoms of depression in patients with treatment-resistant depression, many of them excluded patients with current suicidal thinking.”

It is well known that having suicidal thoughts increases the risk that patients will attempt suicide, and the risk for suicide attempts is 20 times higher in patients with depression than the general population. The medications currently used to treat patients with suicidal thinking — including lithium and clozapine — can have serious side effects, requiring careful monitoring of blood levels; and while electroconvulsive therapy also can reduce suicidal thinking, its availability is limited and it can have significant side effects, including memory loss.

Primarily used as a general anesthetic, ketamine has been shown in several studies to provide rapid relief of symptoms of depression. In addition to excluding patients who reported current suicidal thinking, many of those studies involved only a single ketamine dose. The current study was designed not only to examine the antidepressant and antisuicidal effects of repeat, low-dose ketamine infusions in depressed outpatients with suicidal thinking that persisted in spite of antidepressant treatment, but also to examine the safety of increased ketamine dosage.

The study enrolled 14 patients with moderate to severe treatment-resistant depression who had suicidal thoughts for three months or longer. After meeting with the research team three times to insure that they met study criteria and were receiving stable antidepressant treatment, participants received two weekly ketamine infusions over a three-week period. The initial dosage administered was 0.5 mg/kg over a 45 minute period — about five times less than a typical anesthetic dose — and after the first three doses, it was increased to 0.75 mg/kg. During the three-month follow-up phase after the ketamine infusions, participants were assessed every other week.

The same assessment tools were used at each visit before, during and after the active treatment phase. At the treatment visits they were administered about 4 hours after the infusions were completed. The assessments included validated measures of suicidal thinking, in which patients were directly asked to rank whether they had specific suicide-related thoughts, their frequency and intensity.

While only 12 of the 14 enrolled participants completed all treatment visits — one dropped out because of ketamine side effects and one had a scheduling conflict — most of them experienced a decrease in suicidal thinking, and seven achieved complete remission of suicidal thoughts at the end of the treatment period. Of those seven participants, two maintained remission from both suicidal thinking and depression symptoms throughout the follow-up period. While there were no serious adverse events at either dose and no major differences in side effects between the two dosage levels, additional studies in larger groups of patients are required before any conclusions can be drawn.

“In order to qualify for this study, patients had to have suicidal thinking for at least three months, along with persistent depression, so the fact that they experienced any reduction in suicidal thinking, let alone remission, is very exciting,” says Ionescu, who is an instructor in Psychiatry at Harvard Medical School. “We only studied intravenous ketamine, but this result opens the possibility for studying oral and intranasal doses, which may ease administration for patients in suicidal crises.”

She adds, “One main limitation of our study was that all participants knew they were receiving ketamine. We are now finishing up a placebo-controlled study that we hope to have results for soon. Looking towards the future, studies that aim to understand the mechanism by which ketamine and its metabolites work for people with suicidal thinking and depression may help us discover areas of the brain to target with new, even better therapeutic drugs.”

 

Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine: Secondary Analysis of an Open-Label Study  << Article in Clinical Psychiatry

Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial Article link for below:

Ketamine was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients, according to researchers at Columbia University Medical Center (CUMC). They also found that ketamine’s anti-suicidal effects occurred within hours after its administration.

The findings were published online last week in the American Journal of Psychiatry.

According to the Centers for Disease Control and Prevention, suicide rates in the U.S. increased by 26.5 percent between 1999 and 2015.

“There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm,” said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. “Currently available antidepressants can be effective in reducing suicidal thoughts in patients with depression, but they can take weeks to have an effect. Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients.”

Most antidepressant trials have excluded patients with suicidal thoughts and behavior, limiting data on the effectiveness of antidepressants in this population. However, previous studies have shown that low doses of ketamine, an anesthetic drug, causes a rapid reduction in depression symptoms and may be accompanied by a decrease in suicidal thoughts.

The 80 depressed adults with clinically significant suicidal thoughts who enrolled in this study were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.

Those in the ketamine group also had greater improvement in overall mood, depression, and fatigue compared with the midazolam group. Ketamine’s effect on depression accounted for approximately one-third of its effect on suicidal thoughts, suggesting the treatment has a specific anti-suicidal effect.

Side effects, mainly dissociation (feeling spacey) and an increase in blood pressure during the infusion, were mild to moderate and typically resolved within minutes to hours after receiving ketamine.

“This study shows that ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression,” said Dr. Grunebaum. “Additional research to evaluate ketamine’s antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster acting and have the potential to help individuals who do not respond to currently available treatments.”

Ketamine for Rapid Reduction of Suicidal Thoughts in major depression – A midazolam controlled trial PDF article

Ketamine for depression | PTSD | 703-844-0184 | NOVA Health Recovery | Fairfax, Virginia 22304
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______________________________________________________________________

Ketamine as a Potential Treatment for Suicidal Ideation A Systematic Review of the Literature 2015

Abstract
Objective To review the published literature on the efficacy
of ketamine for the treatment of suicidal ideation (SI).
Methods The PubMed and Cochrane databases were
searched up to January 2015 for clinical trials and case
reports describing therapeutic ketamine administration to
patients presenting with SI/suicidality. Searches were also
conducted for relevant background material regarding the
pharmacological function of ketamine.
Results Nine publications (six studies and three case
reports) met the search criteria for assessing SI after
administration of subanesthetic ketamine. There were no
studies examining the effect on suicide attempts or death
by suicide. Each study demonstrated a rapid and clinically
significant reduction in SI, with results similar to previously
described data on ketamine and treatment-resistant
depression. A total of 137 patients with SI have been
reported in the literature as receiving therapeutic ketamine.
Seven studies delivered a dose of 0.5 mg/kg intravenously
over 40 min, while one study administered a 0.2 mg/kg
intravenous bolus and another study administered a liquid
suspension. The earliest significant results were seen after
40 min, and the longest results were observed up to
10 days postinfusion.
Conclusion Consistent with clinical research on ketamine
as a rapid and effective treatment for depression, ketamine
has shown early preliminary evidence of a reduction in
depressive symptoms, as well as reducing SI, with minimal
short-term side effects. Additional studies are needed to
further investigate its mechanism of action, long-term
outcomes, and long-term adverse effects (including abuse)
and benefits. In addition, ketamine could potentially be
used as a prototype for further development of rapid-acting
antisuicidal medication with a practical route of administration
and the most favorable risk/benefit ratio.
Key Points
Preliminary data from randomized controlled trials
have demonstrated that ketamine may rapidly and
effectively control treatment-resistant depression,
though the effects are transient.
A small subset of studies has demonstrated similar
results in the effects of ketamine on suicidal ideation.
Ketamine has potential as a rapid treatment for
suicidal ideation and/or a possible model compound
for future drug development.

4 Discussion
With an estimated prevalence of mood disorders ranging
from 3.3 to 21.4 % and the substantially increased risk of
suicide among patients with mood disorders, treatment is
certainly warranted [19]. Current treatment options for
suicidality are limited. They include brain stimulation
therapeutics, such as ECT, and pharmacological intervention
(lithium, clozapine). The efficacy of lithium in treating
suicidality has been documented [20, 21] and has recently been reviewed and pooled in a recent meta-analysis of 48
studies [22]. Clozapine has also been shown to reduce
suicide risk in patients with schizophrenia [23, 24]. The
limitations of both lithium and clozapine include a longer
time to efficacy in this psychiatric emergency/urgency,
compared with the early response to ketamine [25]. Ketamine
seems to be gaining substantial evidence as a pharmacological
option for depression with a fast onset of
action, but its long-term effects need further investigation.
In addition, ketamine probably offers a faster onset of
action in terms of SI, but further work is certainly needed
in this area. Given the risk of suicide and even the
increasing rates of suicide in certain subgroups, such as
soldiers and veterans [26, 27], there is an urgent need for
faster therapeutics for SI and TRD. Importantly, suicidality
and suicide pose a high global burden of patient suffering
to families and society. Although several small-to-moderate
sized studies, in addition to several reviews, have been
published that have examined the efficacy of ketamine in
TRD, there are considerably fewer published data
specifically examining ketamine in patients presenting with
SI. Notably, only three studies have directly examined SI
as the primary outcome [11, 16, 17], while the rest
examined SI as the secondary outcome [4, 15, 18], not
including case reports. This review summarizes the current
published literature regarding ketamine as a treatment for
SI. The data so far show promising trends of ketamine
being an effective and rapid treatment with minimal side
effects.
Pharmacologically, ketamine is an N-methyl-D-aspartate
(NMDA) receptor antagonist. It has been used for anesthesia
in the USA since the 1970s. At subanesthetic doses,
ketamine has been shown to increase glutamate levels [3].
This mechanism is relevant, as glutamate regulation and
expression are altered in patients with major depressive
disorder (MDD). Studies have also demonstrated an
abnormal glutamate–glutamine–gamma-aminobutyric acid
cycle in patients with suicidality [28]. Furthermore, ketamine
has also been shown to work on nicotinic and opioid
receptors [29]. No other class of antidepressant medication
works to modulate the glutamatergic system, and research
continues into this, with the goal of characterizing the full
mechanism of action of ketamine and perhaps developing
other compounds that would have similar effects. Thus,
even if the approval and marketing of ketamine as a rapidacting
antisuicidal and antidepressant medication is not
realized, it could well be a prototype for development of
other medication(s) that retain the mechanism of action
with more favorable qualities and a lesser adverse effect
profile (such as a longer duration of action or less or no
addictive potential). Although the mechanisms explaining
the antisuicidal effect and the NMDA receptor antagonism
of ketamine are still unclear, some of the initial evidence
points to an anti-inflammatory action via the kynurenic
acid pathway. Strong suggestions as to the causal relationship
between inflammation and depression/suicidality
has come from studies demonstrating that cytokines [30,
31] and interferon-b [32] induce depression and suicidality.
Other recent studies have added to the notion of implicating
brain immune activation in the pathogenesis of suicidality.
For instance, one study showed microglial
activation of postmortem brain tissue in suicide victims
[33]. Another study found increased levels of the cytokine
interleukin-6 in cerebrospinal fluid from patients who had
attempted suicide [34]. Higher levels of inflammatory
markers have been shown in suicidal patients than in nonsuicidal
depressed patients [33, 35]. Inflammation leads to
production of both quinolinic acid (an NMDA agonist) and
kynurenic acid (a NMDA antagonist). An increased
quinolinic acid to kynurenic acid ratio leads to NMDA
receptor stimulation. The correlation between quinolinic
acid and Suicide Intent Scale scores indicates that changes
in glutamatergic neurotransmission could be specifically
linked to suicidality [36].
Small randomized controlled trials have demonstrated
the efficacy of ketamine in rapidly treating patients with
both TRD and/or bipolar depression [4, 8, 9, 11, 16–18].
Some studies have also examined suicide items as a secondary
measure in their depression rating scales [4, 7]. In
total, the studies examining ketamine and TRD have nearly
consistently demonstrated that ketamine provides relief
from depressive and suicidal symptoms, starting at 40 min
and lasting for as long as 5 days. Questions still remain as
to the long-term effects of this treatment, how much should
be administered and how often, any serious adverse effects,
and the mechanism of action.
Pharmacologically, ketamine has poor bioavailability
and is best administered via injection [37]. In their landmark
study, Berman et al. [4] found that a subanesthetic
dose (0.5 mg/kg) rapidly improved depressive symptoms.
Most of the subsequent studies have delivered ketamine as
a constant infusion for 40 min at a rate of 0.5 mg/kg.
Others have examined its efficacy after multiple infusions
and observed similar results [8, 13, 16, 38]. Currently, it is
recommended that ketamine be administered in a hospital
setting [39].

______________________________________

Characterizing the course of suicidal ideation response to ketamine

Characterizing the course of suicidal ideation response to ketamine PDF

2018 article from Carlos Zarate discussing the variable course outcomes with Ketamine for suicidality and correlations to serum markers and behavior and longevity of self-harm prior to treatment:

 

Background: : No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic
modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after
ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI
response to ketamine.
Methods: : Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with
DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic
(0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture
modeling to generate SI response classes, and class membership predictors were evaluated using multinomial
logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers.
Results: : The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders
(44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1.
Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for
Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated
with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to
Remitters rather than Responders.
Limitations: : Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma,
rather than CSF, markers were used.
Conclusion: : The results underscore the heterogeneity of SI response to ketamine and its potential independence
from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic
SI were less likely to respond or remit post-ketamine.

1. Introduction
Suicide poses a serious threat to public health. Worldwide, suicide
accounts for approximately 1 million deaths, and 10 million suicide
attempts are reported annually (World Health Organization, 2014). In
the United States, the national suicide rate has increased by approximately
28% over the last 15 years (Curtin et al., 2016). At the same
time, relatively few interventions for suicide risk exist. While treatments
such as clozapine and lithium have demonstrated effects on
suicidal behavior over weeks to months, these effects may be limited to
specific diagnoses (Cipriani et al., 2005; Griffiths et al., 2014). Currently,
no FDA-approved medications exist to treat suicidal ideation
(SI), leaving those who experience a suicidal crisis with limited options
for a reprieve of symptoms. Consequently, a critical need exists for
rapid-acting treatments that can be used in emergency settings.
A promising off-label agent for this purpose is the rapid-acting antidepressant
ketamine, which past studies have suggested reduces suicidal
thoughts (Diazgranados et al., 2010a; Murrough et al., 2015; Price
et al., 2009). A recent meta-analysis of 167 patients with a range of
mood disorder diagnoses found that ketamine reduced suicidal
thoughts compared to placebo as rapidly as within a few hours, with
effects lasting as long as seven days (Wilkinson et al., 2017). These
results are reinforced by newer findings of reduced active suicidal
ideation post-ketamine compared to a midazolam control(Grunebaum et al., 2018). As the efficacy literature develops in the era
of personalized medicine, two important issues must be addressed.
First, little is known about the acute course of SI following ketamine.
The speed with which antidepressant response occurs, and how much
improvement can be expected on average, has been documented for
single administrations of ketamine (Mathew et al., 2012; Sanacora
et al., 2017); in the limited available literature, researchers have
emulated previous studies examining antidepressant effect, where a
cutoff of 50% improvement demarcated response (Nierenberg and
DeCecco, 2001). Nevertheless, it remains unknown whether this categorization
accurately reflects the phenomenon of suicidal thoughts.
Empirically-derived approaches to the description of SI trajectory after
ketamine may be useful in operationalizing “response” in future clinical
trials.
Second, identifying demographic, clinical, or biological predictors
of SI response to ketamine would allow researchers and clinicians to
determine who is most likely to exhibit an SI response to ketamine. A
broad literature describes clinical and demographic predictors for suicide
risk (Franklin et al., 2017), and a smaller literature connects suicidal
thoughts and behaviors to plasma markers such as brain-derived
neurotrophic factor (BDNF) and cytokines (Bay-Richter et al., 2015;
Falcone et al., 2010; Isung et al., 2012; Serafini et al., 2017; Serafini
et al., 2013). However, no biomarkers have been shown to predict SI/
behavior response to intervention, a finding reinforced by the National
Action Alliance for Suicide Prevention’s Research Prioritization Task
Force’s Portfolio Analysis (National Action Alliance for Suicide
Prevention: Research Prioritization Task Force, 2015). Notably, predictor
analyses have the potential to reveal insights into personalized
treatments for suicidal individuals, as well as the neurobiology of SI
response. With respect to antidepressant response, for example, this
approach yielded the observation that individuals with a family history
of alcohol dependence may be more likely to exhibit an antidepressant
response to ketamine (Krystal et al., 2003; Niciu et al., 2014; PermodaOsip
et al., 2014).
The goals of this study were to elucidate trajectories of SI response
and identify predictors of that response, with the ultimate goal of
adding to the growing literature surrounding ketamine’s specific effects
on SI. In particular, we sought to determine whether the heterogeneous
patterns of change in SI after ketamine administration were better explained
by a model with two or more latent groups of trajectories rather
than a single average trajectory, using secondary analyses from previously
published clinical trials. These classes were then used to evaluate
potential clinical, demographic, and plasma biomarker predictors
of SI response to ketamine in order to generate hypotheses.. Discussion
This analysis used a data-driven approach to characterize SI response
to ketamine. The data were best explained by three trajectory
classes: one with severe average baseline SI and little to no response to
ketamine (Non-Responders), one with moderate average baseline levels
of SI and significant response to ketamine (Responders), and a third
with moderate average baseline levels of SI and complete remission of
SI by two days post-ketamine (Remitters). These findings suggest a
diversity of post-ketamine changes in SI that may not be captured under
traditional methods of categorizing response to treatment.
Furthermore, we found evidence that SI response and antidepressant
response could be distinguished from each other; one subset of participants
experienced improvement in SI that was partially explained by
improvements in Depressed Mood, while the other group’s improvements
in SI occurred independently of antidepressant response. With
regard to predictors of SI response trajectory, preliminary results suggest
the individuals least likely to experience improvement in SI postketamine
were those with the most severe SI and a history of self-injury.
Few plasma markers emerged as predictors of SI response in this study,
highlighting the limitations of connecting SI ratings of response with
biological markers.
The growth mixture modeling approach used here underscored the
heterogeneity of SI response to ketamine, which would not have been
captured by simply calculating the average trajectory. The class assignment
from this approach also differed from the definition of response
(50% reduction in symptoms) traditionally used in the antidepressant
literature, which often focuses on a specific timepoint rather
than the entire symptom trajectory. In comparing classification using a
50% response at Day 1 and Day 3 with the latent trajectory classes, we
found representation of almost every SI class across each responder
group, highlighting the potential limitations of the 50% response approach.
Further study is needed to determine which of these approaches
will prove more fruitful. Complete remission of SI has previously been
used as an outcome measure in clinical trials and in a meta-analysis of
ketamine’s efficacy (Grunebaum et al., 2017; Grunebaum et al., 2018;
Wilkinson et al., 2017), as well as in a study examining the relationship
between SI response to ketamine and changes in nocturnal wakefulness
(Vande Voort et al., 2017). One strength of the present study is that this
data-driven approach provides classifications that directly reflect the
phenomena under study as they are, as opposed to what they should be.
Especially when used in larger samples than the current study, this
approach is particularly promising in its ability to provide a more
nuanced understanding of the nature of SI response to ketamine.
Our results also support the idea that SI response in particular can target. First, it should be noted here that SI classes were not distinguishable
by baseline Depressed Mood scores; patients with the most
severe SI did not differ meaningfully in Depressed Mood scores from
those with the mildest SI. Second, while previous analyses of these data
documented that BMI and family history of alcohol dependence predicted
antidepressant response (Niciu et al., 2014), SI response was not
associated with these variables in the current analysis. Third, the antidepressant
response profiles of the SI classes suggest that SI response
and antidepressant response are not wholly redundant. This aligns with
previous clinical trials and meta-analytic reviews of the literature suggesting
that SI response to ketamine occurs partially independently of
antidepressant response (Grunebaum et al., 2018; Wilkinson et al.,
2017). Nevertheless, this independence did not hold true across both SI
response groups. Specifically, antidepressant and SI response were
clearly linked in Remitters, with depression accounting for half of the
changes in SI; however, in Responders, improvements in SI occurred
independently from improvements in Depressed Mood. These discrepancies
could be related to ketamine’s complex neurobiological
mechanisms or to the potentially low levels of clinical severity observed
in the Remitters.
Interestingly, the current analyses found no baseline demographic
variables that reliably distinguished Responders from Remitters. Some
phenotypic characteristics were uniquely associated with belonging to
the Non-Responder group, suggesting that a long-standing history of
self-injury or SI may indicate resistance to rapid changes in SI.
Relatedly, a recent, randomized clinical trial of repeat-dose ketamine
compared to placebo found that ketamine had no effect on SI in a
sample of patients selected for their longstanding, chronic history of SI
(Ionescu, 2017). These results highlight the importance of patient selection,
particularly for suicide risk. It should be stressed, however, that
SI does not necessarily translate to suicidal attempts or deaths; to our
knowledge, no study has yet linked ketamine with reduced risk of
suicidal behavior. Indeed, in the present study the SI Non-Responders
experienced limited antidepressant effects in response to ketamine, but
may nevertheless have improved on other, unmeasured symptoms that
could provide important benefit and relief. As the ketamine literature
develops, it will be important to identify which clinical symptom profiles
are most likely to have a robust anti-SI and anti-suicidal behavior
response to ketamine and which ones may benefit from other interventions.
While we evaluated a range of potential plasma markers previously
linked to suicidal ideation and behavior, in the present analysis only IL5
was associated with the SI Responder subgroup. Ketamine is known to
have anti-inflammatory effects (Zunszain et al., 2013), but the relationship
between antidepressant response and change in cytokine
levels remains unclear (Park et al., 2017). Cytokines have been linked
to suicidal behavior in the past; a recent meta-analysis found that lower
levels of IL-2 and IL-4, and higher levels of TGFbeta, were associated
with suicidal thoughts and behaviors (Serafini et al., 2013); however, toour knowledge IL-5 has not previously been linked to SI. Given the large
number of comparisons and lack of precedent in the literature, this
result may have been spurious and should be interpreted with caution.
A number of other results may reflect meaningful relationships, but the
high degree of variability—and the associated wide confidence intervals—suggests
that larger sample sizes are needed to better elucidate
the nature of any such relationships (e.g. baseline VEGF: χ2 = 6.13,
p = .05, but OR (95% CI) 13.33 (0.93–200.00)). Somewhat surprisingly,
plasma BDNF levels were not associated with responder class.
Previous studies of bipolar, but not MDD, samples found that plasma
BDNF levels were associated with SI response after ketamine
(Grunebaum, 2017; Grunebaum et al., 2017), suggesting that the mixed
diagnostic composition of this study may explain differences from
previous work. Studies exploring the relationship between BDNF and
antidepressant response to ketamine have also yielded mixed findings
(Haile et al., 2014; Machado-Vieira et al., 2009). Other data-driven
approaches have considered both biological and behavioral variables in
characterizing depression (Drysdale et al., 2017); a similar approach
might prove useful for predicting SI response.
The present study is associated with several strengths as well as
limitations. Strengths include the relatively large sample size of participants
who received ketamine, the use of composite SI scores from
previous exploratory factor analyses as opposed to individual items,
and the combination of clinical and biological markers as potential
predictors of class membership. Limitations include patient selection
methods, as these patients were part of an antidepressant trial and were
not selected for active suicidal thoughts, as well as the exploratory
nature of the analysis. As stated above, suicidal thoughts do not necessarily
equate to suicidal behavior, and class membership would thus
not necessarily correspond with an overall reduction in suicide risk.
Another limitation is that results were collapsed across several clinical
trials with slight variations in study design, and findings were thus only
extended to Day 3 rather than a week after ketamine administration. As
a result, only a subset of the sample could be used for predictive analyses.
In addition, plasma—rather than CSF—markers were used, and
the latter might better indicate underlying biology due to proximity to
the brain, though certain markers such as plasma BDNF may be related
to platelet storage, rather than the brain (Chacón-Fernández et al.,
2016). Comparison of results to trajectories of suicide-specific measures,
such as the Scale for Suicide Ideation (Beck et al., 1979), may also
give further insight into specific SI content. Finally, many clinical
predictors were collected upon hospital admission; future analyses
could use formal assessments, such as the Childhood Traumatic Questionnaire
(Bernstein et al., 1994), assessment of personality disorders,
or diagnoses such as post-traumatic stress disorder (PTSD) as potential
indicators of response.
Despite these limitations, the study demonstrates the utility of a
data-driven approach for characterizing the heterogeneity of SI response
to a rapid-acting intervention. This allows for a more finegrained
analysis of symptoms than would be permitted by traditionalapproaches, such as overall average response or dichotomization at
50% reduction in symptoms. This study identified several findings of
note. These included distinguishing at least three patterns of SI response
to ketamine and finding that subjects who exhibited more severe SI at
baseline were not likely to experience an SI response to ketamine.

 

____________________________________

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Science Article on how Ketamine may work rapidly

703-844-0184 | Ketamine 22306 | Ketamine for depression |

 

In contrast to most antidepressant medications, which can take several weeks to reduce depressive symptoms, ketamine — a commonly used veterinary anesthetic — can lift a person out of a deep depression within minutes of its administration, and its effects can last several weeks. Researchers have long-wondered how ketamine can both act quickly and be so long-lasting.

Now, researchers led by Mark Rasenick, distinguished professor of physiology and psychiatry in the University of Illinois at Chicago College of Medicine, describe the molecular mechanisms behind ketamine’s ability to squash depression and keep it at bay. They report their findings in the journal Molecular Psychiatry.

Two-thirds of participants in clinical studies who did not respond to traditional antidepressants experienced fast and lasting resolution of their depressive symptoms after being given ketamine intravenously, Rasenick explained. The effects of ketamine typically lasted about a week — much longer than would be expected with ketamine’s six-hour half-life in the body.

Rasenick and his colleagues used a cellular model system to investigate how ketamine acted.

In previous research, Rasenick and his colleagues showed that SSRIs — the most commonly prescribed class of antidepressants, which includes Prozac and Zoloft — work in the brain by moving molecules called G proteins off of “lipid rafts” on the cell membrane, where the G proteins are held inactive. G proteins produce cyclic AMP, which nerve cells need to signal properly. People with depression, Rasenick found, tend to have a greater proportion of their G proteins packed into these membrane patches, along with dampened brain cell signaling, which may contribute to symptoms of depression, including a feeling of overall numbness.

In the earlier research, when Rasenick exposed rat brain cells to SSRIs, the drug accumulated in the lipid rafts, and G proteins moved out of the rafts. The movement was gradual, over the span of several days, which Rasenick thinks is the reason why SSRIs and most other antidepressants can take a long time to begin working.

In his current research, Rasenick and his colleagues performed a similar experiment with ketamine and noticed that the G proteins left the rafts much faster. G proteins began migrating out of the lipid rafts within 15 minutes. And the long-lasting effects of ketamine may be due to the fact that the G proteins were very slow to move back into the lipid rafts, Rasenick explained.

The finding contradicts the long-held idea that ketamine works solely by blocking a cellular receptor called the NMDA receptor, which sits on the surface of nerve cells and helps transmit signals.

In fact, when the researchers knocked out the NMDA receptor, ketamine still had the same effect on the cells — quickly moving G proteins out of lipid rafts on the cell membrane.

“When G proteins move out of the lipid rafts, it allows for better communication among brain cells, which is known to help alleviate some of the symptoms of depression,” Rasenick said. “Whether they are moved out by traditional antidepressants or ketamine, it doesn’t matter, although with ketamine, the G proteins are very slow to move back into the lipid rafts, which would explain the drugs long-term effects on depressive symptoms.”

“This further illustrates that the movement of G proteins out of lipid rafts is a true biomarker of the efficacy of antidepressants, regardless of how they work,” Rasenick explained. “It confirms that our cell model is a useful tool for showing the effect of potential new antidepressant drug candidates on the movement of G proteins and the possible efficacy of these drugs in treating depression.”

Story Source:

Materials provided by University of Illinois at ChicagoNote: Content may be edited for style and length.


Journal Reference:

  1. Nathan H. Wray, Jeffrey M. Schappi, Harinder Singh, Nicolas B. Senese, Mark M. Rasenick. NMDAR-independent, cAMP-dependent antidepressant actions of ketamineMolecular Psychiatry, 2018; DOI: 10.1038/s41380-018-0083-8

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Psychology Today Article: Ketamine: Old Drug, New Tricks

 

Ketamine has been used as an anesthetic for 50 years, and for decades the clinicians prescribing it have noticed sudden, appreciable anti-suicide and antidepressant effects in their patients. Case reports of desperate suicidal depressionrelieved within half an hour were discussed in the waning years of the 20th century, but actual research papers with small trials have only started trickling in within the last two decades.

Even after all this time, the research done thus far has not led to ketamine being mainstream FDA-approved as standard therapy for depression or suicidal ideation. For one thing, the kind of ketamine used in the US for most of the last 50 years is an IV drip requiring nursing and vital sign monitoring. In my neck of the woods, IV ketamine treatment is $3,000 (not covered by insurance or Medicare), usually completed in six treatments over two weeks. Not exactly within reach for many of my patients with resistant depression (who tend to decline in socioeconomic status over time).

In the case studies, folks’ depression rather notoriously rebounded back from ketamine therapy and then became resistant, though that didn’t happen to everyone. But how could we study how effective ketamine is? It’s generic, so there’s no pharmaceutical company with the millions to blow on state-of-the-art, beautiful randomized controlled trials to bring before the FDA. The patient population for ketamine is also a difficult one. Suicidal folks and depressed people with illness resistant to standard therapy or meds are more likely to give a drug company an expensive and public failure rather than profit, no matter that this is a population desperately in need of new ideas and new thinking. However, new formulations and the slow grind of publicly funded studies means new life for this elderly drug.

Before we talk about how ketamine works, let’s talk about how mental illness arises in terms of the actual pathology in the brain. (Note: This will necessarily be an oversimplification.) In short, most mental illness develops at the intersection of too much emotional or physical stress and genetic vulnerability leading to limitations in efficient brain functioning. This happens when brain becomes overwhelmed with excitatory signals: too much stress, too much activation of the fight-or-flight nervous system leading to specific over-activation of certain brain areas (like the left prefrontal cortex, the hippocampus, or the amygdala) without compensatory time or resources for recovery and repair.

The emotional and physical stressors could be, for example, a death in the family, extended work stress, viral illness that affects the brain, medications that affect the brain, or traumatic brain injury. The genetic vulnerability could be an increased inefficiency in being able to make specific neurotransmitters or brain fertilizers that help in recovery and repair, or an increased genetic ability to send excitatory ions through cell membranes, or many more complex issues we haven’t yet figured out.

Under this theory, almost any intervention could decrease symptoms of mental illness if it increases general neuron recovery and repair—or the efficiency of neurotransmitter use in the recovery and repair pathway—or reduces neurotoxic activation of the excitatory pathway (or “excitotoxicity“). Interventions such as regular exercise, meditationpsychotherapy, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, lithium, magnesium, anti-seizure meds and many other treatment paradigms can be at least partially effective to decrease symptoms. Keep in mind, sometimes the disease is a tank, and the spear in your arsenal (regular exercise, for example) is never going to be enough to take out that tank. Sometimes you need anti-tank missiles (such as low dose antipsychotics for severe resistant depression).

Ketamine is, among many other things, an NMDA receptor antagonist(though even this characterization is complicated). This means that ketamine blocks the action at the NMDA receptor, normally turned on by the major excitatory neurotransmitter in the nervous system, glutamate. NMDA receptor over-activation is ground zero for excitotoxiticy, kind of like a gas pedal that is stuck in the downward position. So far, though, not a single FDA-approved psychiatric medication in general practice specifically unsticks that gas pedal. But ketamine does. (So will, to a much lesser extent, magnesium* and the supplement NAC, which decreases glutamate concentrations). This gas pedal unsticking is how ketamine can seemingly do the impossible: take a dangerously suicidal patient and make them feel much, much better in less than an hour.

Wikimedia Commons
Source: Wikimedia Commons

In 2016, a new formulation of ketamine, esketamine, was granted FDA “breakthrough therapy” designation for major depressive disorder with imminent risk of suicide. It’s a nasal spray used in Europe for anesthesia, but never used in the US before. It has three to four times the affinity for the NMDA receptor as ketamine and fewer intolerable side effects (such as hallucinations, dissociation, and dangerous fluctuations of vital signs). A phase two study of esketamine was published in April 2018, a randomized controlled trial of suicidal depressed patients. They agreed to be monitored on an inpatient unit for five days after the first administration of the medicine, followed by twice-a-week administration for four weeks in addition to standard antidepressant treatment. To empathize how ill the population in this study was, three (placebo) patients out of 68 made suicide attempts during the follow up period, and half needed additional suicide precautions during their inpatient stay (usually decreased time between nursing checks which is, at the low end, every 15 minutes on a standard inpatient unit). Esketamine results separated from those of placebo treatment by four hours and at 24 hours, with rapid relief from suicidal thoughts and depressive symptoms, but there seemed to be no difference with esketamine and placebo at 25 days.

This study seems to support the old case study observations, that ketamine can be amazingly helpful short term, but is not really a long-term intervention. But it’s hard to tell, and we need more data. No one really knows why there’s such a rapid ketamine poop-out, but from a clinical perspective, who cares? A fast intervention that decreases suicidal ideation could save lives while our other, proof-tested, slower interventions take their time to work. This could also shorten inpatient hospital stays for depression, freeing up precious resources and getting people back to their families, work, and communities. While the use in observed settings such as inpatient units and emergency rooms is likely to accelerate, we need way more-real world data before we start prescribing nasal spray in outpatient treatment, especially for dangerously suicidal patients.

Ketamine studies have also opened the doors for other NMDA receptor antagonist interventions. Some drugs in development include new formulations of dextromethorphan and rapastinel. Given that psychiatric drugs have been endless renditions of the same tricyclic antidepressants,  SSRIs, dopamine blockers, and dopamine partial agonists for decades, we could use a new approach.

And remember, there are plenty of ways to unstick that gas pedal early in the game, with proper self care and healthy living. Modern life, in America at least, doesn’t much incentivize vacation or sleep, both of which help that recovery and repair cycle. As a psychiatrist I’ll use whatever evidence-based intervention I can at any stage to treat the patient where he or she is to make them start getting better in the moment. As a health writer I can suggest eating a (mostly) home-cooked whole foods diet, avoiding a lot of alcohol and smoking, and getting enough physical movement, rest, and recharging time. In the brain, it’s all about reducing that excitotoxicity. In life, it’s all about a clear head, good energy, and serenity.

*Magnesium is also felt to work, in some respects, by antagonizing NMDA receptors “

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Traditional antidepressants may take weeks to work on individuals. There have been associations with increased suicidality in some studies. The need for a more rapidly acting antidepressant is important. The study below investigated the antidepressant effect of Ketamine by looking through an FDA database and observing associations of pain and depression reduction with the use of Ketamine. They were clearly present. Of note, minocycline and Diclofenac also seemed to be associated with improved depression parameters.

Ketamine provides both pain relief and anti-depression effects in refractory patients, who by definition, have failed multiple therapies.   ::

 

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Ketamine for Pain Management, Treatment of Depression << Article Link

Article below:

Ketamine may alleviate depression, pain, and adverse effects associated with opioid treatment, and may thus represent an attractive adjunct therapy for pain management, according to a novel population analysis recently published in Scientific Reports.1

Nearly half of all patients with depression taking conventional antidepressants discontinue their treatment prematurely.2 Researchers have sought alternatives to standard antidepressants, for which therapeutic effects are delayed by 2 to 10 weeks.3

Ketamine, an N-methyl-D-aspartate antagonist, was shown to provide acute benefits for treatment-resistant depression, bipolar depression, and major depressive disorder with suicidal ideation, when administered intravenously, however, those studies were conducted on limited samples (20 to 57 participants).4-7

The history of ketamine as an illicit drug favored for its hallucinogenic effects presents ethical obstacles to its use in large clinical trials. Researchers from the University of California San Diego in La Jolla, therefore employed an Inverse-Frequency Analysis approach to investigate whether ketamine, when administered in addition to other therapeutics, has antidepressant properties.

The team applied the inverse frequency analysis method, which looks for negative statistical patterns in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) post-marketing database of more than 8 million patient records. They observed reductions in depression and pain in patients receiving ketamine, as indicated by negative log odds ratio (logOR) values (logOR, -0.67 ± 0.034 and logOR, -0.41 ± 0.019, respectively). “The data we analyzed are indirect and skewed by cases of bad or lethal adverse effects. Nevertheless the statistics were sufficient to notice the trends,” explained study co-author, Ruben Abagyan, PhD, in an interview with Clinical Pain Advisor.

According to Dr Abagyan, a study recently published by a British team indicates that ketamine might be effective in nearly 40% of patients with severe, treatment-resistant depression, results that are concordant with those from the current study.8

The IFA method was also used to evaluate ketamine efficacy and associated side effects reported in the FAERS database. The investigators found significant reductions in a number of side effects associated with opioid therapies, including constipation (LogOR −0.17 ± 0.023), vomiting (LogOR −0.16 ± 0.025), and nausea (LogOR −0.45 ± 0.034) compared with other drug combinations used for pain management.

The authors concluded that their findings are in line with those from smaller studies, indicating beneficial effects for ketamine as a monotherapy or adjunctive therapy for depression, particularly treatment-resistant depression, with particular indication for patients with suicide ideation, because of its rapid onset of action. “The results should serve as a motivation to conduct a proper clinical trial for the rapid onset treatment of severe depression,” Dr Abagyan noted.

The novel analysis employed in this study may help investigate off-label indications for other drugs. “Ideally the method we proposed should be applied to the actual clinical data rather than the somewhat biased set of un-normalized FAERS reports,” Dr Abagyan added. “The method [can be used] to observe unexpected effects of a treatment by looking at the reduction of the baseline of this effect upon treatment. It can be applied to any effect that is being recorded including cancer, viral diseases mortality, longevity.” he concluded.

 

References

  1. Cohen IV, Makunts T, Atayee R, Abagyan R. Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indicationsSci Rep 2017;7:1450.
  2. Sansone RA, Sansone LA. Antidepressant adherence: are patients taking their medications?. Innov Clin Neurosci. 2012;9(5-6):41-46.
  3. Frazer A, Benmansour S. Mol Psychiatry. Delayed pharmacological effects of antidepressantsMol Psychiatry 2002;7:S23-8.
  4. Price RB, Iosifescu DV, Murrough JW,  et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depressionDepress Anxiety 2014;31:335-343.
  5. DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorderJ Clin Psychiatry 2010;71:1605-1611.
  6. Alberich S, Martínez-Cengotitabengoa M, López P,et al. Efficacy and safety of ketamine in bipolar depression: A systematic reviewRev Psiquiatr Salud Ment 2017;10:104-112.
  7. Larkin, G. L. & Beautrais, A. L. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency departmentInt J Neuropsychopharmacol 2011;8:1127-31.
  8. Singh I, Morgan C, Curran V, et al. Ketamine treatment for depression: opportunities for clinical innovation and ethical foresightLancet Psychiatry 2017;4:419-42

 

Population scale data reveals the antidepressant effects of Ketamine  ::  << Article below

Population scale data reveals the
antidepressant effects of ketamine
and other therapeutics approved
for non-psychiatric indications

Isaac V. Cohen, Tigran Makunts, Rabia Atayee & Ruben Abagyan

Current therapeutic approaches to depression fail for millions of patients due to lag in clinical response
and non-adherence. Here we provide new support for the antidepressant efect of an anesthetic
drug, ketamine, by Inverse-Frequency Analysis of eight million reports from the FDA Adverse Efect
Reporting System. The results of the examination of population scale data revealed that patients who
received ketamine had signifcantly lower frequency of reports of depression than patients who took
any other combination of drugs for pain. The analysis also revealed that patients who took ketamine
had signifcantly lower frequency of reports of pain and opioid induced side efects, implying ketamine’s
potential to act as a benefcial adjunct agent in pain management pharmacotherapy. Further, the
Inverse-Frequency Analysis methodology provides robust statistical support for the antidepressant
action of other currently approved therapeutics including diclofenac and minocycline.

We found that patients listed in the FAERS database who received ketamine in addition to other therapeutics
had signifcantly lower frequency of reports of depression than patients who took any other combination of drugs
for pain (LogOR−0.67±0.034)

Te analysis of the whole FAERS database revealed several other unintentional depression reducing drugs
among antibiotics, cosmeceuticals and NSAIDS.Our data supported previous studies that observed the
psychiatric polypharmacology of minocycline, a tetracycline antibiotic.The NSAID, diclofenac, was also
observed to have some antidepressant properties.It is theorized that both of these drugs may accomplish
antidepressant effects through an anti-inflammatory mechanism.Because of the antidepressant activity of several
NSAIDs, we further separated the non-ketamine pain cohort. Ketamine patients were then compared to
patients who received any other combination of drugs for pain excluding NSAIDs. It was observed that depression
event rates remained low (LogOR−0.56±0.035).As an important side note, we also evaluated efcacy and side efects with the use of ketamine for pain management.
We found that patients who were on ketamine had reduced opioid induced side effects including constipation, vomiting, and nausea. Our data supports ketamine’s
opioid-sparing properties and alludes to the fact that patients may receive benefts of improved pain, reduced
requirement of opioids, and ultimately less opioid reduced side effects.

References
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(NCS-R). JAMA 289, 3095–3105, doi:10.1001/jama.289.23.3095 (2003).
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(2011).
4. Andrade, L. et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric
Epidemiology (ICPE) Surveys. Int J Methods Psychiatr Res 12, 3–21, doi:10.1002/(ISSN)1557-0657 (2003).
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(2012).
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sj.mp.4001015 (2002). Suppl 1.
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A Meta-Analysis of 29 Placebo-Controlled Studies Including 6,934 Patients with Major Depressive Disorder. Psychother Psychosom
85, 171–179, doi:10.1159/000442293 (2016).
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large sample of in-patients with a major depressive episode. Int J Neuropsychopharmacol 12, 181–189, doi:10.1017/
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report. Am J Psychiatry 163, 1905–1917, doi:10.1176/ajp.2006.163.11.1905 (2006).
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patients with treatment-resistant major depressive disorder. J Clin Psychiatry 71, 1605–1611, doi:10.4088/JCP.09m05327blu (2010).
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