The Future, Present, and Past of Ketamine Use to Treat Depression

Ashley Clayton first tried ketamine for depression.

The Future, Present, and Past of Ketamine Use to Treat Depression

Ashley Clayton first tried ketamine for depression. It was like time had collapsed on itself, and all that was left was the present. Initial reactions to doctor-prescribed Ketamine vary. Some patients experience a dream-like state while others are able to make inappropriate jokes and believe they're dead.

Clayton's experience was mild, but disorienting. She still struggles to find the right words to describe it. She felt like she was back in her own skin the next morning after the nausea and fatigue subsided.

Clayton was participating in a Phase 2 clinical trial in 2016 to find the best intravenous dose of ketamine to relieve depression. These trials help to determine the drug's efficacy, dosing and effectiveness before researchers move on to the final testing phase. Clayton tried psychotherapy and a variety of traditional oral antidepressants, but her severe depression and suicidal thoughts persisted.

She realized she needed a different approach after they started to interfere with her work as a Yale University research associate. Yale has a reputable ketamine research center, so she started asking her friends if they could help her enroll in a clinical trial. Six years, countless insurance battles, and nearly 150 ketamine injections later, it's now her sixth year. She says, "It's a lifesaving treatment."

Depression is the third leading cause of disability in the world. 80 percent of people who have been successfully treated for depression will experience a relapse within five years. More than 30 percent of patients will not respond to at least two antidepressant treatment and will be diagnosed as having treatment-resistant depression.

Ketamine was used as an alternative to the anesthetic PCP in clinical practice in 1960s. It has since been discontinued in the U.S. because of the high rate of hallucinations and delirium post-operatively. The FDA approved ketamine in 1970 as a general anesthetic. Today, it is on the World Health Organization's Model List of Essential Medicines. However, research into ketamine's antidepressant properties has only increased in the past few decades.

Yale School of Medicine published in 2000 the first controlled randomized trial that demonstrated ketamine's antidepressant properties. John Krystal (now the chair of Yale's psychiatry section), led the research team that showed that one subanesthetic dose of ketamine, which is less than anesthesia, improved depression and in some cases, resulted in a complete recovery within 24 hours.

It would take many years and a lot of evidence from different research groups before ketamine was recognized as an effective antidepressant. Many doctors were convinced by these preliminary studies and began to incorporate ketamine into their clinical practice in 2010. The FDA approved a ketamine-based treatment for major depression (tradename Spravato), in 2019. This was the first and only time that it had been approved to treat treatment-resistant depression. It later approved it for suicidal ideation in adults with major depressive disorder. Editor's Note: Janssen Pharmaceuticals is a Smithsonian advertiser. This story was not written by Janssen Pharmaceuticals. They did not influence or give any direction.

Researchers, patients, and pharmaceutical companies have all been fascinated by ketamine's potential antidepressant properties. The treatment is unique in many ways, according to increasing clinical and real-world evidence. Although traditional antidepressants can take several weeks to kick in ketamine may start to work as soon as it is administered. It may also help to build brain resilience over the long-term, according to researchers. The U.S. Drug Enforcement Administration has classified ketamine as a Schedule III substance. This means that it is less likely to cause psychological or physical dependence than Schedule II drugs like cocaine but more than Schedule IV drugs like Xanax.

Ketamine can also cause severe side effects beyond its abuse potential. If the dose is too high, this is called a dissociative episode.

Many people are astonished at the rapid discovery of ketamine's antidepressant effects. This is despite some trepidation. It is reversing everything we thought we knew about depression's neurobiology. Scientists are now using the information they have to reduce the undesirable effects of ketamine and inform other unconventional treatments for depression, like the psychedelic psychoactive psilocybin.

Ketamine not only exerts its effects faster than antidepressants but also has a different effect on the brain than antidepressants that are "monoaminergic". They affect the brain in a different way than the other antidepressant medications, which increase the levels of dopamine, serotonin and norepinephrine, to improve mood. However, ketamine appears to be primarily affecting a different brain chemical, glutamate. This helps brain cells communicate.

Researchers know where ketamine first attaches to the brain's higher brain centers in order to influence cognitive and emotional function. However, it remains to be discovered how ketamine exerts its effects. Researchers believe that ketamine could reverse brain damage caused by chronic stress. Its antidepressant effects may last longer if taken in consecutive doses. This could indicate that it could protect against depression relapse.

Researchers believe that Ketamine is available in two forms. Both are mirror images of each other, similar to your left and right hands. The one is R-ketamine, while the other is Sketamine (sometimes spelled “esketamine”). FDA approved the anesthetic version of ketamine which is equal parts R+ and S+ketamine. The patent expired in 2000 and the generic drug is known as "racemic" or "racemic ketamine. Ashley Clayton has successfully responded to this treatment.

Since at least 2000, doctors have been prescribing racemic ketoamine to depression patients off-label. It is legal to use an approved drug for non-approved purposes, such as prescribing antiseizure medication to relieve nerve pain. This is often done by medical providers when the patient is exhausted with all other options. Many insurance companies don't cover off-label treatment costs, so patients have to decide whether they want to pay large amounts or risk losing their life.

A drug that is widely prescribed for an off label indication might not be FDA approved for the same treatment in many cases. This is especially true if, like racemic ketones, the drug is generic. Husseini Manji, the leader of the Janssen team that developed Spravato, says pharmaceutical companies don't have the financial incentive to invest in new avenues for generic drugs. Spravato, which is pure S-ketamine, was approved by the FDA as an antidepressant. It's also the first FDA-approved ketamine-based drug.

Manji was the director of the National Institutes of Health's mood and anxiety disorders program. He was also a co-author of the 2006 study that replicated Krystal’s findings. Because it doesn't require an anesthesiologist, he suggested that nasal sprays might be the best way to deliver racemic ketamine. The nasal spray would allow for faster brain access, as it could be accessed through the nose. A spray would not deliver enough drug so the team decided to use pure Sketamine. They showed that it was three to four times more potent than RK.

Manji claims that the FDA approval process involved approximately 25 studies, which enrolled thousands of participants. Dissociation, nausea and vertigo are the most common side effects. These symptoms usually resolve within an hour and a quarter after the dose. Many patients suffering from treatment-resistant depression experienced a significant reduction in their depressive symptoms after receiving Spravato along with an oral antidepressant. Manji states that many people require less treatment over time. For example, switching from two-weekly administration to one-time every few weeks.

Carlos Zarate Jr., former colleague at NIH and chief of experimental therapeutics, and pathophysiology at National Institute of Mental Health, said that Spravato's success has prompted other pharmaceutical companies to return more to neuroscience development and antidepressant research after a long hiatus. Many pharmaceutical companies began to shift their investments and focus to immunology and oncology, which, unlike mental health disorders, had clear therapeutic targets. Today, however, there are many companies that specialize in ketamine research and developing. These companies work on innovative delivery systems for the drug, including patches and microneedles.

Some researchers are looking for ways to prolong the antidepressant effects of ketamine using traditional therapies like psychotherapy. Others like Zarate are trying to create a better ketamine that doesn't have the abuse potential or initial dissociative effects. Zarate is currently studying several ketamine metabolites, known as hydroxynorketamines. These metabolites can have rapid and sustained antidepressant effects on animal models. He and his colleagues will begin a clinical study to test a metabolite named (2R,6R-HNK) in patients suffering from treatment-resistant depression later this year. New technologies will soon allow for treatments that work immediately without side effects, he says. "We are not yet there, but we are on the road."

There are many questions that remain to be answered, including which brain receptors ketamine binds. There is evidence that ketamine may activate brain's opioid system. However, it is not clear if this is the key to ketamines antidepressant and misuse potential. Zarate states that there are concerns regarding the abuse potential, which we shouldn't minimize. He explains that part of the solution is to make sure there are standardized procedures in place to stop ketamine being prescribed too loosely.

Clayton is a patient and frequents online patient forums. There, Clayton shares stories of patients who have received "cowboy" treatments such as ketamine lozenges. These are not supported by science and look like something out of the Wild West. Although providers are required to follow Spravato’s risk assessment and mitigation strategy protocol, there is no FDA-approved, standardized procedure for intravenous racemic ketamine dispensing to treat depression. Anesthesiologists have been administering this form of ketamine at independent clinics for years in order to treat chronic pain and other off-label indications. Clayton is concerned that depression patients may be at greater risk as more clinics offer treatment.

Clayton still receives ketamine treatments every two weeks to this day. Clayton tried to participate in Spravato’s clinical trials before its FDA approval but was not able to respond to it. Since then, she has chosen intravenous racemic ketoamine. However, her insurance won't cover it. She explains that the drug is quite inexpensive, but the administration of the infusions takes time and supervision, which can increase the out-of pocket costs to anywhere between $600 and $2,000 per treatment. She relies on the kindness of her doctors and hospital administrators for free care.

It was pure luck that saved her from certain death. She had access to doctors and medical resources that few others have. She is a Yale Family Violence Research Program mental health researcher and has been trained in healthcare advocacy. This means she is better equipped than many to navigate the complex healthcare system. Yet, she admits that it was nearly impossible for her to get the treatment and almost ended up in death.

Despite the numerous hurdles remaining regarding ketamine accessibility, treatment protocols, and side effects, there is still optimism. Both patients and providers hope that ketamine will open the door to new drug treatments and provide a better understanding of depression's neurological underpinnings.

Krystal states that these drugs have profound effects on consciousness. "So we are learning about neurobiology, psychopharmacology and the higher aspects human consciousness as well as the treatment of these diseases and illnesses. This is also exciting.