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Ketamine in the media

Listed below are some interesting news articles we’ve seen about ketamine.

When psychiatrists write a prescription for a typical antidepressant such as Zoloft or Paxil, they don't expect their patients to show much improvement for a few weeks. Clinical trials, however, have shown that low doses of a drug known as ketamine, which is used at higher doses as an anesthetic and is taken recreationally as a hallucinogen (sometimes called "Special K"), can ease the symptoms of depression within hours. Now, scientists have figured out how ketamine works in the brain. In the process, they've uncovered a new molecular pathway involved in clinical depression.

Neuroscientist Lisa Monteggia and her colleagues at the University of Texas Southwestern Medical Center in Dallas began their work on ketamine by verifying what other scientists have shown: 30 minutes after receiving a dose of ketamine, mice prone to depression show an easing of their symptoms. When put in a tub of water, mice considered depressed quickly give up escape attempts and instead float motionless. After receiving ketamine treatment, such mice swim for a longer period of time in the water.

Monteggia's team then moved toward understanding how the drug affects the brain. Scientists already knew that ketamine binds to, and blocks, a receptor in the brain called NMDAR, which triggers its anesthetic effects, so Monteggia's group used other compounds to block NMDARs in mice. As the water test revealed, the animals depression once again lessened, so the researchers knew that ketamine's antidepressant effects also depended on NMDAR. Next, the team studied how levels of certain proteins in the brain changed when mice were given ketamine. Blocking NMDARs with other compounds turns off production of some proteins, but ketamine causes the neurons to make more of a protein called BDNF (brain-derived neurotrophic factor), the researchers report online today in Nature. The findings suggest a new set of molecules that ketamine and NMDAR affects, and that means a new set of molecules involved in depression.

"There was no precedent for this," Monteggia says. "We had no idea why blocking an NMDAR would produce protein." There are two ways of activating NMDARs. Some turn on when the specific neurons fire to accomplish a task—be it learning, memorizing, or thinking. But other NMDARs are activated simply as background noise in the brain. Ketamine, the researchers showed, doesn't block the brain from activating NMDARs when it's using them to send a specific message. But it does block them from creating that background noise. Although scientists have long known about the brain's spontaneous level of background nerve firing, Monteggia's study is the first to suggest a link between such background noise and depression.

"What we're suggesting is that this background activity is important," Monteggia says. She says that the link between spontaneous nerve firing and depression could also explain why electroconvulsive therapy (also known as "electroshock therapy") eases depression--perhaps ECT and ketamine reset the background brain activity. Furthermore, Monteggia's group identified a new molecule that carries out NMDARs' effects on spontaneous brain activity. When the researchers activate this protein, called eEF2, in mice, they see the same fast-acting antidepressant action. A drug that targets eEF2 instead of NMDARs could treat depression, Monteggia says.

Carlos Zarate, a psychiatrist at the National Institute of Mental Health, in Bethesda, Maryland, who led many of the initials studies of ketamine as an antidepressant, says that the study goes far in uncovering a new pathway involved in depression. "It brings about a new series of targets for drugs that has not been pursued at all."

Although ketamine is used for short-term depression treatment in humans, its potential for abuse keeps doctors from prescribing it for the long term. A drug that targets the ketamine pathway in another way could offer antidepressants without the same potential for abuse. The next questions, Zarate says, are whether eEF2 is a safe drug target in humans and what other pathways are involved in depression.

It’s probably not the first place you’d go to find relief from severe clinical depression, but the psychedelic party drug ketamine has revealed itself to be something of a 'miracle drug', performing far more quickly and effectively than traditional antidepressants and mood stabilizers.

Where current treatments take weeks to work - and then might not work at all, depending on the patient - ketamine has been shown to treat the symptoms of depression within hours.

"It’s not subtle. It’s really obvious if it’s going to be effective," Enrique Abreu, a Portland-based doctor who began treating depressed patients with ketamine in 2012, told The Washington Post. "And the response rate is unbelievable. This drug is 75 percent effective, which means that three-quarters of my patients do well. Nothing in medicine has those kind of numbers."

Also known as Special K, ketamine first came on the scene as an hallucinogenic club drug in the 1960s, but has since been embraced by emergency rooms as a quick and easy anesthetic. It’s used as an anesthetic for children with broken bones, during emergency surgery in war zones, and is often given to patients in burn centers as a sedative.
But over the past decade, the drug’s enormous potential in the treatment of mental health issues has become a focus for researchers and psychiatrists trying to come up with a solution to severe depression where currently available medications have failed.

"Since 2006, dozens of studies have reported that it can also reverse the kind of severe depression that traditional antidepressants often don’t touch," Sara Solovitch reports for The Washington Post. "Experts are calling it the most significant advance in mental health in more than half a century."
Why is a new treatment option for depression so exciting? Put simply, for many people with severe depression, the drugs available to them - known as selective serotonin reuptake inhibitors (SSRIs) - pretty much suck. Not only do they take three to eight weeks to actually have an effect, but once you make it through those months of waiting, there’s no guarantee they’ll actually work for you.

As we reported back in July, SSRIs are believed to work by limiting the reabsorption of serotonin into the brain’s presynaptic cell, and this readjustment of serotonin levels appears to help the brain cells send and receive chemical messages more effectively, which can boost a person’s mood. 

But every SSRI has a different chemical make-up, and it’s basically a case of trial-and-error to see which ones will benefit or mess with your unique brain chemistry. And on top of not being super effective for many people, SSRIs are also known to cause a range of negative side effects, such as nausea, dizziness, drowsiness, insomnia, weight gain, and reduced sexual desire or erectile dysfunction. Clearly, there has to be a better way. 

Academic medical centers across the US are now increasingly opting to treat their patients with ketamine, including Yale University, the University of California at San Diego, the Mayo Clinic, and the Cleveland Clinic. The drug is administered by a single intravenous infusion at doses less than those used in anesthesia, which is thought to prevent addictions from developing. 

Patients who’ve had no choice but to keep trawling through the various types of SSRIs for years to see if one fits - while having to deal with the debilitating effects of having untreated depression - are finally seeing results, sometimes as quickly as within 2 hours of taking the drug.

"There is a significant number of people who don’t respond to antidepressants, and we’ve had nothing to offer them other than cognitive behavior therapy, electroshock therapy and transcranial stimulation," L. Alison McInnes, a psychiatrist from the Kaiser Permanente clinic in California, told Solovitch.
Just yesterday, researchers from Vanderbilt University Medical Centre published the results of a study where mice with alcoholism had their depressive-like withdrawal symptoms reversed when treated with ketamine.

So why does ketamine work so well? Scientists aren’t actually sure, but a 2010 study published in Science suggests that by blocking proteins called NMDA receptors, the drug prompts the brain to increase the production of synaptic signaling proteins in the prefrontal cortex - a region thought to regulate complex cognitive, emotional, and behavioral functioning. 

In doing this, it appears to be not only promoting the growth of new synapses, which leads to greater connectivity in the brain, but it’s also switching certain connections on and off, and for whatever reason, this has a rapid anti-depressive effect. SSRIs, on the other hand, target the serotonin and noradrenalin systems in the brain.

The drug isn’t perfect by any means - some patients find the hallucinations it causes to be uncomfortable, and the cost isn’t regulated, which means it can get very expensive depending on where you get it. It's also not a 'cure' - time between doses varies between person to person, but in order to treat the symptoms of severe depression, you need to keep taking it, just like traditional anti-depressants. 

That said, the fact that it's bringing relief to many people who are resistant to SSRIs is really exciting, and with so much support for the drug as a mental health aid in the medical community right now, we're only going to get a better understanding of its potential.

Editors’s note: It has been brought to our attention that despite many positive first-hand accounts from treatment-resistant depression patients, and the researchers and doctors who work with them, some researchers are in opposition of ketamine being touted as a treatment for depression. 

While there have been many studies conducted on the antidepressant effects of ketamine, and positive accounts from patients who have found no success from traditional drugs, criticism has been squared at the limited sample sizes of these studies and the strength of the evidence - most notably, this 2015 review.

"Nearly all ketamine studies had short-term follow-ups," Keith Harris from the University of Queensland, Australia told Science Alert. "Very few tested even modestly long-term affects on substance abuse and other possible effects."

As with many experimental drug treatments with conflicting statements for and against their merits, it will take many years to figure out the true value of ketamine in this space.
What we do know is patients with few alternatives have benefitted from it, and research institutions are investing a lot of time and money into figuring out its potential, and we'll update you with more information as it's made known.

  • Although the molecular action of pharmacotherapeutic treatment for major depressive disorder (MDD) is immediate, it may take weeks for the therapy to be effective. Evidence suggests that ketamine, an arylcycloalkylamine-derived NMDA receptor antagonist, produces rapid-onset antidepressant action in patients with MDD. Twenty-nine studies have evaluated the antidepressant effects of ketamine with response rates from 25–100% and time to attainment of response typically within hours; however, there were no comparators to control for the subjective effects of ketamine in these studies which may indicate an enhanced placebo effect. In animal studies, the acute administration of ketamine consistently produced an anti-depressant like effect of rapid onset in rodent models with depression, although this is not definitive for clinical antidepressant activity.

The mechanism of action is unknown but it is proposed that it is due to the targeting of sites including the AMPA receptor, neurotrophins, MTOR, GSK-3, GABA, and others. Because ketamine can cause psychotomimetic disturbances similar to PCP (phencyclidine) such as visual and auditory hallucinations, sedation and possible sleep disturbances, diarrhea, and impairment of certain types of memory, it is not likely to be a first-line medication for most MDD patients but continues to be recognized as a potential treatment with rapid-onset antidepressant effects.

  • Ketamine Psychedelic Therapy (KPT): A Review of the Results of Ten Years of Research
  • Ketamine is a prescription drug used for general anesthesia. In subanesthetic doses, it induces profound psychedelic experiences and hallucinations. The subanesthetic effect of ketamine was the hypothesized therapeutic mechanism in the authors' use of ketamine-assisted psychotherapy for alcoholism. The results of a controlled clinical trial demonstrated a considerable increase in efficacy of the authors' standard alcoholism treatment when supplemented by ketamine psychedelic therapy (KPT). Total abstinence for more than one year was observed in 73 out of Ill (65.8%) alcoholic patients in the KPT group, compared to 24% (24 out of 100 patients) of the conventional treatment control group (p<0.01). The authors' studies of the underlying psychological mechanisms of KPT have indicated that ketamine-assisted psychedelic therapy of alcoholic patients induces a harmonization of the Minnesota Multiphasic Personality Inventory (MMPI) personality profile, positive transformation of nonverbalized (mostly unconscious) self-concept and emotional attitudes to various aspects of self and other people, positive changes in life values and purposes. important insights into the meaning of life and anincrease in the level of spiritual development. Most importantly, these psychological changes were shown to favor a sober lifestyle. The data from biochemical investigations showed that the phannacological action of KPT affects both monoaminergic and opioidergic neurotransmitter metabolism, i.e., those neurochemical systems which are involved in the pathogenesis of alcohol dependence. The data from EEG computer-assisted analysis demonstrated that ketamine increases theta activity in cerebrocortical regions of alcoholic patients. This is evidence of the reinforcement of limbic cortex interaction during the KPT session.
  • A recent CBS news segment featured a doctor in Florida talking about his success treating fibromyalgia with intravenous (IV) ketamine, a medication usually used for surgical anesthesia. One of his patients described that her fibromyalgia pain was “virtually eliminated” by this treatment.

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I wasn’t surprised to hear this. A few years back, several of my fibromyalgia patients reported mysterious pain reduction that lasted for several weeks after they underwent seemingly unrelated surgeries. In each case, I found the only consistent feature was not the type of surgery they had, but that that they had all received IV ketamine as part of their anesthesia during surgery.

The fascinating—and exciting part—is that although IV ketamine is used in anesthesia to block pain signals only temporarily, for some fibromyalgia patients it seemed to trigger a more long-lasting “cool down” of the pain signals, allowing for a period of sustained pain relief without any further medication. We don’t understand exactly how ketamine might trigger sustained pain relief. We do know that ketamine’s primary action is to block certain receptors (NMDA) that act to transmit pain signals. These NMDA receptors are massively overstimulated in fibromyalgia.

So it’s possible that a large IV dose may act to reset the system; like rebooting a computer (Have you tried turning it on and off again, the magic words any IT service person will tell you!). However, ketamine also activates opiate receptors and boosts levels of other pain lowering chemicals like serotonin, norepinephrine, and dopamine. It may be a combination of these actions that results in a pain “reboot.”

Ketamine’s medical usage has largely been curtailed because it can also be a drug of abuse. As a street drug it is known as Special K. However, resistance to medical usage is slowly changing, as more and more studies show benefit for illnesses that don’t have many treatment options. IV Ketamine has been most well studied as a treatment for resistant depression. A Washington Post article called ketamine for depression “the most significant advance in mental health in more than half a century.”

IV ketamine is slowly becoming more accepted and available for severe depression. In fact, several academic medical centers, including Yale University, the University of California at San Diego, the Mayo Clinic and the Cleveland Clinic, have begun offering IV ketamine treatments off-label for severe depression. This treatment has also shown great promise in complex regional pain syndrome, characterized by severe pain, swelling, and skin changes usually occurring after an injury.

Ketamine given intravenously is a more potent pain reliever than morphine for fibromyalgia. http://www.ncbi.nlm.nih.gov/pubmed/8610220
In one study, more than half of the patients who were treated with IV ketamine reported at least a 50% decrease in their pain levels. http://www.ncbi.nlm.nih.gov/pubmed/10781923 But these two studies only looked at immediate reduction of pain.

To assess for long-term benefits, other researchers gave one dose of IV ketamine and then tracked fibromyalgia pain levels after two weeks and then again at eight weeks. At two weeks, some residual pain benefits remained, but these had disappeared by week eight. http://www.ncbi.nlm.nih.gov/pubmed/21482474 There may be dosage or timing issues at play here, as extrapolating from research on CRPS sustained pain benefit was seen only after subjects received a series of several IV ketamine infusions over several weeks. http://www.ncbi.nlm.nih.gov/pubmed/23703410

For now, IV ketamine for fibromyalgia remains very much an experimental treatment. This means it is usually not covered by insurance and can be expensive. But as research progresses, this is slowly changing and more pain clinics are starting to offer this treatment.

  • The drug ketamine has been used intravenously for years to rapidly treat depression, because it can take effect within hours. Unfortunately, its antidepressant effects fade in 3–5 days, and it has some unpleasant side effects. In larger doses ketamine is used as an anesthetic and sometimes as a club drug, for its ability to induce hallucinations and dissociation. It can be addictive as well.

A 2016 animal study by Todd Gould and colleagues published in the journal Natureidentified a byproduct of ketamine that may be able to provide the drug’s benefits without its side effects.

When the body breaks down ketamine, it produces several chemicals that are known as ketamine metabolites. The researchers found that one of these, called hydroxynorketamine, reversed a depression-like state in mice, without producing the side effects that would be expected of ketamine.

Gould and colleagues also determined that blocking the transformation of ketamine into hydroxynorketamine prevented ketamine’s antidepressant effects.
Ketamine’s unpleasant anesthetic and dissociative effects result from the blockade of a particular receptor for the neurotransmitter glutamate (the NMDA glutamate receptor). Researchers originally thought that the NMDA blockade was linked to ketamine’s antidepressant effects, but this appears not to be the case. Instead, hydroxynorketamine seems to activate a different type of glutamate receptor, the AMPA receptor.

Gould and colleagues plan to test hydroxynorketamine in humans soon. Because it has already been present in the human body following ketamine administration, they expect it to be safe.

There is a Light at the end of the Tunnel I’M READY!