By Lindsey Tanner | APOctober 31 at 12:14 PM

CHICAGO — 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 used ketamine to treat depression patients 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.

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Follow AP Medical Writer Lindsey Tanner at @LindseyTanner .

___

The Associated Press Health & Science Department receives support from the Howard Hughes Medical Institute’s Department of Science Education. The AP is solely responsible for all content

Copyright 2018 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

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A study led by Massachusetts General Hospital (MGH) investigators identifies two subanesthetic dosage levels of the anesthetic drug ketamine that appear to provide significant symptom relief to patients with treatment-resistant depression. In the October 2018 issue of Molecular Psychiatry they describe finding that single intravenous doses of 0.5 mg/kg and 1.0 mg/kg were more effective than an active placebo in reducing depression symptoms over a three-day period. Two lower dosage levels that were tested did not provide significant symptom relief, although some improvement was noted with the lowest 0.1 mg/kg dose.

“Treatment resistance in depression is a major issue, with more than half of patients not responding adequately to standard, appropriate antidepressant treatment,” says Maurizio Fava, MD, executive director of the Clinical Trials Network & Institute in the MGH Department of Psychiatry and senior author of the Molecular Psychiatry paper. “There are only a few approved therapies that can help some patients with treatment-resistant depression, so we critically need more options to choose from.”

Long used as a general anesthetic drug, ketamine has been found in several studies to rapidly relieve depression symptoms when given at low, subanesthetic doses. Most of those studies used a standard 0.5 mg/kg intravenous dose, leaving determination of the optimal dosage unclear. To investigate that question, the study tested four different ketamine dosages – 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg and 1.0 mg/kg – compared with an “active” placebo, a drug that induces side effects, the lack of which could lead participants to realize they are not receiving the medication being tested, potentially biasing their perception of symptom improvement.

The study enrolled 99 adults with treatment-resistant depression at six research centers – MGH, Baylor College of Medicine/Debakey VA Medical Center, Icahn School of Medicine at Mt. Sinai, Stanford University School of Medicine, University of Texas/Southwestern Medical Center, and Yale University. Participants were randomized into five groups – the four dosage levels and the active control group, with neither they nor the research staff aware of group assignments – and continued taking their previously prescribed antidepressants during the study period.

Participants were assessed with a standard depression rating scale the day they received the infusion and 2, 3, 5, 7, 14 and 30 days later. Additional instruments measured aspects of mood and suicidal thought. Dissociative symptoms such as memory loss and feelings of detachment from reality were assessed during and after ketamine infusion, and vital signs were measured after treatment and at all follow-up visits.

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On the standard depression scale, participants receiving ketamine had significantly greater symptom improvement during the three days after infusion than did those in the active control group. Comparison of dosage levels, after adjusting for multiple comparisons, found statistically significant improvement compared to the control group only for participants receiving 0.5 mg/kg and 1.0 mg/kg doses. The low 0.1 mg/kg dose produced significant relief only prior to adjustment, and the 0.2 mg/kg dose did not show any significant benefits. It is possible that the lack of efficacy at the 0.2 mg/kg level could reflect the small size of treatment groups and the fact that participants in that group tended to be more treatment resistant to begin with, the authors note.

For most participants in the higher-dose groups, the benefits of ketamine treatment began to decrease on the third day after treatment and were no longer detectable after five days. There were no significant differences in the occurrence of adverse events among all study participants.

Co-author Cristina Cusin, MD, who directs the MGH Psychiatry ketamine clinic, says “These results support the clinical observation that one size – in this case the most studied dose of 0.5 mg/kg – does not fit all, as some patients may require a lower-than-average dose; and each patient needs a tailored treatment plan that may include ketamine, together with other medications and talk therapy. We still do not understand which factors play a role in determining lack of response to treatments or which is the best possible strategy for patients suffering from severe depression.”

Fava, the Slater Family Professor of Psychiatry at Harvard Medical School, adds, “Along with supporting the efficacy of intravenous ketamine for patients with treatment-resistant depression, our study also suggests that even lower doses may be effective in some patients. Further investigation should examine the efficacy of repeat doses of ketamine, as well as whether higher doses may require less frequent administration.”

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By MEGAN THIELKING @meggophone

OCTOBER 11, 2018

As ketamine clinics pop up across the U.S. to offer experimental infusions for depression, anxiety, and a slew of other conditions, training programs to teach providers how to run these businesses have also started to appear. They promise to teach everyone from anesthesiologists to advanced practice nurses the ins and outs of ketamine, which has been used for decades as an anesthetic but is still under study as a therapy for psychiatric disorders.

The doctors and nurse anesthetists offering the courses say they’re urgently needed to try to bring some standardization to the booming ketamine treatment business. “I think [ketamine] is going to get wider spread use in one capacity or another. I’d like to see that be done appropriately,” said Dr. Gerald Grass, an anesthesiologist who runs the Ketamine Institute, a training program run out of the Sarasota, Fla., practice where he also treats patients with ketamine. But some mental health experts say there isn’t yet enough evidence about how to use ketamine to offer training. They fear some of those signing up for the programs might be trying to break into the business to make a quick buck.

“If I thought there was a standard protocol … then I think [training] could be very useful. But I’m not sure we have that yet,” said Dr. Gerard Sanacora, a psychiatrist, professor, and the director of the Yale Depression Research Program. “There is a real limited amount of data. It’s ethically a challenging and clinically a challenging situation.”

Sanacora said he understands, however, the growing interest in ketamine: Many patients who haven’t benefited from conventional depression treatments are in desperate need of relief.Related: Do you have an experience with ketamine treatment? Share your story with us

Studies suggest that the drug holds potential as a treatment for major depression in some — though nowhere near all — patients. A dose much smaller than what’s used for anesthesia, given through an IV, stems symptoms of severe depression in some patients with treatment-resistant depression, often within hours.

But there are gaping holes in the data on long-term effects of ketamine, potential risks down the road, and the best way to integrate the drug into a broader mental health care plan.

A STAT investigation published last month found wide-ranging inconsistencies among clinics. Some clinics don’t thoroughly screen patients, and experts worry they’re offering the drug to anyone who can afford it. Providers charge anywhere from $350 to close to $1,000 per infusion and many patients get at least six rounds of the treatment. Some clinics, too, offer ketamine for uses that haven’t been well-studied, overhype its efficacy, and tout special blends that experts say aren’t supported by published evidence.

The Ketamine Institute offers two classes. The first, a $4,950 fundamentals course, is “directed to physicians who wish to quickly get the basic training necessary to [safely] and effectively provide ketamine infusion therapy to their patients,” according to the institute’s website. Grass said that course is targeted at providers who might want more information on the research and clinical care, but are familiar with starting IVs. The second, an $8,950 comprehensive course, takes a much deeper dive into the weeds of running a clinic and also gives physicians hands-on experience with patients.Related: Ketamine gives hope to patients with severe depression. But some clinics stray from the science and hype its benefits

Grass said he gets eight to 10 inquiries about the training courses each month. The number of people he’s actually trained: seven. He generally only trains psychiatrists and anesthesiologists and requires applicants to submit a statement about their intentions.

“There are people out there that are looking for alternate streams of revenue,” he said.

He gets inquiries from everyone from cosmetic dermatologists and chiropractors to venture capitalists. He even heard from a provider who was running an alternative weight loss program and wanted to add ketamine “to motivate his patients,” Grass said.

“People will read one or two research papers, see the protocol, and think, ‘Oh, my God, this is easy. I can do this in my office,’” Grass said.

To train under Grass, providers can spend several days shadowing at his clinic. Dr. Ricardo Febres Landauro, a psychiatrist in Austria, flew thousands of miles to take a course in January. He observed patient interactions, pored over his own cases with Grass, and left with a binder stuffed with information on ketamine’s effects, indications, and contraindications.

“After [training] with him, I felt confident,” Landauro said, adding that the course “was a magnificent experience.”STAT Plus: Access to exclusive, in-depth pharma, biotech, business and policy coverage. Join now.

Grass said he trains providers using the evidence in consensus statements published by the American Psychiatric Association and the American Society of Anesthesiologists. In his own practice, however, he deviates in some instances from published research and treatment protocols. He offers a proprietary product called the “Restore Ultra-Rapid Infusion,” which includes three treatments in three days and which the clinic claims lasts longer and is more effective than other ketamine infusions. His clinic promotes the infusions to treat anxiety, depression, PTSD, and “burnout syndrome.” Grass said physicians just starting to use ketamine might not be experienced enough to deviate from the standard.

“It behooves them to learn how to do the standard protocol effectively and safely,” he said.

Another training program, Colorado-based Ketamine Consulting, promotes on its website “turnkey, comprehensive services that propel clients towards success” in establishing their own ketamine clinics. It promises clients will come away with a “profit-generating ketamine clinic, a renewed love of medicine, and the independence that all physicians crave.”

That program is led by Dr. Roman Langston, an anesthesiologist who also provides ketamine to patients at his Denver clinic. Langston said he taps into his own background to give guidance on treatment, but Ketamine Consulting also serves as a one-stop shop for the business side of a clinic. It builds a client’s website, brainstorms branding, creates logos, and sets up a presence on Facebook, Twitter, and LinkedIn. He charges $1,500 a month for a six-month contract.NEWSLETTERS

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Providers are keen on the idea of formal training and a helping hand in launching their clinics. Since starting his consulting practice in summer 2017, Langston has had about 10 clients. Jason Duprat, who runs an online training program called the Ketamine Academy, said roughly 100 people have signed up for the course in just over a year.

“One of my goals was to increase the number of providers,” he said.

The cost of his program: $2,499 upfront, or three payments of $999. Like the Ketamine Institute, Duprat’s online tutorials cover the evidence on treatment protocols and contraindications when using ketamine. His course also emphasizes the business aspects, from the paperwork to set up your own private practice to the best ways to design a website.

“Some of the most common questions are on the business side of things,” Duprat said. The bulk of his clients are nurse anesthetists, like him, or nurse practitioners, Duprat said. That means they don’t necessarily have the know-how to get a clinic off the ground.Related: Companies are racing to develop fast-acting depression drugs — but the process is tricky

Christy Hatcher, a certified registered nurse anesthetist and advanced practice nurse in Minnesota, found that material particularly useful, along with the information on patient care. She signed up for the Ketamine Academy when she was starting the process of opening a clinic in Maple Grove, Minn. She had spent 17 years working in a Minnesota hospital when she decided to open a ketamine practice with another CRNA. They bought the course earlier this year as an “investment” in their clinic.

“It took a lot of the information that is out there and it put it all together for you,” she said. It also led them to bring a mental health nurse practitioner on board.

Their clinic will open in early November. Patients are already calling for appointments.

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