Could ketamine become the next great depression drug?

Patients, researchers and drug companies look to the future after ‘the biggest breakthrough in depression’ in 50 years

Tiffaney Ritchey remembers her first.

“My first suicide attempt came when I was 13,” she says.

For 30 years, Ritchey, now 42, has struggled with chronic depression. She’s gone through enough antidepressants, antipsychotics and other mood medicines to fill the aisles of a CVS: Zoloft, Celexa, Prozac, Wellbutrin, Seroquel, Cymbalta, Lamictal, Trazodone, Effexor, Zyprexa, Latuda.

None of them worked.

She's been hospitalized several times for suicidal ideation and another two times for attempted suicide – most seriously when she was 16. “I was unconscious,” she says. “I almost actually died with that one.”

Sometimes, Ritchey couldn’t get out of bed for weeks or months. For nine years, her depression was so severe that she couldn’t hold a regular job. In 2011, she recalls staying in her pajamas for six months straight.

“My husband had to put me in the shower, because I could not do it myself,” she says. “The depression was just so heavy.”

Depression runs in her family. When Garrett Ritchey was 10 or 11, he started struggling with the same depression that haunted his mother. The teen was bedbound and used a walker to get around the house. A year and a half ago, the depression, coupled with chronic stabbing pain in his lower back, forced him to stop working at the local movie theater, all the while telling his friends that he was doing just fine.

“I literally felt like I was dead inside,” he says. “Every day, I’d ask myself, ‘Is this how I’m going to live the rest of my life?’”

Ritchey, now 19, had seen what his mother went through, and he didn’t want that. But he also noticed her improvement – and a unique treatment she used.

Tiffaney Ritchey was on the verge of "checking out" before she started having ketamine infusions for her depression.
Courtesy: Tiffaney Ritchey/Facebook

In December 2012, Tiffaney Ritchey traveled to Depression Recovery Centers in Scottsdale, Arizona, which was just starting to use an alternative way to help people suffering treatment-resistant depression: ketamine infusions.

Suicidal and desperate, she gave it a shot, knowing it might be her last chance.

“If the ketamine didn’t work, I was checking out,” she says. “Everything in my life was riding on it.”

Long used as an anesthetic and sedative in hospital rooms and framed in recent years as a harmful recreational club drug, the perception of ketamine is getting reinvented yet again. This time, through years of research, ketamine is showing promise as a tool for future depression treatments.

About halfway through her first infusion treatment, Ritchey experienced a happiness she hadn’t felt in years. The feeling from the powerful drug lasted a couple days before she went back for another infusion. As her depression symptoms improved, she’d go weeks and months between infusions.

“The ketamine saved my life,” she says from her home. “Every time I think about it, I just want to cry.”

That optimism about ketamine as a depression deterrent is catching on elsewhere. In the last 15 years, there’s been a tidal wave of research touting the benefits of ketamine in treating depression. In August, a study from the National Institute of Mental Health discovered that ketamine reduces suicidal thoughts – totally independent of the drug's effect on depression or anxiety. In April, a University of Oxford study in the Journal of Psychopharmacology found that approximately a third of patients with treatment-resistant depression saw immediate improvements in their moods. And since 2012, studies from Yale University, Houston’s Baylor College of Medicine and New York’s Mount Sinai School of Medicine found that ketamine is overwhelmingly successful for treatment-resistant patients.

Researchers are the excited about these developments in hopes of combatting the rising number of depression cases nationwide. Almost 7 percent of Americans 18 or older – about 16 million people – suffered at least one major episode of depression in the last year, according to NIMH. The World Health Organization recently found that “depression is the predominant cause of illness and disability" for boys and girls 10 to 19 years old. In the United States, lost productivity and health care expenses from depression cost an estimated $80 billion a year. And those trends are not expected to slow down. National Institutes of Health researchers project depression to be “the second leading cause of disability worldwide and the leading cause of disability in high-income nations, including the United States” within 20 years. 

‘The ketamine saved my life. Every time I think about it, I just want to cry.’

Tiffaney Ritchey

depression sufferer

Now, more than two years after study author Dr. Ronald Duman, a professor of psychiatry and pharmacology at the Yale School of Medicine, said in a press release that ketamine is “the biggest breakthrough in depression research in a half century,” researchers are still trying to figure out the long-term effects of administering it. As more clinics nationwide offer ketamine intravenous infusions, there’s also a race in the pharmaceutical industry to see which company will bring a ketamine-like drug to market first.

“I don’t think anybody really had the hypothesis that this drug was going to have a very rabid, robust response,” says Dr. Gerard Sanacora, director of the Yale depression research program.

From tragedy to ketamine

Whether it was antidepressants or psychotherapy, nothing seemed to help Garrett Brooks.

“He was helpless. He was hopeless,” Dr. Glen Z. Brooks said of his son. “He saw no way out. And there was just nothing that I could do or his mother could do to save him from himself.”

In 1999, the 18-year-old committed suicide. Brooks and his wife tried to keep Garrett's memory alive by starting scholarships and donating to charities. But nothing was ever enough.

Then Brooks found ketamine. 

Dr. Glen Z. Brooks setting up an intravenous ketamine infusion at his New York office.
Timothy Bella

Brooks says he's treated about 500 patients since he opened New York Ketamine Infusions in 2012. At his Lower Manhattan office, Brooks says that he's administered more ketamine infusions than any other practitioner in the country. The vast majority of patients are victims of childhood pain and suffering, and are coping with PTSD and manifestations such as depression or eating disorders. No child or adult is turned away.

“Nothing ever really made a difference for me until I started doing ketamine therapy to treat patients [with] otherwise treatment-resistant depression,” he says. “It was only then that I really had a chance to save other kids.”

Brooks is one of just 18 providers and clinics in the country to offer ketamine infusions, according to the Ketamine Advocacy Network. Now 67, Brooks sees 50 to 55 patients a week, totaling close to 3,000 appointments a year, with each infusion costing around $400. He said he wishes the drug had been available 15 years ago.

“I think it could have made a tremendous difference,” he said, and then paused for a moment to correct himself. “I know it could have made a difference.”

A psychedelic history

Developed in 1962, ketamine was the most widely used battlefield anesthetic during the Vietnam War, as well as a regular anesthetic used in American hospitals. Some veterans began to self-medicate with – and in some cases abuse – ketamine when they returned home. Some mind explorers and New Age spiritualists of the 1970s and 1980s embraced the drug, citing  out-of-body experiences, intense visuals and a number of auditory hallucinations that could result from subanesthetic doses.

Marcia Moore, heiress to the Sheraton Hotel estate, championed ketamine's supposed existential richness in her 1978 book “Journeys Into The Bright World,” only to become one of the first high-profile deaths linked to recreational use the following year. She is believed to have injected herself with a large dose of ketamine on a winter night in the forest, where she passed out and died of hypothermia. 

‘I think [ketamine] could have made a tremendous difference ... I know it could have made a difference.’

Dr. Glen Z. Brooks

founder, New York Ketamine Infusions

By the mid '80s and early '90s, the recreational use of the drug had become a mainstay in the nightclub scene, particularly in New York's dance and rave culture. “Special K” was regarded as a form of psychedelic heroin, and its recreational use remained legal until 1999, when the federal government  classified it a Schedule III controlled substance alongside anabolic steroids and LSD. Anyone who wanted to use, manufacture or sell ketamine had to register with the Drug Enforcement Agency. Today, the recreational use of ketamine and drugs that users are led to believe to be ketamine remains popular in the summer music festival scene.

Ketamine's reputation as a potentially dangerous party drug frustrates practitioners like Brooks.

A vial of ketamine, the longtime anesthetic that is catching on as a depression treatment.
Victoria Arocho/AP

“It’s all just nonsense,” he says. “Ketamine is probably in every operating room in the world, with a proven record of safety. Yeah, there has been some use in some clubs over time, but again, we’re talking about doses that far, far exceed the kind of doses we use here.”

Brooks begins each treatment session with a lengthy discussion on how ketamine infusions affect the patient’s depression symptoms. With his deep, calming voice, lengthy eye contact and smiles at just the right time, patients laud Brooks’ bedside manner. The average first infusion is based on the industry standard of half a milligram per kilogram of a patient’s weight. The drug is diluted in saline and administered intravenously over 45 minutes, often while listening to patients' favorite music. After an infusion, patients generally sit quietly for up to 30 minutes before being allowed to leave. Depending on a patient's size and his or her body’s response to treatment, the effects last from 30 minutes to a couple hours.

“Colors seem a little brighter; music sounds better,” Brooks says of patients' response. “It’s easier to get out of bed.” 

The beginning

Before ketamine was considered for treating depression, research on the drug focused on schizophrenia. In the late '80s, Dr. John Krystal and his colleagues at Yale began to study ketamine's effects in healthy human subjects, showing how it could produce symptoms associated with schizophrenia, such as dissociative states and changes in the sense of time.

One day, Krystal, who now chairs Yale's Department of Psychiatry, was tossing out “wild and wacky ideas” with colleagues. One of them stuck.

“We began to think about what if we approached depression the way that we were approaching schizophrenia?” Krystal recalls.

Fifty years of depression research had largely been centered on norepinephrine and serotonin. But Krystal was enamored with glutamate, a neurotransmitter that helps increase cell activity and brain function. When ketamine targeted NMDA receptors, which play a critical role in the central nervous system and help with breathing, walking and learning, it was believed to have the ability to cause brain cells to establish newer and stronger connections. In late-'90s ketamine studies, the drug was found to have antidepressant effects for several hours. When Krystal published a 2000 study indicating that ketamine could swiftly lift the symptoms of depression, it was the first research of its kind to make the case. The response from the medical community was “resounding silence, ” Krystal said, which “felt that it was too good to be true."

Dr. John Krystal's research on ketamine's use for depression stretches back to the late 90s.
Timothy Bella

“These were patients who had failed everything in the medicine chest that [the industry] had to offer for the treatment of depression,” he says. “It was really quite striking and remarkable.”

Sanacora, who assisted Krystal with the research more than 16 years ago, recalls, “I actually do remember saying, ‘You know, if this is real, this is going to be something really big.’”

A few years later, other researchers echoed their results, helping ketamine depression research become a fast-growing field. There wasn't much outright opposition, but there’s still some skepticism from doctorsabout the hallucinogenic side effects and quiet concern among researchers about some clinicians who administer ketamine treatments. Others say that patients who are so desperate for something to help their depression might be too vulnerable to make informed decisions about ketamine treatment.

Dr. Alan F. Schatzberg of Stanford University School of Medicine wrote a March 2014 commentary in the American Journal of Psychiatry titled, “A Word to the Wise About Ketamine,” outlining the lack of FDA regulation on the drug being administered off-label in psychiatry clinics that have not received approval from any regulatory agency. Schatzberg argues that the drug’s potential for abuse is significant, with clinics charging hundreds of dollars for off-label infusions that have to be conducted over and over again as upkeep for their depression treatment.

“This unbridled enthusiasm needs to be tempered by a more rational and guarded perspective,” Schatzberg wrote. “The recent ketamine studies are exciting, and they open up important avenues for investigation that should be supported; however, until we know more, clinicians should be wary about embarking on a slippery ketamine slope.”

Even proponents of the research say more studies are needed before further advancing the research. Hong Kong recently reported that ketamine was the second-most popular drug of abuse after heroin. And its recreational use worldwide continues to rise. This concerns Krystal, who says the drug must be treated with respect.

“Ketamine is a drug that clearly affects the brain in powerful ways and that we have to acknowledge that it does have an abuse liability,” he said. “In many parts of the world, ketamine abuse is a very substantial public health threat.”

Dr. Gerard Sanacora looks over research at his office at Yale.
Timothy Bella

Sanacora adds, “I do think we have to move about this in a very cautious, prospective way of thinking about it; not just opening up the flood gates and treating everybody.”

While the infusion business remains steady, pharmaceutical companies have their eyes on something even more lucrative: a drug that acts like ketamine but without the high. Companies such as Naurex have hundreds of patients in clinical trials and are investing tens of millions of dollars in research on their drugs. Even industry titan Johnson & Johnson is testing and developing a nasal spray that’s a derivative of ketamine. The goal? To be the first antidepressant that works like ketamine to get approved by the FDA, in hopes of making it to the marketplace within the next decade.

Cerecor, a privately held Baltimore company of fewer than 15 employees, might be the odds-on favorite to hit the market first. With CERC-301, the company’s lead program costing around $33 million in research, Cerecor is in clinical trials with a daily pill, the only company thus far to at least explore the idea of a ketamine-acting drug in pill form. Other companies are looking into ketamine-like drugs delivered intravenously. (Editor's note: Naurex is also in the early stages of developing a ketamine-acting oral pill.)

‘I actually do remember saying, ‘You know, if this is real, this is going to be something really big.’’

Dr. Gerard Sanacora

director, Yale depression research program

Blake Paterson, Cerecor’s founder and a trained anesthesiologist, is aware of the significant toxicities feared in ketamine-like drugs, whether it’s higher blood pressure or potential brain damage, which is why more research is being done.

“It’s not the perfect answer to depression and nothing ever will be,” Paterson says. “… What we’re all about is trying to address that unmet need.”

Back in New York, Brooks welcomes the idea of these new drugs hitting the market down the road, but doesn’t believe intravenous ketamine infusions will go away in the near future.

“In 2015, 2016, intravenous ketamine therapy will remain the gold standard for that class of drugs,” he says. 

‘It’s night and day’

Garrett Ritchey says a side benefit to his ketamine infusions was getting rid of his lower back pain.
Courtesy: Garrett Ritchey/Facebook

By age 18, Garrett Ritchey was taking regular ketamine infusions for his depression. He had no idea it would also have an effect on the stabbing feeling in his lower back. When Scottsdale doctors removed his IV after an infusion in December, he lost it.

“It was all gone,” says Ritchey, who no longer needs a walker to get around his home. “I had forgotten what it was like to live a pain-free life.”

Ritchey, like his mother, has gone through dozens of infusions for his depression and chronic pain. He’s says he’s not dependent on ketamine, and it now serves as more of a boost, going months between infusions. He’s now focusing on pursuing a music career, playing gigs around his hometown. For Ritchey, the change in his quality of life with ketamine is drastic. “It’s night and day,” he says.

The same can’t be said of his mother, who remains dependent on ketamine infusions, and it's hurting her pocketbook. In October 2013, the costs of the infusions, between $750 and $1,000, forced Tiffaney Ritchey to temporarily abandon the treatment. Although she has improved as a whole, her depression returns in waves. 

She’s come to terms with the severity of her situation, and what she has to do to “pull back” from her depression.

“With the ketamine, I do stay stable longer,” Ritchey says. “I’m probably going to need ketamine the rest of my life.”

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