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Ketamine Treatment for Depression

How ketamine works for treatment-resistant depression

Writer: Caroline Miller

Clinical Expert: Lucian Manu, MD

Ketamine, a drug that’s been used as an anesthetic for 50 years, is getting a lot of attention as a promising new treatment for adolescents who haven’t responded to other treatments for depression and suicidality.

Ketamine is what’s called a “dissociative” anesthetic, which means that it can make you feel detached from your body and surroundings, and have hallucinations. It was a popular party drug in the 1990s and 2000s, known as “Special K.” In the last decade ketamine has been used with success for treatment-resistant depression (TRD) in adults — those who haven’t responded to two or more trials of antidepressant medication. It’s increasingly being used for teenagers who haven’t gotten relief from other treatment for depression, too.

In 2019 the FDA approved a form of ketamine called “esketamine” for adults with treatment-resistant depression. Esketamine is delivered in the form of a nasal spray, brand name Spravato.

Esketamine is not currently FDA approved for anyone under 18, but small studies have shown it to be safe and effective for adolescents, and it’s being used off-label for kids who are still depressed after trying other treatments. Insurance companies require proof of two previous trials of antidepressant medication before they will cover ketamine treatment.

One of the advantages of ketamine is that it produces symptom relief very quickly, in less than an hour, rather than the weeks it takes for antidepressants to take effect. “The upside of ketamine is that it’s rapid acting,” says Lucian Manu, MD, a psychiatrist and the founding director of the Stony Brook Treatment Resistant Depression Program. Dr. Manu has treated many patients, including teenagers, with ketamine. “You see results, you see improvements very soon. I don’t want to say right away, but almost.” The immediate response makes ketamine especially attractive for patients who are at high risk for suicide.

How does ketamine work?

Ketamine appears to work by binding to receptors in the brain, Dr. Manu explains, including those called NMDA receptors. When ketamine binds to those receptors, it increases connectivity among neurons, which is thought to affect mood. “There’s a lot of research going on, but somehow it stimulates the formation of new synaptic buds, and the proliferation of new synapses,“ says Dr. Manu.

What happens in a ketamine session?

Because ketamine can affect a patient’s blood pressure and heart rate, it is delivered in a supervised setting, to allow doctors to monitor vital signs. It’s also monitored because ketamine is a controlled substance — a Schedule III drug, which means it has medical use but also a risk of dependence or misuse.

With patients starting on ketamine, Dr. Manu introduces the drug in a prep session before the first treatment. “I give them a very tiny dose of the medication, the smallest amount,” he says, so they will know what to expect.

A treatment session with esketamine, in the form of a nasal spray, usually takes about two hours. The first effect of the drug the patient experiences after taking it is what Dr. Manu calls a psycholytic effect. “The psycholytic experience is basically when your defense mechanisms start to diminish and you start to feel a little bit freer to talk about things,” he explains. “People feel less anxious, less uptight, less guarded.”

During the psycholytic phase, Dr. Manu sees adolescent patients who tend to be reticent to open up. “It’s like a dam is broken. They start talking and free associating.” The clinician guiding and monitoring them has an opportunity to do a little psychotherapy.

Then as the drug continues to take effect, the patient moves into the psychedelic phase. The term psychedelic is derived from the Greek words “psyche” (mind) and “deloun” (to make visible or reveal). With ketamine, as Dr. Many puts it, “the deeper part of the mind is manifested.”

As the patient goes into the psychedelic phase, they turn inward, Dr. Manu says. They may experience intense introspection, as well as hallucinations, “out-of-body” experiences, or a sense of being in a different reality.

The clinician’s role is just to keep an eye on them to make sure they’re safe. After about an hour the patient begins to emerge and talk a bit more with the clinician. “Then they integrate with their therapist,” Dr. Manu adds. “Or we integrate at the next session, the next treatment.”

By integration, Dr. Manu means discussing what the patient has taken from the session. “I encourage them to look back and see what they can extract from the experience, what they remember visually or conceptually or sensorially, and be curious about what that means for their life.”

Because of the anesthetic effect, at the end of a ketamine treatment session, the patient needs a ride home.

How long does a course of ketamine treatment take?

A course of ketamine is split into two phases: induction and maintenance. In the first phase patients usually take ketamine twice a week for about four weeks. Then, when the treatment response is thought to be as strong as possible — the patient’s depression symptoms are reduced or in remission — the frequency of sessions is gradually cut during the maintenance phase.

“So we go from twice a week to once a week. And then if that goes well, we go to every other week and then we try every three weeks,” explains Dr. Manu. “Sometimes patients may have little bumps — their mood may be reactive to different stressors. We may decide to go back up to every two weeks. But essentially the trend is to try to, if possible, wean them off or at least keep them at the lowest number of treatments.”

Dr. Manu describes one patient who began treatment when she was 13 and so depressed, she was unable to function in school. She’s now in college and looking at law schools, and she continues ketamine treatments once every eight weeks.

Ketamine is safe to take with antidepressant medications — in fact esketamine was FDA approved along with an antidepressant. “The original FDA approval was for patients who didn’t respond to one or two antidepressants, and those patients were actually treated with a new antidepressant with ketamine added to it,” Dr. Manu explains. There is a study in progress looking at esketamine as a standalone therapy, he adds, but that’s still in the works.

What is the difference between ketamine and esketamine?

Ketamine was discovered and synthesized in 1962 by a scientist at Parke-Davis who was looking for a better anesthetic— one that worked without weakening the patient’s vital signs. Although the original patent on ketamine expired in the 1980s, a pharmaceutical company wanting to develop it as a drug for depression can’t get a patent on it. “Some people call ketamine an orphan drug,” says Dr. Manu, “because nobody owns it. Everybody owns it.”

But patents are available for new formulations, and Jansson, the pharmaceutical company, found a way to make it patentable. Ketamine is made up of two molecules, called isomers, that are mirrors of each other, called S-ketamine and R-ketamine. Jansson researchers found that the S-ketamine is the stronger isomer and the R-ketamine is a bit weaker. So Janssen got a patent on that S-ketamine part of the molecule. Hence the name esketamine, marketed as Spravato. It’s currently the only form of ketamine that is FDA approved for depression, so it’s the most mainstream in the U.S.

What are the side effects of ketamine?

The most dramatic side effect of ketamine is the dissociative symptoms that characterize it. It can also cause nausea, which can be managed with anti-nausea medication. Some patients report dizziness or fatigue. Blood pressure and heart rate should be monitored by a doctor during a session.

But most adolescents like the experience, Dr. Manu says. “Most of them are very engaged with it. They like what the ketamine brings and what the ketamine provides. They look forward to the treatment because it gives them relief.”

How long do the effects of ketamine last?

Ketamine is rapid acting, but how long the symptom reduction lasts is unpredictable. The maintenance period, in which sessions are farther and farther apart, tests how durable the effect is. “Everybody’s different,” Dr. Manu explains. “We have patients who have difficulty going from once a week to every other week. So I keep them on the once a week longer. Patients who have difficulty going from every other week to every three weeks. So I keep them on the every two weeks longer. So different patients are at different stages of their maintenance treatment.”

Dr. Manu finds that ketamine treatment is more effective alongside evidence-based psychotherapy like CBT. “The treatment is much better when we use psychotherapy as part of it,” he says. “And there are a few studies showing that the treatment response from ketamine can be improved and prolonged when you use even small forms of cognitive behavioral therapy, for example.”

Adding other treatments

Dr. Manu also believes combining treatment modalities can help patients who are not reaching remission with one type of treatment. 

“If we start ketamine and we see that we can’t get them to a lower frequency than what we’re doing today,” he explains, “then I may add TMS.”

TMS, or transcranial magnetic stimulation, is another relatively new treatment for depression that has been shown to help patients who haven’t responded to therapy and medication. TMS works by using high-frequency magnetic pulses to stimulate a brain region that is underactive in people with depression.

And if a patient is doing TMS and still having symptoms, Dr. Manu may also offer the option of switching to or adding ketamine.

Dr. Manu sees combining treatments as becoming more common. “I think it’s the way of the future — instead of trying them sequentially, one after another, after another, you try to try them in synergy.”

This article was last reviewed or updated on September 18, 2023.