Study Shows Rapid Brain Response to Ketamine for Depression

For treatment-resistant depression, the lengthy process of trying different medications can add frustration on top of an already overwhelming condition. That's why many who experience depression and those who treat them are considering wider use of ketamine, a dissociative drug taken by recreational users to feel more detached from reality and themselves.

A new study by clinical researchers at the Karolinska Institutet in Sweden, and published in the June 2020 issue of Translational Psychiatry, is highlighting why this drug works so quickly and how even low doses can be beneficial for those with major depressive disorder.

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

Serotonin is a chemical your body produces that sends signals between your nerve cells, and it's been shown to contribute to mood regulation and feelings of wellbeing.

SSRIs work by increasing levels of serotonin in the brain, 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 allows more serotonin and another feel-good neurotransmitter, dopamine, to be released more efficiently, and this can reduce depressive symptoms.

In the research, this process happened within 24 to 72 hours after the ketamine dose for 72% of participants.

Over 17 million people or about 7% of all adults in the U.S. are dealing with depression. While the majority of those with depression receive some combination of therapy and medication, as much as 35% of people who have suffered a major depressive episode do not receive treatment.

"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 addiction medicine specialist at Providence Saint John's Health Center in Santa Monica, California.

Past, Present, and Potential of Ketamine

Although the recent study was relatively small in terms of participant size, and brief in duration, it does add to the research being done about the effectiveness of ketamine as an antidepressant option. However, this is far from being a new treatment.

According to the European Journal of Anaesthesiology, the history of ketamine starts in the early 1950s, when chemists developed the drug as a veterinary anesthetic. About a decade later, it began being used on humans but was found to produce a trance-like, dissociative state. That's part of the reason it's currently used in emergency rooms, Heinzerling says, for issues like resetting a dislocated shoulder.

The drug's antidepressant effect, though, wasn't widely reported until 2000, in a study published in Biological Psychiatry. 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 form of the drug that is delivered via nasal spray.

"Part of ketamine's utility is that it has many uses, 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 lift mood, reduce anxiety, 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 considered short-lived compared to other types of antidepressants, and because higher doses can cause people to fall into a "k-hole" that significantly impairs perception, 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 it's a narcotic-classed drug, it does have an addiction risk, he adds. It's related to PCP, and has been a party drug with the nickname "Special K." That's why ketamine doses are often administered on-site, where patients can be supervised to make sure they aren't dropping into a k-hole or showing signs of addiction.

Benefits When Used Properly

That said, there are many patients who are finding relief with short-term ketamine usage, Heinzerling adds. The drug is proving beneficial for helping people as they navigate to the treatment that works best for them—which may involve other medications, cognitive behavioral therapy, or other options—a process that can sometimes take years.

For example, he says, a patient is often given a new antidepressant with a very gradually increasing dose, so it may take two weeks to nearly four months to know if it's working the way it should. If not, the patient needs to go back to square 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 helpful. But keep in mind that this is not a first-line treatment, but instead, a short-term aid."