Is Ketamine the Next Big Depression Drug?

Ketamine is an anesthetic used in human and veterinary medicine, and its ability to rapidly reduce depressive symptoms in people who have responded insufficiently to antidepressants has generated great interest in the scientific and clinical communities. A study of 72 patients, presented in 2013 at the American Psychiatric Association annual meeting, found that more than half reported fewer symptoms after one intravenous dose of ketamine.

Ketamine, a drug, which has not been federally approved yet to treat depression, not only works quickly but its effects also can last three to five days or more, said Dr. Carlos Zarate, chief of the section on the neurobiology and treatment of mood disorders at the National Institute of Mental Health.

Those qualities mean it could be useful for patients in danger of committing suicide, Zarate said.

The clinical effectiveness of Ketamine in the latest scientific reports sounds too good to be true, particularly when compared with anything else on the market. The effects take hold within days (if not hours, compared with weeks to months for SSRIs), they seem to work for most people, there seem to be few discernible side effects, and it seems to be equally effective in the treatment of bipolar depression (which is notoriously hard to treat).

Main Facts about Ketamine

* Ketamine acts fast. About 25% of the all recipients claim to start feeling better in just an hour or in a couple of hours. Another 50% of people claim to feel substantially better by the next day.
* Few FDA approved drugs have a reputation as controversial as Ketamine. This reputation is well earned. Originally developed in the 1960s as a short-acting anesthetic for battlefield use, in recent decades it has become notorious as a date-rape drug (‘Special K’), a club drug (‘Vitamin K’) and for its use in veterinary medicine (‘horse tranquilizer’). So, Ketamine is not, as many believe, just a horse tranquilizer. That is a line from the movies that has become an urban legend. Ketamine is an anesthetic, developed over 50 years ago and used safely in tens of millions of medical procedures a year since then. When used under medical supervision, it is a very safe drug. It is listed by the World Health Organization as one of the world’s essential medications.
* When Ketamine was used as a battlefield anesthetic in Vietnam and the first Gulf war, it was anecdotally noted that wounded soldiers such treated developed far fewer cases of PTSD than soldiers with similar injuries that were treated with other anesthetics.
* The effects and side effects of Ketamine are very dose dependent – the more drug you get, the greater the effects. At low dosages, Ketamine repairs nerve cells in the brain damaged by depression. At moderate dosages, Ketamine causes extreme drowsiness and is useful as an anesthetic in surgical procedures – you may well have already had Ketamine in some point of your life before. At high dosages, Ketamine is abused on the street and has several dangerous side effects that do not happen at lower dosages. As a street drug, abusers snort in one day the full ten-year dose for depression, causing severe hallucinations - doing that is not going to have a happy ending.
* Ketamine must be given via IV to be effective. Dose control is critical to achieving the anti-depressant effect, and other modes of administration are not capable of achieving the needed precision.

Low-dose Ketamine Treatment

The respectable researchers at Mayo Clinic have also found that Ketamine is very effective at treating depression when administered over a long period. The study, published in the Journal of Psychopharmacology, revealed that prolonged, low-dose intravenous infusions of Ketamine, have excellent potential in reducing the symptoms of severe depression.

About ten years ago researchers identified that Ketamine has properties that can help alleviate depression. However, given the serious psychiatric side effects of the drug, experts have been looking for the safest ways to use it.

Co-author Timothy Lineberry, M.D., a Mayo Clinic psychiatrist, said: "It's surprising both that it works and how rapidly it has effects. It sometimes can work in hours to reduce depressive symptoms and suicidal ideation. Our goal is to begin to determine how the drug can be administered safely in routine treatment."

A total of 10 patients with either a major depressive disorder or type of bipolar disorder were included in the study. All of the participants failed to respond to anti-depressant medications. The patients were all treated with low-dose ketamine infusions (0.5 mg/kg total dose), up to twice a week, until their symptoms of depression went away.

Ketamine proved to be very effective at helping the patients recover. In addition, the authors found that ketamine infusions at low rates worked just as well as higher infusion rates.

Dr. Lineberry concluded: "While patients and clinicians are excited about ketamine's potential, we know that much more research lies ahead before we know which depressive conditions can be addressed with ketamine safely by clinicians in routine clinical practice."

The researchers evaluated the side effects of the drug with two different psychiatric scales: "the Young Mania Rating Scale" and the "Brief Psychiatric Rating Scale". Eighty percent of the participants showed signs of significant improvement. During the study five patients had no depression symptoms at all, four weeks after the study was completed two of them were still in remission.

Researchers monitored side effects with two psychiatric scales, the Young Mania Rating Scale and the Brief Psychiatric Rating Scale. Eight of 10 patients showed at least 50 percent improvement.

Side effects of the drug included:
* Brief and limited hallucinations
* Drowsiness
* Dizziness

Further Research

The evidence for the antidepressant effectiveness of Ketamine is so overwhelming that quite a few pharmaceutical companies are feverishly working on Ketamine analogues and delivery methods (e.g. nasal sprays) as well as alternative NMDA modulators that can be patented and thus would be worthwhile to put through the highly demanding FDA approval process. Preliminary results are so promising that one can reasonably hope to have truly effective antidepressants available within another decade or so. If this happens, a mental health revolution will be at hand. And it will be sorely needed. Having rapidly acting and unequivocally effective antidepressants widely available and covered by insurance (akin to antibiotics) will make all the difference.

HNK as an Alternative

One of the latest researches discovered that the Hydroxynorketamine (HNK), a by-product of the psychoactive drug ketamine, may treat symptoms of depression just well as ketamine without the unwanted side effects.

"We found that the HNK compound significantly contributes to the antidepressive effects of ketamine in animals but doesn't produce the sedation or anesthesia, which makes HNK an attractive alternative as an antidepressant in humans”, noticed Irving Wainer, PhD, senior investigator with the Intramural Research Program at the National Institute on Aging, in Baltimore, Maryland. Dr. Wainer is listed as a coinventor on a patent application for the use of ketamine metabolites in the treatment of bipolar disorder and major depression. He suggests that HNK, like ketamine, not only produced potent and rapid antidepressant effects but also stimulated neuroregenerative pathways and initiated the regrowth of neurons in rats' brains.

Obviousely, more clinical research is required before offering the NHK administration to overcome depression in humans, however, the preliminary results are quite promising.

Ketamine Self-Administration

Commonly used as an anesthetic for both humans and animals, ketamine is described by the U.S. Drug Enforcement Administration as a dissociative anesthetic with hallucinogenic properties. Some users say that, when taken at high enough doses, the drug can induce a terrifying out-of-body experience known commonly as a "K-hole." The drug is also known to cause anxiety, amnesia and cognitive difficulties.

Medical experts have strictly warned against self-medicating with ketamine. In clinical studies, the drug is typically administered only in small doses, and patients are always supervised closely.

While that might be very tempting to try it to relieve your depression symptoms, we would warn you against such attempts. As you will not be able to determine the proper dosage, the potential positive effect might be overpowered by the unexpected side effects from the drug consumption.

Sources and Additional Information:

Updates 08-22-16

Aug. 18, 2016 -- The experimental drug esketamine (also known as ketamine) has been placed on the fast track for U.S. Food and Drug Administration approval for treating major depression, according to Janssen Pharmaceutical.

Ketamine -- perhaps best known as a street drug -- is listed by the World Health Organization as an important anesthetic and has been used off-label for pain, anxiety, depression and post-traumatic stress disorder, CNN reported.

In 1970, the drug received FDA approval for use in people and was used on American soldiers in Vietnam as an analgesic and sedative. However, doctors became reluctant to use it because it caused minor hallucinogenic side effects.

Depression causes damage to nerves and their transmission pathways, and research leads scientists to believe ketamine remodels those nerves, triggering neuroplastic processes that make new connections among brain cells, Dr. Dan Iosifescu of the Icahn School of Medicine at Mount Sinai in New York City told CNN. "What's unique about ketamine is, this happens in hours or days, while with other depression medications, this happens in weeks to months," he said.


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