How Ketamine Works

[David Baxter PhD]

How Ketamine Works (A Summary of the Two Most Recent Studies)
by Amanda Itzkoff
March 22, 2018

Two New Studies Help Shed Light on How Ketamine Works to Counteract Depression



More and more press releases are calling Ketamine’s antidepressant effects “the biggest thing to happen in psychiatry in 50 years”. The reason for the title is the remarkable speed with which ketamine improves symptoms of depression: in as little as 30 minutes according to some findings. It’s also been somewhat of an answer to prayer for patients with “treatment-resistant depression”, a unique condition characterised by its persistence despite the use of traditional antidepressants. For patients who feel like “they’ve tried everything” psychopharmacology has to offer them, ketamine is emerging as a new hope.

But how exactly ketamine works is bit of a mystery. While many patients were simply grateful for the relief of their condition, scientists continue to pursue answers.

New research has uncovered a mechanism that may partially explain ketamine’s antidepressant effects. Neuroscientist Hailan Hu of Zhejiang University in China explains their findings in brief:

“Ketamine does not directly influence the same chemical messengers as standard antidepressants such as serotonin but rather works via interaction with another chemical, glutamate — not usually associated with mood but rather with brain plasticity. One prominent idea about how it alleviates depression is by promoting the growth of new neural connections”.

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If her findings are correct, the research could be the first step towards developing real relief for depression which the World Health Organization has labelled “the leading cause of disability worldwide”.

Meet the Lateral Habenula: The Dark Twin of the Brains Reward Center
The two new studies out of Zhejiang University dig for deeper understanding of the LHb – the lateral habenula – which is just above the thalamus in the center of the brain. The LHb releases two types of neurotransmitters: excitatory glutamate and inhibitory GABA. Most neurons produce one kind of transmitter. Only two other brain systems, the hippocampus and the brainstem, are able to release both excitatory and inhibitory transmitters.

Disappointment and Depression
Past tests on monkeys have shown that the LHb is linked to emotional disappointment. When the monkeys were denied an expected treat, this region on their brain produced higher levels of inhibitory GABA and they exhibited signs of human depression. When given antidepressants, their GABA levels increased which deepened scientists resolve that the LHb somehow governs emotions related to disappointment.

The First New Study
During the first study researchers injected a drug that blocks NMDA receptors into the LHb of depression-prone rats and saw rapid antidepressant effects. Knowing that ketamine also blocks NMDA receptors they performed the same test and within one hour saw that ketamine was able to stop calcium from flooding into cells causing them to fire (this function that causes depression is known as burst-firing). Antidepressants could not replicate ketamine’s performance.

The Second New Study
The second study looked at what causes the “burst-firing” that triggers depression. They found a protein, Kir4.1 which promotes burst-firing activity in LHb neurons. When they raised these protein levels depression-like behaviors increased, when they blocked this protein, depression-like behaviors decreased. The theory is that the LHb connects to parts of the system that process emotion: the limbic system. The inhibitory GABA produced in the LHb inhibits the limbic system which means “burst-firing” can block reward signals from pleasurable activities. Hu summarized her findings: “Our results provide a simple model of how ketamine leads to disinhibition of the reward center to quickly relieve depression”.

In simplified terms, Ketamine dampens LHb hyperactivity. Hyperactivity in the LHb has been associated with patients who exhibit depressed-like symptoms.

What These New Findings Mean
This new research sheds light on how ketamine works which could help scientists understand how to reproduce ketamine’s effects without some of the side-effects (sometimes patients experience feelings of disassociation and bladder irritation). Research like this can also help further the development of easier treatment administration as ketamine currently has to be administered via IV for the desired effects to take place. Finally, research that fully explains how ketamine works will help make the treatment more accessible for patients as it moves the treatment one step closer to FDA approval and hopefully down-the-road qualifies for insurance coverage.

Sources:

• Getting the Inside Dope on Ketamines Mysterious Ability to Rapidly Relieve Depression - Scientific American
• New Brain Region Knows Why You Are Feeling Down
• Ketamine blocks bursting in the lateral habenula to rapidly relieve depression | Nature
• Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression | Nature

 

[Daniel E.]

High Hopes and Hype for Experimental Depression Drug Ketamine
by Lindsey Tanner, AP Medical Writer
November 1, 2018

Hopes and hype for ketamine to treat depression - YouTube

It was launched decades ago as an anesthetic for animals and people, became a potent battlefield pain reliever in Vietnam and morphed into the trippy club drug Special K.

Now the chameleon drug ketamine is finding new life as an unapproved treatment for depression and suicidal behavior. Clinics have opened around the United States promising instant relief with their "unique" doses of ketamine in IVs, sprays or pills. And desperate patients are shelling out thousands of dollars for treatment often not covered by health insurance, with scant evidence on long-term benefits and risks.

Chicago preschool teacher Lauren Pestikas long struggled with depression and anxiety and made several suicide attempts before trying ketamine earlier this year.

The price tag so far is about $3,000, but "it's worth every dime and penny," said the 36-year-old.

Pestikas said she feels much better for a few weeks after each treatment, but the effects wear off and she scrambles to find a way to pay for another one.

For now, ketamine has not received approval from the U.S. Food and Drug Administration for treating depression, though doctors can use it for that purpose.

Ketamine has been around since the 1960s and is widely used as an anesthesia drug during surgery because it doesn't suppress breathing. Compared to opioids such as morphine, ketamine isn't as addictive and doesn't cause breathing problems. And some studies have shown that ketamine can ease symptoms within hours for the toughest cases.

Its potential effects on depression were discovered in animal experiments in the late 1980s and early 1990s showing that glutamate, a brain chemical messenger, might play a role in depression, and that drugs including ketamine that target the glutamate pathway might work as antidepressants.

Conventional antidepressants like Prozac target serotonin, a different chemical messenger, and typically take weeks to months to kick in—a lag that can cause severely depressed patients to sink deeper into despair.

Ketamine's potential for almost immediate if temporary relief is what makes it so exciting, said Dr.

Jennifer Vande Voort, a Mayo Clinic psychiatrist who has treated patients with depression since February.

"We don't have a lot of things that provide that kind of effect. What I worry about is that it gets so hyped up," she said.

The strongest studies suggest it's most useful and generally safe in providing short-term help for patients who have not benefited from antidepressants. That amounts to about one-third of the roughly 300 million people with depression worldwide.

"It truly has revolutionized the field," changing scientists' views on how depression affects the brain and showing that rapid relief is possible, said Yale University psychiatrist Dr. Gerard Sanacora, who has done research for or consulted with companies seeking to develop ketamine-based drugs.

But to become standard depression treatment, he said, much more needs to be known.

Last year, Sanacora co-authored an American Psychiatric Association task force review of ketamine treatment for mood disorders that noted the benefits but said "major gaps" remain in knowledge about long-term effectiveness and safety. Most studies have been small, done in research settings and not in the real world.

When delivered through an IV, ketamine can cause a rapid increase in heart rate and blood pressure that could be dangerous for some patients. Ketamine also can cause hallucinations that some patients find scary.

"There are some very real concerns," Sanacora said. "We do know this drug can be abused, so we have to be very careful about how this is developed."

Dr. Rahul Khare, an emergency medicine specialist in Chicago, first learned about ketamine's other potential benefits a decade ago from a depressed and anxious patient he was preparing to sedate to fix a repeat dislocated shoulder.

"He said, 'Doc, give me what I got last time. For about three weeks after I got it I felt so much better,'" Khare recalled.

Khare became intrigued and earlier this year began offering ketamine for severe depression at an outpatient clinic he opened a few years ago. He also joined the American Society for Ketamine Physicians, formed a year ago representing about 140 U.S. doctors, nurses, psychologists and others using ketamine for depression or other nonapproved uses.

There are about 150 U.S. ketamine clinics, compared with about 20 three years ago, said society co-founder Dr. Megan Oxley.

Khare said the burgeoning field "is like a new frontier" where doctors gather at meetings and compare notes. He has treated about 50 patients with depression including Pestikas. They're typically desperate for relief after failing to respond to other antidepressants. Some have lost jobs and relationships because of severe depression, and most find that ketamine allows them to function, Khare said.

Typical treatment at his clinic involves six 45-minute sessions over about two weeks, costing $550 each. Some insurers will pay about half of that, covering Khare's office visit cost. Patients can receive "booster" treatments. They must sign a four-page consent form that says benefits may not be long-lasting, lists potential side effects, and in bold letters states that the treatment is not government-approved.

At a recent session, Pestikas's seventh, she leaned back on a reclining white examining-room chair as a nurse hooked her up to a heart and blood pressure monitor. She grimaced as a needle was slipped into the top of her left palm. Khare reached up with a syringe to inject a small dose of ketamine into an IV bag hanging above the chair, then dimmed the lights, pulled the window curtains and asked if she had questions and was feeling OK.

"No questions, just grateful," Pestikas replied, smiling.

Pestikas listened to music on her iPhone and watched psychedelic videos. She said it was like "a controlled acid trip" with pleasant hallucinations. The trip ends soon after the IV is removed, but Pestikas said she feels calm and relaxed the rest of the day, and that the mood boost can last weeks.

Studies suggest that a single IV dose of ketamine far smaller than used for sedation or partying can help many patients gain relief within about four hours and lasting nearly a week or so.

Exactly how ketamine works is unclear, but one idea is that by elevating glutamate levels, ketamine helps nerve cells re-establish connections that were disabled by depression, said ketamine expert Dr. Carlos Zarate, chief of experimental therapies at the National Institute of Mental Health.

A small Stanford University study published in August suggested that ketamine may help relieve depression by activating the brain's opioid receptors.

Janssen Pharmaceuticals and Allergan are among drug companies developing ketamine-like drugs for depression. Janssen leads the effort with its nasal spray esketamine. The company filed a new drug application in September.

Meanwhile, dozens of studies are underway seeking to answer some of the unknowns about ketamine including whether repeat IV treatments work better for depression and if there's a way to zero in on which patients are most likely to benefit.

Until there are answers, Zarate of the mental health institute said ketamine should be a last-resort treatment for depression after other methods have failed.

 

[David Baxter PhD]

I just read a small clinic study of effectiveness in a Canadian outpatient clinic of treatment resistant depression - will try to find the study later but not a large sample size and limited followup time.

As I recall one-third were not helped by ketamine.

Of the others, another third relapsed within two weeks after finishing the series of IV injections.

So on the short term only one third really benefited and for all we know they relapsed after the study ended.

Definitely not the cure-all some people are trying to sell.

 

[Daniel E.]

Might as well use the money to go on vacation. Even if one may not enjoy it much, at least there would be some stimulating novelty.

 

[Daniel E.]

Also, even $1,500 would pay for a good deal of therapy. Most people who go to therapy stop sooner than later compared to the old standard of going weekly for years, if necessary.

Of course, in theory, ketamine would be great for addressing at least any short-term risk of suicide without requiring hospitalization. Like previous articles have said, it would be like going to the ER for anything else (and without having to pay out-of-pocket).

 

[Daniel E.]

Today, CBS's morning show was talking about the nasal spray version which would likely be paid for by insurance if approved by the FDA. They said this could provide hope for people with severe depression:

FDA could approve ketamine nasal spray as depression treatment - CBS News

But it will not be available at pharmacies:

Taking the drug will be a lot more complicated than taking Prozac. It has been formulated so that it can be delivered as a nasal spray, but people have to get the drug at a doctor’s office, and they won’t be allowed to drive for at least 24 hours, said Gerard Sanacora, a Yale University psychiatrist who has been involved in the clinical trials.

Ketamine seems to ease depression; soon we'll see what else it does, says Faye Flam | Their View | pressofatlanticcity.com

 

[Daniel E.]

It was approved:

Fast-Acting Depression Drug, Ketamine, Newly Approved, Could Help Millions - The New York Times