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A new study shows that weekly ketamine infusions are associated with continued and maintained reductions in depressive symptoms among patients with treatment-resistant depression.
The findings, which are considered novel among studies assessing ketamine administration for patients with treatment-resistant depression, evidence the promising role the controversial drug could play in psychiatric care.
A team of investigators, led by Jennifer L. Phillips, PhD, an associate scientist in the Mood Disorders Research Unit at The Royal’s Institute of Mental Health Research, conducted a randomized, double-blind crossover comparison of single ketamine infusion versus active placebo control midazolam. The assessment, held with 41 participants with treatment-resistant depression at single treatment center, observed patients receive 6 open-label ketamine infusions 3 times per week over 2 once patients had a relapse of depressive symptoms.
Patients who reported a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale (MADRS) received another 4 additional infusions once weekly in a maintenance phase.
Those administered a single ketamine infusion reported significantly reduced depressive symptoms at the primary efficacy endpoint of 24 hours post-care versus those treated with midazolam. The therapy showed cumulative antidepressant effects over repeated infusions, as well a doubling of antidepressant response rate in patients, according to linear mixed models.
Investigators found that 59% of patients met the response criteria following repeated infusions, with 3 infusions serving as the median dosage required to reach achieved response. In patients receiving weekly maintenance infusions, no further improvement in MADRS scores were reported.
The first-of-its-kind findings come just 1 month following the US Food and Drug Administration (FDA) approval of esketamine nasal spray (Spravato) for the treatment of patients with treatment-resistant depression. At the time, the therapy made history as the first novel treatment indicated for depression in 30 years—and headlines as one of the first hallucinogenic drugs to reach indication for a common condition.
Dennis Charney, MD, Dean of Icahn School of Medicine at Mount Sinai and a member of the Yale University team that led pioneering antidepressant ketamine trials in the 1990s, told MD Magazine®that microdosing or implementing controversial therapies for psychiatric care require what any other trial requires: control, safety, and a carefully-assessed standard for efficacy.
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.
The newest FDA-approved medication to treat severe depression, a nasal spray based on the anesthetic (and misused hallucinogenic party drug) ketamine, will soon be available to veterans treated within the Department of Veterans Affairs.
In a move that may help thousands of former service members with depression that has not improved with other treatments, VA officials announced Tuesday that the department’s doctors are now authorized to prescribe Spravato, the brand name for esketamine, a molecular variation of ketamine.
The decision to offer a drug hailed by many as a breakthrough in treatment for its speedy results — often relieving symptoms in hours and days, not weeks — shows the VA’s “commitment to seek new ways to provide the best health care available for our nation’s veterans,” Secretary Robert Wilkie said in a release.
“We’re pleased to be able to expand options for Veterans with depression who have not responded to other treatments,” Wilkie added.
The treatment will be available to veterans based on a physician’s assessment and only will be administered to patients who have tried at least two antidepressant medications and continue to have symptoms of major depressive disorder.
An estimated 16 million Americans have had at least one major episode of depression, and of those, 1 in 3 are considered treatment-resistant. In the veteran population of 20 million, the estimated diagnosis rate of depression is 14 percent — up to 2.8 million veterans. Between one-third and half of those veterans may be treatment-resistant.
The lack of effective medications for difficult-to-treat patients prompted the Food and Drug Administration to place esketamine on a fast track, expediting its review of the drug to ensure that it went to patent as soon as safely possible, according to administration officials.
“Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process, including a robust discussion with our external advisory committees, were important in our decision to approve this treatment,” said Dr. Tiffany Farchione, acting director of the FDA’s Center for Drug Evaluation and Research Division of Psychiatry Products, in a release.
As with any other medication, there are risks. Spravato carries a boxed warning for side effects that include misuse, the reason it is administered under a doctor’s supervision. The list of side effects includes sedation and blood pressure spikes and disassociation, such as feelings of physical paralysis and out-of-body experiences. It also can cause suicidal thoughts and behaviors.
Acknowledging the dangers, FDA made esketamine available only through a restricted distribution system.
A veteran prescribed Spravato would inhale the nasal spray at a medical facility while under supervision of a medical provider, and would be monitored for at least two hours after receiving the dose. A typical prescription includes twice-weekly doses the first month, followed by a single dose weekly or biweekly as needed. Spravato cannot be dispensed for home use.
Spravato is made by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. It is the first major antidepressant medication to hit the market in 30 years.
Allergan needs a win with rapastinel, while Lundbeck’s chief exec faces her second clinical challenge.
Welcome to your weekly digest of approaching regulatory and clinical readouts. After a tough 2018 Allergan needs some good news, and it will soon find out if its depression project rapastinel will provide it. Three phase III trials of the project are due to yield topline data in the first half of this year.
Rapastinel targets the NMDA receptor, making it similar to Johnson & Johnson’s ketamine enantiomer esketamine. The J&J candidate is under US review with a PDUFA date of May 2019, though continuing US government shutdown could put approval in doubt.
Although the two projects are often mentioned in the same breath they act differently: rapastinel is a partial agonist of the NMDA receptor, while esketamine blocks it. This way, Allergan hopes, its project might not have the same psychomimetic effects as ketamine and, to a lesser extent, esketamine.
Dissociation – becoming less aware of one’s surroundings – has been seen with the J&J project. Allergan will want to show a safety edge with rapastinel, but stronger efficacy versus esketamine would not go amiss either. Still, Bernstein analysts only give rapastinel a 50% chance of success.
The three phase III trials of rapastinel test the project on top of standard antidepressants in patients with a partial response to the existing drugs. The primary endpoint of all three is change in Montgomery-Asberg depression rating scale (MADRS) at three weeks.
Esketamine itself had mixed results in its pivotal programme: the Transform-2 trial met its primary endpoint, but Transform-3 and Transform-1 did not. Across the three studies, which tested esketamine on top of an oral antidepressant, the reduction in MADRS score at four weeks was 3.2-4.1 points.
Allergan is also developing an oral NMDA modulator, AGN-241751, but this has only just entered phase II. The company, which faced calls for a break-up last year, needs a nearer-term boost, and with 2024 sales forecasts of $505m rapastinel is its biggest pipeline hope.
The two upcoming phase III readouts for Lundbeck’s antipsychotic Rexulti in bipolar mania might not be game changing: there are already approved drugs for this indication, and existing off-label use of antipsychotics is being fuelled by increasing genericisation.
Some analysts do not think that success in bipolar mania will add materially to Rexulti sales, but the downside risk of a second negative trial readout is substantially greater given the lack of other catalysts.
The two bipolar trials have enrolled 322 and 333 patients, the active cohorts given 2-4mg of Rexulti for 21 days, with a six-month follow-up. The primary endpoint is change in the Young-mania rating scale, and a key secondary endpoint is clinical global impression-bipolar (CGI BP) severity-of-illness score in mania.
Even if there is improvement in severity of illness, success in bipolar mania will at best be a nice-to-have addition to Rexulti’s current uses in schizophrenia and major depressive disorder, according to analysts at Leerink.
A more exciting event for Lundbeck will be whether Rexulti can have an impact on agitation in Alzheimer’s disease, where Bernstein analysts reckon success could add $1bn of sales. However, previous data have been mixed.
For now, if Rexulti does not deliver the goods in the more immediate bipolar indication, the market could seize it as an opportunity to punish the stock further.
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Potential for abuse and strategies for containing any risks from an experimental depression treatment from Johnson & Johnson will be in focus at an Food and Drug Administration panel next week.
J&J’s nasal spray, esketamine, a close cousin of the party drug ketamine, will be considered by an FDA advisory panel on Feb. 12. While agency staff seemed satisfied that the likelihood of abuse is low, they raised questions about safety issues connected to a dreamlike sensation the medication can create in some users.
“Ketamine abuse is relatively uncommon in the general population,” agency staff said in a report ahead of next week’s meeting. Just 1.3 percent of people over age 12 abuse the drug, lower than abuse rates for other hallucinogens like ecstasy and LSD.
At the same time, reviewers worried that patients could get into accidents or otherwise be harmed if they leave a doctor’s office while still experiencing disassociation, a known side effect of ketamine — and a sought-after experience for casual users who have dubbed the spacey feeling the “K-hole.”
It takes roughly 90 minutes for disassociation symptoms from esketamine to resolve, according to the report. FDA staff also cited elevated blood pressure as a safety concern.
Esketamine is a key part of J&J’s pharmaceutical pipeline, as the company faces flagging sales this year weighed down by drug pricing scrutiny and looming generic competition. Its shares, which rose 2.3 percent this year through Thursday’s close, were were little changed in early trading on Friday.
In addition to weighing in on the drug’s safety and a proposed risk-evaluation and mitigation strategy, FDA staff will ask advisers to vote on whether esketamine effectively treated the depression of patients who weren’t helped by other therapies. They’ll also discuss whether additional studies are needed before or after the drug is potentially approved.
The staff report noted there were six deaths among patients taking the J&J drug, of which three were suicide in the esketamine depression program, but they didn’t see a clear link to the drug itself.
“Given the small number of cases, the severity of the patients’ underlying illness, and the lack of a consistent pattern among these cases, it is difficult to consider these deaths as drug related,” staff reviewers noted.
A decision on whether to allow the drug on the market is expected by March 4. Esketamine has the FDA’s breakthrough-therapy designation in treatment-resistant depression as well as for depressed people at risk of suicide. Results from a study in suicidal patients are expected this year. Allergan is also testing a fast-acting antidepressant, rapastinel, which is about a year behind esketamine in testing.
‘Special K’ Drug vs Ketamine Therapy: The Differences in Intentions, Use and Application
The Differences Between ‘Special K’ and Ketamine Therapy
Some know it as a veterinary tranquilizer, others know it as a party drug. For others still, it might be a life-line, the only hope to get their life back from the throes of crippling depression. We are talking about a drug called ketamine or ‘Special K’.
Ketamine’s many names and uses make it a difficult drug to understand. The scientific research on ketamine is evolving so rapidly that not even medical professionals can’t agree on how it should be used.
This article takes all of the information about ketamine, or ‘Special K’, and breaks it down so that it’s simple, accurate, and concise. If you’re wondering about the many differences between using ketamine as a street drug and using it therapeutically, then you’ve come to the right place.
Special K: Ketamine as a Street Drug
Most people first learn about ketamine when they hear about the street drug called ‘Special K’. Other names for the drug when used recreationally are: Ketalar, Ketaject, Vitamin K, and Super K. While this drug is not as widely used as Marijuana or some other illicit substances, it has a strong hold on certain niche markets, like the clubbing and raving scenes.
Although doctors and veterinarians began using ketamine in the 1960s, it wasn’t introduced into the party scene until much later. The trend actually began in India, in the Goa trance music scene of the 1980s, and made its way to the western world from there. By the 1990s, ketamine was a major force in the psychedelic drug scene throughout Europe and the United States.
Despite small ups and downs since its introduction in the ‘90s, Special K has remained a steadily popular drug among high school and college students. The US’s National Institute on Drug Abuse has found that 1.2 percent of high school seniors report that they’ve used ketamine in the last year. While that’s much lower than some other drugs, it’s still significant given the seriousness of ketamine’s effects and the dangers of its potential side effects.
An overdose of ketamine can lead to death. Even non-lethal doses can cause side effects like chest pain, memory loss, and trouble breathing. Those who use Special K recreationally often become addicted, and eventually lose their jobs, relationships, and lives to the drug.
Ketamine Therapy: How Doctors Are Using Ketamine to Change Lives
“At this point, any new depression treatment that makes it to the finish line is a huge win.” That’s Dr. George Papakostas speaking to Time Magazine about the desperate need that medical providers have for depression medications. He says that whatever drug does make across that finish line is “going to have a major impact.”
That drug may very well be ketamine.
Despite its reputation as a street drug or a horse tranquilizer, multiple scientific studies have found the drug is a very effective remedy for a number of ailments (such as PTSD), but especially depression.
Ketamine, along with drugs like phencyclidine (popularly known as PCP) and dextromethorphan (often called DXM or ‘Robo’), belongs to a class of drugs called dissociative anesthetics. These kinds of drugs tend to give the users a ‘floating’ sensation, as if they’re detached from their bodies and their surroundings.
Special K is a particularly fast acting form of dissociative anesthetic, which is why it works so well as both a party drug and a numbing agent in surgeries. In medical settings, Ketamine is often used as an initial anesthetic before other, more powerful painkillers like morphine can kick in. But it’s not these anesthetic effects that make the ketamine drug so effective as an antidepressant.
However it works, the scientific results are pretty clear: regular, therapeutic doses of ketamine helps eliminate the symptoms of depression.
One study from February of 2018 observed “significant improvement of depressive symptoms” in a double-blind clinical trial of 67 adults with treatment-resistant depression (a type of depression that doesn’t respond to other medications like Prozac). Further, the study found that the improvements in the patients were sustained throughout the entire 9-week period of the study. That’s not just a good finding, it’s a breakthrough for treating a condition that has long eluded medical professionals.
Although ketamine has not yet been approved in a prescription pill or nasal spray form for treating depression, there are treatment centers that can offer completely legal ketamine therapy for depression. One of these centers, based in Los Angles, is called Ketamine Clinics.
At these centers doctors are able to administer ketamine drugs in a controlled and calm setting through intravenous or infusion methods.
Why People Use Ketamine Drugs: Therapy Vs. Thrill Seeking
Although the ketamine drug used in therapy is technically the same as the Special K drug used in wild raves, the motivations and outcomes of the experiences are very different.
Using Special K to Get High:
When people use Special K as a street drug, they are looking for a high. Some might be seeking a thrilling experience at a rave, while others might be trying to escape from a life that they find overwhelming. Many end up dangerously addicted to the drug after repeated use.
Almost immediately after the drug is ingested, the user begins to feel the effects of the ketamine. At lower doses, ketamine may merely make the user feel ‘dreamy’. But, at higher doses, ketamine can have extreme euphoric and hallucinogenic effects. When these effects are at their most extreme, the user can become immobilized and go into a ‘K-Hole’.
Ketamine’s effects on mobility and memory are so drastic that it is often used as a date rape drug. In this way, the high of Special K can quickly turn into a horrible low.
This dark side of ketamine is made more dangerous by the fact that recreational users are often getting their supply from unregulated sources, like the Chinese black market or the ‘dark web’. Unregulated drugs like this can be cut with toxic chemicals or other drugs, and they can have very inconsistent potencies, making it nearly impossible to determine a safe dose.
In short, ketamine is like many other street drugs when it’s used illicitly: it offers a quick, dangerous high that can easily lead to addiction.
Using Ketamine as Therapy:
John Abenstein, MD, the president of the American Society of Anesthesiologists, has said that “Outside of the clinic, ketamine can cause tragedies, but in the right hands, it is a miracle.”
It’s this miracle, and not a fun ‘high’, that people are seeking when they use ketamine for therapy.
Many people’s lives have been plagued by depression, bipolar disorder, and PTSD. People lose their jobs because they can’t find the will to leave their beds in the morning. Their friendships fall apart and their marriages often end in divorce. Some severely depressed people end up taking their own lives. These tragedies are all too common.
Ketamine therapy offers real hope for millions of people who struggle with these psychological problems daily. It’s especially important for those ‘treatment resistant’ patients who have found no relief from other treatments like SSRIs.
Even though there is not yet a prescription ketamine medication for depression, many people’s lives have already been changed by ketamine therapy in clinics. In fact, there is a whole Ketamine Advocacy Network whose mission is to “spread awareness of ketamine therapy for treatment-resistant depression, bipolar, and PTSD, and to make this treatment available and affordable for all who need it.”
Ketamine therapy is about so much more than a fun party or a weekend escape. It’s about healing lives that have been fractured by crippling disorders.
Intravenous Infusions for Therapy Vs. Snorting or Injecting to Get High
In its recreational drug form, ketamine tends to be a white powder or a crystallized chunk that can be broken apart. In order to get high, people snort the drug as lines of powder, take it orally in pill forms, or inject it intravenously using hypodermic needles.
All of these forms of recreational use present their own dangers, such as infection, the spread of disease through used needles, or incorrect dosing.
Using ketamine in a medical facility is a very different sort of experience.
The ‘route of administration’ (ROA), or how the drug gets into the body, is very important for ketamine’s therapeutic qualities to work. Most therapeutic doses of the ketamine drug are given intravenously.
The intravenous infusions are given over an elongated period, usually about a half an hour in length. This method allows the practitioners to control the dosage and to spread out the rate of delivery so that the drug can enter the bloodstream in a consistent and steady manner, rather than all at once.
Intravenous infusions also allow the drug to enter directly into the bloodstream. Other ROAs, like pills, can lead to a large percentage of the drug being metabolized by the body before reaching the brain. You can read more about why intravenous infusions are most effective on the Ketamine Advocacy Network website.
How It Feels to Take Ketamine Therapeutically
Therapeutic doses of ketamine definitely won’t send you into a K-Hole, but they can make you a bit woozy. In some cases, people have reported feeling dissociated, but these feeling are usually minor and can even be pleasurable. Still, patients must make sure to arrange a ride home with a friend or family member because they won’t be able to drive.
Many people find that they can go right back to work or school after their ketamine therapy appointment. Others prefer to head home and take a short nap. Either way, the anesthetic effects of the ketamine should be gone shortly after the session.
Although it varies from patient to patient, many people only require ketamine therapy once a week or less in order to see a significant or total reduction in their symptoms!
K-Hole: The Risks of a Special K Drug Overdose
As we’ve mentioned above, a ketamine overdose is not pleasant, and can even be deadly. Although you don’t have to worry about this if you’re just taking therapeutic doses, those who use the drug recreationally must be very careful.
When someone takes high amounts of the Special K drug they can end up in a sort of catatonic state where they can’t move or talk. This is called a K-hole. Some describe it as a near death experience, and that’s not a good thing. It can be a terrifying and even traumatizing experience.
But a K-Hole is not the worst thing that can happen if you take too much ketamine. A ketamine overdose can also lead to vomiting, chest pain, seizures, and even death.
The Future of Ketamine
Depression has plagued humans for millennia. It was first described by Hippocrates as “Melancholia”, and although we know much more about the disease these days, the treatments that are widely available are far from perfect. This is why the advances in ketamine therapy are so exciting.
Doctor Thomas Insel has said that ““Recent data suggest that ketamine, given intravenously, might be the most important breakthrough in antidepressant treatment in decades.” That’s a big deal coming from the director of the Institute of Mental Health.
Ketamine may continue to be a dangerous street drug for some, but for others it’s a beacon of shining hope.
By Tracie White Illustration by Kotryna Zukauskaite
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.
One more reason to treat your depression rapidly with Ketamine:
Depression Linked to Increased Risk of Developing Atrial Fibrillation
NEW YORK—Depression appears to be a risk factor for atrial fibrillation, the most common arrhythmia in the U.S., according to new observational data from the national Multi-Ethnic Study of Atherosclerosis (MESA) study.
Considering that 20% of U.S. adults report depressive symptoms, “our findings identify a large portion of the U.S. population that is potentially at an increased risk of developing atrial fibrillation and who may benefit from more targeted efforts to prevent atrial fibrillation,” Dr. Parveen Garg, from the Keck School of Medicine at the University of Southern California in Los Angeles, told Reuters Health by email.
He presented the study March 22 at the American Heart Association’s Epidemiology and Prevention/Lifestyle and Cardiometabolic Health Scientific Sessions in New Orleans.
The analysis included 6,644 adults (mean age, 62; 53% women, 38% white, 28% black, 22% Hispanic, 12% Chinese-American) with no known heart disease at baseline who were followed for a median of 13 years as part of the MESA study.
In the fully adjusted model, individuals with a Centers for Epidemiologic Studies Depression Scale (CES-D) score of 16 or higher (indicating clinically relevant depressive symptoms) had a 34% (P=0.039) higher risk of developing atrial fibrillation during follow-up compared with those with a CES-D score of less than 2. Similarly, individuals reporting antidepressant use had a significant 36% increase in their risk of developing atrial fibrillation compared with those not on the drugs.
“An important next step is to confirm these results in other studies, especially those with more comprehensive and clinically validated assessments of depression. If confirmed, then it will be important to determine if treating individuals with depression actually reduces their risk of atrial fibrillation,” Dr. Garg said.
Several mechanisms have been proposed to explain a possible link between depression and atrial fibrillation, Dr. Garg explained. Depression can increase systemic inflammation and activate the autonomic nervous system, which increases catecholamine levels, and the hypothalamic-pituitary-adrenal axis, which increases cortisol levels. Depression may also activate the renin-angiotensin-aldosterone system.
“Taken together, these changes may induce atrial fibrillation susceptibility either directly by disrupting the electrophysiologic properties of the atria or indirectly by promoting atrial fibrosis, increasing the atrial pressure,” Dr. Garg said, adding that further research is needed to fully understand the mechanisms involved.
Dr. Gordon Tomaselli, a spokesman for the American Heart Association, said this study “affirms the association between depression and atrial fibrillation in a population that I think is important because it’s a mixed population and not just the standard Caucasian population.”
“There are some associated risk factors in people with depression that might increase their risk of atrial fibrillation, including an increased incidence of hypertension in some patients who have depression as well as other disorders that might be driven by activation of the sympathetic nervous system like anxiety disorder. So there are several reasons why people might have depression and atrial fibrillation,” Dr. Tomaselli, who was not involved in the research, told Reuters Health by phone.
“One question is what should we do about it, and I’m not sure we have an answer from this study except to make sure that we are looking for symptoms of depression,” he said. “We don’t know whether treatment of depression will reduce the incidence of atrial fibrillation. There is some reason to think that it might, but there are other reasons to think that antidepressant drugs actually have some effects on the heart, the ion channels that determine the rhythm of the heart.”
The study had no commercial funding and the authors have no relevant disclosures.
AHA Epidemiology and Prevention – Lifestyle and Cardiometabolic Health Scientific Sessions 2018.
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