On Tuesday (March 5), the U.S. Food and Drug Administration (FDA) approved a ketamine-like nasal spray for patients with depression who haven’t responded to other treatments.
But what makes this newly approved treatment so different?
The drug, called Spravato and made by Janssen Pharmaceuticals, contains the active ingredient esketamine. This substance has the same molecular formula as ketamine but a different chemical structure. (In other words, it contains the same type and number of elements but in a different configuration.) Ketamine is typically used as an anesthetic, but it’s also been used as an illicit party drug.
One reason experts are excited about the nasal spray is that its effects can be seen within several hours to days. Other antidepressants, meanwhile, can take weeks to start working
Antidepressants work by regrowing brain cells and the connections between them, and ketamine appears to have the same effects, said David Olson, an assistant professor of chemistry, biochemistry and molecular medicine at the University of California, Davis. But, these effects likely start much sooner than with other antidepressants, he said.
Still, it’s not entirely clear how the drug works.
Ketamine-like drugs are “dirty”, meaning they likely hit a variety of targets in the brain, Olson told Live Science. “There are a lot of very interesting hypotheses out there, [and] many of them are probably partially valid.”
One idea is that ketamine treats depression by blocking a neurotransmitter called glutamate from binding to the NMDA receptor, and stopping signals from cascading across the brain, Dr. Alan Schatzberg, a professor of psychiatry and behavioral sciences at the Stanford University School of Medicine, told Live Science.
Glutamate is a chemical that brain cells use to send signals to other brain cells. But high levels of it can cause over-excitement in the brain, which can, in turn, damage brain cells.
A more controversial idea is that ketamine binds to opioid receptors, causing a release of naturally occurring opioids in the body. Schatzberg and his team published a small study on this last summer in which they gave patients with depression ketamine twice — once after receiving an opioid-blocking drug, and once after receiving a placebo in place of the opioid blocker. The two treatments took place about a month apart, and neither the participants nor the researchers knew whether patients received the opioid blocker or the placebo. The study found that the patients responded well to the ketamine treatment if they didn’t receive the opioid-blocking drug, but ketamine had no effect on those that did, suggesting an opioid-like role.
“My concern about this compound is that it is a disguised form of opiates,” said Dr. Mark George, a distinguished professor of psychiatry, radiology and neurosciences at the Medical University of South Carolina. While George said he is “overjoyed” for the prospect of a new treatment option, “I’m alarmed that there is pretty clear evidence [that] the way ketamine works is through the opioid system.”
If this is the mechanism that ketamine acts through to treat depression, its effects won’t last and people might develop a tolerance to the drug, possibly even becoming addicted, George told Live Science. But if its antidepressant effects come from other mechanisms, such as blocking the NMDA receptor, then “that’s good,” he said.
Olson, however, said that he is less convinced by the opioid hypothesis and thinks more work needs to be done before ringing the alarm bells.
What’s more, the new drug will see limited use. The medication comes with a risk of sedation and dissociation, such as difficulty with judgment, attention and thinking. Because of that, the nasal spray was approved to be used only under a “restricted distribution system,” according to a statement from the FDA.
This means that only patients with severe depression who haven’t responded to at least two antidepressant treatments can receive the drug. In addition, the treatment is administered only in doctor’s offices, and patients must stay in the office and be monitored for several hours after receiving the treatment.
Ultimately, despite some potential problems with the newly approved drug, experts are hopeful it will come through strong.
“I think that the FDA approval of ketamine is a huge landmark in the history of treating neuropsychiatric diseases,” Olson said. “Ketamine really represents a leap forward in terms of new ideas for attacking depression and related neuropsychiatric diseases.”
A decades-old anesthetic made notorious as a party drug in the 1980s is resurfacing as a potential “game-changing” treatment for severe depression, patients and psychiatrists say, but they remain wary about potential long-term problems.
The Food and Drug Administration earlier this month OKd use of Spravato for patients with depression who have not benefited from other currently available medications. Spravato, the brand name given to the drug esketamine, is a molecule derived from ketamine — known as Special K on the club scene.
Ketamine has been shown in some studies to be useful for treating a wide variety of neurological disorders including depression. Regular, longtime use of it isn’t well understood, psychiatrists say, but the need for a new drug to treat depression is so great that the FDA put Spravato on a fast-track course for approval.
The drug likely will be commercially available in a few weeks, and patients already are requesting it. Restrictions around its use, though — the drug must be administered in a doctor’s office by providers who are certified with the company making it — mean it may be months before it’s widely available, and longer than that before insurers start paying for it.
“I don’t think we know at this point how effective it’s going to be,” said Dr. Craig Nelson, a psychiatrist at the UCSF Depression Center. “There have been a number of studies of ketamine, sometimes showing effects in people who were resistant to other drugs. If we can treat a different group of people, it would be a great advantage.”
Ketamine was developed in the 1960s as a surgical anesthetic for people and animals. The drug can cause hallucinations and a feeling of “dissociation” or unreality, and in the 1980s it took off as a party drug among people seeking those effects. It remained a common anesthetic, though, and in the early 2000s doctors began to notice a connection between ketamine and relief from symptoms of depression and other mood disorders.
Spravato is delivered by nasal spray, which patients give themselves in a doctor’s office. Patients must be monitored while they get the drug and for two hours after to make sure they don’t suffer immediate complications. At the start, patients will get the nasal spray twice a week for four weeks, then taper to regular boosters every few weeks for an indefinite period of time.
Studies of ketamine — and specifically of Spravato — have produced encouraging but inconsistent results. Psychiatrists say that, like most other antidepressants, the drug probably won’t help everyone with difficult-to-treat depression. But there likely will be a subset of patients who get substantial benefits, and that alone may make it an incredible new tool.
About 16 million Americans experience depression every year, and roughly a quarter of them get no benefit from antidepressants on the market. Thought scientists haven’t determined exactly how ketamine works on the brains of people with depression or other mood disorders, it appears to take a different path of attack than any drug already available. That means that people who don’t respond to other antidepressants may find this one works for them.
But a concern among some psychiatrists is that studies have suggested that ketamine may affect the same receptors in the brain that respond to opioids. Ketamine and its derivations may then put patients at risk of addiction — but research so far hasn’t explored that kind of long-term effect.
“There might be some potential problems if you used it too aggressively,” said Dr. Alan Schatzberg, director of the Stanford Mood Disorders Center, who led the research that identified a connection with opioid receptors. “The issue is not so much the short-term use, it’s the repetitive use, and the use over time, as to whether there are going to be untoward consequences.
“It would be hard for me to recommend the use of this drug for chronically depressed people without knowing what the endgame is here,” he added.
Dr. Carolyn Rodriguez, a Stanford psychiatrist who was part of the studies of ketamine and opioid receptors, said she shares Schatzberg’s concerns. But she’s been studying the use of ketamine to treat obsessive-compulsive disorder, and for some patients the results have been so remarkable that the benefits may exceed the risks.
“When I gave ketamine to my first patient, I nearly fell off my chair. Somebody said it was like a vacation from their OCD, and I was just, ‘Wow, this is really possible,’” Rodriguez said. “I want to make sure patients have their eyes wide open. I hope (the FDA approval) spurs more research, so we can really inform consumers.”
Though the new nasal spray is the first formal FDA approval of a ketamine-derived drug, psychiatrists have been using the generic anesthetic for years to study its effect on depression and other mood disorders.
In recent years, clinics have opened around the country offering intravenous infusions of ketamine to people with hard-to-treat depression and other problems. These treatments aren’t specifically FDA-approved but are allowed as off-label use of ketamine. The clinics have faced skepticism from some traditional psychiatrists, but there’s a growing ream of anecdotal evidence that the ketamine IVs work — for some people.
Aptos resident Mary, who suffers from depression and other mood disorders and asked that her last name not be used to protect her privacy, said the already available antidepressants weren’t keeping her symptoms at bay, and she frequently felt “one step away from the abyss.” When she first heard about ketamine, from a support group for people with depression and other mood disorders, she was hesitant.
“I kind of hemmed and hawed, because I’d heard that K was a street drug,” Mary said. “But then I said, ‘What do I have to lose?’ So I went and did it.”
The results were quick: Within four days, “the cloud had lifted,” she said. More than a year later, she is still feeling good with regular infusions every three or four weeks. During the ketamine infusion, Mary said she’ll feel the dissociation, which she described as feeling like she’s viewing the world around her as though it were a movie and not her own life.
She said she’s pleased the FDA approved Spravato, though she hasn’t decided whether she’ll switch from the IV ketamine to the nasal spray. She hopes that the FDA approval will give some validation to ketamine and encourage others to try it.
Mary gets her infusions at Palo Alto Mind Body, where Dr. M Rameen Ghorieshi started offering ketamine two years ago. He’s certified with the maker of Spravato — Janssen Pharmaceuticals, a branch of Johnson and Johnson — to provide the drug, though he doesn’t know when he’ll actually start giving the nasal spray to patients.
Ghorieshi said that although he’s been offering IV ketamine for more than two years, he shares his colleagues’ wariness of the long-term effects of regular use of the drug. He hopes FDA approval will encourage further research.
“At this point we’ve done 1,000 infusions. The outcomes have exceeded my own expectations,” Ghorieshi said. “But anecdotes are not clinical trials. I approach this very cautiously. What I don’t want is 20 or 30 years from now to look back and say, ‘What did we do?’”
An hour before we spoke, Darragh O’Carroll, an emergency room physician from Hawaii, had just given an elderly patient a sedating shot of ketamine. The man had pneumonia and was acting confused and fidgety, making him hard to treat.
“Not only it was a pain control for him when I was putting needles into his neck, but it also kept him still,” O’Carroll says. “And with very minimal risk of lowering his blood pressure.”
Ketamine’s use as an anesthetic — and not as a party drug — is widespread, though not commonly known. In fact, the World Health Organizationestimates ketamine is the most widely used anesthetic in the world and keeps it on their list of essential medicines, a category of drugs that all developed countries should have on hand.
O’Carroll has described ketamine as his “favorite medicine of all time” in an article for Tonic, not only because the anesthetic is incredibly safe and effective, but also because of its versatility. It’s most widely used in surgery, but could also help treat severe asthma, chronic pain, and may even possess anti-tumor properties. In the last two decades, ketamine has also emerged as a potent antidepressant, able to treat symptoms of some mental illnesses in less than 72 hours.
“I think the more research that goes into ketamine, the more uses that we find for it,” O’Carroll says.
From PCP to Painkiller
Ketamine’s story begins with a drug called PCP. Yes, that PCP — phencyclidine or so-called “angel dust,” a drug that when smoked can cause a trance-like state, agitation and out-of-body hallucinations. After it was first synthesized by medicinal chemist Victor Maddox in 1956, the drug was briefly approved as an anesthetic by the FDA for its sedative properties. In tests with a wild rhesus monkey, for example, researchers put their fingers in the previously aggressive animal’s mouth and watched its jaw remain slack.
But while it was safe and effective for pain relief, the side effects of PCP soon became too obvious to ignore.
Some patients under the influence of PCP would feel like they lost their arms or legs or that they were floating in space. It could also cause seizures and delirium. Scientists began seeking a shorter-acting anesthetic without convulsant properties. In 1962, chemistry professor Calvin Stevens discovered a PCP analogue that fit the bill: ketamine.
Ketamine is a potent, sedating painkiller that can cause amnesia and is mostly used in surgery and veterinary medicine. During the Vietnam Invasion, ketamine saw widespread use in the U.S. military because it has several advantages over opioids. First, unlike morphine, ketamine doesn’t suppress blood pressure or breathing. It also doesn’t need to be refrigerated, making it useful in the field or in rural areas that don’t have access to electricity.
Ketamine’s benefits extend beyond use as an anesthetic, though — in some cases it can serve as a balm for the mind as well. A 2008 analysis found that burn victims who were given ketamine were less likely to develop symptoms of post-traumatic stress disorder, even if their injuries were more severe. Those findings have been replicated, such as a 2014 clinical trial of 41 patients, who saw their PTSD symptoms diminish within 24 hours, an effect that lasted for two weeks.
“When somebody gets one of their limbs dramatically blown off or is shot in the face, it’s a very traumatic event,” O’Carroll says. In such a situation, giving ketamine not only provides instant pain relief, it could prevent long-lasting trauma.
Because its chemical structure is so similar to PCP, ketamine can still give lucid hallucinations, such as feeling that your mind has separated from the body — a dissociative state users sometimes call a “K-hole.” One recent study based on users’ written reports even indicated that this kind of experience might be a close analogue to a near-death experience. However, these dissociative states only happen at high doses — the amount of ketamine used to for surgery and to treat depression is typically much lower.
But ketamine’s side effects are less common and easier to manage than PCP. In fact, ketamine is one of the safest drugs used in medicine today and can even be given to young children. For example, ketamine was used to sedatethe boys’ soccer team trapped in a cave in Thailand last year. Putting the kids in a tranquilized state made it easier to rescue them, and ketamine is safer than the opioids or benzodiazepines that are also commonly used as sedatives.
Ketamine as Antidepressant
But it wasn’t until the 1990s that what could turn out to be ketamine’s most important function was discovered. A team from Yale University School of Medicine was examining the role of glutamate, a common neurotransmitter, in depression, and discovered something remarkable: ketamine could rapidly relieve depression symptoms.
“To our surprise, the patients started saying, they were better in a few hours,” Dennis Charney, one of the researchers, told Bloomberg. This rapid relief was unheard of in psychiatry.
Glutamate is associated with neural plasticity, our brain’s ability to adapt and change at the level of the neuron. Ketamine blocks certain glutamate receptors, but not others, and the end effect could be to promote the growth of new neurons while protecting old ones. This could explain how ketamine can help reset the brain, though the theory hasn’t yet been definitively proven.
The prescription meds currently on the market for depression have some major drawbacks. Drugs like Prozac or Wellbutrin can take a few weeks or months to kick in while worsening symptoms in the short term — not a good combination, especially for someone who is extremely depressed, or even suicidal.
It took around a decade for mainstream science to take notice of these early ketamine-depression studies. But once it did, ketamine clinics began popping up all across North America, offering fast relief for depression, anxiety and other mental illnesses. Patients are given an infusion — an IV drip that lasts about an hour — and many people, but not everyone, have seen rapid relief of their symptoms.
Suddenly, ketamine infusions became trendy, though the science to back up some of the medical claims is still inconclusive, according to STAT. However, ketamine infusions are rarely covered by insurance, although that is changing. A typical session can run $700, with many patients taking six sessions or more. But many of these patients have so-called treatment-resistant depression. They’ve tried other medications or therapies without success and some see ketamine as a last resort.
Steven Mandel, a clinical psychologist and anesthesiologist, has used ketamine on patients since it first came on the market around 50 years ago. In 2014, he began using it for patients with depression and opened Ketamine Clinics of Los Angeles, one of the oldest and largest clinics in the country. They’ve done over 8,000 infusions so far.
“Our success rate is better than 83 percent,” Mandel says. For his clinic, success means a 50 percent improvement of depression symptoms for longer than three months.
Ketamine’s success as an antidepressant couldn’t help but attract the attention of major pharmaceutical companies as well. In 2009, Johnson & Johnson began developing their own version of the drug they called esketamine. Rather than an infusion through a vein, it’s dispensed through a nasal spray. The FDA approved their formulation in early March. It was thefirst drug in 35 years to fight depression using a different approach than traditional drugs.
“Esketamine is a giant step forward,” Mandel says. “It means we’re not going to be demonizing mind-altering substances used for therapeutic purposes. It opens the door to research on LSD, on psilocybin, on MDMA and many other agents that could possibly relieve a great deal of suffering.”
But many clinicians have raised concerns about long-term side effects, such as heart and bladder toxicity. Others have been critical of esketamine, saying there isn’t enough data yet to suggest the drug is safe or effective. Husseini Manji, a neuroscientist who helped develop the drug for Johnson & Johnson at their subsidiary Janssen, has pushed back against these claims.
“When you line up the totality of the studies, it was really an overwhelming amount of data that was all in the same direction,” Manji says in a call. Though just two of the five late-state clinical trials showed significant results, the changes in mood in the three that fell short were “almost identical in magnitude” to the others, Manji says. It was enough for the drug to meet standards for FDA approval.
We can probably expect other ketamine-related drugs to come to market soon. ATAI Life Sciences, a company funding research on the use of magic mushrooms for depression, is developing their own ketamine depression drug. The pharmaceutical company Allergan also developed rapastinel, another ketamine-like drug, though it failed to show any real benefits for patients in later trials. Manji says this is unfortunate for people who could be helped by these kinds of drugs.
“From a patient standpoint, we were hoping it would work,” he says, even though he was not involved in rapastinel’s development. “But sometimes if you really haven’t got the mechanism right and you haven’t really threaded the needle, then sometimes you don’t see these results.”
Drug of Abuse?
Even though ketamine’s medical uses are well-established, most people have only heard of ketamine in the context of a party drug. Because of this bad reputation — and what’s perceived as growing misuse of the drug — several countries, such as China and the UK, have tried to place greater restrictions on ketamine. This would make it harder to study and more expensive in clinical use.
“If it was to ever be rescheduled, places that would be first affected would be you know places that need it most,” O’Carroll says. The WHO has asked at least four times for countries to keep access to ketamine open. “The medical benefits of ketamine far outweigh potential harm from recreational use,” Marie-Paule Kieny, assistant director general for Health Systems and Innovation at WHO, said in 2015.
So far, no countries have put greater restrictions on ketamine, and that’s probably a good thing. Ketamine has a rich history, but its future is still being written.
Ketamine was originally approved by the US Food and Drug Administration (FDA) as an anesthetic, but is increasingly being used to treat mood disorders, such as treatment-resistant depression, anxiety disorders, and post-traumatic stress disorder (PTSD).1,2 Several studies have also found it to be effective for treating suicidal ideation.3,4
“Ketamine can play an important role in the treatment of anxiety disorders,” according to Prakash Masand, MD, co-founder, chairman, and CEO of Centers of Psychiatric Excellence (COPE) (https://www.copepsychiatry.com) and adjunct professor at the Academic Medicine Education Institute, Duke-National University of Singapore Medical School (Duke-NUS).
“Nowadays, people with anxiety disorders are treated either with a generic antidepressant, such as an SSRI (selective serotonin reuptake inhibitor), an SNRI (selective norepinephrine reuptake inhibitor), or a benzodiazepine and if they don’t respond to one of these, they get a trial of another or several more,” Dr Masand said.
However, between 30% and 40% of these patients will not achieve remission, despite 3 or 4 different traditional agents, and even with evidence-based nonpharmacologic therapies, such as cognitive behavioral therapy (CBT) or mentalization-based therapy (MBT), he noted.
“No good current strategies are available for these non-responders, so novel agents are being studied — including ketamine, which is accumulating an evidence base as [being] rapidly effective for an array of anxiety disorders, including social anxiety disorder (SAD) and PTSD,” he said.
How Does Ketamine Work?
A growing body of evidence points to the role of glutamate, a widely distributed excitatory neurotransmitter, in mediating response to stress and the formation of traumatic memories.2 Ketamine is an ionotropic glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist. Its antidepressant and anti-anxiety effects are presumed to occur through activating synaptic plasticity by increasing brain-derived neutrophic factor translation and secretion and also by inhibiting glycogen synthase kinase-3 and activating mammalian target of rapamycin signaling.5
Brain-derived neutrophic factor plays a role in behavioral responses to classical antidepressants, but the impact on synaptic plasticity may take several weeks to manifest. In contrast, ketamine-mediated synaptic plasticity changes appear to occur within a matter of hours after ketamine administration.5
“The current thinking is that eventually, 6 to 12 weeks after initiating treatment with traditional antidepressants, dendritic growth and increased synaptic connections occur but with ketamine, these can occur within 24 hours of the infusion,” Dr Masand said.
Ketamine and Anxiety: An Increasing Evidence Base
“Ketamine has been studied and shown [to be] effective with an array of anxiety disorders, including SAD, general anxiety disorder (GAD), and PTSD, although the data on its effectiveness in obsessive compulsive disorder (OCD) are more mixed,” Dr Masand observed.
A small study of patients with GAD and/or SAD (n=12) compared 3 ascending ketamine doses to midazolam. Each was given at 1-week intervals, with midazolam counterbalanced in dosing position across patients. Ketamine was found to dose-dependently improve scores on the Fear Questionnaire. Moreover, it’s impact on decreasing theta frequency in the right frontal sites assessed via electroencelphalogram (EEG) was comparable to that of conventional anxiolytics.6
Glue et al evaluated the efficacy and safety of ketamine in 12 patients with refractory GAD and/or SAD who were not currently depressed using an ascending single-dose at weekly intervals study design. Within 1 hour of dosing, patients reported reduced anxiety, which persisted for up to 7 days.7
A continuation of that study evaluated the impact of maintenance treatment ketamine in patients with GAD and/or SAD (n=20) and found that 18 of the 20 patients reported ongoing improvements in social functioning and/or work functioning during maintenance treatment. The researchers concluded that maintenance therapy ”may be a therapeutic alternative for patients with treatment-refractory GAD/SAD.”8
“What is interesting about this study is that the impact of just one infusion lasted for 14 weeks, suggesting that patient[s] with anxiety disorders might have longer maintenance of response than patients with major depression, where the response has been maintained for only one week,” Dr Masand commented.
A study of patients with anxious and non-anxious bipolar depression (n=21 for both groups) found that both anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group.9 “Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest the need for further investigations into ketamine’s novel role in the treatment of anxious bipolar depression.,” the investigators concluded.9
An open-label trial of ketamine in 10 patients with treatment-refractory OCD found that ketamine’s effects on OCD symptoms, in contrast to depressive symptoms, did not seem to persist or progress after the acute effects of ketamine had dissipated.10
On the other hand, another randomized controlled trial (RCT) of 15 patients with OCD found that anti-OCD effects from a single intravenous dose of ketamine persisted for more than 1 week in some patients with OCD with constant intrusive thoughts, demonstrating that “a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an [SSRI].”11
In PTSD, there is “mounting evidence for a role of the excitatory neurotransmitter glutamate in stress responsiveness, the formation of traumatic memories, and the pathophysiology of PTSD, raising the possibility of identifying novel glutamatergic interventions for this disorder.”12
One double-blind study demonstrated that infusion of ketamine rapidly and significantly reduces symptom severity in patients with PTSD compared with midazolam.2
Another study found that administration of ketamine immediately after witnessing a traumatic event has been shown to prevent the enhancement of passive avoidance learning in mice.13Ketamine may thus target the mechanisms involved in the consolidation of traumatic memory and may enable the brain to reconsolidate memory and release trauma.14
A case study of a child with PTSD reported remission from behavioral dysregulation after receiving procedural ketamine.15
Drawbacks and Potential Adverse Effects
The main concern regarding the use of ketamine for anxiety disorders is the lack of a road map regarding maintenance, Dr Masand noted.
“At COPE, we have found that roughly 30% to 40% of our patients being treated with ketamine require maintenance infusions, and we highly personalize this approach so that patients can identify early signs of recurrence or relapse and we can devise a treatment schedule to prevent them,” he said.
Some patients continue treatment with pharmacotherapy, including standard antidepressants, benzodiazepines, or a mood stabilizer such as valproate and some patients become more receptive to psychotherapies such as CBT,” he stated.
However, “there is very little data regarding what happens long-term in this patient population.”
“Most side effects are mild and transient,” Dr Masand reported. “Patients must be monitored because of potential increases in blood pressure and pulse.”
Additional adverse events include nausea or vomiting, which are also mild and transient. Patients may be pre-treated with prophylactic anti-nausea medication, such as ondansetron, to pre-empt these symptoms, he said.
Some patients experience dissociation, or an out-of-body experience, which is also usually transient but seen by some patients as “annoying,” he noted. “Dissociative experiences are sometimes seen as a biomarker for insufficient response and suggest that the dose should be increased.”
Providers should be aware that cystitis and lower urinary tract pathologies (eg, detrusor over-activity) have been reported in long-term ketamine users, but typically only at high doses.16
Ketamine’s psychedelic effects make it a” popular recreational drug.”16 At lower doses, the predominant effects are stimulating, and users experience mild dissociation with hallucinations and a distortion of time and space. However, higher doses can induce more severe, schizophrenia-like symptoms and perceptions.16 Although these effects resolve rapidly, long-term use “can cause more pronounced and persistent neuropsychiatric symptoms. For this reason, ketamine should be “used cautiously with other drugs that alter mood and perception, including alcohol, opioids, benzodiazepines and cannabis.”16
“Ketamine for treatment-resistant depression has a robust evidence base and a rapidly-growing evidence base for its use in anxiety disorders,” Dr Masand said.
“Given the gaps in current treatment, this promising agent is occupying a more promising role in treatment of anxiety disorders, such as PTSD. Considering how common PTSD is, ketamine can make an important difference for a large number of people who suffer from this debilitating condition,” he concluded.
First Person Account of Ketamine Therapy: An Interview with Kimberly Palmer
To gain insight into the experience of ketamine treatment in a person with depression and anxiety, Psychiatry Advisor interviewed Kimberly Palmer of Los Angeles, California. Ms Palmer received treatment at the Ketamine Clinics of Los Angeles (https://www.ketamineclinics.com). Ms Palmer works as a program manager for a consulting company where she organizes and runs corporate events for small groups.
Psychiatry Advisor:What made you decide to pursue ketamine treatment?
Ms Palmer:I was raised in an abusive home, and as an adult I had severe major depression, as well as anxiety. I was treated with medications, such as antidepressants, but they had many adverse events and they ended up making me feel like a zombie, so I discontinued them. I managed okay for a while, but then I had another major depressive episode.
I was receiving psychotherapy at the time and it was only moderately helpful — not enough to stop the episode. Fortunately, I knew someone who works at a ketamine clinic. She told me how many patients had been helped by ketamine and I was interested, mostly because the adverse events of ketamine seemed mild and are not long-term.
Psychiatry Advisor: What were your experiences during your infusion?
Ms Palmer: I felt incredible during the infusion. The best way I can describe it is by referring to the movie Avatar, specifically the scene in which the protagonist is walking through a jungle at night for the first time and touching all the plants, which light up with pretty colors—very vivid, colorful, and not linear. There was the sensation of being on a sort of roller coaster, riding through different scenes.
At one point, it felt as though my chair was on a cloud. Then suddenly, the chair disappeared and I was floating on the cloud. It was a wonderful experience.
Psychiatry Advisor: How did the ketamine treatment affect you afterwards?
Ms Palmer: After only one treatment, it was as if a switch had flipped in my brain that allowed me to digest things and move beyond my trauma. Before the infusion, a lot of what was going on with me had to do with self-esteem issues and negative self-talk. These were behaviors learned over many years. After the infusion, the negative self-talk immediately disappeared. All of those thoughts — such as telling myself I am not good enough — that were preventing me from working through emotional issues, were resolved. I was able to start looking at things more objectively rather than taking them personally, and not take on responsibility for other people’s emotions and reactions.
I am currently working with a therapist and a life coach to help me feel more comfortable with communication because I was raised not to ask for things and to put up with anything I’m asked to do. As a result, I have developed a much more positive outlook of myself and the world.
Psychiatry Advisor: How many ketamine treatments have you had?
Ms Palmer: Over a 6-month period I had 6 treatments, which were all very helpful. Then, 6 months after the conclusion of this first series of treatments, some new issues came up, so I received 2 more — one regular 60-minute treatment and one extended 90-minute treatment.
Recently, with the holidays coming up, I decided to pre-empt the effect of some stressors and have another treatment. My most recent infusion took place the day after my father passed away. I noticed that during the infusion, I was able to steer myself away from negative thoughts about that issue. Although I cannot control what visions or experiences I might have, I do have some control over the direction of my thoughts and the after-effects have been positive and helpful.
Psychiatry Advisor: Did you have any adverse events from the treatments?
Ms Palmer: I had no negative physical effects. I had one mild bad reaction, when I came to the treatment session in an agitated state because I had gotten into a fight with someone right before. I was sad and crying by the time I finished the infusion. But I was in a bad headspace before I even walked into the room. And my experience was not scary, only sad.
Psychiatry Advisor: What impact has your treatment had on your day-to-day life?
Ms Palmer: My depression had interrupted my schooling. I was in school for 3 and a half years and then I hit a roadblock. After the treatments, I was able to complete my studies and graduated with a BA in business administration and management.
My job is stressful. I counterbalance the stress with hobbies like surfing and photography. But there are still stressors, and I have a dog who is reaching the end of life, which is affecting me. The ketamine treatments have helped me to manage those stressors.
Ketamine’s remarkable effect bolsters a new theory of mental illness.
A Vaccine for Depression?
Ketamine’s remarkable effect bolsters a new theory of mental illness.
One sunny day this fall, I caught a glimpse of the new psychiatry. At a mental hospital near Yale University, a depressed patient was being injected with ketamine. For 40 minutes, the drug flowed into her arm, bound for cells in her brain. If it acts as expected, ketamine will become the first drug to quickly stop suicidal drive, with the potential to save many lives. Other studies of ketamine are evaluating its effect as a vaccination against depression and post-traumatic stress. Between them, the goal is nothing less than to redefine our understanding of mental illness itself.
Depression is the most common mental illness in the United States, affecting 30 percent of Americans at some point in their lives. But despite half a century of research, ubiquitous advertising, and blockbuster sales, antidepressant drugs just don’t work very well. They treat depression as if it were caused by a chemical imbalance: Pump in more of one key ingredient, or sop up another, and you will have fixed the problem.
But the correspondence between these chemicals (like serotonin) and depression is relatively weak. An emerging competitive theory, inspired in part by ketamine’s effectiveness, has it that psychiatric disease is less about chemical imbalance than structural changes in the brain—and that a main cause of these changes is psychological stress. “I really do think stress is to mental illness as cigarettes are to heart disease,” says Gerard Sanacora, the psychiatry professor running the ketamine trial at Yale.
The theory describes stress grinding down individual neurons gradually, as storms do roof shingles. This, in turn, changes the nature of their connections to one another and the structure of the brain. Ketamine, along with some similar molecules, acts to strengthen the neuron against that damage, affecting not just the chemistry of the brain but also its structure.
Mental hospitals don’t usually see patients until they break: a brain shaped by vulnerable genes, wrecked by the stress of loss or trauma. This isn’t how it works with other sicknesses: heart disease, cancer, AIDS. Detected early, these conditions can often be managed. Crises averted.
If Sanacora and like-minded researchers are right, we may be on the cusp of a sea change that allows for a similar approach to mental health. The new approaches may prevent mental illness before it hits, by delivering a vaccination for the mind.
The need for progress could hardly be more urgent: Of all illnesses, neuropsychiatric diseases are estimated to put the heaviest burden on society. Nearly half of Americans are affected by some sort of mental disorder at some point in life. Suicides, 90 percent of them among the mentally ill, take 40,000 Americans every year—more than murder or car crashes. Since 2005, the suicide rate among U.S. war veterans has nearly doubled; in the first half of 2012, more service members died by suicide than in combat. Few medical failures are more flagrant than psychiatry’s impotence to save these people.
At the same time, treatment can be woefully ineffective. Less than a third of depression patients respond to a drug within 14 weeks, according to the 2006 STAR*D trial, the largest clinical test of antidepressants. After six months and multiple drugs, only half of patients recovered. Thirty-three percent don’t respond to any drug at all. When the pills do work, they are slow—a deadly risk, given that people with mood disorders kill themselves more often than anyone else.
Our treatments work so poorly in part because we don’t really understand what they do. Serotonin, the most common target for current antidepressants, is a neurotransmitter, a chemical that carries messages in the brain. But it was first found, in 1935, in the gut. Serotonin’s name comes from blood serum, where Cleveland Clinic scientists discovered it in 1948, noting that the chemical helps with clotting.
When Betty Twarog, a 25-year-old Ph.D. student at Harvard, later found serotonin in neurons, she wasn’t taken seriously. At that time, brain signals were thought to be purely electrical impulses that leapt between cells. Twarog called this old idea “sheer intellectual idiocy,” as Gary Greenberg reports in his book Manufacturing Depression. Working at the Cleveland Clinic in 1953, she found serotonin in the brains of rats, dogs, and monkeys.
Twarog didn’t know yet what serotonin was doing there, but a clue came soon from D.W. Woolley, a biochemist at Rockefeller University, in New York. In 1954 Woolley pointed out in a paper that lysergic acid diethylamide, or LSD, is chemically similar to serotonin and is processed similarly in the brain. Since LSD “calls forth in man mental disturbances resembling those of schizophrenia,” he wrote, another drug affecting serotonin might be used to treat schizophrenia. Twarog’s original paper would take years to percolate through the male-dominated field, but her work and Woolley’s would become accepted as evidence of how important chemicals like serotonin could be to brain signaling. The discovery was a breakthrough for neuroscience—but it also birthed a misleading, long-lived belief about mental illness. “The thesis of this paper,” Woolley wrote, “is that … serotonin has an important role to play in mental processes and that the suppression of its action results in a mental disorder. In other words, it is the lack of serotonin which is the cause of the disorder.”
Around the same time, other researchers stumbled on the first antidepressants, iproniazid and imipramine. Intended to treat tuberculosis and schizophrenia, respectively, these drugs also happened to make some patients “inappropriately happy.” Researchers found that the drugs elevated levels of serotonin, along with related neurotransmitters.1 This began a huge search to find chemically similar drugs that worked better as antidepressants.
Drug companies often say mood disorder is caused by a “chemical imbalance.” But the evidence for this story is slim.
Iproniazid was the first of a class of medicines that block an enzyme from breaking down serotonin, as well as dopamine and norepinephrine, two other neurotransmitters. The chief downside of these drugs, called monoamine oxidase inhibitors (MAOIs), is that they require a strict diet: no aged cheeses, wine, beer, or cured meats. Combined with these foods, the drugs can cause deadly spikes in blood pressure, a hassle that often inclines patients to ditch them. (The novelist David Foster Wallace took an MAOI for decades; in part to escape the food restrictions, he got off the drug months before his suicide.) On the other hand, tricyclic antidepressants, like imipramine, work by blocking the re-absorption of serotonin and norepinephrine. The cost is a host of side effects, from dry mouth to weight gain to erectile dysfunction and loss of libido.
The next generation of drugs focused on fine-tuning the same mechanisms, and had somewhat improved side effects. A new class of drugs known as selective serotonin reuptake inhibitors, or SSRIs, arrived in the ’80s, bringing huge commercial successes like Prozac, Zoloft, and Paxil. Since SSRIs are more specifically focused on serotonin, they were heralded as cleaner options; but they are not much more effective at lifting mood than the older drugs. We often take for granted the diabetes analogy for depression: If you are depressed, it is because you need serotonin, just as a diabetic person needs insulin. Drug companies often say that mood disorder is caused by a “chemical imbalance” in serotonin or a signal like it. One ad for Zoloft, the blockbuster antidepressant, featured a sad white circle crawling cutely beneath a gray cloud; the voice-over boasted that depression may be “related to an imbalance of natural chemicals in the brain. Zoloft works to correct this imbalance.”
But the evidence for this story is slim. Prozac raises serotonin levels within hours yet doesn’t change mood for weeks. When scientists deplete serotonin in healthy people, it does not make them sad. And when doctors measure serotonin levels in the cerebrospinal fluid of depressed people, they do not find a consistent deficiency; one 2008 study even found increased levels of serotonin in depressed people’s brains. The drug tianeptine, discovered in the late ‘80s, decreases serotonin levels yet relieves depression. And studies have shown that people falling in love show lower, not higher, levels of serotonin.
Serotonin is clearly not just a feel-good chemical. If a serotonin-based drug like Zoloft makes you happier, it works in some other, indirect way. As psychiatrist Ronald Pies, editor of Psychiatric Times, put it in 2011, “The ‘chemical imbalance’ notion was always a kind of urban legend—never a theory seriously propounded by well-informed psychiatrists.”
Stress in moderation is not harmful, but motivating. Cortisol, a stress hormone, cycles daily; synchronizing with sunlight, it helps arouse us for the day. In health, the hormone spikes when we need to pay attention: a test, a job interview, a date. Studies on rodents and humans confirm that brief, mild increases in stress are good for the brain, particularly for memory. During these spikes, neurons are born and expand in the hippocampus, the seahorse-shaped finger of tissue responsible for forming new memories and understanding three-dimensional space, and rodents learn better. The student who gets stressed while studying is more alert and remembers more than the one who feels no urgency—up to a point. The problem comes when stress is either too intense at one moment, as in a rape or violent attack, or too sustained, as in long-term poverty, neglect, or abuse.
Stress changes brain architecture differently, depending on how long it lasts. After chronic stress, like childhood trauma, the effect of hormones on brain cells inverts: Neurons in the hippocampus and the prefrontal cortex, which is responsible for mood and impulse control, start to shrink, while those in the amygdala, the almond-shaped seat of fear and anxiety, expand like overgrown shrubbery. But people are differently vulnerable, depending on genes and on prior life experience. “If you take two people and subject them to the same stressful event, for one of them it will be harmful and for the other, no,” says Maurizio Popoli, a professor of pharmacology at the University of Milan. “It is because they perceive the stress differently.”
Stress hormones’ most important effect is to flood parts of the brain with glutamate, the brain’s “go” signal. Used by 80 percent of neurons in the cortex, this key neurotransmitter drives mental processes from memory to mood. Glutamate triggers neurons to generate sudden bursts of electricity that release more glutamate, which can in turn trigger electrical bursts in nearby neurons.
This cellular signaling is called excitation and is fundamental to how information is processed in the brain. Like sexual excitability, it ebbs and flows; a “refractory period” follows each neural firing, or spike, during which the neuron cannot be excited. Other neurotransmitters, like serotonin, are called “modulatory,” because they change the sensitivity of neurons that secrete glutamate (among others). Less than 1 percent of neurons in the cortex signal with these modulators. As Popoli puts it, these modulators are “very important for fine-tuning the machine. But the machine itself is an excitatory machine,” driven by glutamate.
Glutamate moves like a ship between neurons. The sea it sails is called the synapse, the shore it departs from is the presynaptic neuron, and the destination, on the synapse’s far side, is the postsynaptic neuron. Another component, called a glial cell, works to remove glutamate ships from the synapse and recycle them. The glutamate system is affected at each of these points by stress hormones: They push the first neuron to send more ships, interfere with the glial cell’s recycling, and block the docks on the distant shore. All of these changes increase the number of glutamate ships left in the synapse, flooding the cell with aberrant signals. Indeed, depressed people’s brains, or at least animal models of depression, show all three of these problems, leading to long-lasting excesses of glutamate in key portions of the brain.
This superabundance of glutamate makes a neuron fire sooner than it should and triggers a cascade of signals inside the cell, damaging its structure. Glutamate binds to the neuron and allows in a flood of positively charged particles, including calcium, which are vital to making a neuron fire. But in excess, calcium activates enzymes that break down the neuron. Each neuron has tree-like branches, called dendrites, which are used to communicate with other neurons. When overdosed in glutamate, this canopy of branches shrinks, like a plant doused with herbicide. First the “twigs,” called spines, disappear. After prolonged stress, whole branches recede.
This harmful process, called excitotoxicity, is thought to be involved in bipolar disorder, depression, epilepsy, and neurodegenerative diseases like Alzheimer’s, Huntington’s, and Parkinson’s. In depressed brains, many areas are shrunken and underactive, including part of the prefrontal cortex and the hippocampus. The brain changes that cause mood disorders, Sanacora and his colleagues believe, come in part from chronic stress overexciting neurons with glutamate.
Ketamine works faster than any other drug, and for up to 65 percent of patients who don’t respond to existing treatments.
We usually think of our brains’ adaptability as a good thing. Just as neurons grow during development, the wiring in the adult brain can change. After strokes or other brain injuries, neural signals re-route themselves around damage, allowing even very old people to re-learn lost skills. Psychotherapy and meditation can change patterns of brain activity in ways that persist after treatment.2
But the neuroplasticity hypothesis of mental disorder highlights the drawback of such neural liberalism: The human brain’s flexibility allows regeneration, but also renders it vulnerable to being altered by stress. Subjected to the trauma of war, a bad breakup, or a bout of homelessness, a person with a genetic predisposition may find his mind stuck in a loop of chronic fear or depression.
The mood drugs in wide use now focus on modulatory neurotransmitters like serotonin. Ketamine, however, works directly on glutamate signaling. If ketamine is tapping into the root of the problem, this might explain why it works faster, better, and more often than more popular antidepressants.
Not everybody accepts the idea that glutamate and stress are central to depression. Some experts see the effects of stress as downstream effects, not the root cause of mood disorder. “The mechanism of action of a good treatment does not have to be the inverse of a disease mechanism,” says Eric Nestler, an expert on addiction and depression at Mt. Sinai Hospital. Serotonin drugs and ketamine may affect depression indirectly, without a serotonin or glutamate abnormality at the root of depression. Nestler also points out that depression probably includes a diversity of subtypes, without any single cause. He treats depression not as a unified disease, but a constellation of symptoms, each with discrete neural roots.
Even so, we do know that ketamine works faster than any other drug, and for up to 65 percent of patients who don’t respond to existing treatments.
If ketamine turns out to be a psychiatric savior, it will be one with a surprising history. Since 1962 it has been a go-to anesthetic for children in emergency rooms, because it kills pain, muffles consciousness, and rarely causes breathing or heart problems. Children given ketamine enter “a trance like state of sensory isolation” free of pain, memory, and awareness, as one review put it. Emergency room doctors rely on ketamine to make sure kids have no awareness or memory of, say, the trauma of having a shattered arm set back into place.
On the other hand, ketamine is a well-known recreational drug with potential for abuse. The dissociative trip caused by a moderate dose of ketamine has made it popular in clubs and raves since the 1970s, especially in Asian cities like Hong Kong. Its sedative effect made “special K” a date-rape drug. Doctors, patients, and the government agencies that fund research are often suspicious of a drug known to cause hallucinations, as they have been of psychedelics like psilocybin and ecstasy, despite their potential for treating depression or anxiety. Each tends to show fast results after a single dose, like ketamine.
In 1999, the same year ketamine was declared a controlled substance in the United States, Yale researchers happened upon its antidepressant power. A team co-led by Dennis Charney, now dean of the Icahn School of Medicine at Mt. Sinai, in Manhattan, and John Krystal, now chair of the department of psychiatry at Yale, used ketamine to study glutamate: Since ketamine was known to block glutamate receptors, it might show what role the excitatory neurotransmitter plays in the depressed brain. To their surprise, they found that the drug made patients feel better, often within hours. A single dose, much smaller than what’s used for anesthesia, tended to last for weeks.
Since 1999, a dozen studies have replicated the results, often on patients who failed to respond to other drugs. Ketamine also works for bipolar people in depressive phases, without triggering mania, as classic antidepressants sometimes do. The majority of depressed people studied have responded to ketamine. For patients who are often suicidal, this fast response can be lifesaving. Some 50 doctors in the U.S. now offer ketamine infusions for depression.
The first evidence in humans that ketamine might work to prevent mood disorder came from the battlefield.
Many leaders in the field see the emergence of ketamine, and future fast antidepressants based on glutamate, as a great leap forward for the field. “In my mind,” Sanacora told NPR recently, “it is the most exciting development in mood-disorder treatment in the last 50 years.”
Ketamine and the old antidepressants both result in fuller neural “trees,” but by different routes, at different speeds. Prozac and other serotonin-based drugs take four to six weeks to kick in. A landmark 2003 Science study by Columbia University’s René Hen and Ronald Duman, now at Yale, found that serotonin-based antidepressants only work if they spur birth of new neurons in the hippocampus.3 These new neurons take four to six weeks to mature, roughly the same amount of time that conventional antidepressants take to lift a depressed person’s spirits. A 2010 paper argued that SSRIs like Prozac may work by dampening glutamate release in response to stress. So even old-school antidepressants, when they work, may act on the glutamate system.
Ketamine, on the other hand, seems to act directly on mature neurons, fertilizing them to grow branches more robustly, or protecting them against damage. Ketamine’s key effect is to block glutamate receptors of one type. This causes less calcium to flow into the neuron, reducing the risk of the neuron shrinking or self-destructing.
Today ketamine is offered by psychiatrists and anesthesiologists, at prices ranging from $300 to $1,000 per dose, for people who are morbidly depressed or have chronic pain. Insurance doesn’t usually cover the cost of an infusion, because even though it is FDA approved as an anesthetic, it has not been approved as an antidepressant. Each new use of a drug requires multiphase clinical trials for FDA approval, usually funded by pharmaceutical companies, which have little incentive to invest in a drug they can’t monetize. Ketamine got its original patent in 1966, and that expired long ago. So even if drug companies steered ketamine through the expensive approval process as an antidepressant, doctors could still prescribe the cheap, generic versions already available for anesthesia instead of pricier, patented versions intended for depression. This is an old story. Lithium carbonate, which also acts on glutamate receptors, is still one of the most reliable drugs for treating bipolar disorder. But lithium, which is an element, can’t be patented. So, despite their effectiveness, these generic pills do not attract many corporate dollars.
One tough truth about mood disorder is that not all forms may ever be curable. Brain-imaging studies have shown structural differences between the white matter in healthy versus bipolar brains. Differences in personality and sleep patterns also persist in bipolar people, even between manic or depressed episodes. The structural changes likely have genetic roots, and once they arise, are difficult or impossible to reverse.
Nevertheless, if a drug prevents a mood disorder from manifesting, it might prevent harmful anatomical changes from ever taking place. Just as a vaccine triggers the body to arm itself against a particular virus, a drug like ketamine, given before the crisis that triggers a breakdown, might protect the brain against the effects of stress. Like a vaccine, the drug might only need to be given once for lasting resilience.
The first evidence in humans that ketamine might work to prevent mood disorder, not just treat it, came from the battlefield. U.S. soldiers injured in Iraq were treated with various anesthetics, including ketamine. Since ketamine can cause hallucinations, surgeons worried that it might make trauma worse: Scary combat-related hallucinations could put soldiers at higher risk of mental illness.
But they found the opposite. Out of 25,000 service members wounded in Iraq between 2002 and 2007, the data showed, veterans treated with ketamine for burns had lower rates of post-traumatic stress disorder. Among civilians and soldiers hospitalized for burns, as many as 45 percent end up with PTSD. But soldiers treated with ketamine on the battlefield got PTSD about half as often—even though they had more severe burns requiring more surgeries and longer hospital stays.
Mental hospitals don’t usually see patients until they break: This isn’t how it works with other sicknesses.
Rebecca Brachman, a neuroscientist and recent doctoral graduate from Columbia University, and her supervisor, Christine Denny, tried giving ketamine to mice and then exposing them to stressors.4 The researchers tested several types of stress, including one in which subject mice are “bullied” by more aggressive mice for two weeks. After this daily hazing, mice ordinarily develop the rodent equivalent of PTSD and depression: freezing in a new space, refusing to interact with other mice, and not moving in a forced swim test. But the mice “vaccinated” before the bullying fared far better: They didn’t act depressed afterward. Brachman and Denny found that the protection from a single dose lasted for weeks, even though ketamine only stays in the body for a few hours. Though they haven’t tested it yet, it is possible that, like a vaccine, this protection could last for much longer. Their rodent research suggests ketamine may work even better as a prophylactic than as an antidepressant.
Denny says that we may eventually routinely use ketamine to prevent PTSD in combat veterans, rape victims, or survivors of car crashes or mass shootings. Ketamine seems to be most strongly protective in mice when given before stressful events, Brachman says. Since we can’t predict most traumatic life events, this would limit the drug’s utility. But if injected after a trauma yet before the psychological damage sets in—as with the burned soldiers—ketamine may still be protective. Denny is investigating this possibility now.
And in some situations, violent shock is predictable. “You don’t know when an earthquake will happen,” Brachman says, “but we do know when we’re about to send U.N. workers into an area devastated by a disaster.” When people know they are going into an acutely traumatic situation, she imagines, a preventive drug given ahead of time might protect their brains from the long-lasting effects of stress. Think of earthquake aid workers, fire fighters, or rescue workers in Syria, dragging mangled people from rubble.
The idea that a single injection could prevent mood disorders is a radical departure from current psychiatric thinking. But there are some precedents: Talk therapy and mindfulness meditation have long focused on building resilience to stress. Bipolar patients take “neuroprotective” drugs like lithium not to treat current symptoms, but as a protection against future breakdowns, for instance.
Not everyone is confident that ketamine is a safe bet, to be sure. Ketamine’s long-term safety is not known, says Nestler. No lasting ill effects are seen in anesthesia patients, who take much larger doses, but they haven’t received routine treatments, the way it is administered as an antidepressant.
Plus, ketamine’s reputation as a street drug is tough to shake. Many doctors consider the hallucinogenic an unacceptable risk for patients, who they fear may develop a taste for the high. Yale’s Sanacora points out that patients in his trial, who are screened for drug or alcohol abuse, often find the trip feeling unpleasant or disturbing. The psychedelic experience is surreal, he points out, not the mellowing pleasure of a drug like alcohol, Xanax, or heroin. Extreme ketamine trips, referred to as falling in a “K-hole,” are often compared to near-death or unsettling out-of-body experiences; they hardly sound like fun to most people.
But since the antidepressant dose is far lower than the one taken to get high, many patients don’t even notice. Drug companies are also competing to develop a less trippy alternative. Johnson & Johnson is testing a nasal spray form of esketamine, a version of ketamine with less psychoactive impact. A company called Naurex has finished phase II trials of Rapastinel, an injected drug that partially blocks the same glutamate receptors as ketamine, but is not psychedelic.
The ketamine pioneers emphasize that their prevention research is the beginning of a new road, raising hopes, rather than offering an immediate cure. Brachman and Denny stress that ketamine may not be the drug that ultimately makes it into widespread use; like the anti-tubercular drugs in the 1950s that spawned the antidepressant era, it is the first to trail-blaze this new class of psychiatric prophylactics. “What this work shows us is that we can intervene beforehand and create some sort of self-reinforcing stress resilience,” Brachman says. “We didn’t know that before; that’s what’s important. Everything else—should we use it, how should we use it—that all comes later.”
Taylor Beck is a journalist based in Brooklyn. Before writing, he worked in brain imaging labs studying memory, aging, and dreams.
1. Maxwell, R.A. & Eckhardt, S.B. Drug Discovery Humana Press, New York, NY (1990).
2. Kennedy, S.H., et al. Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. American Journal of Psychiatry 164, 778-788 (2007).
3. Vogel, G. Depression drugs’ powers may rest on new neurons. Science301, 757 (2003).
*Images reprinted from Popoli, M., Yan, Z., McEwen, B., & Sanacora, G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nature Reviews Neuroscience 13, 22-37 (2011).
The San Francisco Veterans Affairs Medical Center is administering ketamine to veterans with post-traumatic stress disorder and depression.
Tobias Marton, the director of the ketamine infusion program at the center, said that since the program first launched two years ago, they have treated about 40 patients who had virtually exhausted all other options.
“They’ve done everything we’ve asked them to do and they remain with very severe symptoms and with a poor or impaired quality of life,” he said. “Despite (past treatments), there remains a high risk of suicide (with some veterans).”
While it was not clear where the 40 patients are from, the option is something that is available to Humboldt County veterans who are suffering from PTSD or depression.
Marton said that in general, about a third of people diagnosed with depression don’t respond to first, second and third lines of treatment.
In contrast, ketamine infusion has yielded “impressive outcomes.”
Many people know of ketamine as a party drug, often referred to as Special K, but it is mainly used medically for anesthesia or pain treatment.
Miracle of medicine
“We know ketamine has rapid and powerful anti-suicide properties,” he said. “To have another tool, a potentially powerful tool to have an impact on suicide rates is really exciting.”
While Marton is proceeding with “cautious optimism,” Boris Nikolov, the CEO of Neurosciences Medical Clinic in Miami, Florida, which has a ketamine clinic, believes the application might be a medical breakthrough.
“It’s one of the greatest discoveries in the field of depression,” he said. “This is one of the miracles in medicine.”
Nikolov’s clinic has treated 120 patients with ketamine, including his wife who has PTSD as a result of severe child abuse.
“Ketamine really helped her,” he said. “That was a really big part of her recovery.”
Nikolov said most medicines that treat depression take from two to four weeks to start working. Ketamine begins working within hours after it is administered, a process which usually involves an IV infusion over the course of about an hour.
“What’s most important is the strong and fast effect of ketamine in patients who are very seriously depressed, or want to hurt themselves,” he said. “When they finish treatment, they’re totally different people. There is no other medication that does that.”
Brad Burge, the director of strategic communication at the Multidisciplinary Association for Psychedelic Studies, or MAPS, said there has been “an explosion of treatment that’s outpaced research.”
“It means that people are going to have another option, an alternative to conventional medications,” he said.
According to Burge, MAPS believes the best form of ketamine infusion involves pairing with other forms of psychotherapy such as group or individual counseling.
While ketamine is an FDA-approved drug which has been used as an anesthetic as well as a pain reliever, it isn’t officially sanctioned by the FDA to be used for treating mental health disorders. However, Marton said that ketamine has been administered in this fashion for over 18 years now.
A company is currently in the process of trying to get an intranasal product approved by the FDA which would administer ketamine through the nasal passage, according to Marton. He expects the FDA’s decision to be announced sometime around March 2019.
If the product is approved, he said, VA clinics in rural communities like the one in Eureka would likely be able to start offering ketamine treatments as well.
For now, only the location in San Francisco is able to offer the treatment, but Marton said anyone within their service realm, which includes Humboldt County, is invited to consult with the VA about seeking treatment.
“We want to be as thoughtful as we can,” he said. “As we understand more about it … (we) might be able to start helping people who we haven’t been able to help despite throwing everything we have at them.”
NOVA Heath Recovery Ketamine Treatment Center | Call 703–844-0184 for a Ketamine Treatment | Alexandria, Va 22306 | 7 days a week and evening appointments as well! We also evaluate depression, ADHD, PTSD. Intranasal Ketamine available. The email is EMAIL@novahealthrecovery.com
Learn How Ketamine Can Treat Post Traumatic Stress Disorder
For decades, ketamine has been used as a medicinal intervention for treating depression, anxiety, mood disorders, and post-traumatic stress disorder (PTSD). While most ketamine advocates recognize its therapeutic potential for treating depression, the many benefits available to those suffering from PTSD are less understood.
Do you or a loved one suffer from post-traumatic stress disorder? If so, ketamine infusion therapy may be able to help alleviate your symptoms and provide the relief you need. However, public knowledge about medicinal ketamine is lacking. In this article, we go over everything there is to know about ketamine for treating PTSD.
PTSD 101: What You Need to Know
Post-traumatic stress disorder has a medical diagnostic code of ICD-10, which is the code used for reimbursing treatment through your insurance provider. PTSD, unlike other mental illnesses, is characterized by its triggering from a single or series of traumatic events. This explains why PTSD is common among military veterans and first responders.
According to a summary article from Mayo Clinic, PTSD is a mental health condition triggered by a terrifying experience. The sufferer subsequently experiences flashbacks, night terrors, and anxiety attacks that they cannot control as a result of the event. It takes a significant amount of time, therapy, and self-care to overcome the trauma of PTSD.
There is no known cure for PTSD. However, many experimental medicinal interventions are breaking ground when it comes to finding a cure. For example, the psychoactive drugs MDMA and ketamine have both been studied for their potential to alleviate the negative effects of PTSD.
Ketamine Infusion Therapy
Since the early 2000s, ketamine has gained popularity among medical providers for its application in infusion therapies. In recent years, clinics all around the world have embraced the healing power of ketamine by offering ketamine infusion therapy. This unique therapy involves one or more intravenous injections of ketamine under the supervision of an anesthesiologist.
What Is Ketamine?
Although ketamine has garnered a reputation as a party drug, its primary value is in its ability to provide fast-acting and potent relief for those with chronic pain issues. Ketamine was first synthesized in the 1960s and was later adopted as an anesthetic in veterinary medicine by the end of the decade. However, use in humans was initially sparse.
Ketamine is both an analgesic and anesthetic drug, which means its primary quality is to reduce or prevent pain. This makes ketamine highly effective for treating major depressive disorder, chronic back pain, and PTSD.
Ketamine and PTSD
Ketamine infusion clinics across the United States are now offering specialty treatments for those suffering from PTSD. For example, the renowned Ketamine Clinics of Los Angeles has treated hundreds of PTSD patients over the years. Led by Dr. Steven Mandel, M.D., the team at Ketamine Clinics of LA has a proven track record of helping relieve the pain of PTSD.
An increasing amount of scientific research has proven that ketamine is effective in treating PTSD. Most notably, a breakthrough 2014 study in JAMA Psychiatry discovered that a single intravenous subanesthetic dose of ketamine resulted in “significant and rapid reduction in PTSD symptom severity.”
Over the past few years, many articles and news reports have heralded ketamine as a potential wonder drug for treating PTSD. A recent article published by Medscape discussed how a team of researchers at the Icahn School of Medicine at Mount Sinai in New York City used ketamine to fight depressive symptoms in patients with PTSD and severe depression.
Is Ketamine Safe for PTSD?
There is no doubt that ketamine is a novel treatment for many PTSD sufferers. Since it is a relatively new medicinal intervention, there is some skepticism within the medical community regarding whether it is safe for human use. However, many of these doubts have been quelled over the years thanks to numerous studies and experiences that have proven its safety.
The most compelling evidence suggesting that ketamine infusion is safe in humans comes from a 2014 clinical study. This study managed to safely administer low doses of ketamine to treat neuropathic pain states in adults. Over the two-week monitoring period, the patients exhibited numerous benefits while experiencing only marginal or negligible side effects.
It should be noted that ketamine is not safe if taken recreationally. Since its inception, ketamine has gained a reputation as a party drug for its ability to induce dissociative states and euphoria. However, ketamine is not safe to use unless administered by a licensed physician. It is possible to overdose on ketamine, and the side effects of using high doses of ketamine can be fatal.
Ketamine: A PTSD Prevention Tool?
Interestingly, ketamine has found success as a tool for preventing the onset of PTSD. In one case, a research team gave a family of mice a low dose of ketamine before exposing them to electric shocks. Usually, mice exhibit symptoms of PTSD after being exposed to such a severe stressor. However, the mice that were given ketamine did not exhibit these symptoms at all.
Typically, traumatized mice freeze up when they are placed back in the cage in which they were shocked. In this case, the mice who were sedated with ketamine did not freeze when placed in the cage or froze for a significantly reduced duration. This led the research team to believe that ketamine may have value in both preventing and treating PTSD in humans.
Is Ketamine Right for You?
Ketamine may be an appropriate treatment option for you if you have treatment-resistant PTSD. In other words, you must first be diagnosed with PTSD and have sought the traditional frontline treatments for the condition before considering ketamine infusion therapy. We recommend speaking with your doctor about your PTSD symptoms and the appropriate therapies available to you. Usually, SSRIs or benzodiazepine pharmaceutical drugs, in conjunction with cognitive behavioral therapy (CBT) is the first method of treatment. However, if you do not respond well to this treatment option you should consider seeking ketamine therapy.
NOVA Heath Recovery Ketamine Treatment Center | Call 703–844-0184 for a Ketamine Treatment | Alexandria, Va 22306 | 7 days a week and evening appointments as well! We also evaluate depression, ADHD, PTSD. Intranasal Ketamine available. The email is EMAIL@novahealthrecovery.com
Ketamine for Depression: Does it work?
What is Ketamine?
Ketamine, also known as Ketalar, Ketaset, and Ketanest, is a medication that’s currently FDA approved only as an anesthetic but it’s showing great potential as a treatment for severe depression. In fact, numerous Ketamine Clinics have begun to appear throughout the United States to solve this problem. Depressed patients with stubborn symptoms get relief within hours rather than weeks with conventional anti-depressants. Doctors can only prescribe ketamine for depression off-label because studies are relatively new, but experts are saying that ketamine is one of the biggest breakthroughs in severe depression treatment to come along in decades .
Ketamine is a powerful pain reliever and a relaxant, but at higher doses it can also induce unconsciousness and disturbances in how a person experiences sight and sound. In high doses, it can produce hallucinations and delusions and its ability to create strong dissociative experiences have made it popular in the club scene where it’s known as “Special K”. An overdose of ketamine can be fatal and it can be addictive if patients don’t follow their doctor’s prescription guidelines. Currently, ketamine is scheduled as a class III drug and it’s created a lot of controversy among experts who disagree about whether it’s safe for doctors to prescribe it as a treatment for chronic depression. Despite the intrigue and the need for additional research to establish its safety and efficacy, ketamine clinics are now offering infusion treatments to patients all over the United States .
Effects of Ketamine
As a street drug, ketamine creates a sense of dissociation and can change a person’s sense of hearing and sight, but for patients with severe depression, ketamine relieves mood problems within hours or sometimes moments for about 85% of those treated. While conventional anti-depressants can take several weeks to take effect, studies have shown that ketamine often improves depression symptoms almost immediately. Patients typically feel better within hours .
Doctors, dentists, and psychiatrists prescribe ketamine to help their patients achieve a variety of different health goals. Doctors often use ketamine in FDA approved situations such as procedures involving cardiac catheterization, orthopedics, skin grafting, or diagnostics involving the eye, ear, nose, and throat. Surgical dentists may also use ketamine as an anesthesia during tooth extractions. After other treatment options have been attempted and failed, doctors may use ketamine to treat certain types of seizures in patients with status epilepticus .
Researchers demonstrated in 2014 that ketamine reduced symptoms of post-traumatic stress disorder in 41 patients and there are other exciting possibilities on the horizon in terms of PTSD treatment. Treatment-resistant depression and substance use disorders could both be treated with this drug, though many medical professionals view ketamine treatment for these mental health issues as controversial .
Ketamine for Pain Management (CRPS)
Central Sensitization is a process the central nervous system goes through which causes Complex Regional Pain Syndrome (CRPS/RSD) and other types of chronic pain. In central sensitization the number of NMDA receptors increases which amplifies a patients’ experience of pain. Ketamine interferes with NMDA receptors which puts a damper on pain signaling, providing pain relief and a desensitization to pain for patients affected by CRPS .
At low doses, ketamine can relieve chronic pain and potentiate the effects of sedatives. Researchers believe that ketamine could provide an alternative to more addictive painkillers like morphine if the FDA approves it for this use .
Ketamine for Anesthesia
In the 1960’s doctors used ketamine as an anesthetic on the battlefields in Vietnam because administration lends itself well to use in disaster zones; doctors don’t need electricity, an oxygen supply, or even highly trained staff to give patients ketamine. Since that time, the FDA has only approved ketamine for use as an anesthetic in hospitals and medical settings. As an anesthetic, ketamine doesn’t lower the patient’s breathing rate or blood pressure, which makes it safer than other anesthesia options. It’s for this reason that veterinarians use ketamine more than any other type of anesthetic for surgery on animals .
Ketamine for Depression
Depression is a major issue in the United States and though there are many anti-depressants on the market, about one-third of patients don’t experience any relief from their symptoms using the drugs that are currently available. Ketamine acts on depression by rebalancing a different set of neurotransmitters and receptors (the NMDA/glutamate receptors and GABA receptors) than the old-school Selective Serotonin Reuptake Inhibitors (which function by blocking reabsorption of serotonin). By blocking glutamate receptors in the brain, the majority of patients with ‘Treatment Resistant Depression’ are able to experience relief from their symptoms using ketamine .
Even though ketamine has yet to be approved by the FDA for use in treating depression, patients are flocking to ketamine clinics to receive the treatment off-label. It provides fast relief, which is vitally important in cases where patients feel suicidal and for depressed patients who have tried all of the other anti-depressants available with no luck, ketamine offers new hope. Infusion treatments take about 1 hour at a clinic, but the results are long-lasting with most patients returning only once every one to two weeks over a specified period of time. The treatment is expensive, but the results are promising enough that patients are willing to pay out-of-pocket for it .
The FDA hasn’t yet approved ketamine for use as an anti-depressant, but both Esketamine and Rapastinel (developed by Johnson & Johnson and Allergan respectively) have been fast-tracked as breakthrough drugs. The demand for these two medications is projected to grow rapidly in the coming years. Still, doctors can only prescribe ketamine for depression off-label since ketamine has been FDA approved for use as an anesthetic, not as an anti-depressant. Researchers have cautioned doctors to avoid over-prescribing this drug because the long-term health and well-being of patients could be at risk. Ketamine has a high potential for abuse, after all and experts claim that the evidence does not exist to prove that this drug is safe .
Ketamine as Drugs of Abuse
Ketamine is abused as a recreational drug and it has effects that are similar to Phenylcyclidine (PCP), LSD, dextromethorphan (DXM) and nitrous oxide (laughing gas). Ketamine is a dissociative anesthetic that can alter one’s sense of sight and sound and also produce profound relaxation, hallucinations, and delusions for about an hour. The effects of the drug come on almost immediately. It has been used as a rape drug that can render women unable to speak or to move .
People who abuse ketamine have developed serious bladder and kidney problems such as ulcerative cystitis, stomach issues, and memory loss. In fact, street users even risk developing depression as a result of addiction and dependence on the drug .
How is Ketamine used for depression?
Doctors may prescribe ketamine by itself or in tandem with other anti-depressants . Many experts on depression recommend that ketamine only be used as a short-term depression treatment option while other anti-depressants are taking effect. Though there are convenient ketamine nasal sprays in research and development by Johnson & Johnson, the high-potential for abuse of this drug has made many doctors and psychiatrists wary of using this drug to treat depression long-term. Further, some medical organizations are concerned that the long-term effects of chronic ketamine use is not well-understood. According to these organizations, more research is needed to establish the safety of this drug .
Promising Remedy for ‘Treatment Resistant Depressions’
Thomas Insel, the director of the National Institute of Mental Health says, “Recent data suggest that ketamine, given intravenously might be the most important breakthrough anti-depressant in decades.” Conventional anti-depressants aren’t able to help about one-third of patients with major depression, but new ketamine drugs such as esketamine (in development by Johnson and Johnson) may offer new hope. Infusion therapies available through ketamine clinics across the United States report a high success rate of 60% to 70% treating Treatment Resistant Depression as well as Major Depression with risk of suicide .
Fast-Tracked by FDA
Two drugs, Johnson & Johnson’s Esketamine and Allergan’s Rapastinel, were both upgraded to ‘fast-track’ status by the FDA in 2016 due to their importance and promise in treating treatment resistant depression.
Depression is the leading cause of disability in the world and currently, 12% of Americans (about 29 million people) are taking anti-depressant medications. The suicide rate is higher now than it has been in over 30 years. And about one-third of depressed Americans don’t experience relief taking conventional anti-depressants. In the interest of capitalizing on the market value of depression, which is projected to almost double by the year 2024, the FDA will review the use of these new ketamine-based depression drugs in 2018 and 2019, allowing Johnson & Johnson and Allergan to go through an abbreviated version of the normally lengthy FDA approval process for new drug therapies .
Drug trials have shown that 60% to 70% of patients with Treatment-Resistant Depression have been responsive to ketamine. Esketamine, a nasal spray developed by Johnson & Johnson, is in Phase III clinical trials right now. They are expected to receive FDA approval later in 2018, and once that happens, it will open doors for administering ketamine outside a clinic setting.
Rapastinel, which was developed by Allergan, is out of Phase III and awaiting FDA approval. The drug can be administered within 30 seconds intravenously and Allergan is working to develop an oral version of the drug as well .
How Ketamine Therapy Works
Ketamine therapy is usually performed at a ketamine clinic. Patients receive an intravenous infusion of the drug with relief from depression symptoms that can last for several weeks.
Ketamine Infusion or Intravenous Therapy (Infusion Process)
Ketamine can be injected directly into muscle tissue or it can be given intravenously. Researchers for Johnson & Johnson have also recently developed new treatment protocol called Esketamine that’s awaiting FDA approval. Using Esketamine, patients will be able to self-administer the drug as a nasal mist .
Patients must receive a referral from a doctor to go to a ketamine clinic. There, patients can receive an intravenous infusion of ketamine. On the first visit, a doctor will assess the patient before hooking the patient up to a ketamine IV. Patients then experience a variety of sensations during the infusion and for up to 2 hours following the infusion. Many patients report feeling a sense of deep relaxation and the ability to reflect on past traumas and anxieties calmly .
How does it work?
Researchers have demonstrated that a deficiency in certain vital connections between certain neurons in the brain may cause depression. Ketamine works as an NMDA receptor antagonist (NMDA is a glutamate receptor also known as N-methyl-d-aspartate) and an AMPA receptor stimulator. As such, ketamine stimulates the development of new receptors and synapses in the brain which helps patients regulate their mood, sleep better, and experience better focus .
Ketamine works by interfering with and rebalancing the glutamatergic system (glutamate and GABA) to stimulate new synaptic connections, better memory, and brain plasticity . During ketamine infusions, patients may feel capable of exploring traumatic memories more calmly to reframe the past or they may feel a pleasant sensation of relaxation or floating . Effects from an infusion can last for up to a week or two.
Intranasal ketamine formulas work by binding to a receptor called N-methyl-d-aspartate. In the brain, ketamine blocks the neurotransmitter glutamate which causes communication between the conscious mind and other parts of the mind (such as mood centers) to be blocked. In low doses, it relieves depression, but in higher doses, it can cause patients to feel an uncomfortable sense of dissociation from the body similar to a near death experience .
While most anti-depressant medications must build up in the body over the course of several weeks in order to have an effect, ketamine’s mood-altering benefits happen as the drug leaves the body. Researchers don’t know why this is the case, or even exactly how the drug achieves its strong anti-depressant effects but the fact is, ketamine works quickly to relieve depression symptoms in 85% of patients who are resistant to other forms of therapy . Standard anti-depressants target the neurotransmitters serotonin, norepinephrine, and dopamine, but ketamine is different. Ketamine blocks glutamate and stimulates synaptic plasticity or the ability of the brain to change and grow .
Doctors don’t fully understand how ketamine works or the potential effects that patients may experience from taking tiny doses of this drug over and over again. What is known is that recreational users can suffer ulcerative cystitis or cognitive issues as a result of prolonged use .
Ketamine Infusion Dose/Dosage
Researchers are working to find the perfect ketamine dose for depression patients. The risk of overdosing on this drug is high for the recreational user because there is only a slight difference between a dosage that leads to desirable effects and one that can cause a lethal overdose. The goal for researchers is to find an exact dosage that’s high enough to get rid of symptoms of depression but low enough to prevent patients from experiencing hearing and sight disturbances as well as the other negative effects from the drug . Ketamine produces only temporary effects on severe depression. Patients must continue to return to the clinic for infusions every few weeks to keep their depression symptoms in check .
Ketamine therapy cost? Is ketamine therapy covered by insurance?
Ketamine therapy is rarely covered by insurance and it’s pricey. Patients typically pay between $400 and $800 per infusion in many centers.
Ketamine Infusion Side-Effects
Ketamine use can cause a variety of side effects including:
Extreme fatigue or exhaustion
Nervousness or restlessness
Puffy or swollen eyelids, lips, or tongue
Hives, itching, or rash
Difficulty thinking or learning
Loss of appetite
Fast heartbeat, slow heartbeat, irregular heartbeat
Chest pain or discomfort
Inability to control eye movement
Difficulty urinating, frequent urination, cloudy or bloody urine
Paleness, bluish lips, skin, or fingernails
Increased pressure in the brain and the eyes 
Off-label ketamine infusion therapy is an unregulated business that has gotten the attention of both clinicians and medical organizations. There are currently ketamine clinics in a number of cities throughout the United States .
s ketamine therapy addictive?
Patients who use ketamine long-term may develop a tolerance and addiction to the drug over time. In medical settings, ketamine is safe to use because the dosage is carefully calibrated and monitored, but there is a high potential for abuse when patients use ketamine recreationally as a street drug. If patients don’t follow their doctor’s prescription for ketamine it can have extremely negative mental and physical effects particularly on the brain and bladder .
Ketamine-Based Drugs in Late Stage Trials
Both Rapastinel and Esketamine are ketamine-based drugs that have been ‘fast-tracked’ by the FDA because the FDA has identified them as “breakthrough drugs” .
Allergan developed Rapastinel, a ketamine drug that can be administered in 30 seconds intravenously. It works on the same receptors as ketamine, but it doesn’t produce hallucinations. An oral version of Rapastinel is also in development. The FDA considers Rapastinel to be a “breakthrough drug” which means that Allergan can speed through the lengthy drug approval process and get the drug to market by 2019 .
The FDA has designated Esketamine a “breakthrough therapy”, which means that the drug developers, a subsidiary of Johnson & Johnson, can speed through the lengthy drug approval process to get the drug on the market more quickly. Esketamine can be administered like a nasal decongestant, which would make it more convenient than intravenous therapy for depression patients. Experts feel that Esketemine would be most appropriately used as an adjunct therapy in combination with other anti-depressant medications, not as a standalone treatment for depression .
According to one recent study, when administered in combination with other oral antidepressants, Esketamine reduced patients’ depression symptoms more than oral anti-depressants alone. The anti-depressant effects of using a conventional anti-depressant in conjunction with Esketamine occurred within only about 1 week. When used alone, Esketamine effects seem to last 1 to 7 days in most patients. Esketamine is in Phase 3 testing with the FDA for use as a drug for ‘Treatment Resistant Depression’ and Major Depression with risk of suicide. Johnson & Johnson will file for FDA approval for this drug as a depression treatment in 2018 .
Risks of Ketamine Abuse
Ketamine abuse is a serious problem. It is possible to become addicted to ketamine. Patients may begin to need higher doses of the drug in order to experience the positive effects. An overdose of ketamine can be deadly. The effects of using ketamine chronically over a long period of time have not been established, but recreational drug users who have used ketamine long-term have developed ulcerative cystitis as well as cognitive issues .
The Ketamine Controversy
While ketamine can literally save lives by relieving the symptoms of major, Treatment Resistant Depression, including the risk of suicide, research still has not established the safety of ketamine for long-term use. The lethal dose of ketamine is only slightly higher than the therapeutic dose and its addictive properties mean that it could cause depressed patients more problems than it solves. Ketamine clinics have popped up all over the country to cash in on the high demand for a depression treatment that really works, but the research hasn’t demonstrated that this drug is safe for chronic use. So this is an instance where the buyer needs to beware. The FDA has fast-tracked these drugs because it’s constituents see market potential, but important research still needs to be done on this drug to demonstrate it’s safety and long-term efficacy.
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New Drug Combo Shows Promise for Treatment of Depression and Addiction
The combination of naltrexone and ketamine can help treat both symptoms of addiction and depression, a preliminary study by Yale University researchers suggests.
Substance abuse and depression are common in many patients, and efforts to treat both conditions simultaneously have had limited success. One recent study suggested that the antidepressant effects of ketamine might blunted by administration of naltrexone, used to limit cravings of those addicted to opioid drugs and alcohol.
A preliminary study of five patients suffering from both depression and substance abuse disorders suggest that isn’t the case. The study was published Jan. 9 in the journal JAMA Psychiatry.
The results “raise the possibility that for people who have depression complicated by substance abuse disorders, the combination of ketamine and naltrexone may be a strategy to explore in the effort to optimally treat both conditions,” said senior author John Krystal, Yale’s Robert L. McNeil Jr. Professor of Translational Research; professor of psychiatry, neuroscience, and psychology; and chair of the Department of Psychiatry.
Krystal and lead author Gihyun Yoon, assistant professor of psychiatry, treated the five patients suffering from depression and alcohol use disorder with a long-lasting form of naltrexone and then administered ketamine. Four of the five responded to the first ketamine dose and all five found relief from depression after multiple doses.
The study also challenges the idea that ketamine might produce antidepressant effects by stimulating opiate receptors.
Krystal cautioned that larger studies are needed to confirm beneficial effects of the combination treatment.
Krystal and Yoon have provisional patents on the use of ketamine and naltrexone to treat comorbid depression and substance abuse.
The study was primarily funded by the U.S. Department of Veterans Affairs.
Publication: Gihyun Yoon, et al., “Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder,” JAMA Psychiatry, 2019; doi:10.1001/jamapsychiatry.2018.3990
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Geuris “Jerry” Rivas, a native of New York, was diagnosed with severe obsessive-compulsive disorder when he was 15. Obsessions with organizing and reorganizing the belongings in his bedroom — posters, comic books, videos — took over most of his life.
Forced by germ obsessions to compulsively wash and rewash his hands, he started wearing gloves all day to both protect him from the germs and stop him from washing his hands raw. Now, at 36, OCD symptoms continue to cost him jobs and relationships. He’s managed to turn his organizational skills into a profession — he’s a home organizer and house cleaner — but still he struggles daily with his obsessions.
“It’s caused me a great deal of suffering,” Rivas says. “I’ve tried many, many medications. I’ve wasted so much of my life.”
In 2012, running out of answers, Rivas took part in the first clinical trial to test ketamine as a treatment for OCD. While ketamine is approved by the U.S. Food and Drug Administration as an anesthetic, it is also an illicit party drug known as “Special K,” with hallucinogenic effects and the potential for abuse. Over the past 10 years, dozens of small studies of ketamine’s ability to treat a variety of mood and anxiety disorders have reported remarkable results — including the sudden alleviation of treatment-resistant depression, bipolar disorder and post-traumatic stress disorder. And these effects lasted days, sometimes weeks, after the hallucinogenic effects of the drug wore off.
With a single infusion of the drug, Rivas experienced for two weeks what it was like to live without the compulsions and obsessions that had for years controlled his life.
“I felt like, for the first time, I was able to function like a regular person,” he says.
Pros and cons
Ketamine has brought hope to a psychiatric field desperate to find new treatments for severe OCD, a chronic condition marked by debilitating obsessions and repetitive behaviors. Current treatments, which include antidepressants such as Prozac, can take months to have any effect on the disease, if they work at all.
“Severe OCD takes such a toll on patients,” says Carolyn Rodriguez, MD, PhD, who as a researcher at Columbia University ran the OCD trial. Now an assistant professor of psychiatry and behavioral sciences at Stanford, she has continued to explore the pros and cons of using ketamine to treat OCD. “The constant, intrusive thoughts that something is contaminated, the checking and rechecking, the repetitive behaviors. It interferes with your life, your jobs, your relationships.”
Ketamine was developed in the 1960s and has been used for decades as an anesthetic during surgery. It remains a mystery just how the drug works in the brain, and there are safety concerns. There is evidence from people who take the drug routinely — in much higher doses — that chronic, high-frequency ketamine use may be associated with increased risk of bladder inflammation and cognitive impairment, Rodriguez says. And if taken regularly, it can lead to dependence.
But researchers like Rodriguez are intrigued about the drug’s potential to help them identify a whole new line of medicines for fast-acting treatment of mental health disorders.
“What most excites me about ketamine is that it works in a different way than traditional antidepressants,” Rodriguez says. “Using ketamine, we hope to understand the neurobiology that could lead to safe, fast-acting treatments. I feel that is part of my mission as a physician and researcher.”
‘Right out of a movie’
Rodriguez’s interest in ketamine as a treatment for OCD was sparked about a decade ago when she was starting out as a research scientist at Columbia. A small, placebo-controlled study published in 2006 by a mentor of hers, Carlos Zarate, MD, now chief of the section on neurobiology and treatment of mood disorders at the National Institute of Mental Health, had shown that ketamine induced dramatic improvement in treatment-resistant depression within two hours of infusion. It was a landmark study, drawing attention among the psychiatric community and launching a new field of research into the use of ketamine to treat various mood and anxiety disorders.
“What most excites me about ketamine is that it works in a different way than traditional antidepressants.”
Rodriguez, intent on searching for better, faster treatments for her patients like Rivas with OCD, took note. There was an emerging theory that ketamine affects the levels of the neurotransmitter glutamate in the brain and increasing evidence that glutamate plays a role in OCD symptoms, she says. Perhaps ketamine could help regulate OCD symptoms as well as depression.
In 2013, Rodriguez and colleagues published their results from that first clinical trial of ketamine in OCD patients. The trial randomized 15 patients with OCD to ketamine or placebo.
In those patients who were given ketamine, the effect was immediate. Patients reported dramatic decreases in their obsessive-compulsive symptoms midway through the 40-minute infusion, according to the study. The diminished symptoms lasted throughout the following week in half of the patients. Most striking were comments by the patients quoted in the study: “I tried to have OCD thoughts, but I couldn’t,” said one. Another said, “I feel as if the weight of OCD has been lifted.” A third said, “I don’t have any intrusive thoughts. … This is amazing, unbelievable. This is right out of a movie.” And while nearly all initially had dissociative effects like feelings of unreality, distortions of time or hallucinations, they were gone within two hours after the start of the infusion.
“Carolyn’s study was quite exciting,” Zarate says, adding that there were a number of similar, small but rigorous studies following his 2006 study that found fast-acting results using ketamine to treat bipolar disorder and post-traumatic stress disorder.
“We had no reason to believe that ketamine could wipe out any symptoms of these disorders within hours or days,” he says.
So how does it work?
Virtually all of the antidepressants used in the past 60 years work the same way: by raising levels of serotonin or one or two other neurotransmitters. Ketamine, however, doesn’t affect serotonin levels. Exactly what it does remains unclear.
“There’s a recognition that people like me and others are using the drug to treat patients now. There’s an incredible need for something.”
Since coming to Stanford in 2015, Rodriguez has been funded by the National Institute of Mental Health for a large clinical trial of ketamine’s effects on OCD. This five-year trial aims to follow 90 OCD patients for as long as six months after they’ve been given a dose of ketamine or an alternative drug. Rodriguez and her research team want to observe how ketamine changes participants’ brains, as well as test for side effects.
Ultimately, Rodriguez says, she hopes the study will lead to the discovery of other fast-acting drugs that work in the brain like ketamine but without its addictive potential.
Recent research in the field indicates that the glutamate hypothesis that triggered her pilot study might be further refined.
“Ketamine is a complicated drug that works on many different receptor sites,” she says. “Researchers have fixated on the NMDA receptor, one of the glutamate-type receptors, but it might not be the only receptor bringing benefit.”
In May 2016, researchers from NIMH and the University of Maryland — Zarate among them — published a study conducted in mice showing that a chemical byproduct, or metabolite, created as the body breaks down ketamine might hold the secret to its rapid antidepressant actions. This metabolite, hydroxynorketamine, reversed depressionlike symptoms in mice without triggering any of the anesthetic, dissociative or addictive side effects associated with ketamine, Zarate says.
“Ideally, we’d like to test hydroxynorketamine and possibly other drugs that act on glutamate pathways without ketamine-like side effects as possible alternatives to ketamine in OCD,” Rodriguez says.
Beyond the clubs
Meanwhile, dozens of commercial ketamine clinics have popped up across the country, making treatments available to patients who are searching for help to stop their suffering now. Medical insurance companies usually cover ketamine’s FDA-approved use as an anesthetic but won’t cover its use for other purposes, such as mental health disorders. So patients who have run out of treatment options are paying hundreds of dollars a dose for repeated ketamine infusions.
“The fact that these clinics exist is due to the desperation of patients,” says Rodriguez.
She and other researchers are calling for guidelines to protect patients and more research to learn how to use the drug safely.
“I think it’s a game changer, and it’s here to stay,” says David Feifel, MD, PhD, professor emeritus of psychiatry at UC-San Diego, who studies the effect of ketamine on clinical depression. Feifel began prescribing the drug for patients with treatment-resistant depression in 2010.
“I’ve found it to be very safe,” Feifel says, adding that the American Psychiatric Association this year issued safety guidelines on how to use ketamine clinically for treatment of depression.
“There’s a recognition that people like me and others are using the drug to treat patients now,” he says. “There’s an incredible need for something.”
The drug hasn’t worked for everyone he’s treated, Feifel says, but for many it’s been “life-changing.”
Rodriguez says she understands what motivates the clinicians to prescribe the drug now to patients in dire straits — those who are suicidal or who have tried every possible medication and therapeutic option and continue to suffer each day.
“I see it as a way to treat people whose OCD is very, very severe,” she says. “People who can’t come out of the house, who are suicidal, who have no other options.
“I just don’t like the idea of people being in pain,” Rodriguez adds. “I want to see science translated into treatments now.”
Meanwhile, researchers are learning more about the drug. Janssen Pharmaceutical is testing the efficacy of a version of ketamine, known as esketamine, as a therapy for treatment-resistant depression and for major depressive disorder with imminent risk for suicide. The FDA has fast-tracked both investigations. At Stanford, Alan Schatzberg, MD, a professor of psychiatry and behavioral sciences, along with other faculty including Rodriguez, is studying the mechanism of action for ketamine in treating depression.
Rodriguez is also interested in using ketamine to kick-start a type of cognitive behavioral therapy called exposure and response prevention, an evidence-based psychological treatment designed to help patients overcome OCD. The therapy involves teaching patients with OCD to face anxieties by refraining from ritualizing behaviors, then progressing to more challenging anxieties as they experience success.
Relaxation and other techniques also help patients tolerate their anxiety — for example, postponing the compulsion to wash their hands for at least 30 minutes, then extending that time period.
“My goal isn’t to have people taking ketamine for long periods of time,” Rodriguez says. But perhaps a short-term course of ketamine could provide its own kind of exposure and response prevention by allowing patients to experience that it is possible not to be controlled by their OCD, she says.
Rivas well remembers that infusion of ketamine he received during Rodriguez’s first clinical trial to test the drug. The rush made him feel “like Superman.”
“I felt like my body was bigger, that I was more muscular, that I could tackle anything,” he says. But that feeling only lasted the duration of the 40-minute infusion. His OCD symptoms disappeared immediately and were still gone for two weeks after.
“I was amazed that something like that would work and work so fast,” he says. His OCD symptoms today are still intrusive, but he manages to keep them under control by taking antidepressants and seeing a therapist. Still, each day when he comes home from work, he has to put gloves on before he enters his apartment building, and as soon as he enters his apartment, he must wash his hands.
“It’s a ritual now,” he says. “There has never been a time that I haven’t done that, except those two weeks after the ketamine.”
When he heard that certain private ketamine clinics are now offering the drug as treatment for OCD, he said he understands why patients take the risks and pay the high prices. As more research has become available, he’s begun considering it himself.
“I’ve been suffering through my OCD for so long, I’ve gotten to the point where I’d try anything,” he says.
USING KETAMINE TO TREAT SEVERE MENTAL ILLNESS conversation with Stanford psychiatrist Carolyn Rodriguez, MD, PhD, about how she got interested in the use of ketamine to treat obsessive-compulsive disorder and how she is determined to find out why, in studies, the drug has provided relief from symptoms.
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