(CNN)A single dose of ketamine may be able to curb harmful drinking behavior by “rewriting drinking memories,” according to a study published Tuesday in the journal Nature Communications.The researchers say that, when coupled with an exercise involving beer that pulls memories of alcohol to the foreground, there’s evidence that the drug can disrupt how the brain associates these cues — like the smell or taste of beer — to its perceived “reward,” making relapse less likely.”It’s those kinds of associations that we’re trying to break down,” explained study author Ravi Das, an associate professor at University College London who specializes in psychopharmacology. “We’re not talking about people’s explicit recollection of the fact that they drank in the past.” FDA approves ketamine-like nasal spray for depressionKetamine is a powerful medication used in hospitals primarily as an anesthetic, though it has also been used illegally as a club drug, often referred to as Special K. It generates an intense high and dissociative effects. “It’s an intriguing approach that builds on existing literature in a couple of areas,” said Dr. Henry Kranzler, a professor of psychiatry at the University of Pennsylvania Perelman School of Medicine, who was not involved in the study.Earlier studies have explored ketamine for alcohol, cocaine and opioid addiction — but many had small sample sizes, limited follow-up and lack of placebo, according to experts. Das said it’s also difficult to blind participants to whether they’ve received ketamine or a placebo because of its “strong effects.”Other research has shown the drug’s potential to counter depression and suicidal ideation. In March, a close relative of ketamine — called esketamine and sold under the name Spravato in the form of a nasal spray — was approved by the US Food and Drug Administration for treatment-resistant depression.The new study recruited 90 “beer-preferring” people with potentially harmful drinking patterns from internet ads and separated them into groups: those who underwent an exercise involving alcohol-related cues and received intravenous ketamine in a controlled environment; those who completed the exercise but received a placebo; and those who received ketamine alone. While the authors said participants “showed a clearly harmful and problematic pattern of drinking,” they were not seeking treatment for an alcohol use disorder and had not been formally diagnosed with such. But there was some heterogeneity between the groups. While the first group reduced their drinking to the largest degree, they also happened to drink more to begin with — “and therefore their consumption was more likely to decline, a phenomenon known as regression to the mean,” explained Matt Field, a professor of psychology at the University of Sheffield in the UK, in an emailed statement.After the treatment, there wasn’t a significant difference between the three groups in terms of how much alcohol they drank. Nine months later, average weekly consumption was roughly the same across the board. The authors say this may have been influenced by losing participants to follow-up.Field said the findings are “promising,” but the claim that the full treatment protocol “leads to ‘unprecedented’ long-lasting reductions in alcohol consumption are not justified on the basis of this data.”Das pointed out other layers to the data, however: Those who completed the exercise and received ketamine had less desire to drink, and they drank less frequently. In addition, there was a correlation among that group between concentrations of ketamine and its breakdown products in the blood, and the reduction in how much participants drank.”People all vary in how quickly they metabolize” and excrete ketamine and its byproducts, Das said. “That level of individual variability with ketamine actually predicts drinking outcomes subsequently.”
The group that received ketamine alone saw improvements, too, but not to the same degree as those presented with alcohol-related cues, according to the authors.Kranzler said the study is an intriguiguing proof-of-principle that he suspects will spur subsequent studies needed to replicated these findings.But an important question, he added, “is to what degree could combined psychosocial intervention — cognitive behavioral intervention, for example — synergize with or at least augment the pharmacological effect” of ketamine.”That’s the kind of treatment study that I think would make a lot of sense,” he added. “So this wouldn’t be used in isolation.”
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A single dose of ketamine may cut down problematic drinking. Taken in the right context, the hallucinogenic drug may be able to weaken the pull of the cues that trigger people to drink beer, researchers report November 26 in Nature Communications.
Ketamine’s influence on people’s drinking was modest. Still, the results might be a time when “small effects tell a big story,” says addiction researcher David Epstein of the National Institute on Drug Abuse in Baltimore. “If a seemingly small one-time experience in a lab produces any effects that are detectable later in real life, the data are probably pointing toward something important.”
The study hinges on the idea that addiction, in a way, is a memory disorder. People learn to associate a drug or alcohol with the good feelings it brings. Cues in the world, such as the smell or picture of a beer, can trigger those memories — and cravings. “We’re trying to break down those memories to stop that process from happening, and to stop people from relapsing,” says study coauthor Ravi Das, a psychopharmacologist at University College London.
Ketamine is an anesthetic, that at lower doses, has also shown promise as a treatment for severe depression (SN: 3/21/19). The drug can also affect memories. One of ketamine’s effects in the body is to interfere with a molecule called NMDA, which is involved in reforming memories after they are called up.
Das and his colleagues recruited 90 people who said they drank too much beer, though none was formally diagnosed with alcohol addiction. First, participants were exposed to pictures of beer and even got to drink one in the lab. During the experience, they rated their beer cravings, enjoyment of drinking, and after the beer was gone, the desire to have another one.
A few days later, the participants returned to the lab and were split into three groups. People in one group were again shown pictures of beer to jog their memories. To make the memory recall extra strong, the researchers served up actual beer, but then, in a twist, took it away before participants could drink it. The bait-and-switch maneuver was key, Das says. “You have to generate the element of surprise,” he says.
As a comparison, a second group was shown images of orange juice instead of beer. Then people in both of these groups got an intravenous dose of ketamine. A third group had beer memories called up, but received no ketamine.
A week after the procedure, the people who had their beer memories jogged before receiving ketamine reported less desire to drink, and less enjoyment of beer — a reduction that wasn’t as strong for the other two groups of participants. The people who had their beer-drinking memories jogged and received ketamine also reported drinking less.
The results were surprising, Das says, because attempts to curb people’s drinking in their daily lives are rarely successful (SN: 8/9/17). “You get jaded. Not a lot seems to work,” he says.
Nine months after the procedure, all of the participants, including those who hadn’t received ketamine, had roughly halved their beer drinking — an across-the-board drop that could be explained by the self-awareness that comes simply from enrolling in a study, says Epstein. “Behavior can change for all sorts of reasons that aren’t specific to the experimental treatment,” he says. The interesting thing here, he says, is the initial decline in drinking among people who had ketamine while they were reminded of beer.
More research is needed to confirm ketamine’s short-term effect on drinking, and see how long it might last. Das and his colleagues plan on testing ketamine on more people with problematic drinking habits in clinical trials. The researchers are also trying to weaken other sorts of problematic memories, such as those involved in post-traumatic stress disorder.
As a drug that can be abused, ketamine comes with baggage that may make people reluctant to see it as a way to treat addictions. But if a single dose of ketamine can slow excessive drinking, “then that’s quite an easy trade-off from a health perspective,” Das says. “If it works, it works.”
What if a single dose of ketamine could make a heavy drinker dramatically cut back on booze?
A team at University College London thinks that ketamine may be able to “rewrite” memories that shape a person’s relationship with alcohol. Scientists say that participants who were given ketamine as part of an experimental study dramatically reduced their average alcohol intake for months after the initial dose. Their research was published Tuesday in Nature Communications.
Ketamine — sometimes known as a club drug called Special K that can produce hallucinations — has been shown to be a powerful and fast-acting treatment for depression. Researchers also are looking into whether ketamine can help patients with post-traumatic stress disorder.
The U.K. findings may signal yet another use for the drug for hard-to-treat conditions.
In general, the treatment options for alcoholism “aren’t particularly effective for the majority of people, particularly over the long term,” says Ravi Das, a UCL psychopharmacologist and the study’s lead researcher.
Das thinks part of the problem is that current remedies don’t necessarily help patients deal with positive memories of drinking that could make them want to drink again.
“When people become addicted, they’re learning that kind of behavior in response to things in their environment,” he says. “Those memories, those associative trigger memories, can be really long lasting and really kind of ingrained. And current treatments don’t target those.”
The researchers thought ketamine might be able to target a heavy drinker’s memories, particularly if people had their memories of drinking triggered just before they received a dose of the drug.
To test this, they recruited 90 people who drank much more than average — an average of about four to five pints of beer a day, or about five times the U.K.’s recommended maximum — but had not previously been diagnosed with alcoholism and were not receiving treatment.
On the first day of the experiment, participants were shown pictures of alcoholic drinks and were asked to rate how strong their urge to drink was. All of them were then allowed to drink a beer.
The next day, they were divided into three groups, and none of them received beer. One group did the exercise in which they saw pictures of drinks — to stimulate their memories — and then received a dose of ketamine. The second group saw the drinks and then got a placebo drug. The final group was shown no pictures and received ketamine.
The results were dramatic. Ten days later, those people who did the memory exercise and got ketamine reported a significant drop in their alcohol intake. A follow-up nine months into the experiment showed that their alcohol consumption was half of what it had been.
Meanwhile, the group that got ketamine and didn’t have their memories triggered saw a smaller but still significant reduction in drinking, both at the 10-day mark and nine months later. The placebo group also reported a decrease, albeit a more modest one.
So why would stimulating memories of drinking prior to a ketamine dose seem to be so effective in reducing alcohol consumption? Das says ketamine is thought to block certain receptors in the brain that help to “restabilize” a memory — such as pleasure from drinking. “You’re kind of stopping the restabilization, and the memory is weakened,” he notes.
John Krystal, head of the psychiatry department at Yale School of Medicine, was among the first researchers to study how ketamine could be helpful to patients who have depression. He says ketamine doesn’t erase memories but can help rewrite them.
“You can help them have a better and more balanced approach to it,” Krystal says. “Like instead of the idea that alcohol is always good no matter how much you drink … someone could instead say, ‘You know, I don’t really need to drink this much.’ “
That lines up with what the participants in the U.K. experiment reported. Das says they “kind of felt the urge to drink less” and “that might be because of this reduction in the way that environmental triggers can spark off the urge to drink.”
Krystal, who was not involved in the research, says this suggests that ketamine could be useful for other conditions that are exacerbated by certain kinds of memories. The drug, he says, could “help them to get control of what they really think and believe about things like alcohol or other drugs, abuse or their traumatic experiences, which otherwise kind of take over their lives in ways that are very maladaptive.”
“I would say this is a very cool study,” Krystal says. “And I think if the findings can be replicated, then it opens up a new window about a strategy to treat alcohol-use disorders.”
Still, he cautions that this is a fairly new idea and that “there are a lot of complexities here that need to be worked out.” Complexities such as whether people with high tolerance to alcohol respond differently to ketamine or whether there’s something inherent about ketamine that makes people want to drink less even without memory recall. “That’s just the nature of research — no single study can really answer all of the questions,” Krystal says.
Das says he hopes that one day, following more study and testing, ketamine could be used in clinical settings to help patients with alcoholism.
A single ketamine infusion improved several treatment outcomes in adults with cocaine dependence who were engaged in mindfulness-based behavior modification, according to study data published in the American Journal of Psychiatry.
Individuals seeking treatment for cocaine dependence (n=55) were randomly assigned to receive a 40-minute intravenous infusion of either ketamine (0.5 mg/kg) or midazolam (0.025 mg/kg) as part of a five-week trial. Patients were hospitalized for five days in a psychiatric research unit, during which time they received daily sessions of mindfulness-based relapse prevention. On day 2, patients received their infusion; on day 5, they were discharged. Patients then attended twice-weekly follow-up visits for four weeks, at which they continued their sessions and were assessed for various clinical variables. Cocaine use after discharge was assessed via patient interview and urine toxicology screening. A six-month follow-up interview was also conducted by telephone.
Demographic and clinical variables were similar in patients who received ketamine (n=27) and patients who received midazolam (n=28). Route of cocaine ingestion was controlled for in all analyses. A total of 48.2% of patients in the ketamine group remained abstinent during the last two weeks of the trial compared with 10.7% of the midazolam group. The odds of end-of-study abstinence in the ketamine group was nearly six times that in the midazolam group (odds ratio, 5.7; 95% CI, 1.3-25.1; P =.02). Per Cox regression analysis, the ketamine group was 53% less likely to relapse compared with the midazolam group (hazard ratio, 0.47; 95% CI, 0.24-0.92; P =.03). In addition, craving scores were 58.1% lower in the ketamine group than in the midazolam group (P =.01). At the six-month telephone follow-up interview, 12 patients (44%) in the ketamine group reported abstinence compared with none in the midazolam group. The percentage of abstinent individuals was significantly associated with treatment group (P <.001).
A single ketamine infusion was associated with significantly improved treatment outcomes compared with midazolam in a cohort of adults with cocaine dependence. Further research in a larger sample is needed to confirm these findings.
A new study finds that a nasal spray formulated from the anesthetic ketamine is a safe, fast-acting and effective treatment for treatment-resistant depression. Researchers presented the findings this week at the annual meeting of the American Psychiatric Association.
Esketamine, the intranasal formulation of ketamine, recently received FDA approval as a depression treatment when used with an oral antidepressant, based in part on findings from this study. The results open the door to a potential new alternative for the estimated 30% of depression patients suffering from treatment-resistant depression.
The study included 197 adults from 39 outpatient centers over a two-year period. All of the participants had either moderate or severe depression and hadn’t responded well to at least two antidepressants in the past. Participants were randomly assigned to one of two groups: The first switched from their current antidepressant treatment to esketamine nasal spray and a new oral antidepressant; the other switched from their current treatment to a placebo nasal spray and a new antidepressant.
The results showed significant improvements in depression symptoms among those in the esketamine group compared to the placebo group four weeks into the study, with signs of improvement starting much earlier.
“The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression,” the study concluded.
“Not only was adjunctive esketamine therapy effective, the improvement was evident within the first 24 hours,” said Michael Thase, M.D., one of the study authors. “The novel mechanism of action of esketamine, coupled with the rapidity of benefit, underpins just how important this development is for patients with difficult-to-treat depression.”
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.
Patients with major depressive disorder (MDD) have an increased onset risk of aging-related somatic diseases such as heart disease, diabetes, obesity and cancer. This suggests mechanisms of accelerated biological aging among the depressed, which can be indicated by a shorter length of telomeres. We examine whether MDD is associated with accelerated biological aging, and whether depression characteristics such as severity, duration, and psychoactive medication do further impact on biological aging. Data are from the Netherlands Study of Depression and Anxiety, including 1095 current MDD patients, 802 remitted MDD patients and 510 control subjects. Telomere length (TL) was assessed as the telomere sequence copy number (T) compared to a single-copy gene copy number (S) using quantitative polymerase chain reaction. This resulted in a T/S ratio and was converted to base pairs (bp). MDD diagnosis and MDD characteristics were determined by self-report questionnaires and structured psychiatric interviews. Compared with control subjects (mean bp = 5541), sociodemographic-adjusted TL was shorter among remitted MDD patients (mean bp = 5459; P = 0.014) and current MDD patients (mean bp = 5461; P = 0.012). Adjustment for health and lifestyle variables did not reduce the associations. Within the current MDD patients, separate analyses showed that both higher depression severity (P<0.01) and longer symptom duration in the past 4 years (P = 0.01) were associated with shorter TL. Our results demonstrate that depressed patients show accelerated cellular aging according to a ‘dose–response’ gradient: those with the most severe and chronic MDD showed the shortest TL. We also confirmed the imprint of past exposure to depression, as those with remitted MDD had shorter TL than controls
In this large cohort study we demonstrated that currently
depressed persons had shorter TL than never-depressed controls.
Based on an estimated mean telomere shortening rate of 14–20
bp per year as found in this and other studies,20,23,26 the
differences observed indicate 4–6 years of accelerated aging for
the current MDD sample as compared to controls. We also showed
evidence for the imprint of past exposure to depression since
those with remitted MDD also had shorter TL than control
subjects. These observed associations remained significant after
controlling for lifestyle and somatic health variables, suggesting that the shortened telomeres were not simply due to unhealthylifestyle or poorer somatic health among depressed persons.
Finally, the association between MDD and TL showed a ‘dose–
response’ gradient, since the most severely and chronically
depressed patients had the shortest telomeres.
MDD is thus associated with shortened TL, which resembles
accelerated biological aging. The disorder has previously also been
associated with dysregulations of the hypothalamus–pituitary–
adrenal (HPA) axis,43,45 the immune system,46,47 the autonomic
nervous system (ANS)48,49 and increased oxidative stress.50
Shortened telomeres, in turn, are suggested to be a consequence
or a concomitant of these dysregulated biological stress systems.
In line with this, several in vitro and in vivo studies found increased
cortisol,51 oxidative stress52 and pro-inflammatory cytokines53
to be associated with shorter TL. Dysregulations of these stress systems could contribute to telomere shortening in MDD patients.9,12
However, the exact biological mechanisms that mediate the relation
between depression and telomere shortening, as well as the
direction of the link, remain to be further explored.
Studies of the World Health Organization suggest that in the year 2020, depressive disorder will be the illness with the highest
burden of disease. Especially unipolar depression is the psychiatric disorder with the highest prevalence and incidence, it is cost-intensive and has a relatively high morbidity. Lately, the biological process involved in the aetiology of depression has been the focus of research.
Since its emergence, the monoamine hypothesis has been adjusted and extended considerably. An increasing body of evidence points to
alterations not only in brain function, but also in neuronal plasticity. The clinical presentations demonstrate these dysfunctions by accompanying cognitive symptoms such as problems with memory and concentration. Modern imaging techniques show volume reduction of the hippocampus and the frontal cortex. These findings are in line with post-mortem studies of patients with depressive disorder and they point to a significant decrease of neuronal and glial cells in cortico-limbic regions which can be seen as a consequence of alterations in
neuronal plasticity in this disorder. This could be triggered by an increase of free radicals which in turn eventually leads to cell death and consequently atrophy of vulnerable neuronal and glial cell population in these regions. Therefore, research on increased oxidative stress in unipolar depressive disorder, mediated by elevated concentrations of free radicals, has been undertaken. This review gives a comprehensive overview over the current literature discussing the involvement of oxidative stress and free radicals in depression.
Membrane damage in blood of patients with depression has
been shown by elevated of omega 3- fatty-acids [45] and by increased
lipid peroxidation products in patients with DD [42, 45,
[46, 47]. Furthermore, DNA-strand brakes have been reported in
the blood of these patients [48]. DD has been linked to increased
serum levels of malondialdehyde (MDA), a breakdown product of
oxidized apolipoprotein B-containing lipoproteins, and thus a
marker of the rate of peroxide breakdown [49, 50].
In patients with DD (Depressive Disorders), elevated levels of MDA adversely affect
the efficiency of visual-spatial and auditory-verbal working memory,
short-term declarative memory and delayed recall declarative
memory [51]. Higher concentration of plasma MDA in patients
with recurrent depression is associated with the severity of depressive
symptoms, both at the beginning of antidepressant pharmacotherapy,
and after 8 weeks of treatment. Statistically significant
differences were found in the intensity of depressive symptoms,
measured on therapy onset versus the examination results after
8 weeks of treatment [51]. Although this is used as a marker of lipid peroxidation, it is considered to be less stable than 8-iso-PGF2a, and more susceptible to confounding factors such as antioxidants from diet [52]. Therefore, the best way to investigate oxidative disruptions to lipids in humans is via assessing levels of F2-
isoprostanes [52-54]. These are stable compounds produced in the
process of lipid peroxidation [52, 54]. 8-iso-PGF2a are specific F2-
isoprostane molecules produced during the peroxidation of arachnidonic acid. However, the mean serum level of 8-iso-PGF2a was shown to be significantly higher in a group of patients with DD,
controlling for lifestyle variables such as body mass index, alcohol
consumption, and physical activity [55, 56]. Cerebral membrane
abnormalities and altered membrane phospholipids have been suggested by an increased choline-containing compound seen in the
putamen of patients with DD [57] which has been interpreted as a
result of increased oxidative stress in patients with DD.
Results
115 articles met the inclusion criteria. Lower TAC was noted in acute episodes (AEs) of depressed patients (p<0.05). Antioxidants, including serum paraoxonase, uric acid, albumin,
high-density lipoprotein cholesterol and zinc levels were lower than controls (p<0.05); the serum uric acid, albumin and vitamin C levels were increased after antidepressant therapy
(p<0.05). Oxidative damage products, including red blood cell (RBC) malondialdehyde (MDA), serum MDA and 8-F2-isoprostanes levels were higher than controls (p<0.05). After
antidepressant medication, RBC and serum MDA levels were decreased (p<0.05). Moreover, serum peroxide in free radicals levels were higher than controls (p<0.05). There were
no difference
Conclusion
This meta-analysis supports the facts that the serum TAC, paraoxonase and antioxidant levels are lower, and the serum free radical and oxidative damage product levels are higher
than controls in depressed patients. Meanwhile, the antioxidant levels are increased and the oxidative damage product levels are decreased after antidepressant medication. The
pathophysiological relationships between oxidative stress and depression, and the potential benefits of antioxidant supplementation deserve further research.
Some studies have demonstrated that depressed patients’ oxidative product levels in their peripheral blood [3, 4], red blood cells (RBC) [4], mononuclear cells [5], urine [6], cerebrospinal
fluid [7] and postmortem brains [8] were abnormal. Antioxidant system disturbance in peripheral blood has also been reported [9]. Autoimmune responses against neoepitopes
induced by oxidative damage of fatty acid and protein membranes have been reported [10, 11].
Lower glutathione (GSH) levels [12] and a negative relationship between anhedonia severity
and occipital GSH levels [13] were found through magnetic resonance spectroscopy (MRS).
Oxidative stress is defined as a persistent imbalance between oxidation and anti-oxidation, which leads to the damage of cellular macromolecules [14, 15]. The free radicals consist of reactive
oxygen species (ROS) and reactive nitrogen species (RNS). The main ROS includes superoxide anion, hydroxy radical and hydrogen peroxide, and the RNS consists of nitric oxide
(NO), nitrogen dioxide and peroxynitrite. Nitrite is often used as a marker of NO activity. Interestingly, the brain appears to be more susceptible to the ROS/RNS because of the high
content of unsaturated fatty acids, high oxygen consumption per unit weight, high content of key ingredients of lipid peroxidation (LP) and scarcity of antioxidant defence systems [16].
The oxidative products include products of oxidative damage of LP, protein and DNA in depression. As a product of LP, abnormal malondialdehyde (MDA) levels in depression have
been reported [17]. 8-F2-isoprostane (8-iso-PGF2α) is another product of LP [18] that is considered
to be a marker of LP because of its chemical stability [19]. The protein carbonyl (PC), 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-oxo-7, 8-dihydroguanosine (8-oxoGuo) are
the markers of protein, DNA and RNA oxidative damage, respectively [3, 20, 21]. The oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to the generation of new epitopes modified (neoepitopes). The antibodies against oxidative neoepitopes
in depression have been found [10, 11, 22–24]. On the other hand, the antioxidant defence systems can be divided into enzymatic and non-enzymatic antioxidants. The nonenzymatic
antioxidants include vitamins C and E, albumin, uric acid, high-density lipoprotein cholesterol (HDL-C), GSH, coenzyme Q10 (CoQ10), ceruloplasmin, zinc, selenium, and so on.
The enzymatic antioxidants include superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), glutathione reductase (GR), paraoxonase 1 (PON1), and so on.
Discussion
The present findings support oxidative stress may be disordered in depressed patients, which is demonstrated by abnormal oxidative stress marker levels. In this meta-analysis, at first we
found in depressed patients: 1) the serum TAC, PON, uric acid, albumin, HDL-C and zinc levels were lower than controls; 2) the serum peroxide, MDA, 8-iso-PGF2α and RBC MDA levels
were higher than controls. To explore the effect of the antidepressant therapy to oxidative stress
markers, we reviewed the studies which had changes. And it came to the conclusions: 1) the serum uric acid, albumin, and vitamin C levels were increased; 2) the serum nitrite, RBC and
serum MDA levels were decreased.
The serum antioxidant levels are significantly lower in depression in our study and previous
reports, including PON, albumin, zinc, uric acid HDL-C, CoQ10 [146] and GSH [4, 38].
Meanwhile, the oxidative damage product levels are significantly higher. The body couldn’t
scavenge the excess free radicals (peroxide), leading to damages of main parts of cellular macromolecules
such as fatty acids, protein, DNA, RNA and mitochondria. The longitudinal antidepressant
therapy can reverse these abnormal oxidative stress parameters. It has proved
these phenomena occur in depression, such as increased levels of MDA, 8-iso-PGF2α, 8-oxoGuo
and 8-OHdG [3, 21]. Oxidative stress plays a crucial role in the pathophysiology of
depression. Some genes may be a potential factor. Lawlor et al (2007) reported the R allele of
PON1Q192R was associated with depression [147]. In addition, poor appetite, psychological
stressors, obesity, metabolic syndrome, sleep disorders, cigarette smoking and unhealthy lifestyle
may also contribute to it [148]. Furthermore, oxidative stress activates the immuneinflammatory
pathways [148]. But some studies supported decrease in albumin, zinc and
HDL-C levels was probably related to increased levels of pro-inflammatory cytokines (such as
interleukin-1 (IL-1) and IL-6) [59, 70–72, 117] during an acute phase response, which illustrated the activated immune-inflammatory pathways also activates the oxidative stress. These two mechanisms influence each other. On the other hand, the oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to generation of newepitopes modified (neoepitopes). Oxidative neoepitopes reported up to now include the conjugated oleic and azelaic acid, MDA, phosphatidyl inositol (Pi), NO-modified adducts and oxidized low density lipoprotein (oxLDL) [11, 22–24]. Maes et al reported the levels of serum IgG antibody against the oxLDL and IgM antibodies against the conjugated oleic and azelaic acid, MDA, Pi and NO-modified adducts were increased in depression [11, 22–24]. Depleted antioxidant defence in depression suggests that antioxidant supplements may be useful in clinical management. Preliminary evidence has indicated that patients treated with CoQ10 showed improvement in depressive symptoms and decrease in hippocampal oxidative DNA damage [149]. In our analyses, vitamin C and E levels did not differ between depressed patients and controls, but many studies have reported that vitamin C and E supplements could improve depressive moods [150, 151].
Oxidative stress has been implicated in the cognitive decline, especially in memory impairment. The purpose of this study was to determine the concentration of malondialdehyde (MDA) in patients with recurrent depressive disorders (rDD) and to define relationship between plasma levels of MDA and the cognitive performance. The study comprised 46 patients meeting criteria for rDD. Cognitive function assessment was based on: The Trail Making Test , The Stroop Test, Verbal Fluency Test and Auditory-Verbal Learning Test. The severity of depression symptoms was assessed using the Hamilton Depression Rating Scale (HDRS). Statistically significant differences were found in the intensity of depression symptoms, measured by the HDRS on therapy onset versus the examination results after 8 weeks of treatment (P < 0.001). Considering the 8-week pharmacotherapy period, rDD patients presented better outcomes in cognitive function tests. There was no statistically significant correlation between plasma MDA levels, and the age, disease duration, number of previous depressive episodes and the results in HDRS applied on admission and on discharge. Elevated levels of MDA adversely affected the efficiency of visual-spatial and auditory-verbal working memory, short-term declarative memory and the delayed recall declarative memory. 1. Higher concentration of plasma MDA in rDD patients is associated with the severity of depressive symptoms, both at the beginning of antidepressants pharmacotherapy, and after 8 weeks of its duration. 2. Elevated levels of plasma MDA are related to the impairment of visual-spatial and auditory-verbal working memory and short-term and delayed declarative memory.
Antioxidant /Antidepressant-like Effect of Ascorbic acid (Vitamine C) and Fluoxetine
Another study investigated the influence of ascorbic acid
(which is an antioxidant with antidepressant-like effects in animals)
on both depressive-like behaviour induced by a chronic unpredictable
stress (CUS) paradigm and on serum markers of oxidative
stress and in cerebral cortex and hippocampus of mice [120]. The
CUS-model is an animal model for induced depression-like behaviour
in animals. Depressive-like behaviour induced by CUS was
accompanied by significantly increased lipid peroxidation (cerebral
cortex and hippocampus), decreased catalase (CAT) (cerebral cortex
and hippocampus) and glutathione reductase (GR) (hippocampus)
activities and reduced levels of glutathione (cerebral cortex).
Repeated ascorbic acid as well as fluoxetine administration significantly
reversed CUS-induced depressive-like behaviour as well as
oxidative damage. No alterations were observed in locomotor activity
and glutathione peroxidase (GPx) activity in the same sample.
These findings pointed to a rapid and robust effect of ascorbic acid
in reversing behavioural and biochemical alterations induced in an
animal model [120]. Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress.
ummary: A new study reveals psychedelics increase dendrites, dendritic spines and synapses, while ketamine may promote neuroplasticity. The findings could help develop new treatments for anxiety, depression and other related disorders.
Source: UC Davis.
A team of scientists at the University of California, Davis is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety, and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.
“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.
Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.
“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.
Psychedelics show similar effects to ketamine
Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.
Fairfax | NOVA Ketamine IV Ketamine for depression | Fairfax, Va 22306 | 703-844-0184
Summary: A new study reveals psychedelics increase dendrites, dendritic spines and synapses, while ketamine may promote neuroplasticity. The findings could help develop new treatments for anxiety, depression and other related disorders.
Source: UC Davis.
A team of scientists at the University of California, Davis is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety, and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.
“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.
Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.
“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.
Psychedelics show similar effects to ketamine
Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.
Psychedelic drugs such as LSD and ayahuasca change the structure of nerve cells, causing them to sprout more branches and spines, UC Davis researchers have found. This could help in “rewiring” the brain to treat depression and other disorders. In this false-colored image, the rainbow-colored cell was treated with LSD compared to a control cell in blue. NeuroscienceNews.com image is credited to Calvin and Joanne Ly.
Behavioral studies also hint at the similarities between psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder (PTSD), and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.
These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.
“Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives,” Olson said.
Psychedelic drugs, ketamine change structure of neurons
Psychedelics as Possible Treatments for Depression and PTSD
A team of scientists at the University of California, Davis, is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety and related disorders.
In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines) and the number of connections between neurons (synapses). These structural changes could suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.
“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.
Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.
“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.
Psychedelics show similar effects to ketamine
Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.
Behavioral studies also hint at the similarities between psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder, or PTSD, and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.
These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.
“Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives,” Olson said.
Additional co-authors on the Cell Reports “Psychedelics Promote Structural and Functional Neural Plasticity.” study are Calvin Ly, Alexandra Greb, Sina Soltanzadeh Zarandi, Lindsay Cameron, Jonathon Wong, Eden Barragan, Paige Wilson, Michael Paddy, Kassandra Ori-McKinney, Kyle Burbach, Megan Dennis, Alexander Sood, Whitney Duim, Kimberley McAllister and John Gray.
Olson and Cameron were co-authors on the ACS Chemical Neuroscience paper along with Charlie Benson and Lee Dunlap.
The work was partly supported by grants from the National Institutes of Health.
Calvin Ly, Alexandra C. Greb, Lindsay P. Cameron, …, Kassandra M. Ori-McKenney, John A. Gray, David E. Olson Correspondence deolson@ucdavis.edu
In Brief Ly et al. demonstrate that psychedelic compounds such as LSD, DMT, and DOI increase dendritic arbor complexity, promote dendritic spine growth, and stimulate synapse formation. These cellular effects are similar to those produced by the fast-acting antidepressant ketamine and highlight the potential of psychedelics for treating depression and related disorders.
Highlights Serotonergic psychedelics increase neuritogenesis, spinogenesis, and synaptogenesis
Psychedelics promote plasticity via an evolutionarily conserved mechanism
TrkB, mTOR, and 5-HT2A signaling underlie psychedelicinduced plasticity
Noribogaine, but not ibogaine, is capable of promoting structural neural plasticity
SUMMARY Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.
INTRODUCTION Neuropsychiatric diseases, including mood and anxiety disorders, are some of the leading causes of disability worldwide and place an enormous economic burden on society (Gustavsson et al., 2011; Whiteford et al., 2013). Approximately one-third of patients will not respond to current antidepressant drugs, and those who do will usually require at least 2–4 weeks of treatment before they experience any beneficial effects (Rush et al., 2006). Depression, post-traumatic stress disorder (PTSD), and addiction share common neural circuitry (Arnsten, 2009; Russo et al., 2009; Peters et al., 2010; Russo and Nestler, 2013) and have high comorbidity (Kelly and Daley, 2013). A preponderance of evidence from a combination of human imaging, postmortem studies, and animal models suggests that atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders and is precipitated and/or exacerbated by stress (Arnsten, 2009; Autry and Monteggia, 2012; Christoffel et al., 2011; Duman and Aghajanian, 2012; Duman et al., 2016; Izquierdo et al., 2006; Pittenger and Duman, 2008; Qiao et al., 2016; Russo and Nestler, 2013). These structural changes, such as the retraction of neurites, loss of dendritic spines, and elimination of synapses, can potentially be counteracted by compounds capable of promoting structural and functional neural plasticity in the PFC (Castre´ n and Antila, 2017; Cramer et al., 2011; Duman, 2002; Hayley and Litteljohn, 2013; Kolb and Muhammad, 2014; Krystal et al., 2009; Mathew et al., 2008), providing a general solution to treating all of these related diseases. However, only a relatively small number of compounds capable of promoting plasticity in the PFC have been identified so far, each with significant drawbacks (Castre´ n and Antila, 2017). Of these, the dissociative anesthetic ketamine has shown the most promise, revitalizing the field of molecular psychiatry in recent years. Ketamine has demonstrated remarkable clinical potential as a fast-acting antidepressant (Berman et al., 2000; Ionescu et al., 2016; Zarate et al., 2012), even exhibiting efficacy in treatmentresistant populations (DiazGranados et al., 2010; Murrough et al., 2013; Zarate et al., 2006). Additionally, it has shown promise for treating PTSD (Feder et al., 2014) and heroin addiction (Krupitsky et al., 2002). Animal models suggest that its therapeutic effects stem from its ability to promote the growth of dendritic spines, increase the synthesis of synaptic proteins, and strengthen synaptic responses (Autry et al., 2011; Browne and Lucki, 2013; Li et al., 2010).
Like ketamine, serotonergic psychedelics and entactogens have demonstrated rapid and long-lasting antidepressant and anxiolytic effects in the clinic after a single dose (Bouso et al., 2008; Carhart-Harris and Goodwin, 2017; Grob et al., 2011; Mithoefer et al., 2013, 2016; Nichols et al., 2017; Sanches et al., 2016; Oso´ rio et al., 2015), including in treatment-resistant populations (Carhart-Harris et al., 2016, 2017; Mithoefer et al., 2011; Oehen et al., 2013; Rucker et al., 2016). In fact, there have been numerous clinical trials in the past 30 years examining the therapeutic effects of these drugs (Dos Santos et al., 2016), with 3,4-methylenedioxymethamphetamine (MDMA) recently receiving the ‘‘breakthrough therapy’’ designation by the Food and Drug Administration for treating PTSD. Furthermore, classical psychedelics and entactogens produce antidepressant and anxiolytic responses in rodent behavioral tests, such as the forced swim test (Cameron et al., 2018) and fear extinction learning (Cameron et al., 2018; Catlow et al., 2013; Young et al., 2015), paradigms for which ketamine has also been shown to be effective (Autry et al., 2011; Girgenti et al., 2017; Li et al., 2010). Despite the promising antidepressant, anxiolytic, and anti-addictive properties of serotonergic psychedelics, their therapeutic mechanism of action remains poorly understood, and concerns about safety have severely limited their clinical usefulness. Because of the similarities between classical serotonergic psychedelics and ketamine in both preclinical models and clinical studies, we reasoned that their therapeutic effects might result from a shared ability to promote structural and functional neural plasticity in cortical neurons. Here, we report that serotonergic psychedelics and entactogens from a variety of chemical classes (e.g., amphetamine, tryptamine, and ergoline) display plasticity-promoting properties comparable to or greater than ketamine. Like ketamine, these compounds stimulate structural plasticity by activating the mammalian target of rapamycin (mTOR). To classify the growing number of compounds capable of rapidly promoting induced plasticity (Castre´ n and Antila, 2017), we introduce the term ‘‘psychoplastogen,’’ from the Greek roots psych- (mind), -plast (molded), and -gen (producing). Our work strengthens the growing body of literature indicating that psychoplastogens capable of promoting plasticity in the PFC might have value as fast-acting antidepressants and anxiolytics with efficacy in treatment-resistant populations and suggests that it may be possible to use classical psychedelics as lead structures for identifying safer alternatives.
DISCUSSION Classical serotonergic psychedelics are known to cause changes in mood (Griffiths et al., 2006, 2008, 2011) and brain function (Carhart-Harris et al., 2017) that persist long after the acute effects of the drugs have subsided. Moreover, several psychedelics elevate glutamate levels in the cortex (Nichols, 2004, 2016) and increase gene expression in vivo of the neurotrophin BDNF as well as immediate-early genes associated with plasticity (Martin et al., 2014; Nichols and Sanders-Bush, 2002; Vaidya et al., 1997). This indirect evidence has led to the reasonable hypothesis that psychedelics promote structural and functional neural plasticity, although this assumption had never been rigorously tested (Bogenschutz and Pommy, 2012; Vollenweider and Kometer, 2010). The data presented here provide direct evidence for this hypothesis, demonstrating that psychedelics cause both structural and functional changes in cortical neurons.
Prior to this study, two reports suggested that psychedelics might be able to produce changes in neuronal structure. Jones et al. (2009) demonstrated that DOI was capable of transiently increasing the size of dendritic spines on cortical neurons, but no change in spine density was observed. The second study showed that DOI promoted neurite extension in a cell line of neuronal lineage (Marinova et al., 2017). Both of these reports utilized DOI, a psychedelic of the amphetamine class. Here we demonstrate that the ability to change neuronal structure is not a unique property of amphetamines like DOI because psychedelics from the ergoline, tryptamine, and iboga classes of compounds also promote structural plasticity. Additionally, D-amphetamine does not increase the complexity of cortical dendritic arbors in culture, and therefore, these morphological changes cannot be simply attributed to an increase in monoamine neurotransmission. The identification of psychoplastogens belonging to distinct chemical families is an important aspect of this work because it suggests that ketamine is not unique in its ability to promote structural and functional plasticity. In addition to ketamine, the prototypical psychoplastogen, only a relatively small number of plasticity-promoting small molecules have been identified previously. Such compounds include the N-methyl-D-aspartate (NMDA) receptor ligand GLYX-13 (i.e., rapastinel), the mGlu2/3 antagonist LY341495, the TrkB agonist 7,8-DHF, and the muscarinic receptor antagonist scopolamine (Lepack et al., 2016; Castello et al., 2014; Zeng et al., 2012; Voleti et al., 2013). We observe that hallucinogens from four distinct structural classes (i.e., tryptamine, amphetamine, ergoline, and iboga) are also potent psychoplastogens, providing additional lead scaffolds for medicinal chemistry efforts aimed at identifying neurotherapeutics. Furthermore, our cellular assays revealed that several of these compounds were more efficacious (e.g., MDMA) or more potent (e.g., LSD) than ketamine. In fact, the plasticity-promoting properties of psychedelics and entactogens rivaled that of BDNF (Figures 3A–3C and S3). The extreme potency of LSD in particular might be due to slow off kinetics, as recently proposed following the disclosure of the LSD-bound 5-HT2B crystal structure (Wacker et al., 2017). Importantly, the psychoplastogenic effects of psychedelics in cortical cultures were also observed in vivo using both vertebrate and invertebrate models, demonstrating that they act through an evolutionarily conserved mechanism. Furthermore, the concentrations of psychedelics utilized in our in vitro cell culture assays were consistent with those reached in the brain following systemic administration of therapeutic doses in rodents (Yang et al., 2018; Cohen and Vogel, 1972). This suggests that neuritogenesis, spinogenesis, and/or synaptogenesis assays performed using cortical cultures might have value for identifying psychoplastogens and fast-acting antidepressants. It should be noted that our structural plasticity studies performed in vitro utilized neurons exposed to psychedelics for extended periods of time. Because brain exposure to these compounds is often of short duration due to rapid metabolism, it will be interesting to assess the kinetics of psychedelic-induced plasticity. A key question in the field of psychedelic medicine has been whether or not psychedelics promote changes in the density of dendritic spines (Kyzar et al., 2017). Using super-resolution SIM, we clearly demonstrate that psychedelics do, in fact, increase the density of dendritic spines on cortical neurons, an effect that is not restricted to a particular structural class of compounds. Using DMT, we verified that cortical neuron spine density increases in vivo and that these changes in structural plasticity are accompanied by functional effects such as increased amplitude and frequency of spontaneous EPSCs.
We specifically designed these experiments to mimic previous studies of ketamine (Li et al., 2010) so that we might directly compare these two compounds, and, to a first approximation, they appear to be remarkably similar. Not only do they both increase spine density and neuronal excitability in the cortex, they seem to have similar behavioral effects. We have shown previously that, like ketamine, DMT promotes fear extinction learning and has antidepressant effects in the forced swim test (Cameron et al., 2018). These results, coupled with the fact that ayahuasca, a DMT-containing concoction, has potent antidepressant effects in humans (Oso´ rio et al., 2015; Sanches et al., 2016; Santos et al., 2007), suggests that classical psychedelics and ketamine might share a related therapeutic mechanism. Although the molecular targets of ketamine and psychedelics are different (NMDA and 5-HT2A receptors, respectively), they appear to cause similar downstream effects on structural plasticity by activating mTOR. This finding is significant because ketamine is known to be addictive whereas many classical psychedelics are not (Nutt et al., 2007, 2010). The exact mechanisms by which these compounds stimulate mTOR is still not entirely understood, but our data suggest that, at least for classical psychedelics, TrkB and 5-HT2A receptors are involved. Although most classical psychedelics are not considered to be addictive, there are still significant safety concerns with their use in medicine because they cause profound perceptual disturbances and still have the potential to be abused. Therefore, the identification of non-hallucinogenic analogs capable of promoting plasticity in the PFC could facilitate a paradigm shift in our approach to treating neuropsychiatric diseases. Moreover, such compounds could be critical to resolving the long-standing debate in the field concerning whether the subjective effects of psychedelics are necessary for their therapeutic effects (Majic et al., 2015 ). Although our group is actively investigating the psychoplastogenic properties of non-hallucinogenic analogs of psychedelics, others have reported the therapeutic potential of safer structural and functional analogs of ketamine (Moskal et al., 2017; Yang et al., 2015; Zanos et al., 2016). Our data demonstrate that classical psychedelics from several distinct chemical classes are capable of robustly promoting the growth of both neurites and dendritic spines in vitro, in vivo, and across species. Importantly, our studies highlight the similarities between the effects of ketamine and those of classical serotonergic psychedelics, supporting the hypothesis that the clinical antidepressant and anxiolytic effects of these molecules might result from their ability to promote structural and functional plasticity in prefrontal cortical neurons. We have demonstrated that the plasticity-promoting properties of psychedelics require TrkB, mTOR, and 5-HT2A signaling, suggesting that these key signaling hubs may serve as potential targets for the development of psychoplastogens, fast-acting antidepressants, and anxiolytics. Taken together, our results suggest that psychedelics may be used as lead structures to identify next-generation neurotherapeutics with improved efficacy and safety profiles.
Also below is a great article on DMT and neuroplasticity:
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.
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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 [19]. 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 [22]. 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 [25]. 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 [3]. 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 [28]. Furthermore, ketamine has also been shown to work on nicotinic and opioid receptors [29]. 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 [32] 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 [33]. Another study found increased levels of the cytokine interleukin-6 in cerebrospinal fluid from patients who had attempted suicide [34]. 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 [36]. 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 [37]. In their landmark study, Berman et al. [4] 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 [39].
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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.
703-844-0184 NOVA Health Recovery LLC Ketamine therapy in Fairfax, Virginia
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Traditional antidepressants may take weeks to work on individuals. There have been associations with increased suicidality in some studies. The need for a more rapidly acting antidepressant is important. The study below investigated the antidepressant effect of Ketamine by looking through an FDA database and observing associations of pain and depression reduction with the use of Ketamine. They were clearly present. Of note, minocycline and Diclofenac also seemed to be associated with improved depression parameters.
Ketamine provides both pain relief and anti-depression effects in refractory patients, who by definition, have failed multiple therapies. ::
Ketamine may alleviate depression, pain, and adverse effects associated with opioid treatment, and may thus represent an attractive adjunct therapy for pain management, according to a novel population analysis recently published in Scientific Reports.1
Nearly half of all patients with depression taking conventional antidepressants discontinue their treatment prematurely.2 Researchers have sought alternatives to standard antidepressants, for which therapeutic effects are delayed by 2 to 10 weeks.3
Ketamine, an N-methyl-D-aspartate antagonist, was shown to provide acute benefits for treatment-resistant depression, bipolar depression, and major depressive disorder with suicidal ideation, when administered intravenously, however, those studies were conducted on limited samples (20 to 57 participants).4-7
The history of ketamine as an illicit drug favored for its hallucinogenic effects presents ethical obstacles to its use in large clinical trials. Researchers from the University of California San Diego in La Jolla, therefore employed an Inverse-Frequency Analysis approach to investigate whether ketamine, when administered in addition to other therapeutics, has antidepressant properties.
The team applied the inverse frequency analysis method, which looks for negative statistical patterns in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) post-marketing database of more than 8 million patient records. They observed reductions in depression and pain in patients receiving ketamine, as indicated by negative log odds ratio (logOR) values (logOR, -0.67 ± 0.034 and logOR, -0.41 ± 0.019, respectively). “The data we analyzed are indirect and skewed by cases of bad or lethal adverse effects. Nevertheless the statistics were sufficient to notice the trends,” explained study co-author, Ruben Abagyan, PhD, in an interview with Clinical Pain Advisor.
According to Dr Abagyan, a study recently published by a British team indicates that ketamine might be effective in nearly 40% of patients with severe, treatment-resistant depression, results that are concordant with those from the current study.8
The IFA method was also used to evaluate ketamine efficacy and associated side effects reported in the FAERS database. The investigators found significant reductions in a number of side effects associated with opioid therapies, including constipation (LogOR −0.17 ± 0.023), vomiting (LogOR −0.16 ± 0.025), and nausea (LogOR −0.45 ± 0.034) compared with other drug combinations used for pain management.
The authors concluded that their findings are in line with those from smaller studies, indicating beneficial effects for ketamine as a monotherapy or adjunctive therapy for depression, particularly treatment-resistant depression, with particular indication for patients with suicide ideation, because of its rapid onset of action. “The results should serve as a motivation to conduct a proper clinical trial for the rapid onset treatment of severe depression,” Dr Abagyan noted.
The novel analysis employed in this study may help investigate off-label indications for other drugs. “Ideally the method we proposed should be applied to the actual clinical data rather than the somewhat biased set of un-normalized FAERS reports,” Dr Abagyan added. “The method [can be used] to observe unexpected effects of a treatment by looking at the reduction of the baseline of this effect upon treatment. It can be applied to any effect that is being recorded including cancer, viral diseases mortality, longevity.” he concluded.
Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications
Isaac V. Cohen, Tigran Makunts, Rabia Atayee & Ruben Abagyan
Current therapeutic approaches to depression fail for millions of patients due to lag in clinical response
and non-adherence. Here we provide new support for the antidepressant efect of an anesthetic
drug, ketamine, by Inverse-Frequency Analysis of eight million reports from the FDA Adverse Efect
Reporting System. The results of the examination of population scale data revealed that patients who
received ketamine had signifcantly lower frequency of reports of depression than patients who took
any other combination of drugs for pain. The analysis also revealed that patients who took ketamine
had signifcantly lower frequency of reports of pain and opioid induced side efects, implying ketamine’s
potential to act as a benefcial adjunct agent in pain management pharmacotherapy. Further, the
Inverse-Frequency Analysis methodology provides robust statistical support for the antidepressant
action of other currently approved therapeutics including diclofenac and minocycline.
We found that patients listed in the FAERS database who received ketamine in addition to other therapeutics had signifcantly lower frequency of reports of depression than patients who took any other combination of drugs for pain (LogOR−0.67±0.034)
Te analysis of the whole FAERS database revealed several other unintentional depression reducing drugs
among antibiotics, cosmeceuticals and NSAIDS.Our data supported previous studies that observed the
psychiatric polypharmacology of minocycline, a tetracycline antibiotic.The NSAID, diclofenac, was also
observed to have some antidepressant properties.It is theorized that both of these drugs may accomplish
antidepressant effects through an anti-inflammatory mechanism.Because of the antidepressant activity of several
NSAIDs, we further separated the non-ketamine pain cohort. Ketamine patients were then compared to
patients who received any other combination of drugs for pain excluding NSAIDs. It was observed that depression
event rates remained low (LogOR−0.56±0.035).As an important side note, we also evaluated efcacy and side efects with the use of ketamine for pain management.
We found that patients who were on ketamine had reduced opioid induced side effects including constipation, vomiting, and nausea. Our data supports ketamine’s
opioid-sparing properties and alludes to the fact that patients may receive benefts of improved pain, reduced
requirement of opioids, and ultimately less opioid reduced side effects.
References
1. Murray, C. J. & Lopez, A. D. Evidence-based health policy–lessons from the Global Burden of Disease Study. Science 274, 740–743,
doi:10.1126/science.274.5288.740 (1996).
2. Kessler, R. C. et al. Te epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication
(NCS-R). JAMA 289, 3095–3105, doi:10.1001/jama.289.23.3095 (2003).
3. Bromet, E. et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med 9, 90, doi:10.1186/1741-7015-9-90
(2011).
4. Andrade, L. et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric
Epidemiology (ICPE) Surveys. Int J Methods Psychiatr Res 12, 3–21, doi:10.1002/(ISSN)1557-0657 (2003).
5. Sansone, R. A. & Sansone, L. A. Antidepressant adherence: are patients taking their medications? Innov Clin Neurosci 9, 41–46
(2012).
6. Frazer, A. & Benmansour, S. Delayed pharmacological effects of antidepressants. Mol Psychiatry 7, S23–28, doi:10.1038/
sj.mp.4001015 (2002). Suppl 1.
7. Braun, C., Bschor, T., Franklin, J. & Baethge, C. Suicides and Suicide Attempts during Long-Term Treatment with Antidepressants:
A Meta-Analysis of 29 Placebo-Controlled Studies Including 6,934 Patients with Major Depressive Disorder. Psychother Psychosom
85, 171–179, doi:10.1159/000442293 (2016).
8. Seemüller, F. et al. Te controversial link between antidepressants and suicidality risks in adults: data from a naturalistic study on a
large sample of in-patients with a major depressive episode. Int J Neuropsychopharmacol 12, 181–189, doi:10.1017/
S1461145708009139 (2009).
9. Rush, A. J. et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D
report. Am J Psychiatry 163, 1905–1917, doi:10.1176/ajp.2006.163.11.1905 (2006).
10. Price, R. B. et al. Efects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant
depression. Depress Anxiety 31, 335–343, doi:10.1002/da.22253 (2014).
11. DiazGranados, N. et al. Rapid resolution of suicidal ideation afer a single infusion of an N-methyl-D-aspartate antagonist in
patients with treatment-resistant major depressive disorder. J Clin Psychiatry 71, 1605–1611, doi:10.4088/JCP.09m05327blu (2010).
12. Alberich, S. et al. Efcacy and safety of ketamine in bipolar depression: A systematic review. Rev Psiquiatr Salud Ment (2016).
13. Larkin, G. L. & Beautrais, A. L. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the
emergency department. Int J Neuropsychopharmacol 14, 1127–1131, doi:10.1017/S1461145711000629 (2011).
14. Miyaoka, T. et al. Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog
Neuropsychopharmacol Biol Psychiatry 37, 222–226, doi:10.1016/j.pnpbp.2012.02.002 (2012).
15. Rosenblat, J. D. et al. Anti-infammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis.
Bipolar Disord 18, 89–101, doi:10.1111/bdi.2016.18.issue-2 (2016).
16. FDA Adverse Event Reporting System (FAERS): Latest Quarterly Data Files. http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEfects/ucm082193.htm (Accessed 2016).
17. The Adverse Event Reporting System (AERS): Older Quarterly Data Files. http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEfects/ucm083765.htm (Accessed 2016).
18. Questions and Answers on FDA’s Adverse Event Reporting System (FAERS) http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEfects/default.htm (Acessed 2016).
Ketamine in Fairfax | Alexandria |Lyme disease treatment| 703-844-0184 | Dr. Sendi | Alexandria | Virginia Ketamine | www.novahealthrecovery.com|22308
Ketamine in Fairfax | Alexandria |Lyme disease treatment| 703-844-0184 | Dr. Sendi | Alexandria | Virginia Ketamine | www.novahealthrecovery.com|22308
Ketamine has been found to be useful in a range of painful conditions and metal health disorders. There is a report, listed below, of Ketamine used for Lyme disease treatment. Seeing the neuropathic nature of Lyme disease infection, Ketamine treatment presents an opportunity to lessen suffering and better one’s pain management:
Could ketamine help manage pain in patients with post-treatment
Lyme disease syndrome?
Sunday, September 17, 2017
http://danielcameronmd.com/ketamine-help-manage-pain-patients-post-treatment-lyme-diseasesyndrome/
by Daniel J. Cameron, MD, MPH
In the International Medical Case Reports Journal, researchers describe a 31-year-old woman with
PTLDS “whose pain was refractory to treatment options such as radiofrequency ablation, vitamin
infusion therapy, opioid analgesics, and other pharmacotherapies.” [2] Her pain began gradually, 3 years
prior and a short time after being diagnosed and treated for Lyme disease, explains Hanna from the
Florida Spine Institute in Clearwater, Florida. “The patient complained of diffuse body pain (6–7/10),
fatigue, headache, and brain fog (7–8/10).” [2]
The woman’s pain worsened despite treatment, increasing during everyday activity. “Her current
treatment regimen,” according to Hanna and colleagues, “included fentanyl transdermal patches,
clonazepam, oxycodone hydrochloride, and citalopram hydrobromide.” Physical therapy, IV vitamin
infusions, trigger point injections and a radiofrequency ablation procedure did not alleviate her pain.
The authors’ surmised that the woman’s pain may be related to an immune dysfunction brought on by
the infection. Ketamine exhibits anti-inflammatory and immunomodulatory actions, explains Hanna,
which may be useful in the treatment of PTLDS. [2] It is also an anesthetic and has been proven
successful “in placebo-controlled clinical trials for the treatment of depression, suicidal ideations, and
pain.”
The patient was prescribed ketamine off label for pain. “Ketamine has been utilized off-label as an
effective option for treating certain neuropathic pain conditions that currently do not have gold standard
treatment options such as complex regional pain syndrome (CRPS) and fibromyalgia,” states Hanna. [2]
Ketamine was found to effectively lessen the woman’s pain, decreasing it by approximately 71%.
Furthermore, her pain relief was achieved without using increased doses of opioid analgesics. And, in
fact, the patient was able to reduce her fentanyl dosage by 40%, from 125 ?g to 75 ?g, every 48 hours,
explains Hanna. “The patient’s depression and suicidal ideations were also eliminated post-ketamine
infusion.”
Given these findings, Hanna suggests, “Opioid-sparing therapies, such as ketamine, should be used more
frequently for the management of chronic pain.”
The authors did not address the concerns raised by physicians as to whether a persistent Lyme disease
infection or tick-borne co-infection might underlie the illness.
“Central sensitization” has been coined to describe
numerous neuropathic pain conditions resulting from a
nociceptive insult that triggers a prolonged but reversible
increase in the excitability and synaptic efficacy of neurons
in central nociceptive pathways.26 Ketamine is thought to
de-sensitize centrally mediated pain via repeated NMDA
receptor blockade.27 However, it is likely that ketamine acts
via multiple mechanisms to produce analgesia in neuropathic
pain conditions. Neuropathic pain has been associated with
increased glial activation and subsequent release of proinflammatory
cytokines. Interestingly, ketamine produces
pharmacological effects that reduce cell excitotoxicity via
NMDA antagonism and reduce inflammation by suppressing
the hyperactivation of microglia.28 Moreover, ketamine
produces immunomodulatory actions that may also be
uniquely beneficial to conditions that may have an autoimmune
component, such as PTLDS. Thus, ketamine appears
to produce a robust polypharmacological “entourage effect”
that is highly effective in treating neuropathic pain conditions
– which are notoriously difficult to treat with more
conventional analgesic drugs.
Ketamine in Fairfax |Lyme disease treatment| 703-844-0184 | Dr. Sendi | Alexandria | Virginia Ketamine | www.novahealthrecovery.com
Ketamine in Fairfax |Lyme disease treatment| 703-844-0184 | Dr. Sendi | Alexandria | Virginia Ketamine | www.novahealthrecovery.com
Lyme Disease Causes, Diagnosis and Treatment
Lyme disease is a bacterial infection transmitted by ticks. Lyme disease was first recognized in 1975, after researchers investigated why unusually large numbers of children were being diagnosed with juvenile rheumatoid arthritis in Lyme, Conn., and two neighboring towns.
The investigators discovered that most of the affected children lived near wooded areas likely to harbor ticks. They also found that the children’s first symptoms typically started in the summer months coinciding with the height of the tick season.
Several of the patients reported having a peculiar skin rash just before developing arthritis symptoms, and many also recalled being bitten by a tick at the rash site.
Further investigations resulted in the discovery that tiny deer ticks infected with a spiral-shaped bacterium or spirochete (which was later named Borrelia burgdorferi) were responsible for the outbreak of arthritis in Lyme. Ordinary “wood ticks” and “dog ticks” do not carry the infection.
The ticks most commonly infected with B. burgdorferi usually feed and mate on deer during part of their life cycle. The recent growth of the deer population in the northeast and the building of suburban developments in rural areas where deer ticks are commonly found have probably contributed to the increasing number of people with the disease.
The number of reported cases of Lyme disease, as well as the number of geographic areas in which it is found, has been increasing. Lyme disease has been reported in nearly all states in this country, although most cases are concentrated in the coastal northeast, Mid-Atlantic States, Wisconsin, and Minnesota, and northern California. Lyme disease is also found in large areas of Asia and Europe. Recent reports suggest that it is present in South America, too.
In addition to causing arthritis, Lyme disease can also cause heart, brain, and nerve problems.
How Is Lyme Disease Transmitted?
Lyme disease is transmitted through a bite from a specific type of tick. The animals that most often carry these insects are white-footed field mice, deer, racoons, opossums, skunks, weasels, foxes, shrews, moles, chipmunks, squirrels, and horses. The majority of these ticks have been found in New York, Connecticut, Massachusetts, Maryland, New Jersey, Minnesota, and Wisconsin.
What Are the Symptoms of Lyme Disease?
In the early stages of Lyme disease, you may experience flu-like symptoms that can include a stiff neck, chills, fever, swollen lymph nodes, headaches, fatigue, muscle aches, and joint pain. You also may experience a large, expanding skin rash around the area of the tick bite. In more advanced disease, nerve problems and arthritis, especially in the knees, may occur.
Here are some more details:
Erythma migrans. Erythema migrans is the telltale rash which occurs in about 70% to 80% of cases and starts as a small red spot that expands over a period of days or weeks, forming a circular, triangular, or oval-shaped rash. Sometimes the rash resembles a bull’s-eye because it appears as a red ring surrounding a central clear area. The rash, which can range in size from that of a dime to the entire width of a person’s back, appears between three days and a few weeks of a tick bite, usually occurring at the site of a bite. As infection spreads, several rashes can appear at different sites on the body.
Erythema migrans is often accompanied by symptoms such as fever, headache, stiff neck, body aches, and fatigue. These flu-like symptoms may resemble those of common viral infections and usually resolve within days or a few weeks.
Arthritis. After several weeks of being infected with Lyme disease, approximately 60% of those people not treated with antibiotics develop recurrent attacks of painful and swollen joints that last a few days to a few months. The arthritis can shift from one joint to another; the knee is most commonly affected and usually one or a few joints are affected at any given time. About 10% to 20% of untreated patients will go on to develop lasting arthritis. The knuckle joints of the hands are only very rarely affected.
Neurological symptoms. Lyme disease can also affect the nervous system, causing symptoms such as stiff neck and severe headache (meningitis), temporary paralysis of facial muscles (Bell’s palsy), numbness, pain or weakness in the limbs, or poor coordination. More subtle changes such as memory loss, difficulty with concentration, and a change in mood or sleeping habits have also been associated with Lyme disease. People with these latter symptoms alone usually don’t have Lyme disease as their cause.
Nervous system abnormalities usually develop several weeks, months, or even years following an untreated infection. These symptoms often last for weeks or months and may recur. These features of Lyme disease usually start to resolve even before antibiotics are started. Patients with neurologic disease usually have a total return to normal function.
Heart problems. Fewer than one out of 10 Lyme disease patients develops heart problems, such as an irregular, slow heartbeat, which can be signaled by dizziness or shortness of breath. These symptoms rarely last more than a few days or weeks. Such heart abnormalities generally appear several weeks after infection, and usually begin to resolve even before treatment.
Other symptoms. Less commonly, Lyme disease can result in eye inflammation and severe fatigue, although none of these problems is likely to appear without other Lyme disease symptoms being present.
Lyme disease imitates a variety of illnesses and its severity can vary from person to person. If you have been bitten by a tick and live in an area known to have Lyme disease, see your doctor right away so that a proper diagnose can be made and treatment started
How Is Lyme Disease Diagnosed?
Lyme disease may be difficult to diagnose because many of its symptoms mimic those of other disorders. Although a tick bite is an important clue for diagnosis, many patients cannot recall having been bitten by a tick. This is not surprising because the tick is tiny, and a tick bite is usually painless.
The easiest way for a doctor to diagnose Lyme disease is to see the unique bull’s-eye rash. If there is no visible rash (as is the case in about one-fourth of those infected), the doctor might order a blood test three to four weeks after the onset of the suspected infection to look for antibodies against the bacteria. Unfortunately, the Lyme disease bacterium itself is difficult to isolate or culture from body tissues or fluids. These blood tests are:
ELISA. This blood test measures the levels of antibodies against the Lyme disease bacteria that are present in the body. Antibodies are molecules or small substances tailor-made by the immune system to lock onto and destroy specific microbial invaders.
Western blot. This blood test identifies antibodies directed against a panel of proteins found on the Lyme bacteria. The test is ordered when the ELISA result is either positive or uncertain.
The presence of antibodies, however, does not prove that the bacterium is the cause of a patient’s symptoms. The presence of specific antibodies suggests a prior infection, which may or may not still be active.
Note: In the first few weeks following infection (when the rash first appears), antibody tests are not reliable because a patient’s immune system has not produced enough antibodies to be detected. Antibiotics given to a patient early during infection may also prevent antibodies from reaching detectable levels, even though the Lyme disease bacterium is the cause of the patient’s symptoms.
Other tests. Some patients experiencing nervous system symptoms may also undergo a spinal tap. A spinal tap is a procedure in which spinal fluid is removed from the spinal canal for the purpose of diagnosis in a laboratory. Through this procedure, doctors can detect brain and spinal cord inflammation and can look for antibodies against the Lyme disease bacterium in the spinal fluid.
How Is Lyme Disease Treated?
In its early stages, Lyme disease can be effectively treated with antibiotics. In general, the sooner such therapy is begun following infection, the quicker and more complete the recovery. Antibiotics, such as doxycycline or amoxicillin taken orally for two to four weeks, can speed the healing of the rash and can usually prevent subsequent symptoms such as arthritis or neurological problems. There is no compelling evidence that prolonged antibiotic therapy is more effective than two weeks of therapy. Prolonged antibiotic use may have serious side effects.
Intravenous (IV) antibiotics may be used for more serious cases and for someone whose nervous system has been affected. Lyme disease with arthritis also can be treated with antibiotics. Most patients experience full recovery.
Patients younger than 9 years or pregnant or lactating women with Lyme disease are treated with amoxicillin or penicillin because doxycycline can stain the permanent teeth developing in young children or unborn babies. Patients allergic to penicillin are given erythromycin or related antibiotics.
Doctors prefer to treat Lyme disease patients experiencing heart symptoms with antibiotics such as Rocephin, Claforan, or penicillin given intravenously for about two weeks. If these symptoms persist or are severe enough, patients may also be treated with corticosteroids or given a temporary internal cardiac pacemaker. People with Lyme disease rarely experience long-term heart damage.
Following treatment for Lyme disease, some people still have persistent fatigue and achiness. This general malaise can take months to slowly disappear, although it generally does so spontaneously without the use of additional antibiotic therapy. There is no evidence that the Borrelia infection causes systemic exertion intolerance disease (formerly called chronic fatigue syndrome) or fibromyalgia. Although some patients with Lyme disease may develop these problems, as with other patients who get SEID or fibromyalgia, long-term antibiotics will not hasten recovery.
Fortunately, the cause of Lyme disease is known and the disease can be prevented. Essential to prevention is the avoidance of deer ticks. Although generally only about one percent of all deer ticks are infected with the Lyme disease bacterium, in some areas more than half of them harbor the microbe.
Most people with Lyme disease become infected during the late spring, summer, and early fall when immature ticks are out looking for their meal. Except in warm climates, few people are bitten by deer ticks during winter months.
Deer ticks are most often found in wooded areas and nearby grasslands, and are especially common where the two areas merge, including neighborhood yards where deer occasionally roam. Ticks do not survive long on sunny lawns, they dry out quickly and die.
Try these tips to prevent tick bites:
Wear long sleeves and tightly woven clothing that is light in color when walking in wooded areas so the ticks can be seen more easily.
Wear your shirt tucked into your pants, and your pants tucked into your socks or boots.
Walk in the center of trails through the woods to avoid picking up ticks from overhanging grass and brush.
Keep grass trimmed as short as possible.
Apply tick repellents with DEET to your clothing, shoes and socks before going out. Another tick repellent called permethrin, designed to be placed on the clothing can be used alone or in combination with DEET. (Although highly effective, these repellents can cause some serious side effects, particularly when high concentrations are used repeatedly on the skin. Infants and children may be especially at risk for adverse reactions.)
Check yourself, your family, and your pets routinely for ticks, especially after a trip outdoors.
Shower and shampoo your hair if you think you may have been exposed to ticks.
Check your clothes for ticks and wash them immediately in order to remove any ticks.
If an infected tick bites, it will not transmit the infection until it has had the opportunity to have its blood meal. This takes time, thus there is value in inspecting your body after outdoor activities in areas where Lyme disease is known to occur. Newly attached ticks can be easily removed before they transmit the infection.
Pregnant women should be especially careful to avoid ticks in Lyme disease areas because the infection can be transferred to the unborn child. Such a prenatal infection can make the woman more likely to miscarry.
Preventative antibiotics are not generally used following all tick bites, but may be used in some special circumstances; a recent study showed that such preventive use of antibiotics is very effective.
If you are bitten by a tick, the best way to remove it is by taking the following steps:
Tug gently but firmly with blunt tweezers near the “head” of the tick until it releases its hold on the skin
To lessen the chance of contact with the bacterium, try not to crush the tick’s body or handle the tick with bare fingers
Swab the bite area thoroughly with an antiseptic to prevent infection
DO NOT use kerosene, Vaseline, fingernail polish, or a cigarette butt
DO NOT squeeze the tick’s body with your fingers or tweezers.
Is There a Vaccine for Lyme Disease?
In 1998, the FDA approved a vaccine for Lyme disease called LYMErix. Although some people reported getting sick from the vaccine, the FDA found no evidence that it was dangerous. However, in February 2002, the makers of the vaccine pulled it off the market due to poor sales. Currently, there is no available vaccine on the market for Lyme disease.
What Is the Outlook for People With Lyme Disease?
Most people with Lyme disease respond well to antibiotic therapy and recover fully. Some people may have persistent symptoms or symptoms that recur, making further antibiotic treatment necessary. If left untreated, Lyme disease can cause permanent damage to the heart, nervous system, and joints.
A bout with Lyme disease and successful treatment are no guarantee that the illness will be prevented in the future. The disease can strike more than once in the same individual if he or she is bitten by another tick and re-infected with the Lyme disease bacterium. The antibody test usually remains positive for months to many years after an infection. The presence of antibodies in the blood is not sufficient reason for continued or re-treatment with antibiotics.
Reference
SOURCES:
Centers for Disease Control and Prevention (CDC).
American College of Rheumatology.
National Institute of Allergy and Infectious Diseases.
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