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.
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.”
The average response rate in published studies testing ketamine for adult TRD is 67% (Wan et al. 2015), which is considerably higher than TRD interventions (e.g., the average response rate for transcranial magnetic stimulation is 45% (Conelea et al. 2017).
Background: Novel interventions for treatment-resistant depression (TRD) in adolescents are urgently needed. Ketamine has been studied in adults with TRD, but little information is available for adolescents. This study investigated efficacy and tolerability of intravenous ketamine in adolescents with TRD, and explored clinical response predictors.
Methods: Adolescents, 12–18 years of age, with TRD (failure to respond to two previous antidepressant trials) were administered six ketamine (0.5 mg/kg) infusions over 2 weeks. Clinical response was defined as a 50% decrease in Children’s Depression Rating Scale-Revised (CDRS-R); remission was CDRS-R score ≤28. Tolerability assessment included monitoring vital signs and dissociative symptoms using the Clinician-Administered Dissociative States Scale (CADSS).
Results: Thirteen participants (mean age 16.9 years, range 14.5–18.8 years, eight biologically male) completed the protocol. Average decrease in CDRS-R was 42.5% (p = 0.0004). Five (38%) adolescents met criteria for clinical response. Three responders showed sustained remission at 6-week follow-up; relapse occurred within 2 weeks for the other two responders. Ketamine infusions were generally well tolerated; dissociative symptoms and hemodynamic symptoms were transient. Higher dose was a significant predictor of treatment response.
Conclusions: These results demonstrate the potential role for ketamine in treating adolescents with TRD. Limitations include the open-label design and small sample; future research addressing these issues are needed to confirm these results. Additionally, evidence suggested a dose–response relationship; future studies are needed to optimize dose. Finally, questions remain regarding the long-term safety of ketamine as a depression treatment; more information is needed before broader clinical use.
Ketamine has much support in the use of hard-to-treat depression and suicidal behaviors. Below are studies and their links, including a meta-analysis, which demonstrate the effect of Ketamine. Also a recent trial by Carlos Zarate shows the heterogenous nature of response to Ketamine . It is difficult to say who is going to be lifted from their depression completely or partially respond, but in the study, Dr. Zarate showed that patients with a long history of suicidal thinking and self-harm will have less of a response in some cases.
Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients
Repeat intravenous treatment with low doses of the anesthetic drug ketamine quickly reduced suicidal thoughts in a small group of patients with treatment-resistant depression. In their report receiving Online First publication in the Journal of Clinical Psychiatry, a team of Massachusetts General Hospital (MGH) investigators report the results of their study in depressed outpatients who had been experiencing suicidal thought for three months or longer.
“Our finding that low doses of ketamine, when added on to current antidepressant medications, quickly decreased suicidal thinking in depressed patients is critically important because we don’t have many safe, effective, and easily available treatments for these patients,” says Dawn Ionescu, MD, of the Depression Clinical and Research Program in the MGH Department of Psychiatry, lead and corresponding author of the paper. “While several previous studies have shown that ketamine quickly decreases symptoms of depression in patients with treatment-resistant depression, many of them excluded patients with current suicidal thinking.”
It is well known that having suicidal thoughts increases the risk that patients will attempt suicide, and the risk for suicide attempts is 20 times higher in patients with depression than the general population. The medications currently used to treat patients with suicidal thinking — including lithium and clozapine — can have serious side effects, requiring careful monitoring of blood levels; and while electroconvulsive therapy also can reduce suicidal thinking, its availability is limited and it can have significant side effects, including memory loss.
Primarily used as a general anesthetic, ketamine has been shown in several studies to provide rapid relief of symptoms of depression. In addition to excluding patients who reported current suicidal thinking, many of those studies involved only a single ketamine dose. The current study was designed not only to examine the antidepressant and antisuicidal effects of repeat, low-dose ketamine infusions in depressed outpatients with suicidal thinking that persisted in spite of antidepressant treatment, but also to examine the safety of increased ketamine dosage.
The study enrolled 14 patients with moderate to severe treatment-resistant depression who had suicidal thoughts for three months or longer. After meeting with the research team three times to insure that they met study criteria and were receiving stable antidepressant treatment, participants received two weekly ketamine infusions over a three-week period. The initial dosage administered was 0.5 mg/kg over a 45 minute period — about five times less than a typical anesthetic dose — and after the first three doses, it was increased to 0.75 mg/kg. During the three-month follow-up phase after the ketamine infusions, participants were assessed every other week.
The same assessment tools were used at each visit before, during and after the active treatment phase. At the treatment visits they were administered about 4 hours after the infusions were completed. The assessments included validated measures of suicidal thinking, in which patients were directly asked to rank whether they had specific suicide-related thoughts, their frequency and intensity.
While only 12 of the 14 enrolled participants completed all treatment visits — one dropped out because of ketamine side effects and one had a scheduling conflict — most of them experienced a decrease in suicidal thinking, and seven achieved complete remission of suicidal thoughts at the end of the treatment period. Of those seven participants, two maintained remission from both suicidal thinking and depression symptoms throughout the follow-up period. While there were no serious adverse events at either dose and no major differences in side effects between the two dosage levels, additional studies in larger groups of patients are required before any conclusions can be drawn.
“In order to qualify for this study, patients had to have suicidal thinking for at least three months, along with persistent depression, so the fact that they experienced any reduction in suicidal thinking, let alone remission, is very exciting,” says Ionescu, who is an instructor in Psychiatry at Harvard Medical School. “We only studied intravenous ketamine, but this result opens the possibility for studying oral and intranasal doses, which may ease administration for patients in suicidal crises.”
She adds, “One main limitation of our study was that all participants knew they were receiving ketamine. We are now finishing up a placebo-controlled study that we hope to have results for soon. Looking towards the future, studies that aim to understand the mechanism by which ketamine and its metabolites work for people with suicidal thinking and depression may help us discover areas of the brain to target with new, even better therapeutic drugs.”
Ketamine was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients, according to researchers at Columbia University Medical Center (CUMC). They also found that ketamine’s anti-suicidal effects occurred within hours after its administration.
The findings were published online last week in the American Journal of Psychiatry.
According to the Centers for Disease Control and Prevention, suicide rates in the U.S. increased by 26.5 percent between 1999 and 2015.
“There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm,” said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. “Currently available antidepressants can be effective in reducing suicidal thoughts in patients with depression, but they can take weeks to have an effect. Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients.”
Most antidepressant trials have excluded patients with suicidal thoughts and behavior, limiting data on the effectiveness of antidepressants in this population. However, previous studies have shown that low doses of ketamine, an anesthetic drug, causes a rapid reduction in depression symptoms and may be accompanied by a decrease in suicidal thoughts.
The 80 depressed adults with clinically significant suicidal thoughts who enrolled in this study were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.
Those in the ketamine group also had greater improvement in overall mood, depression, and fatigue compared with the midazolam group. Ketamine’s effect on depression accounted for approximately one-third of its effect on suicidal thoughts, suggesting the treatment has a specific anti-suicidal effect.
Side effects, mainly dissociation (feeling spacey) and an increase in blood pressure during the infusion, were mild to moderate and typically resolved within minutes to hours after receiving ketamine.
“This study shows that ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression,” said Dr. Grunebaum. “Additional research to evaluate ketamine’s antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster acting and have the potential to help individuals who do not respond to currently available treatments.”
Abstract Objective To review the published literature on the efficacy of ketamine for the treatment of suicidal ideation (SI). Methods The PubMed and Cochrane databases were searched up to January 2015 for clinical trials and case reports describing therapeutic ketamine administration to patients presenting with SI/suicidality. Searches were also conducted for relevant background material regarding the pharmacological function of ketamine. Results Nine publications (six studies and three case reports) met the search criteria for assessing SI after administration of subanesthetic ketamine. There were no studies examining the effect on suicide attempts or death by suicide. Each study demonstrated a rapid and clinically significant reduction in SI, with results similar to previously described data on ketamine and treatment-resistant depression. A total of 137 patients with SI have been reported in the literature as receiving therapeutic ketamine. Seven studies delivered a dose of 0.5 mg/kg intravenously over 40 min, while one study administered a 0.2 mg/kg intravenous bolus and another study administered a liquid suspension. The earliest significant results were seen after 40 min, and the longest results were observed up to 10 days postinfusion. Conclusion Consistent with clinical research on ketamine as a rapid and effective treatment for depression, ketamine has shown early preliminary evidence of a reduction in depressive symptoms, as well as reducing SI, with minimal short-term side effects. Additional studies are needed to further investigate its mechanism of action, long-term outcomes, and long-term adverse effects (including abuse) and benefits. In addition, ketamine could potentially be used as a prototype for further development of rapid-acting antisuicidal medication with a practical route of administration and the most favorable risk/benefit ratio. Key Points Preliminary data from randomized controlled trials have demonstrated that ketamine may rapidly and effectively control treatment-resistant depression, though the effects are transient. A small subset of studies has demonstrated similar results in the effects of ketamine on suicidal ideation. Ketamine has potential as a rapid treatment for suicidal ideation and/or a possible model compound for future drug development.
4 Discussion With an estimated prevalence of mood disorders ranging from 3.3 to 21.4 % and the substantially increased risk of suicide among patients with mood disorders, treatment is certainly warranted . Current treatment options for suicidality are limited. They include brain stimulation therapeutics, such as ECT, and pharmacological intervention (lithium, clozapine). The efficacy of lithium in treating suicidality has been documented [20, 21] and has recently been reviewed and pooled in a recent meta-analysis of 48 studies . Clozapine has also been shown to reduce suicide risk in patients with schizophrenia [23, 24]. The limitations of both lithium and clozapine include a longer time to efficacy in this psychiatric emergency/urgency, compared with the early response to ketamine . Ketamine seems to be gaining substantial evidence as a pharmacological option for depression with a fast onset of action, but its long-term effects need further investigation. In addition, ketamine probably offers a faster onset of action in terms of SI, but further work is certainly needed in this area. Given the risk of suicide and even the increasing rates of suicide in certain subgroups, such as soldiers and veterans [26, 27], there is an urgent need for faster therapeutics for SI and TRD. Importantly, suicidality and suicide pose a high global burden of patient suffering to families and society. Although several small-to-moderate sized studies, in addition to several reviews, have been published that have examined the efficacy of ketamine in TRD, there are considerably fewer published data specifically examining ketamine in patients presenting with SI. Notably, only three studies have directly examined SI as the primary outcome [11, 16, 17], while the rest examined SI as the secondary outcome [4, 15, 18], not including case reports. This review summarizes the current published literature regarding ketamine as a treatment for SI. The data so far show promising trends of ketamine being an effective and rapid treatment with minimal side effects. Pharmacologically, ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. It has been used for anesthesia in the USA since the 1970s. At subanesthetic doses, ketamine has been shown to increase glutamate levels . This mechanism is relevant, as glutamate regulation and expression are altered in patients with major depressive disorder (MDD). Studies have also demonstrated an abnormal glutamate–glutamine–gamma-aminobutyric acid cycle in patients with suicidality . Furthermore, ketamine has also been shown to work on nicotinic and opioid receptors . No other class of antidepressant medication works to modulate the glutamatergic system, and research continues into this, with the goal of characterizing the full mechanism of action of ketamine and perhaps developing other compounds that would have similar effects. Thus, even if the approval and marketing of ketamine as a rapidacting antisuicidal and antidepressant medication is not realized, it could well be a prototype for development of other medication(s) that retain the mechanism of action with more favorable qualities and a lesser adverse effect profile (such as a longer duration of action or less or no addictive potential). Although the mechanisms explaining the antisuicidal effect and the NMDA receptor antagonism of ketamine are still unclear, some of the initial evidence points to an anti-inflammatory action via the kynurenic acid pathway. Strong suggestions as to the causal relationship between inflammation and depression/suicidality has come from studies demonstrating that cytokines [30, 31] and interferon-b  induce depression and suicidality. Other recent studies have added to the notion of implicating brain immune activation in the pathogenesis of suicidality. For instance, one study showed microglial activation of postmortem brain tissue in suicide victims . Another study found increased levels of the cytokine interleukin-6 in cerebrospinal fluid from patients who had attempted suicide . Higher levels of inflammatory markers have been shown in suicidal patients than in nonsuicidal depressed patients [33, 35]. Inflammation leads to production of both quinolinic acid (an NMDA agonist) and kynurenic acid (a NMDA antagonist). An increased quinolinic acid to kynurenic acid ratio leads to NMDA receptor stimulation. The correlation between quinolinic acid and Suicide Intent Scale scores indicates that changes in glutamatergic neurotransmission could be specifically linked to suicidality . Small randomized controlled trials have demonstrated the efficacy of ketamine in rapidly treating patients with both TRD and/or bipolar depression [4, 8, 9, 11, 16–18]. Some studies have also examined suicide items as a secondary measure in their depression rating scales [4, 7]. In total, the studies examining ketamine and TRD have nearly consistently demonstrated that ketamine provides relief from depressive and suicidal symptoms, starting at 40 min and lasting for as long as 5 days. Questions still remain as to the long-term effects of this treatment, how much should be administered and how often, any serious adverse effects, and the mechanism of action. Pharmacologically, ketamine has poor bioavailability and is best administered via injection . In their landmark study, Berman et al.  found that a subanesthetic dose (0.5 mg/kg) rapidly improved depressive symptoms. Most of the subsequent studies have delivered ketamine as a constant infusion for 40 min at a rate of 0.5 mg/kg. Others have examined its efficacy after multiple infusions and observed similar results [8, 13, 16, 38]. Currently, it is recommended that ketamine be administered in a hospital setting .
Characterizing the course of suicidal ideation response to ketamine
2018 article from Carlos Zarate discussing the variable course outcomes with Ketamine for suicidality and correlations to serum markers and behavior and longevity of self-harm prior to treatment:
Background: : No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI response to ketamine. Methods: : Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic (0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture modeling to generate SI response classes, and class membership predictors were evaluated using multinomial logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers. Results: : The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders (44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1. Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to Remitters rather than Responders. Limitations: : Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma, rather than CSF, markers were used. Conclusion: : The results underscore the heterogeneity of SI response to ketamine and its potential independence from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic SI were less likely to respond or remit post-ketamine.
1. Introduction Suicide poses a serious threat to public health. Worldwide, suicide accounts for approximately 1 million deaths, and 10 million suicide attempts are reported annually (World Health Organization, 2014). In the United States, the national suicide rate has increased by approximately 28% over the last 15 years (Curtin et al., 2016). At the same time, relatively few interventions for suicide risk exist. While treatments such as clozapine and lithium have demonstrated effects on suicidal behavior over weeks to months, these effects may be limited to specific diagnoses (Cipriani et al., 2005; Griffiths et al., 2014). Currently, no FDA-approved medications exist to treat suicidal ideation (SI), leaving those who experience a suicidal crisis with limited options for a reprieve of symptoms. Consequently, a critical need exists for rapid-acting treatments that can be used in emergency settings. A promising off-label agent for this purpose is the rapid-acting antidepressant ketamine, which past studies have suggested reduces suicidal thoughts (Diazgranados et al., 2010a; Murrough et al., 2015; Price et al., 2009). A recent meta-analysis of 167 patients with a range of mood disorder diagnoses found that ketamine reduced suicidal thoughts compared to placebo as rapidly as within a few hours, with effects lasting as long as seven days (Wilkinson et al., 2017). These results are reinforced by newer findings of reduced active suicidal ideation post-ketamine compared to a midazolam control(Grunebaum et al., 2018). As the efficacy literature develops in the era of personalized medicine, two important issues must be addressed. First, little is known about the acute course of SI following ketamine. The speed with which antidepressant response occurs, and how much improvement can be expected on average, has been documented for single administrations of ketamine (Mathew et al., 2012; Sanacora et al., 2017); in the limited available literature, researchers have emulated previous studies examining antidepressant effect, where a cutoff of 50% improvement demarcated response (Nierenberg and DeCecco, 2001). Nevertheless, it remains unknown whether this categorization accurately reflects the phenomenon of suicidal thoughts. Empirically-derived approaches to the description of SI trajectory after ketamine may be useful in operationalizing “response” in future clinical trials. Second, identifying demographic, clinical, or biological predictors of SI response to ketamine would allow researchers and clinicians to determine who is most likely to exhibit an SI response to ketamine. A broad literature describes clinical and demographic predictors for suicide risk (Franklin et al., 2017), and a smaller literature connects suicidal thoughts and behaviors to plasma markers such as brain-derived neurotrophic factor (BDNF) and cytokines (Bay-Richter et al., 2015; Falcone et al., 2010; Isung et al., 2012; Serafini et al., 2017; Serafini et al., 2013). However, no biomarkers have been shown to predict SI/ behavior response to intervention, a finding reinforced by the National Action Alliance for Suicide Prevention’s Research Prioritization Task Force’s Portfolio Analysis (National Action Alliance for Suicide Prevention: Research Prioritization Task Force, 2015). Notably, predictor analyses have the potential to reveal insights into personalized treatments for suicidal individuals, as well as the neurobiology of SI response. With respect to antidepressant response, for example, this approach yielded the observation that individuals with a family history of alcohol dependence may be more likely to exhibit an antidepressant response to ketamine (Krystal et al., 2003; Niciu et al., 2014; PermodaOsip et al., 2014). The goals of this study were to elucidate trajectories of SI response and identify predictors of that response, with the ultimate goal of adding to the growing literature surrounding ketamine’s specific effects on SI. In particular, we sought to determine whether the heterogeneous patterns of change in SI after ketamine administration were better explained by a model with two or more latent groups of trajectories rather than a single average trajectory, using secondary analyses from previously published clinical trials. These classes were then used to evaluate potential clinical, demographic, and plasma biomarker predictors of SI response to ketamine in order to generate hypotheses.. Discussion This analysis used a data-driven approach to characterize SI response to ketamine. The data were best explained by three trajectory classes: one with severe average baseline SI and little to no response to ketamine (Non-Responders), one with moderate average baseline levels of SI and significant response to ketamine (Responders), and a third with moderate average baseline levels of SI and complete remission of SI by two days post-ketamine (Remitters). These findings suggest a diversity of post-ketamine changes in SI that may not be captured under traditional methods of categorizing response to treatment. Furthermore, we found evidence that SI response and antidepressant response could be distinguished from each other; one subset of participants experienced improvement in SI that was partially explained by improvements in Depressed Mood, while the other group’s improvements in SI occurred independently of antidepressant response. With regard to predictors of SI response trajectory, preliminary results suggest the individuals least likely to experience improvement in SI postketamine were those with the most severe SI and a history of self-injury. Few plasma markers emerged as predictors of SI response in this study, highlighting the limitations of connecting SI ratings of response with biological markers. The growth mixture modeling approach used here underscored the heterogeneity of SI response to ketamine, which would not have been captured by simply calculating the average trajectory. The class assignment from this approach also differed from the definition of response (50% reduction in symptoms) traditionally used in the antidepressant literature, which often focuses on a specific timepoint rather than the entire symptom trajectory. In comparing classification using a 50% response at Day 1 and Day 3 with the latent trajectory classes, we found representation of almost every SI class across each responder group, highlighting the potential limitations of the 50% response approach. Further study is needed to determine which of these approaches will prove more fruitful. Complete remission of SI has previously been used as an outcome measure in clinical trials and in a meta-analysis of ketamine’s efficacy (Grunebaum et al., 2017; Grunebaum et al., 2018; Wilkinson et al., 2017), as well as in a study examining the relationship between SI response to ketamine and changes in nocturnal wakefulness (Vande Voort et al., 2017). One strength of the present study is that this data-driven approach provides classifications that directly reflect the phenomena under study as they are, as opposed to what they should be. Especially when used in larger samples than the current study, this approach is particularly promising in its ability to provide a more nuanced understanding of the nature of SI response to ketamine. Our results also support the idea that SI response in particular can target. First, it should be noted here that SI classes were not distinguishable by baseline Depressed Mood scores; patients with the most severe SI did not differ meaningfully in Depressed Mood scores from those with the mildest SI. Second, while previous analyses of these data documented that BMI and family history of alcohol dependence predicted antidepressant response (Niciu et al., 2014), SI response was not associated with these variables in the current analysis. Third, the antidepressant response profiles of the SI classes suggest that SI response and antidepressant response are not wholly redundant. This aligns with previous clinical trials and meta-analytic reviews of the literature suggesting that SI response to ketamine occurs partially independently of antidepressant response (Grunebaum et al., 2018; Wilkinson et al., 2017). Nevertheless, this independence did not hold true across both SI response groups. Specifically, antidepressant and SI response were clearly linked in Remitters, with depression accounting for half of the changes in SI; however, in Responders, improvements in SI occurred independently from improvements in Depressed Mood. These discrepancies could be related to ketamine’s complex neurobiological mechanisms or to the potentially low levels of clinical severity observed in the Remitters. Interestingly, the current analyses found no baseline demographic variables that reliably distinguished Responders from Remitters. Some phenotypic characteristics were uniquely associated with belonging to the Non-Responder group, suggesting that a long-standing history of self-injury or SI may indicate resistance to rapid changes in SI. Relatedly, a recent, randomized clinical trial of repeat-dose ketamine compared to placebo found that ketamine had no effect on SI in a sample of patients selected for their longstanding, chronic history of SI (Ionescu, 2017). These results highlight the importance of patient selection, particularly for suicide risk. It should be stressed, however, that SI does not necessarily translate to suicidal attempts or deaths; to our knowledge, no study has yet linked ketamine with reduced risk of suicidal behavior. Indeed, in the present study the SI Non-Responders experienced limited antidepressant effects in response to ketamine, but may nevertheless have improved on other, unmeasured symptoms that could provide important benefit and relief. As the ketamine literature develops, it will be important to identify which clinical symptom profiles are most likely to have a robust anti-SI and anti-suicidal behavior response to ketamine and which ones may benefit from other interventions. While we evaluated a range of potential plasma markers previously linked to suicidal ideation and behavior, in the present analysis only IL5 was associated with the SI Responder subgroup. Ketamine is known to have anti-inflammatory effects (Zunszain et al., 2013), but the relationship between antidepressant response and change in cytokine levels remains unclear (Park et al., 2017). Cytokines have been linked to suicidal behavior in the past; a recent meta-analysis found that lower levels of IL-2 and IL-4, and higher levels of TGFbeta, were associated with suicidal thoughts and behaviors (Serafini et al., 2013); however, toour knowledge IL-5 has not previously been linked to SI. Given the large number of comparisons and lack of precedent in the literature, this result may have been spurious and should be interpreted with caution. A number of other results may reflect meaningful relationships, but the high degree of variability—and the associated wide confidence intervals—suggests that larger sample sizes are needed to better elucidate the nature of any such relationships (e.g. baseline VEGF: χ2 = 6.13, p = .05, but OR (95% CI) 13.33 (0.93–200.00)). Somewhat surprisingly, plasma BDNF levels were not associated with responder class. Previous studies of bipolar, but not MDD, samples found that plasma BDNF levels were associated with SI response after ketamine (Grunebaum, 2017; Grunebaum et al., 2017), suggesting that the mixed diagnostic composition of this study may explain differences from previous work. Studies exploring the relationship between BDNF and antidepressant response to ketamine have also yielded mixed findings (Haile et al., 2014; Machado-Vieira et al., 2009). Other data-driven approaches have considered both biological and behavioral variables in characterizing depression (Drysdale et al., 2017); a similar approach might prove useful for predicting SI response. The present study is associated with several strengths as well as limitations. Strengths include the relatively large sample size of participants who received ketamine, the use of composite SI scores from previous exploratory factor analyses as opposed to individual items, and the combination of clinical and biological markers as potential predictors of class membership. Limitations include patient selection methods, as these patients were part of an antidepressant trial and were not selected for active suicidal thoughts, as well as the exploratory nature of the analysis. As stated above, suicidal thoughts do not necessarily equate to suicidal behavior, and class membership would thus not necessarily correspond with an overall reduction in suicide risk. Another limitation is that results were collapsed across several clinical trials with slight variations in study design, and findings were thus only extended to Day 3 rather than a week after ketamine administration. As a result, only a subset of the sample could be used for predictive analyses. In addition, plasma—rather than CSF—markers were used, and the latter might better indicate underlying biology due to proximity to the brain, though certain markers such as plasma BDNF may be related to platelet storage, rather than the brain (Chacón-Fernández et al., 2016). Comparison of results to trajectories of suicide-specific measures, such as the Scale for Suicide Ideation (Beck et al., 1979), may also give further insight into specific SI content. Finally, many clinical predictors were collected upon hospital admission; future analyses could use formal assessments, such as the Childhood Traumatic Questionnaire (Bernstein et al., 1994), assessment of personality disorders, or diagnoses such as post-traumatic stress disorder (PTSD) as potential indicators of response. Despite these limitations, the study demonstrates the utility of a data-driven approach for characterizing the heterogeneity of SI response to a rapid-acting intervention. This allows for a more finegrained analysis of symptoms than would be permitted by traditionalapproaches, such as overall average response or dichotomization at 50% reduction in symptoms. This study identified several findings of note. These included distinguishing at least three patterns of SI response to ketamine and finding that subjects who exhibited more severe SI at baseline were not likely to experience an SI response to ketamine.
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