Ketamine acts fast to treat depression and its effects last — but how?

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 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.

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Now, researchers led by Mark Rasenick, distinguished professor of physiology and psychiatry at 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.

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 drug’s 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.”

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(Source: today.uic. edu)

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  1. Study Shows Rapid Brain Response to Ketamine for Depression

    Key Takeaways
    A new investigation shows a greater perception of how ketamine reduces depressive signs immediately.
    The drug can probably create advantageous changes in the cerebellum for better habitat management.
    Because of its side effects and addiction potential, it should only be taken under preventive supervision.
    For treatment-resistant depression, the lengthy process of seeking different medications can add frustration on top of an already amazing condition. That is why many who undergo depression and those who treat them are reflecting wider use of ketamine, a dissociative drug, is taken by recreational users to feel more detached from reality and themselves.

    A new study by clinical researchers at the Karolinska Institute in Sweden, and declared in the June 2020 issue of Translational Psychiatry, is highlighting why this drug works so swiftly and how also low doses can be advantageous for those with major depressive dysfunction.1

    Researchers used brain scans of 30 members who had tried the several commonly prescribed antidepressant treatment—selective serotonin reuptake inhibitors (SSRIs), such as Celexa, Lexapro, Prozac, Paxil, and Zoloft—and not obtained relief from their distress. After a low dose of 0.5mg of ketamine, the scans showed that they had an enhanced number of serotonin 1B receptors.

    Serotonin is a compound your body produces that sends signals connecting your nerve cells, and it’s been shown to contribute to mood management and feelings of wellbeing.

    SSRIs work by raising levels of serotonin in the head, but if there are not enough receptors to “catch” the chemical, they often don’t work as well as they could. Increasing the number of receptors leaves more serotonin and different feel-good neurotransmitter, dopamine, to be released further efficiently, and this can reduce depressive indications.

    In the research, this method happened within 24 to 72 hours after the ketamine dose for 72% of members.1

    Over 17 million people or about 7% of all grown-ups in the U.S. are dealing with depression.2 While the preponderance of those with depression receive some mixture of therapy and medicine, as much as 35% of people who have suffered a significant depressive episode do not accept treatment.

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    “These results aren’t surprising, since one of the most compelling aspects of ketamine is that it works very quickly, sometimes within hours,” says Keith Heinzerling, MD, internist, and habit medicine specialist at Providence Saint John’s Health Center in Santa Monica, California.

    For someone who is feeling self-destructive or experiencing other severe, debilitating symptoms of depression, this can be what gets them past that enough to be managed.
    — KEITH HEINZERLING, MD
    Yesterday, Now, and Potential of Ketamine
    Although the recent study was relatively small in terms of participant size, and brief, it does add to the research being done about the effectiveness of ketamine as an antidepressant option. Nevertheless, this is far from being a new treatment.

    According to the European Journal of Anesthesiology, the history of buy ketamine online starts in the early 1950s, when chemists formed the drug as a veterinary anesthetic.3 About a decade later, it began being used on individuals but was found to produce a trance-like, dissociative case. That’s part of the reason it’s currently used in emergency rooms, Heinzerling states, for issues like resetting a dislocated shoulder.

    It has a short-term analgesic effect for disorder control, but it also causes brief memory loss. So, you may go through this traumatic moment of having your shoulder popped back into place, for example, but you won’t remember it.
    — KEITH HEINZERLING, MD
    The drug’s antidepressant effect, though, wasn’t widely reported until 2000, in a study published in Biological Psychiatry.4 Although that was an even smaller study—only seven participants—it did kick off a wider investigation of the medication, which eventually led to FDA approval in 2019 of esketamine, a kind of drug that is given via nasal spray.

    “Part of ketamine’s service is that it has many advantages, and has been extensively used on the battlefield, as well as in the rescue of the Thai soccer team from a cave [in 2019],” says Alex Dimitriu, MD, founder of Menlo Park Psychiatry & Sleep Medicine. “It can elevate mood, reduce stress, and improve sleep. But it absolutely shouldn’t be seen as something you can use on your own as a way to self-medicate.”

    Possible Side Effects

    Because the effects of ketamine are recognized as short-lived related to other types of antidepressants, and because greater doses can create people to fall into a “k-hole” that significantly impairs judgment, it is unlikely ketamine would be prescribed as a standalone, long-term treatment for those with depression, even those who are treatment-resistant, says Heinzerling.

    Also, since Ketamine Crystals a narcotic-classed drug, it does have an addiction risk, he adds.5 It’s related to PCP and has been a party drug with the nickname “Special K.” Buy ketamine in Europe, That’s why ketamine doses are often administered on-site, where patients can be controlled to make sure they aren’t falling into a k-hole or showing signs of dependence.

    The Swedish researchers in the recent study noted that classification of the receptor is important, because it may lead to the development of drugs that have a similar response as ketamine, but without the adverse effects.

    Benefits When Ketamine is Used Properly
    That stated, there are many victims who are finding satisfaction with short-term ketamine usage, Heinzerling adds. The drug is establishing beneficial for helping personalities as they navigate to the treatment that works best for them—which may involve other medicines, cognitive behavioral healing, or other options—a process that can sometimes take ages.

    For example, he says, a sufferer is often given a new antidepressant with a very progressively rising dose, so it may take two weeks to nearly four months to know if it’s acting the way it should. If not, the patient needs to go back to intersection one, trying another treatment—for another four months, and so on.

    “Making this more challenging is that even if you do find a medication that works for you, it might stop working at some point,” says Heinzerling. “Then you have to go through the process again. So, a treatment like ketamine that can fill in the gap is very important. But keep in mind that this is not a first-line strategy, but instead, a short-term aid.”

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    What This Means For You
    Similar to any kind of depression treatment, the use of ketamine needs to be discussed with your healthcare professional, particularly since it’s a checked substance with an addiction risk. If you’re feeling depression, talk with your doctor about treatment options that could be a fit for you. If you are having any thoughts of suicide, help is available 24/7 Email us

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